disseminated intravascular coagulation (dic) and...
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Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the LabPaul Riley PhD MBA Diagnostica Stago Inc
Learning Objectives
Describe the basic pathophysiology of DIC
Demonstrate a diagnostic and management approach for DIC
Compare markers of thrombin amp plasmin generation in DIC including D-Dimer fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs)
Correlate DIC theory and testing to specific clinical cases
DIC = Death is Coming
What is Hemostasis
Blood Circulation
ARTERIES
VEINS
Occurs through blood vessels
The heart pumps the blood
Arteries carry oxygenated blood away from the heart under high pressure
Veins carry de-oxygenated blood back to the heart under low pressure
Hemostasis
The mechanism that maintains blood fluidity
Keeps a balance between bleeding and clotting
2 major roles Stop bleeding by repairing holes in blood vessels Clean up the inside of blood vessels Removes temporary clot that stopped bleeding Sweeps off needless deposits that may cause blood flow
blockages
Learning Objectives
Describe the basic pathophysiology of DIC
Demonstrate a diagnostic and management approach for DIC
Compare markers of thrombin amp plasmin generation in DIC including D-Dimer fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs)
Correlate DIC theory and testing to specific clinical cases
DIC = Death is Coming
What is Hemostasis
Blood Circulation
ARTERIES
VEINS
Occurs through blood vessels
The heart pumps the blood
Arteries carry oxygenated blood away from the heart under high pressure
Veins carry de-oxygenated blood back to the heart under low pressure
Hemostasis
The mechanism that maintains blood fluidity
Keeps a balance between bleeding and clotting
2 major roles Stop bleeding by repairing holes in blood vessels Clean up the inside of blood vessels Removes temporary clot that stopped bleeding Sweeps off needless deposits that may cause blood flow
blockages
DIC = Death is Coming
What is Hemostasis
Blood Circulation
ARTERIES
VEINS
Occurs through blood vessels
The heart pumps the blood
Arteries carry oxygenated blood away from the heart under high pressure
Veins carry de-oxygenated blood back to the heart under low pressure
Hemostasis
The mechanism that maintains blood fluidity
Keeps a balance between bleeding and clotting
2 major roles Stop bleeding by repairing holes in blood vessels Clean up the inside of blood vessels Removes temporary clot that stopped bleeding Sweeps off needless deposits that may cause blood flow
blockages
What is Hemostasis
Blood Circulation
ARTERIES
VEINS
Occurs through blood vessels
The heart pumps the blood
Arteries carry oxygenated blood away from the heart under high pressure
Veins carry de-oxygenated blood back to the heart under low pressure
Hemostasis
The mechanism that maintains blood fluidity
Keeps a balance between bleeding and clotting
2 major roles Stop bleeding by repairing holes in blood vessels Clean up the inside of blood vessels Removes temporary clot that stopped bleeding Sweeps off needless deposits that may cause blood flow
blockages
Blood Circulation
ARTERIES
VEINS
Occurs through blood vessels
The heart pumps the blood
Arteries carry oxygenated blood away from the heart under high pressure
Veins carry de-oxygenated blood back to the heart under low pressure
Hemostasis
The mechanism that maintains blood fluidity
Keeps a balance between bleeding and clotting
2 major roles Stop bleeding by repairing holes in blood vessels Clean up the inside of blood vessels Removes temporary clot that stopped bleeding Sweeps off needless deposits that may cause blood flow
blockages
Hemostasis
The mechanism that maintains blood fluidity
Keeps a balance between bleeding and clotting
2 major roles Stop bleeding by repairing holes in blood vessels Clean up the inside of blood vessels Removes temporary clot that stopped bleeding Sweeps off needless deposits that may cause blood flow
blockages
Bleeding =
Hemorrhage
Blood clot =
Thrombosis
Two Major Diseases Linked to Hemostatic Abnormalities
Physiology of Hemostasis
Wound Sealing
EFFRACbreak in vessel
FIBRINOLYSIS
clot destruction
PRIMARYHEMOSTASIS
PLASMATICCOAGULATION
strong clot
wound sealing blood flow plusmn stopped
The Three Steps of Hemostasis
Primary Hemostasis Interaction between vessel wall platelets and adhesive proteins platelet clot
Coagulation Consolidation of the platelet thrombus insoluble fibrin net
bull Coagulation factors and inhibitors
Fibrinolysis Clot lysis clot is digested
bull Fibrinolytic activators and inhibitors
Vessel Wall
Intact endothelium non thrombogenic Synthesis of vasodilators (prostacyclin) No reaction either with platelets or factors
Sub endotheliumTissue Endothelium
blood
When a vessel wall is damaged Exposure of the subendothelium Platelet adhesion Initiation of the mechanisms of coagulation and fibrinolysis
PlateletsFactors
Sub endotheliumTissue Endothelium
blood
Vessel Wall Damage
Aim is to clog the damaged vessel ( asymp bricks without cement )
Primary Hemostasis
Platelet Structure UnactivatedActivated
GpIb-IX-V
GpIIb-IIIa
α granules (raw materials)PF4 β-TG Fibrinogen VWF Factor V and PAI-1
dense granules (energy and glue)ATP ADP SerotoninCa2+ Mg2+ P
Hillman Robert S Ault Kenneth A Rinder Henry M Hematology in Clinical Practice 4th Edition McGraw-Hill New York NY 2005
Primary Hemostasis
2) activation2nd shape changeamp release
platelet at rest 1) adhesion1st shape change
3) aggregation(not reversible)
Vasoconstriction occurs first
Platelets then aggregate on the break in the vessel wall
Primary Hemostasis AssaysRoutine Platelet count PT APTT TT
Follow-up von Willebrand Factor Antigen determination Activity Factor VIII PFA-100 Platelet aggregation studies
SpecializedSend Out Activation markers (b-TG PF4 GPV) Specialized tests for platelet function
Aim is to strengthen the platelet plug
Coagulation
Coagulation is a balancebetween pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
THROMBIN
Fibrinogen Fibrin
bull Triggering agentsbull pro-enzyme enzyme (serine-protease FIIa FVIIa FIXa FXa)bull Cofactors (FVa amp FVIIIa)
bull Serine-protease inhibitor Antithrombin (AT) bull Cofactorsinhibitors Protein C Sbull Tissue factor pathway inhibitor (TFPI)
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Coagulation Cascade Schematic
Coagulation factors
Historic name
Fibrinogen
Prothrombin
Proaccelerin
Proconvertin
Anti-hemophilic factor A
Anti-hemophilic factor B
Stuart factor
Rosenthal factor
Hageman factor
Fibrin Stabilizing Factor
Factor
I
II
V
VII
VIII
IX
X
XI
XII
XIII
Function
Substrate
Pro-enzyme
Pro-cofactor
Pro-enzyme
Pro-cofactor
Pro-enzyme
Pro-enzyme
Pro-enzyme
Pro-enzyme
Pro-enzyme
Pro-enzyme = Zymogen activation Active Enzyme
Coagulation Assay Mechanisms
aPTT Based
PT Based
PT Based
Fibrin Under Microscope
Weisel JW Structure of fibrin impact on clot stability J Thromb Haemost 2007 5 Suppl 1 116-24
Low thrombin concentration
High thrombin concentration
Fibrin Formation
Soluble FibrinPolymer
ThrombinFibrinogen
FM+ fibrinopeptides A amp B
Stabilized Fibrin clot(not soluble)
ThrombinXIII XIIIa
(Digestion of Fibrin)
Fibrinolysis
Fibrinolysis Overview
Destroys fibrin fibers
Destroys the scab (dried wound)
Maintains vessel integrity
Fibrinolysis Overview
Fibrin =cement fibers
Plasmin
Plasmin digests fibrin
t-PA
Pro Urokinase
Urokinase
PAI-1PAI-1
Plasminogen Plasmin
1st Step
2nd Step
Fibrinolysis Cascade
t-PA tissue-type plasminogen activator PAI-1 Plasminogen activator inhibitor 1 PK Prekallikrein FDP Fibrinogen degradation products AP Antiplasmin = a2AP alpha 2 Antiplasmin a2MG alpha 2 Macroglobulin
Extrinsic pathway(endothelia l cells)
Intrinsic pathway(plasma)
Fibrin clot
D-dimerFibrin degradation products
Fibrin
TAFIa
APAntiplasmin(amp a2-MG)
PK Kallikrein
XII
Fibrinolysis Releases D-dimers
D-dimer presence fibrin has been formed and digested in patients body
Normal D-dimer level no thrombosis occurred in the patient
Basic Pathophysiology of DIC
Disseminated Intravascular Coagulation (DIC)
Massive activation of coagulation leading to clots forming in multiple locations around the bodyRapid consumption of clotting factors leading to bleedingParadoxical condition leading to both clotting and bleedingA confusing disorder from both diagnostic and therapeutic standpoints Many unrelated diseases can trigger DIC Lack of uniformity in clinical manifestation Lack of uniformity in the laboratory diagnosis Lack of uniformity or consensus on management
Clinical Manifestations of DICOrgan Ischemic Hemorrhagic
Skin Pupura Fulminans Petechiae
Gangrene Echymoses
Acral cyanosis Oozing
CNS Deliriumcoma Intracranial
Infarcts Bleeding
Renal OliguriaAzotemia Hematuria
Cortical Necrosis
Cardiovascular Myocardial dysfunction
Pulmonary DyspneaHypoxia Hemorrhagic lung
Infarct
Gastrointestinal Ulcers infarcts Massive hemorrhage
Endocrine Adrenal infarcts
Purpura Fulminans with DIC Due to Meningococcal Sepsis
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Clinical Conditions Associated With DIC
Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33
Frequency of DIC in Selected Disease States
Disease Frequency
Gram-negative sepsis 30-50
Severe trauma and systemic inflammation 50-70
Metastasized tumors 15
Abruptio placentaamniotic fluid embolism 50
Severe preeclampsia 7
Giant hemangioma 25
Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92
Masao Nakagawa Modified from a research report on the incidence of disseminated intravascular coagulation (DIC) and underlying diseases in Japan Ministry of Health Labour and Welfare Research report published in Fiscal Year 1998 57-64 199 httpwwwrecomodulincomendicindexhtml Accessed Apr 21 2017
Underlying Diseases in DIC Patients
In a Japanese survey from 1997 on incidence of DIC and underlying diseases in 652 divisions and departments of university hospitals DIC occurred in 2193 patients with the number of patient with infections (including sepsis) and hematologic tumors (including leukemia) accounted for 28 and 23 respectively
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Epidemiology of DIC
Impact of DIC Status on Mortality - 1
Okamoto K Wada H Hatada T Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Frequency and hemostatic abnormalities in pre-DIC patients Thromb Res 2010 126 74-8
Patients with positivity of DIC tend to have worse mortality outcomes compared to negative patients or those with pre-DIC
Impact of DIC Status on Mortality - 2
Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4
Patients with positivity of either Overt or Non-Overt DIC tend to have worse mortality outcomes compared to negative patients
Impact of Age on Mortality in DIC Patients
Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4
Older patients with DIC (black bars) generally tend to have worse outcomes compared to non-DIC patients (grey bars)
Pathophysiology of DIC
Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33
Pathogenesis of DIC in Sepsis
Allen KS Sawheny E Kinasewitzet GT Anticoagulant modulation of inflammation in severe sepsis World J Crit Care Med 2015 4 105-15
Bacteria in sepsis infections cause release of TF from immune cells leading to coagulation activation and proinflammatory cytokines cause endothelial cell activation impairing the anticoagulation and fibrinolysis process resulting in DIC
Host Response in Severe Sepsis
Exaggerated inflammation as a result of the host response to sepsis is collateral tissue damage and cell death further resulting in release of danger molecules continuing the inflammatory process in a downward spiral
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Organ Failure in Severe Sepsis
Sepsis associated with microvascular thrombosis as a result of TF mediated coagulation activation results in release of neutrophil extracellular traps (NETs) tissue hypoperfusion and mitochondrial damage resulting in a downward spiral leading to organ failure
Angus DC van der Poll T Severe Sepsis and Septic Shock N Engl J Med 2013 369 840-51
Mechanism of DIC in Organ Failure
Underlying condition(sepsis trauma)
Cytokines
TF-mediatedactivation of coagulation
Depression of inhibitory systems
Reducesfibrinolysis
Fibrin deposition
Organ failure
Inadequate fibrin removal
Fibrinformation
Note impaired fibrinolysis in relation to the clinical need not in absolute value (FDPs are )
Levi M de Jonge E van der Poll T ten Cate H Disseminated intravascular coagulation ThrombHaemost 1999 82 695-705
Interaction of Inflammation and Coagulation in Sepsis
Binding of TF thrombin and other activation coagulation factors to PARs and fibrin to TLRs on inflammatory cells results in inflammation through release of proinflammatory cytokines and chemokines
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Mechanism of Multiple Organ Failure in DIC
Wheeler AP Bernard GR Treating Patients with Severe Sepsis N Engl J Med 1999 340207-14
Inflammatory activation and microvascular thrombosis contributes to multiple organ failure in DIC
lipopolysaccharides
cytokines
coagulation activation
mononuclear cell
tissue factor
Diverse and Opposing Effects of Thrombin
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Coagulation and Fibrinolysis in DIC
Soluble fibrin Polymer
XIIIa
D-Dimer
E
Fibrin clot
Fibrin Degradation Products
Fibrinogen Thrombin
Fibrinogen Degradation
Products
D E
Plasmin
DFM + fibrinopeptides
Soluble FM ComplexesPre-throm
boticPost-throm
botic
Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis Semin Thromb Hemost 2008 34 33-8
Mechanism of DIC
THROMBOSIS
Fibrin
Blood activationEndothelial lysisTF expression
BLEEDING
FDPs
D-Dimer
Plasmin
Pathophysiology of DIC
1st step abnormal activation of coagulation Injury of vessel wall cells venous stasis release of large quantities of
thromboplastin influx of activated cells (monocytes macrophages)
Results in an intravascular deposition of fibrin
Morbidity from disseminated microthrombosis in small and midsize vessels leading to multiple organ failure
Second step Consumption and depletion of coagulation factors inhibitors (Protein C
Protein S AT) and platelets Local fibrinolytic response
bull Local plasmin generation dissolves the thrombusbull Disseminated overwhelming fibrinolytic response leading to production of
FDP and D-Dimer
Bleeding
Pathophysiology of DIC - Mechanism
Systemic activation of coagulation
Intravasculardepositionof fibrin
Thrombosis of small and midsize vessels
and organ failure
Depletion of platelets and
coagulation factors
Bleeding
Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92
Pathophysiology of DIC ndash 2 Types of Clinical pictures
Chronic = non - overt DICMay be unrecognized clinically
Acute = overt DIClife threatening bleedingor multiple organ failure
Sub-Acute and Non-Overt DIC Clinical Findings
Compensated non-overt DIC Steady low level or intermittent activation
bull Compensated by increased production of coagulation components and platelets
Few or no clinical signs or multiple microvascular thrombosis sometimes not clinically obvious
Risk of decompensation leading to overt DIC
Pathophysiology of Overt DIC
Massive activation of coagulation and fibrinolysis
Does not allow for compensatory efforts
Rapid depletion of coagulation factors inhibitors and platelets
Thrombosis multiple organ failures
Bleeding complications and shock
Physiopathology of DIC ndash Overt DIC Findings
Thrombin generation
Thrombosis
Renal liver respiratory failures coma skin necrosis gangrene venous thromboembolism hypotension edema
Cytokine and kinin generation (shock)bull Tachycardia hypotension edema
Plasmin generationHemorrhage
bull Spontaneous bruising petechiae intracranial gastrointestinal and respiratory tract bleeding persistent bleeding at venipuncture sites at surgical wounds
bull Tachycardia hypotension edema
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Pathogenesis Pathways in DIC
Cytokines
TF-mediated dysfunctional impairedthrombin anticoagulant fibrinolysisgeneration mechanism due to PAI-1 deficiency
fibrin inadequateformation fibrin removal
Fibrin deposition
Inflammation
Coagulation
Stago Celebrates Lab Week 2017
NA
Stago 247 Educational Webinar Sites
wwwstago-edvantagecomUS based KOLsPACE accredited ndash all 1 hourAccessible from mobile devicesVirtual exhibit hall
wwwstagowebinarscomMostly European KOLs30 ndash 45 min including 15 min discussion
Stago Educational Apps
HaemoscoreClinical scoring algorithmsApple and AndroidTablet or phone
iHemostasisCoagulation diagramsCase studiesApple amp AndroidTablet only
BREAK
Diagnostic and Management Approach for DIC
Diagnosis of DIC
Clinical diagnosis is obvious in cases of overt DIC
Laboratory tests are necessary To makeconfirm the diagnosis To assess stage of the patient To assess the treatment efficacy
Lab Diagnosis of DIC ndash Markers of Factor Consumption
Routinescreening assays PT APTT Platelets Fibrinogen Thrombin time
Other coagulation assays Factor assays AntithrombinGeneration of Thrombin FMFSPsGeneration of Plasmin D-dimer FDPs
Important to recognize simultaneous formation of thrombin and plasmin
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122
Lab Diagnosis of DIC ndash Screening Tests
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122
Platelet count usually decreasedPT abnormal in 70 of cases (short half-life of FVII)APTT abnormal in 50 of casesThrombin time usually prolonged in overt DIC normal in non-overt DIC and no relation with syndrome severityFibrinogen low in lt 50 of cases sensitivity 22 specificity 87 overall predictive value 64 Normal fibrinogen level should not exclude DIC diagnosis (acute phase reactant initial high
fibrinogen level) repeat testing assesses progression
Screening tests not clinically specific or sensitive for DIC
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Laboratory Changes in Overt DIC
DIC Diagnostic Practices Over Time
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
British Journal of Haematology Overt DIC Score
Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
ISTH Step by Step DIC Algorithm
Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6
US Based Validation of ISTH DIC Score
When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Differential Diagnosis in DIC
aHUS atypical hemolytic uremic syndrome
HUS hemolytic uremic syndrome
HIT heparin-induced thrombocytopenia
ITP immune thrombocytopenic purpura
TTP thrombotic thrombocytopenic purpura
DIC and MAHA
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)
When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation
DIC Management Goals
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction
DIC Management and Treatment
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)
requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)
Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia
DIC Management Strategies
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant Factor Concentrate Treatment
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis
Anticoagulant Factor Concentrate Treatment Trials
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise
Markers of Thrombin amp Plasmin Generation in DIC
D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC
Cut-off value
Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen
degradation products Sensitive assay typically with cutoff adapted for DIC
D-dimer FDPs and DIC
D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC
Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80
Follow Up of DIC State of Disease
Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8
Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility
FMD-Dimer in DIC Major Differences
onset of thrombosis
days
Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8
FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)
D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)
of Abnormal Results in Patients with Confirmed and Suspected DIC
0
20
40
60
80
100
94 85 90N = 62
Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32
Positivity of Test Results ISTH Score and Disease State
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
Red bar positive for 2 points of DIC score
Pink bar positive for 1-2 points of DIC score
HT hematopoietic tumor
IF infection
SC solid cancer
Markers in Patients with or without DIC
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
HT hematopoietic tumorIF infectionSC solid cancer
Comparing an Automated FM vs Manual FSP Test
Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71
Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)
Automated (Mitsubishi) vs Automated (Stago)
In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago
Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC
Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
Non Overt DIC Overt DIC
AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC
Trends in Markers of DIC for Different Patients
Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00
Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients
Trends in Markers of DIC for Different Patients
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes
28 day outcome survival
28 day outcome death
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines
DIC Case Studies
Case Study 1 - Presentation
18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE
WBC count 77 KμL 423 ndash 907 x KμL
RBC count 17 MμL 137 ndash 175 x MμL
Hemoglobin 67 gdL 137 ndash 175 gdL
Hematocrit 195 401 ndash 510
MCV 95 fL 790 ndash 922 fL
MPV 12 fL 94 ndash 124 fL
Platelet count 9 KμL 161 ndash 347 KμL
Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0
Lymphocytes monocytes eosinophils basophils all below normal range
PT 47 sec (corrected on mixing study) 116 ndash 152 sec
APTT 75 sec (corrected on mixing study) 253 ndash 373 sec
Fibrinogen lt 76 mgdL 177 ndash 466 mgdL
D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Microscopy
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Arrow shows giant platelets in this peripheral smear Promyelocytes apparent
Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)
DIC due to TF release by APL blasts
Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases
Transfusions to replace factors along with platelets and RBCs during APL treatment
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started
Case Study 2 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L
PT 30 sec 113 ndash 146 sec
APTT 75 sec 25 ndash 34 sec
D-dimer 078 microgml FEU lt050 microgml FEU
Fibrinogen 92 mgdl 150-400 mgdl
pH 728 738 to 742
PaO2 570 mmHg 80-100 mmHg
WBC 33 times 103mm3 40-11 times 103mm3
ALT 111 IUL 0ndash34 IUL
AST 61 IUL 0ndash34 IUL
BUN 303 mgdL 08-13 mgdL
Case Study 2 ndash Lab Results
Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures
Case Study 2 ndash Diagnosis
60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior
Case Study 3 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L
PT 228 sec 113 ndash 146 sec
APTT 45 sec 25 ndash 34 sec
D-dimer 080 microgml FEU lt050 microgmL FEU
Fibrinogen 82 mgdL 150-400 mgdL
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 134 gdL 14-16 gdL
WBC 81 times 103mm3 40-11 times 103mm3
ALT 32 IUL 0ndash34 IUL
AST 28 IUL 0ndash34 IUL
BUN 09 mgdL 08-13 mgdL
Case Study 3 ndash Lab Results
Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment
Case Study 3 ndash Diagnosis and Therapy
Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91
Case Study 4 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L
PT 28 sec 113 ndash 146 sec
APTT 71 sec 25 ndash 34 sec
D-dimer 31 microgmL FEU lt050 microgml FEU
Fibrinogen 92 mgdL 150-400 mgdl
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 158 gdL 14-16 gdL
WBC 71 times 103mm3 40-11 times 103mm3
ALT 60 IUL 0ndash34 IUL
AST 47 IUL 0ndash34 IUL
BUN 38 mgdL 08-13 mgdL
Case Study 4 ndash Lab Results
Lyme disease with DICProvide antibiotics with supportive measures
Case Study 4 ndash Diagnosis
55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis
Case Study 5 ndash Presentation
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
Case Study 5 ndash Lab Results and Time Course
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
TEST RESULT REFERENCE RANGE
Platelet count 33 x 109L 150-450 x 109L
PT 215 sec 103 ndash 128 sec
APTT 44 sec 26 ndash 36 sec
D-dimer 20 microgmL FEU lt025 microgml FEU
Fibrinogen 34 mgdL 200-375 mgdl
FII FV FVIII Low Not reported (NR)
FVII FIX FX vWF Normal NR
Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)
DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic
dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR
(C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen
(D) Illustration demonstrating repair
Case Study 5 ndash Diagnosis and Treatment
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography
Case Study 6 ndash Presentation
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
Case Study 6 ndash Lab Results
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L
PT 63 sec gt control 113 ndash 146 sec
INR 658 1 ndash 125
APTT 80 sec gt control 25 ndash 34 sec
D-dimer gt200 microgmL DDU 02 microgmL DDU
Urine exam Proteinuria and hematuria 150-400 mgdl
Albumin 28 gdL NR
Hb 58 gdL NR
LDH 1196 UL NR
SGPT 144 IU NR
SGOT 88 IU NR
Bilirubin 32 mgdL NR
DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th
day postop
Case Study 6 ndash Diagnosis and Treatment
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure
Case Study 6 ndash Discussion
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Case Study 7 ndash Lab Results vs Time
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
DIC Take Home Messages
Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation
Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers
DIC
Thank you Questions
- Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
- Learning Objectives
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Wound Sealing
- The Three Steps of Hemostasis
- Vessel Wall
- Slide Number 12
- Slide Number 13
- Platelet Structure UnactivatedActivated
- Primary Hemostasis
- Primary Hemostasis Assays
- Slide Number 17
- Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
- Slide Number 19
- Coagulation factors
- Coagulation Assay Mechanisms
- Slide Number 22
- Fibrin Formation
- Slide Number 24
- Fibrinolysis Overview
- Fibrinolysis Overview
- Slide Number 27
- Fibrinolysis Releases D-dimers
- Basic Pathophysiology of DIC
- Disseminated Intravascular Coagulation (DIC)
- Purpura Fulminans with DIC Due to Meningococcal Sepsis
- Clinical Conditions Associated With DIC
- Frequency of DIC in Selected Disease States
- Underlying Diseases in DIC Patients
- Slide Number 36
- Slide Number 37
- Slide Number 38
- Slide Number 39
- Pathophysiology of DIC
- Pathogenesis of DIC in Sepsis
- Host Response in Severe Sepsis
- Organ Failure in Severe Sepsis
- Mechanism of DIC in Organ Failure
- Interaction of Inflammation and Coagulation in Sepsis
- Slide Number 47
- Diverse and Opposing Effects of Thrombin
- Coagulation and Fibrinolysis in DIC
- Mechanism of DIC
- Pathophysiology of DIC
- Pathophysiology of DIC - Mechanism
- Pathophysiology of DIC ndash 2 Types of Clinical pictures
- Sub-Acute and Non-Overt DIC Clinical Findings
- Pathophysiology of Overt DIC
- Physiopathology of DIC ndash Overt DIC Findings
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- BREAK
- Diagnostic and Management Approach for DIC
- Diagnosis of DIC
- Lab Diagnosis of DIC ndash Markers of Factor Consumption
- Lab Diagnosis of DIC ndash Screening Tests
- Slide Number 67
- Slide Number 68
- British Journal of Haematology Overt DIC Score
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- DIC Management Goals
- DIC Management and Treatment
- DIC Management Strategies
- Anticoagulant Factor Concentrate Treatment
- Anticoagulant Factor Concentrate Treatment Trials
- Markers of Thrombin amp Plasmin Generation in DIC
- D-dimer FDPs and DIC
- D-Dimer and FDPs in DIC
- Follow Up of DIC State of Disease
- FMD-Dimer in DIC Major Differences
- of Abnormal Results in Patients with Confirmed and Suspected DIC
- Slide Number 85
- Slide Number 86
- Comparing an Automated FM vs Manual FSP Test
- Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Slide Number 94
- Slide Number 95
- Slide Number 96
- Slide Number 97
- Slide Number 98
- Slide Number 99
- DIC Case Studies
- Case Study 1 - Presentation
- Case Study 1 ndash Lab Results
- Case Study 1 ndash Microscopy
- Case Study 1 ndash Diagnosis and Therapy
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Slide Number 110
- Slide Number 111
- Slide Number 112
- Slide Number 113
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
- Slide Number 124
- Slide Number 125
- DIC Take Home Messages
- Slide Number 127
- Slide Number 128
-
Physiology of Hemostasis
Wound Sealing
EFFRACbreak in vessel
FIBRINOLYSIS
clot destruction
PRIMARYHEMOSTASIS
PLASMATICCOAGULATION
strong clot
wound sealing blood flow plusmn stopped
The Three Steps of Hemostasis
Primary Hemostasis Interaction between vessel wall platelets and adhesive proteins platelet clot
Coagulation Consolidation of the platelet thrombus insoluble fibrin net
bull Coagulation factors and inhibitors
Fibrinolysis Clot lysis clot is digested
bull Fibrinolytic activators and inhibitors
Vessel Wall
Intact endothelium non thrombogenic Synthesis of vasodilators (prostacyclin) No reaction either with platelets or factors
Sub endotheliumTissue Endothelium
blood
When a vessel wall is damaged Exposure of the subendothelium Platelet adhesion Initiation of the mechanisms of coagulation and fibrinolysis
PlateletsFactors
Sub endotheliumTissue Endothelium
blood
Vessel Wall Damage
Aim is to clog the damaged vessel ( asymp bricks without cement )
Primary Hemostasis
Platelet Structure UnactivatedActivated
GpIb-IX-V
GpIIb-IIIa
α granules (raw materials)PF4 β-TG Fibrinogen VWF Factor V and PAI-1
dense granules (energy and glue)ATP ADP SerotoninCa2+ Mg2+ P
Hillman Robert S Ault Kenneth A Rinder Henry M Hematology in Clinical Practice 4th Edition McGraw-Hill New York NY 2005
Primary Hemostasis
2) activation2nd shape changeamp release
platelet at rest 1) adhesion1st shape change
3) aggregation(not reversible)
Vasoconstriction occurs first
Platelets then aggregate on the break in the vessel wall
Primary Hemostasis AssaysRoutine Platelet count PT APTT TT
Follow-up von Willebrand Factor Antigen determination Activity Factor VIII PFA-100 Platelet aggregation studies
SpecializedSend Out Activation markers (b-TG PF4 GPV) Specialized tests for platelet function
Aim is to strengthen the platelet plug
Coagulation
Coagulation is a balancebetween pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
THROMBIN
Fibrinogen Fibrin
bull Triggering agentsbull pro-enzyme enzyme (serine-protease FIIa FVIIa FIXa FXa)bull Cofactors (FVa amp FVIIIa)
bull Serine-protease inhibitor Antithrombin (AT) bull Cofactorsinhibitors Protein C Sbull Tissue factor pathway inhibitor (TFPI)
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Coagulation Cascade Schematic
Coagulation factors
Historic name
Fibrinogen
Prothrombin
Proaccelerin
Proconvertin
Anti-hemophilic factor A
Anti-hemophilic factor B
Stuart factor
Rosenthal factor
Hageman factor
Fibrin Stabilizing Factor
Factor
I
II
V
VII
VIII
IX
X
XI
XII
XIII
Function
Substrate
Pro-enzyme
Pro-cofactor
Pro-enzyme
Pro-cofactor
Pro-enzyme
Pro-enzyme
Pro-enzyme
Pro-enzyme
Pro-enzyme
Pro-enzyme = Zymogen activation Active Enzyme
Coagulation Assay Mechanisms
aPTT Based
PT Based
PT Based
Fibrin Under Microscope
Weisel JW Structure of fibrin impact on clot stability J Thromb Haemost 2007 5 Suppl 1 116-24
Low thrombin concentration
High thrombin concentration
Fibrin Formation
Soluble FibrinPolymer
ThrombinFibrinogen
FM+ fibrinopeptides A amp B
Stabilized Fibrin clot(not soluble)
ThrombinXIII XIIIa
(Digestion of Fibrin)
Fibrinolysis
Fibrinolysis Overview
Destroys fibrin fibers
Destroys the scab (dried wound)
Maintains vessel integrity
Fibrinolysis Overview
Fibrin =cement fibers
Plasmin
Plasmin digests fibrin
t-PA
Pro Urokinase
Urokinase
PAI-1PAI-1
Plasminogen Plasmin
1st Step
2nd Step
Fibrinolysis Cascade
t-PA tissue-type plasminogen activator PAI-1 Plasminogen activator inhibitor 1 PK Prekallikrein FDP Fibrinogen degradation products AP Antiplasmin = a2AP alpha 2 Antiplasmin a2MG alpha 2 Macroglobulin
Extrinsic pathway(endothelia l cells)
Intrinsic pathway(plasma)
Fibrin clot
D-dimerFibrin degradation products
Fibrin
TAFIa
APAntiplasmin(amp a2-MG)
PK Kallikrein
XII
Fibrinolysis Releases D-dimers
D-dimer presence fibrin has been formed and digested in patients body
Normal D-dimer level no thrombosis occurred in the patient
Basic Pathophysiology of DIC
Disseminated Intravascular Coagulation (DIC)
Massive activation of coagulation leading to clots forming in multiple locations around the bodyRapid consumption of clotting factors leading to bleedingParadoxical condition leading to both clotting and bleedingA confusing disorder from both diagnostic and therapeutic standpoints Many unrelated diseases can trigger DIC Lack of uniformity in clinical manifestation Lack of uniformity in the laboratory diagnosis Lack of uniformity or consensus on management
Clinical Manifestations of DICOrgan Ischemic Hemorrhagic
Skin Pupura Fulminans Petechiae
Gangrene Echymoses
Acral cyanosis Oozing
CNS Deliriumcoma Intracranial
Infarcts Bleeding
Renal OliguriaAzotemia Hematuria
Cortical Necrosis
Cardiovascular Myocardial dysfunction
Pulmonary DyspneaHypoxia Hemorrhagic lung
Infarct
Gastrointestinal Ulcers infarcts Massive hemorrhage
Endocrine Adrenal infarcts
Purpura Fulminans with DIC Due to Meningococcal Sepsis
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Clinical Conditions Associated With DIC
Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33
Frequency of DIC in Selected Disease States
Disease Frequency
Gram-negative sepsis 30-50
Severe trauma and systemic inflammation 50-70
Metastasized tumors 15
Abruptio placentaamniotic fluid embolism 50
Severe preeclampsia 7
Giant hemangioma 25
Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92
Masao Nakagawa Modified from a research report on the incidence of disseminated intravascular coagulation (DIC) and underlying diseases in Japan Ministry of Health Labour and Welfare Research report published in Fiscal Year 1998 57-64 199 httpwwwrecomodulincomendicindexhtml Accessed Apr 21 2017
Underlying Diseases in DIC Patients
In a Japanese survey from 1997 on incidence of DIC and underlying diseases in 652 divisions and departments of university hospitals DIC occurred in 2193 patients with the number of patient with infections (including sepsis) and hematologic tumors (including leukemia) accounted for 28 and 23 respectively
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Epidemiology of DIC
Impact of DIC Status on Mortality - 1
Okamoto K Wada H Hatada T Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Frequency and hemostatic abnormalities in pre-DIC patients Thromb Res 2010 126 74-8
Patients with positivity of DIC tend to have worse mortality outcomes compared to negative patients or those with pre-DIC
Impact of DIC Status on Mortality - 2
Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4
Patients with positivity of either Overt or Non-Overt DIC tend to have worse mortality outcomes compared to negative patients
Impact of Age on Mortality in DIC Patients
Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4
Older patients with DIC (black bars) generally tend to have worse outcomes compared to non-DIC patients (grey bars)
Pathophysiology of DIC
Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33
Pathogenesis of DIC in Sepsis
Allen KS Sawheny E Kinasewitzet GT Anticoagulant modulation of inflammation in severe sepsis World J Crit Care Med 2015 4 105-15
Bacteria in sepsis infections cause release of TF from immune cells leading to coagulation activation and proinflammatory cytokines cause endothelial cell activation impairing the anticoagulation and fibrinolysis process resulting in DIC
Host Response in Severe Sepsis
Exaggerated inflammation as a result of the host response to sepsis is collateral tissue damage and cell death further resulting in release of danger molecules continuing the inflammatory process in a downward spiral
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Organ Failure in Severe Sepsis
Sepsis associated with microvascular thrombosis as a result of TF mediated coagulation activation results in release of neutrophil extracellular traps (NETs) tissue hypoperfusion and mitochondrial damage resulting in a downward spiral leading to organ failure
Angus DC van der Poll T Severe Sepsis and Septic Shock N Engl J Med 2013 369 840-51
Mechanism of DIC in Organ Failure
Underlying condition(sepsis trauma)
Cytokines
TF-mediatedactivation of coagulation
Depression of inhibitory systems
Reducesfibrinolysis
Fibrin deposition
Organ failure
Inadequate fibrin removal
Fibrinformation
Note impaired fibrinolysis in relation to the clinical need not in absolute value (FDPs are )
Levi M de Jonge E van der Poll T ten Cate H Disseminated intravascular coagulation ThrombHaemost 1999 82 695-705
Interaction of Inflammation and Coagulation in Sepsis
Binding of TF thrombin and other activation coagulation factors to PARs and fibrin to TLRs on inflammatory cells results in inflammation through release of proinflammatory cytokines and chemokines
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Mechanism of Multiple Organ Failure in DIC
Wheeler AP Bernard GR Treating Patients with Severe Sepsis N Engl J Med 1999 340207-14
Inflammatory activation and microvascular thrombosis contributes to multiple organ failure in DIC
lipopolysaccharides
cytokines
coagulation activation
mononuclear cell
tissue factor
Diverse and Opposing Effects of Thrombin
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Coagulation and Fibrinolysis in DIC
Soluble fibrin Polymer
XIIIa
D-Dimer
E
Fibrin clot
Fibrin Degradation Products
Fibrinogen Thrombin
Fibrinogen Degradation
Products
D E
Plasmin
DFM + fibrinopeptides
Soluble FM ComplexesPre-throm
boticPost-throm
botic
Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis Semin Thromb Hemost 2008 34 33-8
Mechanism of DIC
THROMBOSIS
Fibrin
Blood activationEndothelial lysisTF expression
BLEEDING
FDPs
D-Dimer
Plasmin
Pathophysiology of DIC
1st step abnormal activation of coagulation Injury of vessel wall cells venous stasis release of large quantities of
thromboplastin influx of activated cells (monocytes macrophages)
Results in an intravascular deposition of fibrin
Morbidity from disseminated microthrombosis in small and midsize vessels leading to multiple organ failure
Second step Consumption and depletion of coagulation factors inhibitors (Protein C
Protein S AT) and platelets Local fibrinolytic response
bull Local plasmin generation dissolves the thrombusbull Disseminated overwhelming fibrinolytic response leading to production of
FDP and D-Dimer
Bleeding
Pathophysiology of DIC - Mechanism
Systemic activation of coagulation
Intravasculardepositionof fibrin
Thrombosis of small and midsize vessels
and organ failure
Depletion of platelets and
coagulation factors
Bleeding
Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92
Pathophysiology of DIC ndash 2 Types of Clinical pictures
Chronic = non - overt DICMay be unrecognized clinically
Acute = overt DIClife threatening bleedingor multiple organ failure
Sub-Acute and Non-Overt DIC Clinical Findings
Compensated non-overt DIC Steady low level or intermittent activation
bull Compensated by increased production of coagulation components and platelets
Few or no clinical signs or multiple microvascular thrombosis sometimes not clinically obvious
Risk of decompensation leading to overt DIC
Pathophysiology of Overt DIC
Massive activation of coagulation and fibrinolysis
Does not allow for compensatory efforts
Rapid depletion of coagulation factors inhibitors and platelets
Thrombosis multiple organ failures
Bleeding complications and shock
Physiopathology of DIC ndash Overt DIC Findings
Thrombin generation
Thrombosis
Renal liver respiratory failures coma skin necrosis gangrene venous thromboembolism hypotension edema
Cytokine and kinin generation (shock)bull Tachycardia hypotension edema
Plasmin generationHemorrhage
bull Spontaneous bruising petechiae intracranial gastrointestinal and respiratory tract bleeding persistent bleeding at venipuncture sites at surgical wounds
bull Tachycardia hypotension edema
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Pathogenesis Pathways in DIC
Cytokines
TF-mediated dysfunctional impairedthrombin anticoagulant fibrinolysisgeneration mechanism due to PAI-1 deficiency
fibrin inadequateformation fibrin removal
Fibrin deposition
Inflammation
Coagulation
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wwwstagowebinarscomMostly European KOLs30 ndash 45 min including 15 min discussion
Stago Educational Apps
HaemoscoreClinical scoring algorithmsApple and AndroidTablet or phone
iHemostasisCoagulation diagramsCase studiesApple amp AndroidTablet only
BREAK
Diagnostic and Management Approach for DIC
Diagnosis of DIC
Clinical diagnosis is obvious in cases of overt DIC
Laboratory tests are necessary To makeconfirm the diagnosis To assess stage of the patient To assess the treatment efficacy
Lab Diagnosis of DIC ndash Markers of Factor Consumption
Routinescreening assays PT APTT Platelets Fibrinogen Thrombin time
Other coagulation assays Factor assays AntithrombinGeneration of Thrombin FMFSPsGeneration of Plasmin D-dimer FDPs
Important to recognize simultaneous formation of thrombin and plasmin
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122
Lab Diagnosis of DIC ndash Screening Tests
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122
Platelet count usually decreasedPT abnormal in 70 of cases (short half-life of FVII)APTT abnormal in 50 of casesThrombin time usually prolonged in overt DIC normal in non-overt DIC and no relation with syndrome severityFibrinogen low in lt 50 of cases sensitivity 22 specificity 87 overall predictive value 64 Normal fibrinogen level should not exclude DIC diagnosis (acute phase reactant initial high
fibrinogen level) repeat testing assesses progression
Screening tests not clinically specific or sensitive for DIC
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Laboratory Changes in Overt DIC
DIC Diagnostic Practices Over Time
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
British Journal of Haematology Overt DIC Score
Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
ISTH Step by Step DIC Algorithm
Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6
US Based Validation of ISTH DIC Score
When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Differential Diagnosis in DIC
aHUS atypical hemolytic uremic syndrome
HUS hemolytic uremic syndrome
HIT heparin-induced thrombocytopenia
ITP immune thrombocytopenic purpura
TTP thrombotic thrombocytopenic purpura
DIC and MAHA
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)
When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation
DIC Management Goals
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction
DIC Management and Treatment
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)
requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)
Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia
DIC Management Strategies
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant Factor Concentrate Treatment
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis
Anticoagulant Factor Concentrate Treatment Trials
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise
Markers of Thrombin amp Plasmin Generation in DIC
D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC
Cut-off value
Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen
degradation products Sensitive assay typically with cutoff adapted for DIC
D-dimer FDPs and DIC
D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC
Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80
Follow Up of DIC State of Disease
Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8
Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility
FMD-Dimer in DIC Major Differences
onset of thrombosis
days
Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8
FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)
D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)
of Abnormal Results in Patients with Confirmed and Suspected DIC
0
20
40
60
80
100
94 85 90N = 62
Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32
Positivity of Test Results ISTH Score and Disease State
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
Red bar positive for 2 points of DIC score
Pink bar positive for 1-2 points of DIC score
HT hematopoietic tumor
IF infection
SC solid cancer
Markers in Patients with or without DIC
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
HT hematopoietic tumorIF infectionSC solid cancer
Comparing an Automated FM vs Manual FSP Test
Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71
Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)
Automated (Mitsubishi) vs Automated (Stago)
In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago
Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC
Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
Non Overt DIC Overt DIC
AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC
Trends in Markers of DIC for Different Patients
Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00
Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients
Trends in Markers of DIC for Different Patients
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes
28 day outcome survival
28 day outcome death
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines
DIC Case Studies
Case Study 1 - Presentation
18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE
WBC count 77 KμL 423 ndash 907 x KμL
RBC count 17 MμL 137 ndash 175 x MμL
Hemoglobin 67 gdL 137 ndash 175 gdL
Hematocrit 195 401 ndash 510
MCV 95 fL 790 ndash 922 fL
MPV 12 fL 94 ndash 124 fL
Platelet count 9 KμL 161 ndash 347 KμL
Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0
Lymphocytes monocytes eosinophils basophils all below normal range
PT 47 sec (corrected on mixing study) 116 ndash 152 sec
APTT 75 sec (corrected on mixing study) 253 ndash 373 sec
Fibrinogen lt 76 mgdL 177 ndash 466 mgdL
D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Microscopy
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Arrow shows giant platelets in this peripheral smear Promyelocytes apparent
Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)
DIC due to TF release by APL blasts
Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases
Transfusions to replace factors along with platelets and RBCs during APL treatment
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started
Case Study 2 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L
PT 30 sec 113 ndash 146 sec
APTT 75 sec 25 ndash 34 sec
D-dimer 078 microgml FEU lt050 microgml FEU
Fibrinogen 92 mgdl 150-400 mgdl
pH 728 738 to 742
PaO2 570 mmHg 80-100 mmHg
WBC 33 times 103mm3 40-11 times 103mm3
ALT 111 IUL 0ndash34 IUL
AST 61 IUL 0ndash34 IUL
BUN 303 mgdL 08-13 mgdL
Case Study 2 ndash Lab Results
Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures
Case Study 2 ndash Diagnosis
60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior
Case Study 3 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L
PT 228 sec 113 ndash 146 sec
APTT 45 sec 25 ndash 34 sec
D-dimer 080 microgml FEU lt050 microgmL FEU
Fibrinogen 82 mgdL 150-400 mgdL
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 134 gdL 14-16 gdL
WBC 81 times 103mm3 40-11 times 103mm3
ALT 32 IUL 0ndash34 IUL
AST 28 IUL 0ndash34 IUL
BUN 09 mgdL 08-13 mgdL
Case Study 3 ndash Lab Results
Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment
Case Study 3 ndash Diagnosis and Therapy
Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91
Case Study 4 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L
PT 28 sec 113 ndash 146 sec
APTT 71 sec 25 ndash 34 sec
D-dimer 31 microgmL FEU lt050 microgml FEU
Fibrinogen 92 mgdL 150-400 mgdl
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 158 gdL 14-16 gdL
WBC 71 times 103mm3 40-11 times 103mm3
ALT 60 IUL 0ndash34 IUL
AST 47 IUL 0ndash34 IUL
BUN 38 mgdL 08-13 mgdL
Case Study 4 ndash Lab Results
Lyme disease with DICProvide antibiotics with supportive measures
Case Study 4 ndash Diagnosis
55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis
Case Study 5 ndash Presentation
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
Case Study 5 ndash Lab Results and Time Course
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
TEST RESULT REFERENCE RANGE
Platelet count 33 x 109L 150-450 x 109L
PT 215 sec 103 ndash 128 sec
APTT 44 sec 26 ndash 36 sec
D-dimer 20 microgmL FEU lt025 microgml FEU
Fibrinogen 34 mgdL 200-375 mgdl
FII FV FVIII Low Not reported (NR)
FVII FIX FX vWF Normal NR
Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)
DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic
dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR
(C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen
(D) Illustration demonstrating repair
Case Study 5 ndash Diagnosis and Treatment
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography
Case Study 6 ndash Presentation
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
Case Study 6 ndash Lab Results
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L
PT 63 sec gt control 113 ndash 146 sec
INR 658 1 ndash 125
APTT 80 sec gt control 25 ndash 34 sec
D-dimer gt200 microgmL DDU 02 microgmL DDU
Urine exam Proteinuria and hematuria 150-400 mgdl
Albumin 28 gdL NR
Hb 58 gdL NR
LDH 1196 UL NR
SGPT 144 IU NR
SGOT 88 IU NR
Bilirubin 32 mgdL NR
DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th
day postop
Case Study 6 ndash Diagnosis and Treatment
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure
Case Study 6 ndash Discussion
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Case Study 7 ndash Lab Results vs Time
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
DIC Take Home Messages
Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation
Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers
DIC
Thank you Questions
- Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
- Learning Objectives
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Wound Sealing
- The Three Steps of Hemostasis
- Vessel Wall
- Slide Number 12
- Slide Number 13
- Platelet Structure UnactivatedActivated
- Primary Hemostasis
- Primary Hemostasis Assays
- Slide Number 17
- Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
- Slide Number 19
- Coagulation factors
- Coagulation Assay Mechanisms
- Slide Number 22
- Fibrin Formation
- Slide Number 24
- Fibrinolysis Overview
- Fibrinolysis Overview
- Slide Number 27
- Fibrinolysis Releases D-dimers
- Basic Pathophysiology of DIC
- Disseminated Intravascular Coagulation (DIC)
- Purpura Fulminans with DIC Due to Meningococcal Sepsis
- Clinical Conditions Associated With DIC
- Frequency of DIC in Selected Disease States
- Underlying Diseases in DIC Patients
- Slide Number 36
- Slide Number 37
- Slide Number 38
- Slide Number 39
- Pathophysiology of DIC
- Pathogenesis of DIC in Sepsis
- Host Response in Severe Sepsis
- Organ Failure in Severe Sepsis
- Mechanism of DIC in Organ Failure
- Interaction of Inflammation and Coagulation in Sepsis
- Slide Number 47
- Diverse and Opposing Effects of Thrombin
- Coagulation and Fibrinolysis in DIC
- Mechanism of DIC
- Pathophysiology of DIC
- Pathophysiology of DIC - Mechanism
- Pathophysiology of DIC ndash 2 Types of Clinical pictures
- Sub-Acute and Non-Overt DIC Clinical Findings
- Pathophysiology of Overt DIC
- Physiopathology of DIC ndash Overt DIC Findings
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- BREAK
- Diagnostic and Management Approach for DIC
- Diagnosis of DIC
- Lab Diagnosis of DIC ndash Markers of Factor Consumption
- Lab Diagnosis of DIC ndash Screening Tests
- Slide Number 67
- Slide Number 68
- British Journal of Haematology Overt DIC Score
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- DIC Management Goals
- DIC Management and Treatment
- DIC Management Strategies
- Anticoagulant Factor Concentrate Treatment
- Anticoagulant Factor Concentrate Treatment Trials
- Markers of Thrombin amp Plasmin Generation in DIC
- D-dimer FDPs and DIC
- D-Dimer and FDPs in DIC
- Follow Up of DIC State of Disease
- FMD-Dimer in DIC Major Differences
- of Abnormal Results in Patients with Confirmed and Suspected DIC
- Slide Number 85
- Slide Number 86
- Comparing an Automated FM vs Manual FSP Test
- Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Slide Number 94
- Slide Number 95
- Slide Number 96
- Slide Number 97
- Slide Number 98
- Slide Number 99
- DIC Case Studies
- Case Study 1 - Presentation
- Case Study 1 ndash Lab Results
- Case Study 1 ndash Microscopy
- Case Study 1 ndash Diagnosis and Therapy
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Slide Number 110
- Slide Number 111
- Slide Number 112
- Slide Number 113
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
- Slide Number 124
- Slide Number 125
- DIC Take Home Messages
- Slide Number 127
- Slide Number 128
-
Wound Sealing
EFFRACbreak in vessel
FIBRINOLYSIS
clot destruction
PRIMARYHEMOSTASIS
PLASMATICCOAGULATION
strong clot
wound sealing blood flow plusmn stopped
The Three Steps of Hemostasis
Primary Hemostasis Interaction between vessel wall platelets and adhesive proteins platelet clot
Coagulation Consolidation of the platelet thrombus insoluble fibrin net
bull Coagulation factors and inhibitors
Fibrinolysis Clot lysis clot is digested
bull Fibrinolytic activators and inhibitors
Vessel Wall
Intact endothelium non thrombogenic Synthesis of vasodilators (prostacyclin) No reaction either with platelets or factors
Sub endotheliumTissue Endothelium
blood
When a vessel wall is damaged Exposure of the subendothelium Platelet adhesion Initiation of the mechanisms of coagulation and fibrinolysis
PlateletsFactors
Sub endotheliumTissue Endothelium
blood
Vessel Wall Damage
Aim is to clog the damaged vessel ( asymp bricks without cement )
Primary Hemostasis
Platelet Structure UnactivatedActivated
GpIb-IX-V
GpIIb-IIIa
α granules (raw materials)PF4 β-TG Fibrinogen VWF Factor V and PAI-1
dense granules (energy and glue)ATP ADP SerotoninCa2+ Mg2+ P
Hillman Robert S Ault Kenneth A Rinder Henry M Hematology in Clinical Practice 4th Edition McGraw-Hill New York NY 2005
Primary Hemostasis
2) activation2nd shape changeamp release
platelet at rest 1) adhesion1st shape change
3) aggregation(not reversible)
Vasoconstriction occurs first
Platelets then aggregate on the break in the vessel wall
Primary Hemostasis AssaysRoutine Platelet count PT APTT TT
Follow-up von Willebrand Factor Antigen determination Activity Factor VIII PFA-100 Platelet aggregation studies
SpecializedSend Out Activation markers (b-TG PF4 GPV) Specialized tests for platelet function
Aim is to strengthen the platelet plug
Coagulation
Coagulation is a balancebetween pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
THROMBIN
Fibrinogen Fibrin
bull Triggering agentsbull pro-enzyme enzyme (serine-protease FIIa FVIIa FIXa FXa)bull Cofactors (FVa amp FVIIIa)
bull Serine-protease inhibitor Antithrombin (AT) bull Cofactorsinhibitors Protein C Sbull Tissue factor pathway inhibitor (TFPI)
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Coagulation Cascade Schematic
Coagulation factors
Historic name
Fibrinogen
Prothrombin
Proaccelerin
Proconvertin
Anti-hemophilic factor A
Anti-hemophilic factor B
Stuart factor
Rosenthal factor
Hageman factor
Fibrin Stabilizing Factor
Factor
I
II
V
VII
VIII
IX
X
XI
XII
XIII
Function
Substrate
Pro-enzyme
Pro-cofactor
Pro-enzyme
Pro-cofactor
Pro-enzyme
Pro-enzyme
Pro-enzyme
Pro-enzyme
Pro-enzyme
Pro-enzyme = Zymogen activation Active Enzyme
Coagulation Assay Mechanisms
aPTT Based
PT Based
PT Based
Fibrin Under Microscope
Weisel JW Structure of fibrin impact on clot stability J Thromb Haemost 2007 5 Suppl 1 116-24
Low thrombin concentration
High thrombin concentration
Fibrin Formation
Soluble FibrinPolymer
ThrombinFibrinogen
FM+ fibrinopeptides A amp B
Stabilized Fibrin clot(not soluble)
ThrombinXIII XIIIa
(Digestion of Fibrin)
Fibrinolysis
Fibrinolysis Overview
Destroys fibrin fibers
Destroys the scab (dried wound)
Maintains vessel integrity
Fibrinolysis Overview
Fibrin =cement fibers
Plasmin
Plasmin digests fibrin
t-PA
Pro Urokinase
Urokinase
PAI-1PAI-1
Plasminogen Plasmin
1st Step
2nd Step
Fibrinolysis Cascade
t-PA tissue-type plasminogen activator PAI-1 Plasminogen activator inhibitor 1 PK Prekallikrein FDP Fibrinogen degradation products AP Antiplasmin = a2AP alpha 2 Antiplasmin a2MG alpha 2 Macroglobulin
Extrinsic pathway(endothelia l cells)
Intrinsic pathway(plasma)
Fibrin clot
D-dimerFibrin degradation products
Fibrin
TAFIa
APAntiplasmin(amp a2-MG)
PK Kallikrein
XII
Fibrinolysis Releases D-dimers
D-dimer presence fibrin has been formed and digested in patients body
Normal D-dimer level no thrombosis occurred in the patient
Basic Pathophysiology of DIC
Disseminated Intravascular Coagulation (DIC)
Massive activation of coagulation leading to clots forming in multiple locations around the bodyRapid consumption of clotting factors leading to bleedingParadoxical condition leading to both clotting and bleedingA confusing disorder from both diagnostic and therapeutic standpoints Many unrelated diseases can trigger DIC Lack of uniformity in clinical manifestation Lack of uniformity in the laboratory diagnosis Lack of uniformity or consensus on management
Clinical Manifestations of DICOrgan Ischemic Hemorrhagic
Skin Pupura Fulminans Petechiae
Gangrene Echymoses
Acral cyanosis Oozing
CNS Deliriumcoma Intracranial
Infarcts Bleeding
Renal OliguriaAzotemia Hematuria
Cortical Necrosis
Cardiovascular Myocardial dysfunction
Pulmonary DyspneaHypoxia Hemorrhagic lung
Infarct
Gastrointestinal Ulcers infarcts Massive hemorrhage
Endocrine Adrenal infarcts
Purpura Fulminans with DIC Due to Meningococcal Sepsis
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Clinical Conditions Associated With DIC
Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33
Frequency of DIC in Selected Disease States
Disease Frequency
Gram-negative sepsis 30-50
Severe trauma and systemic inflammation 50-70
Metastasized tumors 15
Abruptio placentaamniotic fluid embolism 50
Severe preeclampsia 7
Giant hemangioma 25
Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92
Masao Nakagawa Modified from a research report on the incidence of disseminated intravascular coagulation (DIC) and underlying diseases in Japan Ministry of Health Labour and Welfare Research report published in Fiscal Year 1998 57-64 199 httpwwwrecomodulincomendicindexhtml Accessed Apr 21 2017
Underlying Diseases in DIC Patients
In a Japanese survey from 1997 on incidence of DIC and underlying diseases in 652 divisions and departments of university hospitals DIC occurred in 2193 patients with the number of patient with infections (including sepsis) and hematologic tumors (including leukemia) accounted for 28 and 23 respectively
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Epidemiology of DIC
Impact of DIC Status on Mortality - 1
Okamoto K Wada H Hatada T Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Frequency and hemostatic abnormalities in pre-DIC patients Thromb Res 2010 126 74-8
Patients with positivity of DIC tend to have worse mortality outcomes compared to negative patients or those with pre-DIC
Impact of DIC Status on Mortality - 2
Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4
Patients with positivity of either Overt or Non-Overt DIC tend to have worse mortality outcomes compared to negative patients
Impact of Age on Mortality in DIC Patients
Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4
Older patients with DIC (black bars) generally tend to have worse outcomes compared to non-DIC patients (grey bars)
Pathophysiology of DIC
Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33
Pathogenesis of DIC in Sepsis
Allen KS Sawheny E Kinasewitzet GT Anticoagulant modulation of inflammation in severe sepsis World J Crit Care Med 2015 4 105-15
Bacteria in sepsis infections cause release of TF from immune cells leading to coagulation activation and proinflammatory cytokines cause endothelial cell activation impairing the anticoagulation and fibrinolysis process resulting in DIC
Host Response in Severe Sepsis
Exaggerated inflammation as a result of the host response to sepsis is collateral tissue damage and cell death further resulting in release of danger molecules continuing the inflammatory process in a downward spiral
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Organ Failure in Severe Sepsis
Sepsis associated with microvascular thrombosis as a result of TF mediated coagulation activation results in release of neutrophil extracellular traps (NETs) tissue hypoperfusion and mitochondrial damage resulting in a downward spiral leading to organ failure
Angus DC van der Poll T Severe Sepsis and Septic Shock N Engl J Med 2013 369 840-51
Mechanism of DIC in Organ Failure
Underlying condition(sepsis trauma)
Cytokines
TF-mediatedactivation of coagulation
Depression of inhibitory systems
Reducesfibrinolysis
Fibrin deposition
Organ failure
Inadequate fibrin removal
Fibrinformation
Note impaired fibrinolysis in relation to the clinical need not in absolute value (FDPs are )
Levi M de Jonge E van der Poll T ten Cate H Disseminated intravascular coagulation ThrombHaemost 1999 82 695-705
Interaction of Inflammation and Coagulation in Sepsis
Binding of TF thrombin and other activation coagulation factors to PARs and fibrin to TLRs on inflammatory cells results in inflammation through release of proinflammatory cytokines and chemokines
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Mechanism of Multiple Organ Failure in DIC
Wheeler AP Bernard GR Treating Patients with Severe Sepsis N Engl J Med 1999 340207-14
Inflammatory activation and microvascular thrombosis contributes to multiple organ failure in DIC
lipopolysaccharides
cytokines
coagulation activation
mononuclear cell
tissue factor
Diverse and Opposing Effects of Thrombin
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Coagulation and Fibrinolysis in DIC
Soluble fibrin Polymer
XIIIa
D-Dimer
E
Fibrin clot
Fibrin Degradation Products
Fibrinogen Thrombin
Fibrinogen Degradation
Products
D E
Plasmin
DFM + fibrinopeptides
Soluble FM ComplexesPre-throm
boticPost-throm
botic
Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis Semin Thromb Hemost 2008 34 33-8
Mechanism of DIC
THROMBOSIS
Fibrin
Blood activationEndothelial lysisTF expression
BLEEDING
FDPs
D-Dimer
Plasmin
Pathophysiology of DIC
1st step abnormal activation of coagulation Injury of vessel wall cells venous stasis release of large quantities of
thromboplastin influx of activated cells (monocytes macrophages)
Results in an intravascular deposition of fibrin
Morbidity from disseminated microthrombosis in small and midsize vessels leading to multiple organ failure
Second step Consumption and depletion of coagulation factors inhibitors (Protein C
Protein S AT) and platelets Local fibrinolytic response
bull Local plasmin generation dissolves the thrombusbull Disseminated overwhelming fibrinolytic response leading to production of
FDP and D-Dimer
Bleeding
Pathophysiology of DIC - Mechanism
Systemic activation of coagulation
Intravasculardepositionof fibrin
Thrombosis of small and midsize vessels
and organ failure
Depletion of platelets and
coagulation factors
Bleeding
Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92
Pathophysiology of DIC ndash 2 Types of Clinical pictures
Chronic = non - overt DICMay be unrecognized clinically
Acute = overt DIClife threatening bleedingor multiple organ failure
Sub-Acute and Non-Overt DIC Clinical Findings
Compensated non-overt DIC Steady low level or intermittent activation
bull Compensated by increased production of coagulation components and platelets
Few or no clinical signs or multiple microvascular thrombosis sometimes not clinically obvious
Risk of decompensation leading to overt DIC
Pathophysiology of Overt DIC
Massive activation of coagulation and fibrinolysis
Does not allow for compensatory efforts
Rapid depletion of coagulation factors inhibitors and platelets
Thrombosis multiple organ failures
Bleeding complications and shock
Physiopathology of DIC ndash Overt DIC Findings
Thrombin generation
Thrombosis
Renal liver respiratory failures coma skin necrosis gangrene venous thromboembolism hypotension edema
Cytokine and kinin generation (shock)bull Tachycardia hypotension edema
Plasmin generationHemorrhage
bull Spontaneous bruising petechiae intracranial gastrointestinal and respiratory tract bleeding persistent bleeding at venipuncture sites at surgical wounds
bull Tachycardia hypotension edema
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Pathogenesis Pathways in DIC
Cytokines
TF-mediated dysfunctional impairedthrombin anticoagulant fibrinolysisgeneration mechanism due to PAI-1 deficiency
fibrin inadequateformation fibrin removal
Fibrin deposition
Inflammation
Coagulation
Stago Celebrates Lab Week 2017
NA
Stago 247 Educational Webinar Sites
wwwstago-edvantagecomUS based KOLsPACE accredited ndash all 1 hourAccessible from mobile devicesVirtual exhibit hall
wwwstagowebinarscomMostly European KOLs30 ndash 45 min including 15 min discussion
Stago Educational Apps
HaemoscoreClinical scoring algorithmsApple and AndroidTablet or phone
iHemostasisCoagulation diagramsCase studiesApple amp AndroidTablet only
BREAK
Diagnostic and Management Approach for DIC
Diagnosis of DIC
Clinical diagnosis is obvious in cases of overt DIC
Laboratory tests are necessary To makeconfirm the diagnosis To assess stage of the patient To assess the treatment efficacy
Lab Diagnosis of DIC ndash Markers of Factor Consumption
Routinescreening assays PT APTT Platelets Fibrinogen Thrombin time
Other coagulation assays Factor assays AntithrombinGeneration of Thrombin FMFSPsGeneration of Plasmin D-dimer FDPs
Important to recognize simultaneous formation of thrombin and plasmin
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122
Lab Diagnosis of DIC ndash Screening Tests
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122
Platelet count usually decreasedPT abnormal in 70 of cases (short half-life of FVII)APTT abnormal in 50 of casesThrombin time usually prolonged in overt DIC normal in non-overt DIC and no relation with syndrome severityFibrinogen low in lt 50 of cases sensitivity 22 specificity 87 overall predictive value 64 Normal fibrinogen level should not exclude DIC diagnosis (acute phase reactant initial high
fibrinogen level) repeat testing assesses progression
Screening tests not clinically specific or sensitive for DIC
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Laboratory Changes in Overt DIC
DIC Diagnostic Practices Over Time
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
British Journal of Haematology Overt DIC Score
Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
ISTH Step by Step DIC Algorithm
Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6
US Based Validation of ISTH DIC Score
When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Differential Diagnosis in DIC
aHUS atypical hemolytic uremic syndrome
HUS hemolytic uremic syndrome
HIT heparin-induced thrombocytopenia
ITP immune thrombocytopenic purpura
TTP thrombotic thrombocytopenic purpura
DIC and MAHA
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)
When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation
DIC Management Goals
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction
DIC Management and Treatment
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)
requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)
Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia
DIC Management Strategies
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant Factor Concentrate Treatment
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis
Anticoagulant Factor Concentrate Treatment Trials
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise
Markers of Thrombin amp Plasmin Generation in DIC
D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC
Cut-off value
Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen
degradation products Sensitive assay typically with cutoff adapted for DIC
D-dimer FDPs and DIC
D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC
Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80
Follow Up of DIC State of Disease
Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8
Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility
FMD-Dimer in DIC Major Differences
onset of thrombosis
days
Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8
FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)
D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)
of Abnormal Results in Patients with Confirmed and Suspected DIC
0
20
40
60
80
100
94 85 90N = 62
Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32
Positivity of Test Results ISTH Score and Disease State
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
Red bar positive for 2 points of DIC score
Pink bar positive for 1-2 points of DIC score
HT hematopoietic tumor
IF infection
SC solid cancer
Markers in Patients with or without DIC
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
HT hematopoietic tumorIF infectionSC solid cancer
Comparing an Automated FM vs Manual FSP Test
Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71
Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)
Automated (Mitsubishi) vs Automated (Stago)
In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago
Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC
Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
Non Overt DIC Overt DIC
AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC
Trends in Markers of DIC for Different Patients
Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00
Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients
Trends in Markers of DIC for Different Patients
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes
28 day outcome survival
28 day outcome death
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines
DIC Case Studies
Case Study 1 - Presentation
18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE
WBC count 77 KμL 423 ndash 907 x KμL
RBC count 17 MμL 137 ndash 175 x MμL
Hemoglobin 67 gdL 137 ndash 175 gdL
Hematocrit 195 401 ndash 510
MCV 95 fL 790 ndash 922 fL
MPV 12 fL 94 ndash 124 fL
Platelet count 9 KμL 161 ndash 347 KμL
Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0
Lymphocytes monocytes eosinophils basophils all below normal range
PT 47 sec (corrected on mixing study) 116 ndash 152 sec
APTT 75 sec (corrected on mixing study) 253 ndash 373 sec
Fibrinogen lt 76 mgdL 177 ndash 466 mgdL
D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Microscopy
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Arrow shows giant platelets in this peripheral smear Promyelocytes apparent
Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)
DIC due to TF release by APL blasts
Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases
Transfusions to replace factors along with platelets and RBCs during APL treatment
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started
Case Study 2 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L
PT 30 sec 113 ndash 146 sec
APTT 75 sec 25 ndash 34 sec
D-dimer 078 microgml FEU lt050 microgml FEU
Fibrinogen 92 mgdl 150-400 mgdl
pH 728 738 to 742
PaO2 570 mmHg 80-100 mmHg
WBC 33 times 103mm3 40-11 times 103mm3
ALT 111 IUL 0ndash34 IUL
AST 61 IUL 0ndash34 IUL
BUN 303 mgdL 08-13 mgdL
Case Study 2 ndash Lab Results
Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures
Case Study 2 ndash Diagnosis
60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior
Case Study 3 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L
PT 228 sec 113 ndash 146 sec
APTT 45 sec 25 ndash 34 sec
D-dimer 080 microgml FEU lt050 microgmL FEU
Fibrinogen 82 mgdL 150-400 mgdL
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 134 gdL 14-16 gdL
WBC 81 times 103mm3 40-11 times 103mm3
ALT 32 IUL 0ndash34 IUL
AST 28 IUL 0ndash34 IUL
BUN 09 mgdL 08-13 mgdL
Case Study 3 ndash Lab Results
Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment
Case Study 3 ndash Diagnosis and Therapy
Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91
Case Study 4 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L
PT 28 sec 113 ndash 146 sec
APTT 71 sec 25 ndash 34 sec
D-dimer 31 microgmL FEU lt050 microgml FEU
Fibrinogen 92 mgdL 150-400 mgdl
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 158 gdL 14-16 gdL
WBC 71 times 103mm3 40-11 times 103mm3
ALT 60 IUL 0ndash34 IUL
AST 47 IUL 0ndash34 IUL
BUN 38 mgdL 08-13 mgdL
Case Study 4 ndash Lab Results
Lyme disease with DICProvide antibiotics with supportive measures
Case Study 4 ndash Diagnosis
55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis
Case Study 5 ndash Presentation
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
Case Study 5 ndash Lab Results and Time Course
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
TEST RESULT REFERENCE RANGE
Platelet count 33 x 109L 150-450 x 109L
PT 215 sec 103 ndash 128 sec
APTT 44 sec 26 ndash 36 sec
D-dimer 20 microgmL FEU lt025 microgml FEU
Fibrinogen 34 mgdL 200-375 mgdl
FII FV FVIII Low Not reported (NR)
FVII FIX FX vWF Normal NR
Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)
DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic
dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR
(C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen
(D) Illustration demonstrating repair
Case Study 5 ndash Diagnosis and Treatment
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography
Case Study 6 ndash Presentation
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
Case Study 6 ndash Lab Results
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L
PT 63 sec gt control 113 ndash 146 sec
INR 658 1 ndash 125
APTT 80 sec gt control 25 ndash 34 sec
D-dimer gt200 microgmL DDU 02 microgmL DDU
Urine exam Proteinuria and hematuria 150-400 mgdl
Albumin 28 gdL NR
Hb 58 gdL NR
LDH 1196 UL NR
SGPT 144 IU NR
SGOT 88 IU NR
Bilirubin 32 mgdL NR
DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th
day postop
Case Study 6 ndash Diagnosis and Treatment
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure
Case Study 6 ndash Discussion
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Case Study 7 ndash Lab Results vs Time
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
DIC Take Home Messages
Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation
Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers
DIC
Thank you Questions
- Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
- Learning Objectives
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Wound Sealing
- The Three Steps of Hemostasis
- Vessel Wall
- Slide Number 12
- Slide Number 13
- Platelet Structure UnactivatedActivated
- Primary Hemostasis
- Primary Hemostasis Assays
- Slide Number 17
- Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
- Slide Number 19
- Coagulation factors
- Coagulation Assay Mechanisms
- Slide Number 22
- Fibrin Formation
- Slide Number 24
- Fibrinolysis Overview
- Fibrinolysis Overview
- Slide Number 27
- Fibrinolysis Releases D-dimers
- Basic Pathophysiology of DIC
- Disseminated Intravascular Coagulation (DIC)
- Purpura Fulminans with DIC Due to Meningococcal Sepsis
- Clinical Conditions Associated With DIC
- Frequency of DIC in Selected Disease States
- Underlying Diseases in DIC Patients
- Slide Number 36
- Slide Number 37
- Slide Number 38
- Slide Number 39
- Pathophysiology of DIC
- Pathogenesis of DIC in Sepsis
- Host Response in Severe Sepsis
- Organ Failure in Severe Sepsis
- Mechanism of DIC in Organ Failure
- Interaction of Inflammation and Coagulation in Sepsis
- Slide Number 47
- Diverse and Opposing Effects of Thrombin
- Coagulation and Fibrinolysis in DIC
- Mechanism of DIC
- Pathophysiology of DIC
- Pathophysiology of DIC - Mechanism
- Pathophysiology of DIC ndash 2 Types of Clinical pictures
- Sub-Acute and Non-Overt DIC Clinical Findings
- Pathophysiology of Overt DIC
- Physiopathology of DIC ndash Overt DIC Findings
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- BREAK
- Diagnostic and Management Approach for DIC
- Diagnosis of DIC
- Lab Diagnosis of DIC ndash Markers of Factor Consumption
- Lab Diagnosis of DIC ndash Screening Tests
- Slide Number 67
- Slide Number 68
- British Journal of Haematology Overt DIC Score
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- DIC Management Goals
- DIC Management and Treatment
- DIC Management Strategies
- Anticoagulant Factor Concentrate Treatment
- Anticoagulant Factor Concentrate Treatment Trials
- Markers of Thrombin amp Plasmin Generation in DIC
- D-dimer FDPs and DIC
- D-Dimer and FDPs in DIC
- Follow Up of DIC State of Disease
- FMD-Dimer in DIC Major Differences
- of Abnormal Results in Patients with Confirmed and Suspected DIC
- Slide Number 85
- Slide Number 86
- Comparing an Automated FM vs Manual FSP Test
- Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Slide Number 94
- Slide Number 95
- Slide Number 96
- Slide Number 97
- Slide Number 98
- Slide Number 99
- DIC Case Studies
- Case Study 1 - Presentation
- Case Study 1 ndash Lab Results
- Case Study 1 ndash Microscopy
- Case Study 1 ndash Diagnosis and Therapy
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Slide Number 110
- Slide Number 111
- Slide Number 112
- Slide Number 113
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
- Slide Number 124
- Slide Number 125
- DIC Take Home Messages
- Slide Number 127
- Slide Number 128
-
The Three Steps of Hemostasis
Primary Hemostasis Interaction between vessel wall platelets and adhesive proteins platelet clot
Coagulation Consolidation of the platelet thrombus insoluble fibrin net
bull Coagulation factors and inhibitors
Fibrinolysis Clot lysis clot is digested
bull Fibrinolytic activators and inhibitors
Vessel Wall
Intact endothelium non thrombogenic Synthesis of vasodilators (prostacyclin) No reaction either with platelets or factors
Sub endotheliumTissue Endothelium
blood
When a vessel wall is damaged Exposure of the subendothelium Platelet adhesion Initiation of the mechanisms of coagulation and fibrinolysis
PlateletsFactors
Sub endotheliumTissue Endothelium
blood
Vessel Wall Damage
Aim is to clog the damaged vessel ( asymp bricks without cement )
Primary Hemostasis
Platelet Structure UnactivatedActivated
GpIb-IX-V
GpIIb-IIIa
α granules (raw materials)PF4 β-TG Fibrinogen VWF Factor V and PAI-1
dense granules (energy and glue)ATP ADP SerotoninCa2+ Mg2+ P
Hillman Robert S Ault Kenneth A Rinder Henry M Hematology in Clinical Practice 4th Edition McGraw-Hill New York NY 2005
Primary Hemostasis
2) activation2nd shape changeamp release
platelet at rest 1) adhesion1st shape change
3) aggregation(not reversible)
Vasoconstriction occurs first
Platelets then aggregate on the break in the vessel wall
Primary Hemostasis AssaysRoutine Platelet count PT APTT TT
Follow-up von Willebrand Factor Antigen determination Activity Factor VIII PFA-100 Platelet aggregation studies
SpecializedSend Out Activation markers (b-TG PF4 GPV) Specialized tests for platelet function
Aim is to strengthen the platelet plug
Coagulation
Coagulation is a balancebetween pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
THROMBIN
Fibrinogen Fibrin
bull Triggering agentsbull pro-enzyme enzyme (serine-protease FIIa FVIIa FIXa FXa)bull Cofactors (FVa amp FVIIIa)
bull Serine-protease inhibitor Antithrombin (AT) bull Cofactorsinhibitors Protein C Sbull Tissue factor pathway inhibitor (TFPI)
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Coagulation Cascade Schematic
Coagulation factors
Historic name
Fibrinogen
Prothrombin
Proaccelerin
Proconvertin
Anti-hemophilic factor A
Anti-hemophilic factor B
Stuart factor
Rosenthal factor
Hageman factor
Fibrin Stabilizing Factor
Factor
I
II
V
VII
VIII
IX
X
XI
XII
XIII
Function
Substrate
Pro-enzyme
Pro-cofactor
Pro-enzyme
Pro-cofactor
Pro-enzyme
Pro-enzyme
Pro-enzyme
Pro-enzyme
Pro-enzyme
Pro-enzyme = Zymogen activation Active Enzyme
Coagulation Assay Mechanisms
aPTT Based
PT Based
PT Based
Fibrin Under Microscope
Weisel JW Structure of fibrin impact on clot stability J Thromb Haemost 2007 5 Suppl 1 116-24
Low thrombin concentration
High thrombin concentration
Fibrin Formation
Soluble FibrinPolymer
ThrombinFibrinogen
FM+ fibrinopeptides A amp B
Stabilized Fibrin clot(not soluble)
ThrombinXIII XIIIa
(Digestion of Fibrin)
Fibrinolysis
Fibrinolysis Overview
Destroys fibrin fibers
Destroys the scab (dried wound)
Maintains vessel integrity
Fibrinolysis Overview
Fibrin =cement fibers
Plasmin
Plasmin digests fibrin
t-PA
Pro Urokinase
Urokinase
PAI-1PAI-1
Plasminogen Plasmin
1st Step
2nd Step
Fibrinolysis Cascade
t-PA tissue-type plasminogen activator PAI-1 Plasminogen activator inhibitor 1 PK Prekallikrein FDP Fibrinogen degradation products AP Antiplasmin = a2AP alpha 2 Antiplasmin a2MG alpha 2 Macroglobulin
Extrinsic pathway(endothelia l cells)
Intrinsic pathway(plasma)
Fibrin clot
D-dimerFibrin degradation products
Fibrin
TAFIa
APAntiplasmin(amp a2-MG)
PK Kallikrein
XII
Fibrinolysis Releases D-dimers
D-dimer presence fibrin has been formed and digested in patients body
Normal D-dimer level no thrombosis occurred in the patient
Basic Pathophysiology of DIC
Disseminated Intravascular Coagulation (DIC)
Massive activation of coagulation leading to clots forming in multiple locations around the bodyRapid consumption of clotting factors leading to bleedingParadoxical condition leading to both clotting and bleedingA confusing disorder from both diagnostic and therapeutic standpoints Many unrelated diseases can trigger DIC Lack of uniformity in clinical manifestation Lack of uniformity in the laboratory diagnosis Lack of uniformity or consensus on management
Clinical Manifestations of DICOrgan Ischemic Hemorrhagic
Skin Pupura Fulminans Petechiae
Gangrene Echymoses
Acral cyanosis Oozing
CNS Deliriumcoma Intracranial
Infarcts Bleeding
Renal OliguriaAzotemia Hematuria
Cortical Necrosis
Cardiovascular Myocardial dysfunction
Pulmonary DyspneaHypoxia Hemorrhagic lung
Infarct
Gastrointestinal Ulcers infarcts Massive hemorrhage
Endocrine Adrenal infarcts
Purpura Fulminans with DIC Due to Meningococcal Sepsis
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Clinical Conditions Associated With DIC
Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33
Frequency of DIC in Selected Disease States
Disease Frequency
Gram-negative sepsis 30-50
Severe trauma and systemic inflammation 50-70
Metastasized tumors 15
Abruptio placentaamniotic fluid embolism 50
Severe preeclampsia 7
Giant hemangioma 25
Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92
Masao Nakagawa Modified from a research report on the incidence of disseminated intravascular coagulation (DIC) and underlying diseases in Japan Ministry of Health Labour and Welfare Research report published in Fiscal Year 1998 57-64 199 httpwwwrecomodulincomendicindexhtml Accessed Apr 21 2017
Underlying Diseases in DIC Patients
In a Japanese survey from 1997 on incidence of DIC and underlying diseases in 652 divisions and departments of university hospitals DIC occurred in 2193 patients with the number of patient with infections (including sepsis) and hematologic tumors (including leukemia) accounted for 28 and 23 respectively
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Epidemiology of DIC
Impact of DIC Status on Mortality - 1
Okamoto K Wada H Hatada T Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Frequency and hemostatic abnormalities in pre-DIC patients Thromb Res 2010 126 74-8
Patients with positivity of DIC tend to have worse mortality outcomes compared to negative patients or those with pre-DIC
Impact of DIC Status on Mortality - 2
Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4
Patients with positivity of either Overt or Non-Overt DIC tend to have worse mortality outcomes compared to negative patients
Impact of Age on Mortality in DIC Patients
Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4
Older patients with DIC (black bars) generally tend to have worse outcomes compared to non-DIC patients (grey bars)
Pathophysiology of DIC
Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33
Pathogenesis of DIC in Sepsis
Allen KS Sawheny E Kinasewitzet GT Anticoagulant modulation of inflammation in severe sepsis World J Crit Care Med 2015 4 105-15
Bacteria in sepsis infections cause release of TF from immune cells leading to coagulation activation and proinflammatory cytokines cause endothelial cell activation impairing the anticoagulation and fibrinolysis process resulting in DIC
Host Response in Severe Sepsis
Exaggerated inflammation as a result of the host response to sepsis is collateral tissue damage and cell death further resulting in release of danger molecules continuing the inflammatory process in a downward spiral
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Organ Failure in Severe Sepsis
Sepsis associated with microvascular thrombosis as a result of TF mediated coagulation activation results in release of neutrophil extracellular traps (NETs) tissue hypoperfusion and mitochondrial damage resulting in a downward spiral leading to organ failure
Angus DC van der Poll T Severe Sepsis and Septic Shock N Engl J Med 2013 369 840-51
Mechanism of DIC in Organ Failure
Underlying condition(sepsis trauma)
Cytokines
TF-mediatedactivation of coagulation
Depression of inhibitory systems
Reducesfibrinolysis
Fibrin deposition
Organ failure
Inadequate fibrin removal
Fibrinformation
Note impaired fibrinolysis in relation to the clinical need not in absolute value (FDPs are )
Levi M de Jonge E van der Poll T ten Cate H Disseminated intravascular coagulation ThrombHaemost 1999 82 695-705
Interaction of Inflammation and Coagulation in Sepsis
Binding of TF thrombin and other activation coagulation factors to PARs and fibrin to TLRs on inflammatory cells results in inflammation through release of proinflammatory cytokines and chemokines
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Mechanism of Multiple Organ Failure in DIC
Wheeler AP Bernard GR Treating Patients with Severe Sepsis N Engl J Med 1999 340207-14
Inflammatory activation and microvascular thrombosis contributes to multiple organ failure in DIC
lipopolysaccharides
cytokines
coagulation activation
mononuclear cell
tissue factor
Diverse and Opposing Effects of Thrombin
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Coagulation and Fibrinolysis in DIC
Soluble fibrin Polymer
XIIIa
D-Dimer
E
Fibrin clot
Fibrin Degradation Products
Fibrinogen Thrombin
Fibrinogen Degradation
Products
D E
Plasmin
DFM + fibrinopeptides
Soluble FM ComplexesPre-throm
boticPost-throm
botic
Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis Semin Thromb Hemost 2008 34 33-8
Mechanism of DIC
THROMBOSIS
Fibrin
Blood activationEndothelial lysisTF expression
BLEEDING
FDPs
D-Dimer
Plasmin
Pathophysiology of DIC
1st step abnormal activation of coagulation Injury of vessel wall cells venous stasis release of large quantities of
thromboplastin influx of activated cells (monocytes macrophages)
Results in an intravascular deposition of fibrin
Morbidity from disseminated microthrombosis in small and midsize vessels leading to multiple organ failure
Second step Consumption and depletion of coagulation factors inhibitors (Protein C
Protein S AT) and platelets Local fibrinolytic response
bull Local plasmin generation dissolves the thrombusbull Disseminated overwhelming fibrinolytic response leading to production of
FDP and D-Dimer
Bleeding
Pathophysiology of DIC - Mechanism
Systemic activation of coagulation
Intravasculardepositionof fibrin
Thrombosis of small and midsize vessels
and organ failure
Depletion of platelets and
coagulation factors
Bleeding
Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92
Pathophysiology of DIC ndash 2 Types of Clinical pictures
Chronic = non - overt DICMay be unrecognized clinically
Acute = overt DIClife threatening bleedingor multiple organ failure
Sub-Acute and Non-Overt DIC Clinical Findings
Compensated non-overt DIC Steady low level or intermittent activation
bull Compensated by increased production of coagulation components and platelets
Few or no clinical signs or multiple microvascular thrombosis sometimes not clinically obvious
Risk of decompensation leading to overt DIC
Pathophysiology of Overt DIC
Massive activation of coagulation and fibrinolysis
Does not allow for compensatory efforts
Rapid depletion of coagulation factors inhibitors and platelets
Thrombosis multiple organ failures
Bleeding complications and shock
Physiopathology of DIC ndash Overt DIC Findings
Thrombin generation
Thrombosis
Renal liver respiratory failures coma skin necrosis gangrene venous thromboembolism hypotension edema
Cytokine and kinin generation (shock)bull Tachycardia hypotension edema
Plasmin generationHemorrhage
bull Spontaneous bruising petechiae intracranial gastrointestinal and respiratory tract bleeding persistent bleeding at venipuncture sites at surgical wounds
bull Tachycardia hypotension edema
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Pathogenesis Pathways in DIC
Cytokines
TF-mediated dysfunctional impairedthrombin anticoagulant fibrinolysisgeneration mechanism due to PAI-1 deficiency
fibrin inadequateformation fibrin removal
Fibrin deposition
Inflammation
Coagulation
Stago Celebrates Lab Week 2017
NA
Stago 247 Educational Webinar Sites
wwwstago-edvantagecomUS based KOLsPACE accredited ndash all 1 hourAccessible from mobile devicesVirtual exhibit hall
wwwstagowebinarscomMostly European KOLs30 ndash 45 min including 15 min discussion
Stago Educational Apps
HaemoscoreClinical scoring algorithmsApple and AndroidTablet or phone
iHemostasisCoagulation diagramsCase studiesApple amp AndroidTablet only
BREAK
Diagnostic and Management Approach for DIC
Diagnosis of DIC
Clinical diagnosis is obvious in cases of overt DIC
Laboratory tests are necessary To makeconfirm the diagnosis To assess stage of the patient To assess the treatment efficacy
Lab Diagnosis of DIC ndash Markers of Factor Consumption
Routinescreening assays PT APTT Platelets Fibrinogen Thrombin time
Other coagulation assays Factor assays AntithrombinGeneration of Thrombin FMFSPsGeneration of Plasmin D-dimer FDPs
Important to recognize simultaneous formation of thrombin and plasmin
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122
Lab Diagnosis of DIC ndash Screening Tests
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122
Platelet count usually decreasedPT abnormal in 70 of cases (short half-life of FVII)APTT abnormal in 50 of casesThrombin time usually prolonged in overt DIC normal in non-overt DIC and no relation with syndrome severityFibrinogen low in lt 50 of cases sensitivity 22 specificity 87 overall predictive value 64 Normal fibrinogen level should not exclude DIC diagnosis (acute phase reactant initial high
fibrinogen level) repeat testing assesses progression
Screening tests not clinically specific or sensitive for DIC
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Laboratory Changes in Overt DIC
DIC Diagnostic Practices Over Time
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
British Journal of Haematology Overt DIC Score
Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
ISTH Step by Step DIC Algorithm
Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6
US Based Validation of ISTH DIC Score
When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Differential Diagnosis in DIC
aHUS atypical hemolytic uremic syndrome
HUS hemolytic uremic syndrome
HIT heparin-induced thrombocytopenia
ITP immune thrombocytopenic purpura
TTP thrombotic thrombocytopenic purpura
DIC and MAHA
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)
When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation
DIC Management Goals
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction
DIC Management and Treatment
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)
requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)
Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia
DIC Management Strategies
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant Factor Concentrate Treatment
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis
Anticoagulant Factor Concentrate Treatment Trials
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise
Markers of Thrombin amp Plasmin Generation in DIC
D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC
Cut-off value
Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen
degradation products Sensitive assay typically with cutoff adapted for DIC
D-dimer FDPs and DIC
D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC
Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80
Follow Up of DIC State of Disease
Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8
Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility
FMD-Dimer in DIC Major Differences
onset of thrombosis
days
Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8
FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)
D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)
of Abnormal Results in Patients with Confirmed and Suspected DIC
0
20
40
60
80
100
94 85 90N = 62
Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32
Positivity of Test Results ISTH Score and Disease State
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
Red bar positive for 2 points of DIC score
Pink bar positive for 1-2 points of DIC score
HT hematopoietic tumor
IF infection
SC solid cancer
Markers in Patients with or without DIC
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
HT hematopoietic tumorIF infectionSC solid cancer
Comparing an Automated FM vs Manual FSP Test
Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71
Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)
Automated (Mitsubishi) vs Automated (Stago)
In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago
Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC
Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
Non Overt DIC Overt DIC
AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC
Trends in Markers of DIC for Different Patients
Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00
Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients
Trends in Markers of DIC for Different Patients
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes
28 day outcome survival
28 day outcome death
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines
DIC Case Studies
Case Study 1 - Presentation
18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE
WBC count 77 KμL 423 ndash 907 x KμL
RBC count 17 MμL 137 ndash 175 x MμL
Hemoglobin 67 gdL 137 ndash 175 gdL
Hematocrit 195 401 ndash 510
MCV 95 fL 790 ndash 922 fL
MPV 12 fL 94 ndash 124 fL
Platelet count 9 KμL 161 ndash 347 KμL
Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0
Lymphocytes monocytes eosinophils basophils all below normal range
PT 47 sec (corrected on mixing study) 116 ndash 152 sec
APTT 75 sec (corrected on mixing study) 253 ndash 373 sec
Fibrinogen lt 76 mgdL 177 ndash 466 mgdL
D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Microscopy
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Arrow shows giant platelets in this peripheral smear Promyelocytes apparent
Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)
DIC due to TF release by APL blasts
Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases
Transfusions to replace factors along with platelets and RBCs during APL treatment
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started
Case Study 2 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L
PT 30 sec 113 ndash 146 sec
APTT 75 sec 25 ndash 34 sec
D-dimer 078 microgml FEU lt050 microgml FEU
Fibrinogen 92 mgdl 150-400 mgdl
pH 728 738 to 742
PaO2 570 mmHg 80-100 mmHg
WBC 33 times 103mm3 40-11 times 103mm3
ALT 111 IUL 0ndash34 IUL
AST 61 IUL 0ndash34 IUL
BUN 303 mgdL 08-13 mgdL
Case Study 2 ndash Lab Results
Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures
Case Study 2 ndash Diagnosis
60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior
Case Study 3 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L
PT 228 sec 113 ndash 146 sec
APTT 45 sec 25 ndash 34 sec
D-dimer 080 microgml FEU lt050 microgmL FEU
Fibrinogen 82 mgdL 150-400 mgdL
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 134 gdL 14-16 gdL
WBC 81 times 103mm3 40-11 times 103mm3
ALT 32 IUL 0ndash34 IUL
AST 28 IUL 0ndash34 IUL
BUN 09 mgdL 08-13 mgdL
Case Study 3 ndash Lab Results
Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment
Case Study 3 ndash Diagnosis and Therapy
Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91
Case Study 4 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L
PT 28 sec 113 ndash 146 sec
APTT 71 sec 25 ndash 34 sec
D-dimer 31 microgmL FEU lt050 microgml FEU
Fibrinogen 92 mgdL 150-400 mgdl
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 158 gdL 14-16 gdL
WBC 71 times 103mm3 40-11 times 103mm3
ALT 60 IUL 0ndash34 IUL
AST 47 IUL 0ndash34 IUL
BUN 38 mgdL 08-13 mgdL
Case Study 4 ndash Lab Results
Lyme disease with DICProvide antibiotics with supportive measures
Case Study 4 ndash Diagnosis
55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis
Case Study 5 ndash Presentation
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
Case Study 5 ndash Lab Results and Time Course
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
TEST RESULT REFERENCE RANGE
Platelet count 33 x 109L 150-450 x 109L
PT 215 sec 103 ndash 128 sec
APTT 44 sec 26 ndash 36 sec
D-dimer 20 microgmL FEU lt025 microgml FEU
Fibrinogen 34 mgdL 200-375 mgdl
FII FV FVIII Low Not reported (NR)
FVII FIX FX vWF Normal NR
Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)
DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic
dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR
(C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen
(D) Illustration demonstrating repair
Case Study 5 ndash Diagnosis and Treatment
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography
Case Study 6 ndash Presentation
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
Case Study 6 ndash Lab Results
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L
PT 63 sec gt control 113 ndash 146 sec
INR 658 1 ndash 125
APTT 80 sec gt control 25 ndash 34 sec
D-dimer gt200 microgmL DDU 02 microgmL DDU
Urine exam Proteinuria and hematuria 150-400 mgdl
Albumin 28 gdL NR
Hb 58 gdL NR
LDH 1196 UL NR
SGPT 144 IU NR
SGOT 88 IU NR
Bilirubin 32 mgdL NR
DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th
day postop
Case Study 6 ndash Diagnosis and Treatment
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure
Case Study 6 ndash Discussion
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Case Study 7 ndash Lab Results vs Time
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
DIC Take Home Messages
Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation
Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers
DIC
Thank you Questions
- Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
- Learning Objectives
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Wound Sealing
- The Three Steps of Hemostasis
- Vessel Wall
- Slide Number 12
- Slide Number 13
- Platelet Structure UnactivatedActivated
- Primary Hemostasis
- Primary Hemostasis Assays
- Slide Number 17
- Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
- Slide Number 19
- Coagulation factors
- Coagulation Assay Mechanisms
- Slide Number 22
- Fibrin Formation
- Slide Number 24
- Fibrinolysis Overview
- Fibrinolysis Overview
- Slide Number 27
- Fibrinolysis Releases D-dimers
- Basic Pathophysiology of DIC
- Disseminated Intravascular Coagulation (DIC)
- Purpura Fulminans with DIC Due to Meningococcal Sepsis
- Clinical Conditions Associated With DIC
- Frequency of DIC in Selected Disease States
- Underlying Diseases in DIC Patients
- Slide Number 36
- Slide Number 37
- Slide Number 38
- Slide Number 39
- Pathophysiology of DIC
- Pathogenesis of DIC in Sepsis
- Host Response in Severe Sepsis
- Organ Failure in Severe Sepsis
- Mechanism of DIC in Organ Failure
- Interaction of Inflammation and Coagulation in Sepsis
- Slide Number 47
- Diverse and Opposing Effects of Thrombin
- Coagulation and Fibrinolysis in DIC
- Mechanism of DIC
- Pathophysiology of DIC
- Pathophysiology of DIC - Mechanism
- Pathophysiology of DIC ndash 2 Types of Clinical pictures
- Sub-Acute and Non-Overt DIC Clinical Findings
- Pathophysiology of Overt DIC
- Physiopathology of DIC ndash Overt DIC Findings
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- BREAK
- Diagnostic and Management Approach for DIC
- Diagnosis of DIC
- Lab Diagnosis of DIC ndash Markers of Factor Consumption
- Lab Diagnosis of DIC ndash Screening Tests
- Slide Number 67
- Slide Number 68
- British Journal of Haematology Overt DIC Score
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- DIC Management Goals
- DIC Management and Treatment
- DIC Management Strategies
- Anticoagulant Factor Concentrate Treatment
- Anticoagulant Factor Concentrate Treatment Trials
- Markers of Thrombin amp Plasmin Generation in DIC
- D-dimer FDPs and DIC
- D-Dimer and FDPs in DIC
- Follow Up of DIC State of Disease
- FMD-Dimer in DIC Major Differences
- of Abnormal Results in Patients with Confirmed and Suspected DIC
- Slide Number 85
- Slide Number 86
- Comparing an Automated FM vs Manual FSP Test
- Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Slide Number 94
- Slide Number 95
- Slide Number 96
- Slide Number 97
- Slide Number 98
- Slide Number 99
- DIC Case Studies
- Case Study 1 - Presentation
- Case Study 1 ndash Lab Results
- Case Study 1 ndash Microscopy
- Case Study 1 ndash Diagnosis and Therapy
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Slide Number 110
- Slide Number 111
- Slide Number 112
- Slide Number 113
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
- Slide Number 124
- Slide Number 125
- DIC Take Home Messages
- Slide Number 127
- Slide Number 128
-
Vessel Wall
Intact endothelium non thrombogenic Synthesis of vasodilators (prostacyclin) No reaction either with platelets or factors
Sub endotheliumTissue Endothelium
blood
When a vessel wall is damaged Exposure of the subendothelium Platelet adhesion Initiation of the mechanisms of coagulation and fibrinolysis
PlateletsFactors
Sub endotheliumTissue Endothelium
blood
Vessel Wall Damage
Aim is to clog the damaged vessel ( asymp bricks without cement )
Primary Hemostasis
Platelet Structure UnactivatedActivated
GpIb-IX-V
GpIIb-IIIa
α granules (raw materials)PF4 β-TG Fibrinogen VWF Factor V and PAI-1
dense granules (energy and glue)ATP ADP SerotoninCa2+ Mg2+ P
Hillman Robert S Ault Kenneth A Rinder Henry M Hematology in Clinical Practice 4th Edition McGraw-Hill New York NY 2005
Primary Hemostasis
2) activation2nd shape changeamp release
platelet at rest 1) adhesion1st shape change
3) aggregation(not reversible)
Vasoconstriction occurs first
Platelets then aggregate on the break in the vessel wall
Primary Hemostasis AssaysRoutine Platelet count PT APTT TT
Follow-up von Willebrand Factor Antigen determination Activity Factor VIII PFA-100 Platelet aggregation studies
SpecializedSend Out Activation markers (b-TG PF4 GPV) Specialized tests for platelet function
Aim is to strengthen the platelet plug
Coagulation
Coagulation is a balancebetween pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
THROMBIN
Fibrinogen Fibrin
bull Triggering agentsbull pro-enzyme enzyme (serine-protease FIIa FVIIa FIXa FXa)bull Cofactors (FVa amp FVIIIa)
bull Serine-protease inhibitor Antithrombin (AT) bull Cofactorsinhibitors Protein C Sbull Tissue factor pathway inhibitor (TFPI)
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Coagulation Cascade Schematic
Coagulation factors
Historic name
Fibrinogen
Prothrombin
Proaccelerin
Proconvertin
Anti-hemophilic factor A
Anti-hemophilic factor B
Stuart factor
Rosenthal factor
Hageman factor
Fibrin Stabilizing Factor
Factor
I
II
V
VII
VIII
IX
X
XI
XII
XIII
Function
Substrate
Pro-enzyme
Pro-cofactor
Pro-enzyme
Pro-cofactor
Pro-enzyme
Pro-enzyme
Pro-enzyme
Pro-enzyme
Pro-enzyme
Pro-enzyme = Zymogen activation Active Enzyme
Coagulation Assay Mechanisms
aPTT Based
PT Based
PT Based
Fibrin Under Microscope
Weisel JW Structure of fibrin impact on clot stability J Thromb Haemost 2007 5 Suppl 1 116-24
Low thrombin concentration
High thrombin concentration
Fibrin Formation
Soluble FibrinPolymer
ThrombinFibrinogen
FM+ fibrinopeptides A amp B
Stabilized Fibrin clot(not soluble)
ThrombinXIII XIIIa
(Digestion of Fibrin)
Fibrinolysis
Fibrinolysis Overview
Destroys fibrin fibers
Destroys the scab (dried wound)
Maintains vessel integrity
Fibrinolysis Overview
Fibrin =cement fibers
Plasmin
Plasmin digests fibrin
t-PA
Pro Urokinase
Urokinase
PAI-1PAI-1
Plasminogen Plasmin
1st Step
2nd Step
Fibrinolysis Cascade
t-PA tissue-type plasminogen activator PAI-1 Plasminogen activator inhibitor 1 PK Prekallikrein FDP Fibrinogen degradation products AP Antiplasmin = a2AP alpha 2 Antiplasmin a2MG alpha 2 Macroglobulin
Extrinsic pathway(endothelia l cells)
Intrinsic pathway(plasma)
Fibrin clot
D-dimerFibrin degradation products
Fibrin
TAFIa
APAntiplasmin(amp a2-MG)
PK Kallikrein
XII
Fibrinolysis Releases D-dimers
D-dimer presence fibrin has been formed and digested in patients body
Normal D-dimer level no thrombosis occurred in the patient
Basic Pathophysiology of DIC
Disseminated Intravascular Coagulation (DIC)
Massive activation of coagulation leading to clots forming in multiple locations around the bodyRapid consumption of clotting factors leading to bleedingParadoxical condition leading to both clotting and bleedingA confusing disorder from both diagnostic and therapeutic standpoints Many unrelated diseases can trigger DIC Lack of uniformity in clinical manifestation Lack of uniformity in the laboratory diagnosis Lack of uniformity or consensus on management
Clinical Manifestations of DICOrgan Ischemic Hemorrhagic
Skin Pupura Fulminans Petechiae
Gangrene Echymoses
Acral cyanosis Oozing
CNS Deliriumcoma Intracranial
Infarcts Bleeding
Renal OliguriaAzotemia Hematuria
Cortical Necrosis
Cardiovascular Myocardial dysfunction
Pulmonary DyspneaHypoxia Hemorrhagic lung
Infarct
Gastrointestinal Ulcers infarcts Massive hemorrhage
Endocrine Adrenal infarcts
Purpura Fulminans with DIC Due to Meningococcal Sepsis
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Clinical Conditions Associated With DIC
Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33
Frequency of DIC in Selected Disease States
Disease Frequency
Gram-negative sepsis 30-50
Severe trauma and systemic inflammation 50-70
Metastasized tumors 15
Abruptio placentaamniotic fluid embolism 50
Severe preeclampsia 7
Giant hemangioma 25
Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92
Masao Nakagawa Modified from a research report on the incidence of disseminated intravascular coagulation (DIC) and underlying diseases in Japan Ministry of Health Labour and Welfare Research report published in Fiscal Year 1998 57-64 199 httpwwwrecomodulincomendicindexhtml Accessed Apr 21 2017
Underlying Diseases in DIC Patients
In a Japanese survey from 1997 on incidence of DIC and underlying diseases in 652 divisions and departments of university hospitals DIC occurred in 2193 patients with the number of patient with infections (including sepsis) and hematologic tumors (including leukemia) accounted for 28 and 23 respectively
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Epidemiology of DIC
Impact of DIC Status on Mortality - 1
Okamoto K Wada H Hatada T Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Frequency and hemostatic abnormalities in pre-DIC patients Thromb Res 2010 126 74-8
Patients with positivity of DIC tend to have worse mortality outcomes compared to negative patients or those with pre-DIC
Impact of DIC Status on Mortality - 2
Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4
Patients with positivity of either Overt or Non-Overt DIC tend to have worse mortality outcomes compared to negative patients
Impact of Age on Mortality in DIC Patients
Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4
Older patients with DIC (black bars) generally tend to have worse outcomes compared to non-DIC patients (grey bars)
Pathophysiology of DIC
Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33
Pathogenesis of DIC in Sepsis
Allen KS Sawheny E Kinasewitzet GT Anticoagulant modulation of inflammation in severe sepsis World J Crit Care Med 2015 4 105-15
Bacteria in sepsis infections cause release of TF from immune cells leading to coagulation activation and proinflammatory cytokines cause endothelial cell activation impairing the anticoagulation and fibrinolysis process resulting in DIC
Host Response in Severe Sepsis
Exaggerated inflammation as a result of the host response to sepsis is collateral tissue damage and cell death further resulting in release of danger molecules continuing the inflammatory process in a downward spiral
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Organ Failure in Severe Sepsis
Sepsis associated with microvascular thrombosis as a result of TF mediated coagulation activation results in release of neutrophil extracellular traps (NETs) tissue hypoperfusion and mitochondrial damage resulting in a downward spiral leading to organ failure
Angus DC van der Poll T Severe Sepsis and Septic Shock N Engl J Med 2013 369 840-51
Mechanism of DIC in Organ Failure
Underlying condition(sepsis trauma)
Cytokines
TF-mediatedactivation of coagulation
Depression of inhibitory systems
Reducesfibrinolysis
Fibrin deposition
Organ failure
Inadequate fibrin removal
Fibrinformation
Note impaired fibrinolysis in relation to the clinical need not in absolute value (FDPs are )
Levi M de Jonge E van der Poll T ten Cate H Disseminated intravascular coagulation ThrombHaemost 1999 82 695-705
Interaction of Inflammation and Coagulation in Sepsis
Binding of TF thrombin and other activation coagulation factors to PARs and fibrin to TLRs on inflammatory cells results in inflammation through release of proinflammatory cytokines and chemokines
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Mechanism of Multiple Organ Failure in DIC
Wheeler AP Bernard GR Treating Patients with Severe Sepsis N Engl J Med 1999 340207-14
Inflammatory activation and microvascular thrombosis contributes to multiple organ failure in DIC
lipopolysaccharides
cytokines
coagulation activation
mononuclear cell
tissue factor
Diverse and Opposing Effects of Thrombin
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Coagulation and Fibrinolysis in DIC
Soluble fibrin Polymer
XIIIa
D-Dimer
E
Fibrin clot
Fibrin Degradation Products
Fibrinogen Thrombin
Fibrinogen Degradation
Products
D E
Plasmin
DFM + fibrinopeptides
Soluble FM ComplexesPre-throm
boticPost-throm
botic
Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis Semin Thromb Hemost 2008 34 33-8
Mechanism of DIC
THROMBOSIS
Fibrin
Blood activationEndothelial lysisTF expression
BLEEDING
FDPs
D-Dimer
Plasmin
Pathophysiology of DIC
1st step abnormal activation of coagulation Injury of vessel wall cells venous stasis release of large quantities of
thromboplastin influx of activated cells (monocytes macrophages)
Results in an intravascular deposition of fibrin
Morbidity from disseminated microthrombosis in small and midsize vessels leading to multiple organ failure
Second step Consumption and depletion of coagulation factors inhibitors (Protein C
Protein S AT) and platelets Local fibrinolytic response
bull Local plasmin generation dissolves the thrombusbull Disseminated overwhelming fibrinolytic response leading to production of
FDP and D-Dimer
Bleeding
Pathophysiology of DIC - Mechanism
Systemic activation of coagulation
Intravasculardepositionof fibrin
Thrombosis of small and midsize vessels
and organ failure
Depletion of platelets and
coagulation factors
Bleeding
Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92
Pathophysiology of DIC ndash 2 Types of Clinical pictures
Chronic = non - overt DICMay be unrecognized clinically
Acute = overt DIClife threatening bleedingor multiple organ failure
Sub-Acute and Non-Overt DIC Clinical Findings
Compensated non-overt DIC Steady low level or intermittent activation
bull Compensated by increased production of coagulation components and platelets
Few or no clinical signs or multiple microvascular thrombosis sometimes not clinically obvious
Risk of decompensation leading to overt DIC
Pathophysiology of Overt DIC
Massive activation of coagulation and fibrinolysis
Does not allow for compensatory efforts
Rapid depletion of coagulation factors inhibitors and platelets
Thrombosis multiple organ failures
Bleeding complications and shock
Physiopathology of DIC ndash Overt DIC Findings
Thrombin generation
Thrombosis
Renal liver respiratory failures coma skin necrosis gangrene venous thromboembolism hypotension edema
Cytokine and kinin generation (shock)bull Tachycardia hypotension edema
Plasmin generationHemorrhage
bull Spontaneous bruising petechiae intracranial gastrointestinal and respiratory tract bleeding persistent bleeding at venipuncture sites at surgical wounds
bull Tachycardia hypotension edema
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Pathogenesis Pathways in DIC
Cytokines
TF-mediated dysfunctional impairedthrombin anticoagulant fibrinolysisgeneration mechanism due to PAI-1 deficiency
fibrin inadequateformation fibrin removal
Fibrin deposition
Inflammation
Coagulation
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BREAK
Diagnostic and Management Approach for DIC
Diagnosis of DIC
Clinical diagnosis is obvious in cases of overt DIC
Laboratory tests are necessary To makeconfirm the diagnosis To assess stage of the patient To assess the treatment efficacy
Lab Diagnosis of DIC ndash Markers of Factor Consumption
Routinescreening assays PT APTT Platelets Fibrinogen Thrombin time
Other coagulation assays Factor assays AntithrombinGeneration of Thrombin FMFSPsGeneration of Plasmin D-dimer FDPs
Important to recognize simultaneous formation of thrombin and plasmin
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122
Lab Diagnosis of DIC ndash Screening Tests
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122
Platelet count usually decreasedPT abnormal in 70 of cases (short half-life of FVII)APTT abnormal in 50 of casesThrombin time usually prolonged in overt DIC normal in non-overt DIC and no relation with syndrome severityFibrinogen low in lt 50 of cases sensitivity 22 specificity 87 overall predictive value 64 Normal fibrinogen level should not exclude DIC diagnosis (acute phase reactant initial high
fibrinogen level) repeat testing assesses progression
Screening tests not clinically specific or sensitive for DIC
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Laboratory Changes in Overt DIC
DIC Diagnostic Practices Over Time
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
British Journal of Haematology Overt DIC Score
Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
ISTH Step by Step DIC Algorithm
Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6
US Based Validation of ISTH DIC Score
When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Differential Diagnosis in DIC
aHUS atypical hemolytic uremic syndrome
HUS hemolytic uremic syndrome
HIT heparin-induced thrombocytopenia
ITP immune thrombocytopenic purpura
TTP thrombotic thrombocytopenic purpura
DIC and MAHA
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)
When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation
DIC Management Goals
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction
DIC Management and Treatment
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)
requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)
Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia
DIC Management Strategies
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant Factor Concentrate Treatment
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis
Anticoagulant Factor Concentrate Treatment Trials
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise
Markers of Thrombin amp Plasmin Generation in DIC
D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC
Cut-off value
Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen
degradation products Sensitive assay typically with cutoff adapted for DIC
D-dimer FDPs and DIC
D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC
Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80
Follow Up of DIC State of Disease
Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8
Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility
FMD-Dimer in DIC Major Differences
onset of thrombosis
days
Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8
FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)
D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)
of Abnormal Results in Patients with Confirmed and Suspected DIC
0
20
40
60
80
100
94 85 90N = 62
Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32
Positivity of Test Results ISTH Score and Disease State
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
Red bar positive for 2 points of DIC score
Pink bar positive for 1-2 points of DIC score
HT hematopoietic tumor
IF infection
SC solid cancer
Markers in Patients with or without DIC
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
HT hematopoietic tumorIF infectionSC solid cancer
Comparing an Automated FM vs Manual FSP Test
Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71
Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)
Automated (Mitsubishi) vs Automated (Stago)
In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago
Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC
Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
Non Overt DIC Overt DIC
AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC
Trends in Markers of DIC for Different Patients
Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00
Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients
Trends in Markers of DIC for Different Patients
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes
28 day outcome survival
28 day outcome death
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines
DIC Case Studies
Case Study 1 - Presentation
18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE
WBC count 77 KμL 423 ndash 907 x KμL
RBC count 17 MμL 137 ndash 175 x MμL
Hemoglobin 67 gdL 137 ndash 175 gdL
Hematocrit 195 401 ndash 510
MCV 95 fL 790 ndash 922 fL
MPV 12 fL 94 ndash 124 fL
Platelet count 9 KμL 161 ndash 347 KμL
Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0
Lymphocytes monocytes eosinophils basophils all below normal range
PT 47 sec (corrected on mixing study) 116 ndash 152 sec
APTT 75 sec (corrected on mixing study) 253 ndash 373 sec
Fibrinogen lt 76 mgdL 177 ndash 466 mgdL
D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Microscopy
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Arrow shows giant platelets in this peripheral smear Promyelocytes apparent
Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)
DIC due to TF release by APL blasts
Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases
Transfusions to replace factors along with platelets and RBCs during APL treatment
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started
Case Study 2 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L
PT 30 sec 113 ndash 146 sec
APTT 75 sec 25 ndash 34 sec
D-dimer 078 microgml FEU lt050 microgml FEU
Fibrinogen 92 mgdl 150-400 mgdl
pH 728 738 to 742
PaO2 570 mmHg 80-100 mmHg
WBC 33 times 103mm3 40-11 times 103mm3
ALT 111 IUL 0ndash34 IUL
AST 61 IUL 0ndash34 IUL
BUN 303 mgdL 08-13 mgdL
Case Study 2 ndash Lab Results
Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures
Case Study 2 ndash Diagnosis
60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior
Case Study 3 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L
PT 228 sec 113 ndash 146 sec
APTT 45 sec 25 ndash 34 sec
D-dimer 080 microgml FEU lt050 microgmL FEU
Fibrinogen 82 mgdL 150-400 mgdL
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 134 gdL 14-16 gdL
WBC 81 times 103mm3 40-11 times 103mm3
ALT 32 IUL 0ndash34 IUL
AST 28 IUL 0ndash34 IUL
BUN 09 mgdL 08-13 mgdL
Case Study 3 ndash Lab Results
Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment
Case Study 3 ndash Diagnosis and Therapy
Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91
Case Study 4 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L
PT 28 sec 113 ndash 146 sec
APTT 71 sec 25 ndash 34 sec
D-dimer 31 microgmL FEU lt050 microgml FEU
Fibrinogen 92 mgdL 150-400 mgdl
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 158 gdL 14-16 gdL
WBC 71 times 103mm3 40-11 times 103mm3
ALT 60 IUL 0ndash34 IUL
AST 47 IUL 0ndash34 IUL
BUN 38 mgdL 08-13 mgdL
Case Study 4 ndash Lab Results
Lyme disease with DICProvide antibiotics with supportive measures
Case Study 4 ndash Diagnosis
55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis
Case Study 5 ndash Presentation
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
Case Study 5 ndash Lab Results and Time Course
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
TEST RESULT REFERENCE RANGE
Platelet count 33 x 109L 150-450 x 109L
PT 215 sec 103 ndash 128 sec
APTT 44 sec 26 ndash 36 sec
D-dimer 20 microgmL FEU lt025 microgml FEU
Fibrinogen 34 mgdL 200-375 mgdl
FII FV FVIII Low Not reported (NR)
FVII FIX FX vWF Normal NR
Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)
DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic
dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR
(C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen
(D) Illustration demonstrating repair
Case Study 5 ndash Diagnosis and Treatment
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography
Case Study 6 ndash Presentation
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
Case Study 6 ndash Lab Results
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L
PT 63 sec gt control 113 ndash 146 sec
INR 658 1 ndash 125
APTT 80 sec gt control 25 ndash 34 sec
D-dimer gt200 microgmL DDU 02 microgmL DDU
Urine exam Proteinuria and hematuria 150-400 mgdl
Albumin 28 gdL NR
Hb 58 gdL NR
LDH 1196 UL NR
SGPT 144 IU NR
SGOT 88 IU NR
Bilirubin 32 mgdL NR
DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th
day postop
Case Study 6 ndash Diagnosis and Treatment
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure
Case Study 6 ndash Discussion
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Case Study 7 ndash Lab Results vs Time
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
DIC Take Home Messages
Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation
Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers
DIC
Thank you Questions
- Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
- Learning Objectives
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Wound Sealing
- The Three Steps of Hemostasis
- Vessel Wall
- Slide Number 12
- Slide Number 13
- Platelet Structure UnactivatedActivated
- Primary Hemostasis
- Primary Hemostasis Assays
- Slide Number 17
- Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
- Slide Number 19
- Coagulation factors
- Coagulation Assay Mechanisms
- Slide Number 22
- Fibrin Formation
- Slide Number 24
- Fibrinolysis Overview
- Fibrinolysis Overview
- Slide Number 27
- Fibrinolysis Releases D-dimers
- Basic Pathophysiology of DIC
- Disseminated Intravascular Coagulation (DIC)
- Purpura Fulminans with DIC Due to Meningococcal Sepsis
- Clinical Conditions Associated With DIC
- Frequency of DIC in Selected Disease States
- Underlying Diseases in DIC Patients
- Slide Number 36
- Slide Number 37
- Slide Number 38
- Slide Number 39
- Pathophysiology of DIC
- Pathogenesis of DIC in Sepsis
- Host Response in Severe Sepsis
- Organ Failure in Severe Sepsis
- Mechanism of DIC in Organ Failure
- Interaction of Inflammation and Coagulation in Sepsis
- Slide Number 47
- Diverse and Opposing Effects of Thrombin
- Coagulation and Fibrinolysis in DIC
- Mechanism of DIC
- Pathophysiology of DIC
- Pathophysiology of DIC - Mechanism
- Pathophysiology of DIC ndash 2 Types of Clinical pictures
- Sub-Acute and Non-Overt DIC Clinical Findings
- Pathophysiology of Overt DIC
- Physiopathology of DIC ndash Overt DIC Findings
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- BREAK
- Diagnostic and Management Approach for DIC
- Diagnosis of DIC
- Lab Diagnosis of DIC ndash Markers of Factor Consumption
- Lab Diagnosis of DIC ndash Screening Tests
- Slide Number 67
- Slide Number 68
- British Journal of Haematology Overt DIC Score
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- DIC Management Goals
- DIC Management and Treatment
- DIC Management Strategies
- Anticoagulant Factor Concentrate Treatment
- Anticoagulant Factor Concentrate Treatment Trials
- Markers of Thrombin amp Plasmin Generation in DIC
- D-dimer FDPs and DIC
- D-Dimer and FDPs in DIC
- Follow Up of DIC State of Disease
- FMD-Dimer in DIC Major Differences
- of Abnormal Results in Patients with Confirmed and Suspected DIC
- Slide Number 85
- Slide Number 86
- Comparing an Automated FM vs Manual FSP Test
- Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Slide Number 94
- Slide Number 95
- Slide Number 96
- Slide Number 97
- Slide Number 98
- Slide Number 99
- DIC Case Studies
- Case Study 1 - Presentation
- Case Study 1 ndash Lab Results
- Case Study 1 ndash Microscopy
- Case Study 1 ndash Diagnosis and Therapy
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Slide Number 110
- Slide Number 111
- Slide Number 112
- Slide Number 113
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
- Slide Number 124
- Slide Number 125
- DIC Take Home Messages
- Slide Number 127
- Slide Number 128
-
When a vessel wall is damaged Exposure of the subendothelium Platelet adhesion Initiation of the mechanisms of coagulation and fibrinolysis
PlateletsFactors
Sub endotheliumTissue Endothelium
blood
Vessel Wall Damage
Aim is to clog the damaged vessel ( asymp bricks without cement )
Primary Hemostasis
Platelet Structure UnactivatedActivated
GpIb-IX-V
GpIIb-IIIa
α granules (raw materials)PF4 β-TG Fibrinogen VWF Factor V and PAI-1
dense granules (energy and glue)ATP ADP SerotoninCa2+ Mg2+ P
Hillman Robert S Ault Kenneth A Rinder Henry M Hematology in Clinical Practice 4th Edition McGraw-Hill New York NY 2005
Primary Hemostasis
2) activation2nd shape changeamp release
platelet at rest 1) adhesion1st shape change
3) aggregation(not reversible)
Vasoconstriction occurs first
Platelets then aggregate on the break in the vessel wall
Primary Hemostasis AssaysRoutine Platelet count PT APTT TT
Follow-up von Willebrand Factor Antigen determination Activity Factor VIII PFA-100 Platelet aggregation studies
SpecializedSend Out Activation markers (b-TG PF4 GPV) Specialized tests for platelet function
Aim is to strengthen the platelet plug
Coagulation
Coagulation is a balancebetween pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
THROMBIN
Fibrinogen Fibrin
bull Triggering agentsbull pro-enzyme enzyme (serine-protease FIIa FVIIa FIXa FXa)bull Cofactors (FVa amp FVIIIa)
bull Serine-protease inhibitor Antithrombin (AT) bull Cofactorsinhibitors Protein C Sbull Tissue factor pathway inhibitor (TFPI)
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Coagulation Cascade Schematic
Coagulation factors
Historic name
Fibrinogen
Prothrombin
Proaccelerin
Proconvertin
Anti-hemophilic factor A
Anti-hemophilic factor B
Stuart factor
Rosenthal factor
Hageman factor
Fibrin Stabilizing Factor
Factor
I
II
V
VII
VIII
IX
X
XI
XII
XIII
Function
Substrate
Pro-enzyme
Pro-cofactor
Pro-enzyme
Pro-cofactor
Pro-enzyme
Pro-enzyme
Pro-enzyme
Pro-enzyme
Pro-enzyme
Pro-enzyme = Zymogen activation Active Enzyme
Coagulation Assay Mechanisms
aPTT Based
PT Based
PT Based
Fibrin Under Microscope
Weisel JW Structure of fibrin impact on clot stability J Thromb Haemost 2007 5 Suppl 1 116-24
Low thrombin concentration
High thrombin concentration
Fibrin Formation
Soluble FibrinPolymer
ThrombinFibrinogen
FM+ fibrinopeptides A amp B
Stabilized Fibrin clot(not soluble)
ThrombinXIII XIIIa
(Digestion of Fibrin)
Fibrinolysis
Fibrinolysis Overview
Destroys fibrin fibers
Destroys the scab (dried wound)
Maintains vessel integrity
Fibrinolysis Overview
Fibrin =cement fibers
Plasmin
Plasmin digests fibrin
t-PA
Pro Urokinase
Urokinase
PAI-1PAI-1
Plasminogen Plasmin
1st Step
2nd Step
Fibrinolysis Cascade
t-PA tissue-type plasminogen activator PAI-1 Plasminogen activator inhibitor 1 PK Prekallikrein FDP Fibrinogen degradation products AP Antiplasmin = a2AP alpha 2 Antiplasmin a2MG alpha 2 Macroglobulin
Extrinsic pathway(endothelia l cells)
Intrinsic pathway(plasma)
Fibrin clot
D-dimerFibrin degradation products
Fibrin
TAFIa
APAntiplasmin(amp a2-MG)
PK Kallikrein
XII
Fibrinolysis Releases D-dimers
D-dimer presence fibrin has been formed and digested in patients body
Normal D-dimer level no thrombosis occurred in the patient
Basic Pathophysiology of DIC
Disseminated Intravascular Coagulation (DIC)
Massive activation of coagulation leading to clots forming in multiple locations around the bodyRapid consumption of clotting factors leading to bleedingParadoxical condition leading to both clotting and bleedingA confusing disorder from both diagnostic and therapeutic standpoints Many unrelated diseases can trigger DIC Lack of uniformity in clinical manifestation Lack of uniformity in the laboratory diagnosis Lack of uniformity or consensus on management
Clinical Manifestations of DICOrgan Ischemic Hemorrhagic
Skin Pupura Fulminans Petechiae
Gangrene Echymoses
Acral cyanosis Oozing
CNS Deliriumcoma Intracranial
Infarcts Bleeding
Renal OliguriaAzotemia Hematuria
Cortical Necrosis
Cardiovascular Myocardial dysfunction
Pulmonary DyspneaHypoxia Hemorrhagic lung
Infarct
Gastrointestinal Ulcers infarcts Massive hemorrhage
Endocrine Adrenal infarcts
Purpura Fulminans with DIC Due to Meningococcal Sepsis
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Clinical Conditions Associated With DIC
Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33
Frequency of DIC in Selected Disease States
Disease Frequency
Gram-negative sepsis 30-50
Severe trauma and systemic inflammation 50-70
Metastasized tumors 15
Abruptio placentaamniotic fluid embolism 50
Severe preeclampsia 7
Giant hemangioma 25
Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92
Masao Nakagawa Modified from a research report on the incidence of disseminated intravascular coagulation (DIC) and underlying diseases in Japan Ministry of Health Labour and Welfare Research report published in Fiscal Year 1998 57-64 199 httpwwwrecomodulincomendicindexhtml Accessed Apr 21 2017
Underlying Diseases in DIC Patients
In a Japanese survey from 1997 on incidence of DIC and underlying diseases in 652 divisions and departments of university hospitals DIC occurred in 2193 patients with the number of patient with infections (including sepsis) and hematologic tumors (including leukemia) accounted for 28 and 23 respectively
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Epidemiology of DIC
Impact of DIC Status on Mortality - 1
Okamoto K Wada H Hatada T Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Frequency and hemostatic abnormalities in pre-DIC patients Thromb Res 2010 126 74-8
Patients with positivity of DIC tend to have worse mortality outcomes compared to negative patients or those with pre-DIC
Impact of DIC Status on Mortality - 2
Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4
Patients with positivity of either Overt or Non-Overt DIC tend to have worse mortality outcomes compared to negative patients
Impact of Age on Mortality in DIC Patients
Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4
Older patients with DIC (black bars) generally tend to have worse outcomes compared to non-DIC patients (grey bars)
Pathophysiology of DIC
Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33
Pathogenesis of DIC in Sepsis
Allen KS Sawheny E Kinasewitzet GT Anticoagulant modulation of inflammation in severe sepsis World J Crit Care Med 2015 4 105-15
Bacteria in sepsis infections cause release of TF from immune cells leading to coagulation activation and proinflammatory cytokines cause endothelial cell activation impairing the anticoagulation and fibrinolysis process resulting in DIC
Host Response in Severe Sepsis
Exaggerated inflammation as a result of the host response to sepsis is collateral tissue damage and cell death further resulting in release of danger molecules continuing the inflammatory process in a downward spiral
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Organ Failure in Severe Sepsis
Sepsis associated with microvascular thrombosis as a result of TF mediated coagulation activation results in release of neutrophil extracellular traps (NETs) tissue hypoperfusion and mitochondrial damage resulting in a downward spiral leading to organ failure
Angus DC van der Poll T Severe Sepsis and Septic Shock N Engl J Med 2013 369 840-51
Mechanism of DIC in Organ Failure
Underlying condition(sepsis trauma)
Cytokines
TF-mediatedactivation of coagulation
Depression of inhibitory systems
Reducesfibrinolysis
Fibrin deposition
Organ failure
Inadequate fibrin removal
Fibrinformation
Note impaired fibrinolysis in relation to the clinical need not in absolute value (FDPs are )
Levi M de Jonge E van der Poll T ten Cate H Disseminated intravascular coagulation ThrombHaemost 1999 82 695-705
Interaction of Inflammation and Coagulation in Sepsis
Binding of TF thrombin and other activation coagulation factors to PARs and fibrin to TLRs on inflammatory cells results in inflammation through release of proinflammatory cytokines and chemokines
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Mechanism of Multiple Organ Failure in DIC
Wheeler AP Bernard GR Treating Patients with Severe Sepsis N Engl J Med 1999 340207-14
Inflammatory activation and microvascular thrombosis contributes to multiple organ failure in DIC
lipopolysaccharides
cytokines
coagulation activation
mononuclear cell
tissue factor
Diverse and Opposing Effects of Thrombin
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Coagulation and Fibrinolysis in DIC
Soluble fibrin Polymer
XIIIa
D-Dimer
E
Fibrin clot
Fibrin Degradation Products
Fibrinogen Thrombin
Fibrinogen Degradation
Products
D E
Plasmin
DFM + fibrinopeptides
Soluble FM ComplexesPre-throm
boticPost-throm
botic
Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis Semin Thromb Hemost 2008 34 33-8
Mechanism of DIC
THROMBOSIS
Fibrin
Blood activationEndothelial lysisTF expression
BLEEDING
FDPs
D-Dimer
Plasmin
Pathophysiology of DIC
1st step abnormal activation of coagulation Injury of vessel wall cells venous stasis release of large quantities of
thromboplastin influx of activated cells (monocytes macrophages)
Results in an intravascular deposition of fibrin
Morbidity from disseminated microthrombosis in small and midsize vessels leading to multiple organ failure
Second step Consumption and depletion of coagulation factors inhibitors (Protein C
Protein S AT) and platelets Local fibrinolytic response
bull Local plasmin generation dissolves the thrombusbull Disseminated overwhelming fibrinolytic response leading to production of
FDP and D-Dimer
Bleeding
Pathophysiology of DIC - Mechanism
Systemic activation of coagulation
Intravasculardepositionof fibrin
Thrombosis of small and midsize vessels
and organ failure
Depletion of platelets and
coagulation factors
Bleeding
Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92
Pathophysiology of DIC ndash 2 Types of Clinical pictures
Chronic = non - overt DICMay be unrecognized clinically
Acute = overt DIClife threatening bleedingor multiple organ failure
Sub-Acute and Non-Overt DIC Clinical Findings
Compensated non-overt DIC Steady low level or intermittent activation
bull Compensated by increased production of coagulation components and platelets
Few or no clinical signs or multiple microvascular thrombosis sometimes not clinically obvious
Risk of decompensation leading to overt DIC
Pathophysiology of Overt DIC
Massive activation of coagulation and fibrinolysis
Does not allow for compensatory efforts
Rapid depletion of coagulation factors inhibitors and platelets
Thrombosis multiple organ failures
Bleeding complications and shock
Physiopathology of DIC ndash Overt DIC Findings
Thrombin generation
Thrombosis
Renal liver respiratory failures coma skin necrosis gangrene venous thromboembolism hypotension edema
Cytokine and kinin generation (shock)bull Tachycardia hypotension edema
Plasmin generationHemorrhage
bull Spontaneous bruising petechiae intracranial gastrointestinal and respiratory tract bleeding persistent bleeding at venipuncture sites at surgical wounds
bull Tachycardia hypotension edema
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Pathogenesis Pathways in DIC
Cytokines
TF-mediated dysfunctional impairedthrombin anticoagulant fibrinolysisgeneration mechanism due to PAI-1 deficiency
fibrin inadequateformation fibrin removal
Fibrin deposition
Inflammation
Coagulation
Stago Celebrates Lab Week 2017
NA
Stago 247 Educational Webinar Sites
wwwstago-edvantagecomUS based KOLsPACE accredited ndash all 1 hourAccessible from mobile devicesVirtual exhibit hall
wwwstagowebinarscomMostly European KOLs30 ndash 45 min including 15 min discussion
Stago Educational Apps
HaemoscoreClinical scoring algorithmsApple and AndroidTablet or phone
iHemostasisCoagulation diagramsCase studiesApple amp AndroidTablet only
BREAK
Diagnostic and Management Approach for DIC
Diagnosis of DIC
Clinical diagnosis is obvious in cases of overt DIC
Laboratory tests are necessary To makeconfirm the diagnosis To assess stage of the patient To assess the treatment efficacy
Lab Diagnosis of DIC ndash Markers of Factor Consumption
Routinescreening assays PT APTT Platelets Fibrinogen Thrombin time
Other coagulation assays Factor assays AntithrombinGeneration of Thrombin FMFSPsGeneration of Plasmin D-dimer FDPs
Important to recognize simultaneous formation of thrombin and plasmin
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122
Lab Diagnosis of DIC ndash Screening Tests
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122
Platelet count usually decreasedPT abnormal in 70 of cases (short half-life of FVII)APTT abnormal in 50 of casesThrombin time usually prolonged in overt DIC normal in non-overt DIC and no relation with syndrome severityFibrinogen low in lt 50 of cases sensitivity 22 specificity 87 overall predictive value 64 Normal fibrinogen level should not exclude DIC diagnosis (acute phase reactant initial high
fibrinogen level) repeat testing assesses progression
Screening tests not clinically specific or sensitive for DIC
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Laboratory Changes in Overt DIC
DIC Diagnostic Practices Over Time
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
British Journal of Haematology Overt DIC Score
Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
ISTH Step by Step DIC Algorithm
Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6
US Based Validation of ISTH DIC Score
When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Differential Diagnosis in DIC
aHUS atypical hemolytic uremic syndrome
HUS hemolytic uremic syndrome
HIT heparin-induced thrombocytopenia
ITP immune thrombocytopenic purpura
TTP thrombotic thrombocytopenic purpura
DIC and MAHA
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)
When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation
DIC Management Goals
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction
DIC Management and Treatment
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)
requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)
Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia
DIC Management Strategies
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant Factor Concentrate Treatment
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis
Anticoagulant Factor Concentrate Treatment Trials
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise
Markers of Thrombin amp Plasmin Generation in DIC
D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC
Cut-off value
Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen
degradation products Sensitive assay typically with cutoff adapted for DIC
D-dimer FDPs and DIC
D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC
Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80
Follow Up of DIC State of Disease
Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8
Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility
FMD-Dimer in DIC Major Differences
onset of thrombosis
days
Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8
FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)
D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)
of Abnormal Results in Patients with Confirmed and Suspected DIC
0
20
40
60
80
100
94 85 90N = 62
Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32
Positivity of Test Results ISTH Score and Disease State
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
Red bar positive for 2 points of DIC score
Pink bar positive for 1-2 points of DIC score
HT hematopoietic tumor
IF infection
SC solid cancer
Markers in Patients with or without DIC
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
HT hematopoietic tumorIF infectionSC solid cancer
Comparing an Automated FM vs Manual FSP Test
Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71
Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)
Automated (Mitsubishi) vs Automated (Stago)
In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago
Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC
Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
Non Overt DIC Overt DIC
AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC
Trends in Markers of DIC for Different Patients
Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00
Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients
Trends in Markers of DIC for Different Patients
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes
28 day outcome survival
28 day outcome death
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines
DIC Case Studies
Case Study 1 - Presentation
18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE
WBC count 77 KμL 423 ndash 907 x KμL
RBC count 17 MμL 137 ndash 175 x MμL
Hemoglobin 67 gdL 137 ndash 175 gdL
Hematocrit 195 401 ndash 510
MCV 95 fL 790 ndash 922 fL
MPV 12 fL 94 ndash 124 fL
Platelet count 9 KμL 161 ndash 347 KμL
Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0
Lymphocytes monocytes eosinophils basophils all below normal range
PT 47 sec (corrected on mixing study) 116 ndash 152 sec
APTT 75 sec (corrected on mixing study) 253 ndash 373 sec
Fibrinogen lt 76 mgdL 177 ndash 466 mgdL
D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Microscopy
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Arrow shows giant platelets in this peripheral smear Promyelocytes apparent
Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)
DIC due to TF release by APL blasts
Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases
Transfusions to replace factors along with platelets and RBCs during APL treatment
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started
Case Study 2 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L
PT 30 sec 113 ndash 146 sec
APTT 75 sec 25 ndash 34 sec
D-dimer 078 microgml FEU lt050 microgml FEU
Fibrinogen 92 mgdl 150-400 mgdl
pH 728 738 to 742
PaO2 570 mmHg 80-100 mmHg
WBC 33 times 103mm3 40-11 times 103mm3
ALT 111 IUL 0ndash34 IUL
AST 61 IUL 0ndash34 IUL
BUN 303 mgdL 08-13 mgdL
Case Study 2 ndash Lab Results
Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures
Case Study 2 ndash Diagnosis
60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior
Case Study 3 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L
PT 228 sec 113 ndash 146 sec
APTT 45 sec 25 ndash 34 sec
D-dimer 080 microgml FEU lt050 microgmL FEU
Fibrinogen 82 mgdL 150-400 mgdL
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 134 gdL 14-16 gdL
WBC 81 times 103mm3 40-11 times 103mm3
ALT 32 IUL 0ndash34 IUL
AST 28 IUL 0ndash34 IUL
BUN 09 mgdL 08-13 mgdL
Case Study 3 ndash Lab Results
Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment
Case Study 3 ndash Diagnosis and Therapy
Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91
Case Study 4 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L
PT 28 sec 113 ndash 146 sec
APTT 71 sec 25 ndash 34 sec
D-dimer 31 microgmL FEU lt050 microgml FEU
Fibrinogen 92 mgdL 150-400 mgdl
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 158 gdL 14-16 gdL
WBC 71 times 103mm3 40-11 times 103mm3
ALT 60 IUL 0ndash34 IUL
AST 47 IUL 0ndash34 IUL
BUN 38 mgdL 08-13 mgdL
Case Study 4 ndash Lab Results
Lyme disease with DICProvide antibiotics with supportive measures
Case Study 4 ndash Diagnosis
55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis
Case Study 5 ndash Presentation
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
Case Study 5 ndash Lab Results and Time Course
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
TEST RESULT REFERENCE RANGE
Platelet count 33 x 109L 150-450 x 109L
PT 215 sec 103 ndash 128 sec
APTT 44 sec 26 ndash 36 sec
D-dimer 20 microgmL FEU lt025 microgml FEU
Fibrinogen 34 mgdL 200-375 mgdl
FII FV FVIII Low Not reported (NR)
FVII FIX FX vWF Normal NR
Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)
DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic
dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR
(C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen
(D) Illustration demonstrating repair
Case Study 5 ndash Diagnosis and Treatment
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography
Case Study 6 ndash Presentation
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
Case Study 6 ndash Lab Results
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L
PT 63 sec gt control 113 ndash 146 sec
INR 658 1 ndash 125
APTT 80 sec gt control 25 ndash 34 sec
D-dimer gt200 microgmL DDU 02 microgmL DDU
Urine exam Proteinuria and hematuria 150-400 mgdl
Albumin 28 gdL NR
Hb 58 gdL NR
LDH 1196 UL NR
SGPT 144 IU NR
SGOT 88 IU NR
Bilirubin 32 mgdL NR
DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th
day postop
Case Study 6 ndash Diagnosis and Treatment
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure
Case Study 6 ndash Discussion
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Case Study 7 ndash Lab Results vs Time
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
DIC Take Home Messages
Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation
Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers
DIC
Thank you Questions
- Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
- Learning Objectives
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Wound Sealing
- The Three Steps of Hemostasis
- Vessel Wall
- Slide Number 12
- Slide Number 13
- Platelet Structure UnactivatedActivated
- Primary Hemostasis
- Primary Hemostasis Assays
- Slide Number 17
- Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
- Slide Number 19
- Coagulation factors
- Coagulation Assay Mechanisms
- Slide Number 22
- Fibrin Formation
- Slide Number 24
- Fibrinolysis Overview
- Fibrinolysis Overview
- Slide Number 27
- Fibrinolysis Releases D-dimers
- Basic Pathophysiology of DIC
- Disseminated Intravascular Coagulation (DIC)
- Purpura Fulminans with DIC Due to Meningococcal Sepsis
- Clinical Conditions Associated With DIC
- Frequency of DIC in Selected Disease States
- Underlying Diseases in DIC Patients
- Slide Number 36
- Slide Number 37
- Slide Number 38
- Slide Number 39
- Pathophysiology of DIC
- Pathogenesis of DIC in Sepsis
- Host Response in Severe Sepsis
- Organ Failure in Severe Sepsis
- Mechanism of DIC in Organ Failure
- Interaction of Inflammation and Coagulation in Sepsis
- Slide Number 47
- Diverse and Opposing Effects of Thrombin
- Coagulation and Fibrinolysis in DIC
- Mechanism of DIC
- Pathophysiology of DIC
- Pathophysiology of DIC - Mechanism
- Pathophysiology of DIC ndash 2 Types of Clinical pictures
- Sub-Acute and Non-Overt DIC Clinical Findings
- Pathophysiology of Overt DIC
- Physiopathology of DIC ndash Overt DIC Findings
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- BREAK
- Diagnostic and Management Approach for DIC
- Diagnosis of DIC
- Lab Diagnosis of DIC ndash Markers of Factor Consumption
- Lab Diagnosis of DIC ndash Screening Tests
- Slide Number 67
- Slide Number 68
- British Journal of Haematology Overt DIC Score
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- DIC Management Goals
- DIC Management and Treatment
- DIC Management Strategies
- Anticoagulant Factor Concentrate Treatment
- Anticoagulant Factor Concentrate Treatment Trials
- Markers of Thrombin amp Plasmin Generation in DIC
- D-dimer FDPs and DIC
- D-Dimer and FDPs in DIC
- Follow Up of DIC State of Disease
- FMD-Dimer in DIC Major Differences
- of Abnormal Results in Patients with Confirmed and Suspected DIC
- Slide Number 85
- Slide Number 86
- Comparing an Automated FM vs Manual FSP Test
- Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Slide Number 94
- Slide Number 95
- Slide Number 96
- Slide Number 97
- Slide Number 98
- Slide Number 99
- DIC Case Studies
- Case Study 1 - Presentation
- Case Study 1 ndash Lab Results
- Case Study 1 ndash Microscopy
- Case Study 1 ndash Diagnosis and Therapy
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Slide Number 110
- Slide Number 111
- Slide Number 112
- Slide Number 113
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
- Slide Number 124
- Slide Number 125
- DIC Take Home Messages
- Slide Number 127
- Slide Number 128
-
Aim is to clog the damaged vessel ( asymp bricks without cement )
Primary Hemostasis
Platelet Structure UnactivatedActivated
GpIb-IX-V
GpIIb-IIIa
α granules (raw materials)PF4 β-TG Fibrinogen VWF Factor V and PAI-1
dense granules (energy and glue)ATP ADP SerotoninCa2+ Mg2+ P
Hillman Robert S Ault Kenneth A Rinder Henry M Hematology in Clinical Practice 4th Edition McGraw-Hill New York NY 2005
Primary Hemostasis
2) activation2nd shape changeamp release
platelet at rest 1) adhesion1st shape change
3) aggregation(not reversible)
Vasoconstriction occurs first
Platelets then aggregate on the break in the vessel wall
Primary Hemostasis AssaysRoutine Platelet count PT APTT TT
Follow-up von Willebrand Factor Antigen determination Activity Factor VIII PFA-100 Platelet aggregation studies
SpecializedSend Out Activation markers (b-TG PF4 GPV) Specialized tests for platelet function
Aim is to strengthen the platelet plug
Coagulation
Coagulation is a balancebetween pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
THROMBIN
Fibrinogen Fibrin
bull Triggering agentsbull pro-enzyme enzyme (serine-protease FIIa FVIIa FIXa FXa)bull Cofactors (FVa amp FVIIIa)
bull Serine-protease inhibitor Antithrombin (AT) bull Cofactorsinhibitors Protein C Sbull Tissue factor pathway inhibitor (TFPI)
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Coagulation Cascade Schematic
Coagulation factors
Historic name
Fibrinogen
Prothrombin
Proaccelerin
Proconvertin
Anti-hemophilic factor A
Anti-hemophilic factor B
Stuart factor
Rosenthal factor
Hageman factor
Fibrin Stabilizing Factor
Factor
I
II
V
VII
VIII
IX
X
XI
XII
XIII
Function
Substrate
Pro-enzyme
Pro-cofactor
Pro-enzyme
Pro-cofactor
Pro-enzyme
Pro-enzyme
Pro-enzyme
Pro-enzyme
Pro-enzyme
Pro-enzyme = Zymogen activation Active Enzyme
Coagulation Assay Mechanisms
aPTT Based
PT Based
PT Based
Fibrin Under Microscope
Weisel JW Structure of fibrin impact on clot stability J Thromb Haemost 2007 5 Suppl 1 116-24
Low thrombin concentration
High thrombin concentration
Fibrin Formation
Soluble FibrinPolymer
ThrombinFibrinogen
FM+ fibrinopeptides A amp B
Stabilized Fibrin clot(not soluble)
ThrombinXIII XIIIa
(Digestion of Fibrin)
Fibrinolysis
Fibrinolysis Overview
Destroys fibrin fibers
Destroys the scab (dried wound)
Maintains vessel integrity
Fibrinolysis Overview
Fibrin =cement fibers
Plasmin
Plasmin digests fibrin
t-PA
Pro Urokinase
Urokinase
PAI-1PAI-1
Plasminogen Plasmin
1st Step
2nd Step
Fibrinolysis Cascade
t-PA tissue-type plasminogen activator PAI-1 Plasminogen activator inhibitor 1 PK Prekallikrein FDP Fibrinogen degradation products AP Antiplasmin = a2AP alpha 2 Antiplasmin a2MG alpha 2 Macroglobulin
Extrinsic pathway(endothelia l cells)
Intrinsic pathway(plasma)
Fibrin clot
D-dimerFibrin degradation products
Fibrin
TAFIa
APAntiplasmin(amp a2-MG)
PK Kallikrein
XII
Fibrinolysis Releases D-dimers
D-dimer presence fibrin has been formed and digested in patients body
Normal D-dimer level no thrombosis occurred in the patient
Basic Pathophysiology of DIC
Disseminated Intravascular Coagulation (DIC)
Massive activation of coagulation leading to clots forming in multiple locations around the bodyRapid consumption of clotting factors leading to bleedingParadoxical condition leading to both clotting and bleedingA confusing disorder from both diagnostic and therapeutic standpoints Many unrelated diseases can trigger DIC Lack of uniformity in clinical manifestation Lack of uniformity in the laboratory diagnosis Lack of uniformity or consensus on management
Clinical Manifestations of DICOrgan Ischemic Hemorrhagic
Skin Pupura Fulminans Petechiae
Gangrene Echymoses
Acral cyanosis Oozing
CNS Deliriumcoma Intracranial
Infarcts Bleeding
Renal OliguriaAzotemia Hematuria
Cortical Necrosis
Cardiovascular Myocardial dysfunction
Pulmonary DyspneaHypoxia Hemorrhagic lung
Infarct
Gastrointestinal Ulcers infarcts Massive hemorrhage
Endocrine Adrenal infarcts
Purpura Fulminans with DIC Due to Meningococcal Sepsis
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Clinical Conditions Associated With DIC
Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33
Frequency of DIC in Selected Disease States
Disease Frequency
Gram-negative sepsis 30-50
Severe trauma and systemic inflammation 50-70
Metastasized tumors 15
Abruptio placentaamniotic fluid embolism 50
Severe preeclampsia 7
Giant hemangioma 25
Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92
Masao Nakagawa Modified from a research report on the incidence of disseminated intravascular coagulation (DIC) and underlying diseases in Japan Ministry of Health Labour and Welfare Research report published in Fiscal Year 1998 57-64 199 httpwwwrecomodulincomendicindexhtml Accessed Apr 21 2017
Underlying Diseases in DIC Patients
In a Japanese survey from 1997 on incidence of DIC and underlying diseases in 652 divisions and departments of university hospitals DIC occurred in 2193 patients with the number of patient with infections (including sepsis) and hematologic tumors (including leukemia) accounted for 28 and 23 respectively
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Epidemiology of DIC
Impact of DIC Status on Mortality - 1
Okamoto K Wada H Hatada T Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Frequency and hemostatic abnormalities in pre-DIC patients Thromb Res 2010 126 74-8
Patients with positivity of DIC tend to have worse mortality outcomes compared to negative patients or those with pre-DIC
Impact of DIC Status on Mortality - 2
Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4
Patients with positivity of either Overt or Non-Overt DIC tend to have worse mortality outcomes compared to negative patients
Impact of Age on Mortality in DIC Patients
Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4
Older patients with DIC (black bars) generally tend to have worse outcomes compared to non-DIC patients (grey bars)
Pathophysiology of DIC
Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33
Pathogenesis of DIC in Sepsis
Allen KS Sawheny E Kinasewitzet GT Anticoagulant modulation of inflammation in severe sepsis World J Crit Care Med 2015 4 105-15
Bacteria in sepsis infections cause release of TF from immune cells leading to coagulation activation and proinflammatory cytokines cause endothelial cell activation impairing the anticoagulation and fibrinolysis process resulting in DIC
Host Response in Severe Sepsis
Exaggerated inflammation as a result of the host response to sepsis is collateral tissue damage and cell death further resulting in release of danger molecules continuing the inflammatory process in a downward spiral
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Organ Failure in Severe Sepsis
Sepsis associated with microvascular thrombosis as a result of TF mediated coagulation activation results in release of neutrophil extracellular traps (NETs) tissue hypoperfusion and mitochondrial damage resulting in a downward spiral leading to organ failure
Angus DC van der Poll T Severe Sepsis and Septic Shock N Engl J Med 2013 369 840-51
Mechanism of DIC in Organ Failure
Underlying condition(sepsis trauma)
Cytokines
TF-mediatedactivation of coagulation
Depression of inhibitory systems
Reducesfibrinolysis
Fibrin deposition
Organ failure
Inadequate fibrin removal
Fibrinformation
Note impaired fibrinolysis in relation to the clinical need not in absolute value (FDPs are )
Levi M de Jonge E van der Poll T ten Cate H Disseminated intravascular coagulation ThrombHaemost 1999 82 695-705
Interaction of Inflammation and Coagulation in Sepsis
Binding of TF thrombin and other activation coagulation factors to PARs and fibrin to TLRs on inflammatory cells results in inflammation through release of proinflammatory cytokines and chemokines
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Mechanism of Multiple Organ Failure in DIC
Wheeler AP Bernard GR Treating Patients with Severe Sepsis N Engl J Med 1999 340207-14
Inflammatory activation and microvascular thrombosis contributes to multiple organ failure in DIC
lipopolysaccharides
cytokines
coagulation activation
mononuclear cell
tissue factor
Diverse and Opposing Effects of Thrombin
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Coagulation and Fibrinolysis in DIC
Soluble fibrin Polymer
XIIIa
D-Dimer
E
Fibrin clot
Fibrin Degradation Products
Fibrinogen Thrombin
Fibrinogen Degradation
Products
D E
Plasmin
DFM + fibrinopeptides
Soluble FM ComplexesPre-throm
boticPost-throm
botic
Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis Semin Thromb Hemost 2008 34 33-8
Mechanism of DIC
THROMBOSIS
Fibrin
Blood activationEndothelial lysisTF expression
BLEEDING
FDPs
D-Dimer
Plasmin
Pathophysiology of DIC
1st step abnormal activation of coagulation Injury of vessel wall cells venous stasis release of large quantities of
thromboplastin influx of activated cells (monocytes macrophages)
Results in an intravascular deposition of fibrin
Morbidity from disseminated microthrombosis in small and midsize vessels leading to multiple organ failure
Second step Consumption and depletion of coagulation factors inhibitors (Protein C
Protein S AT) and platelets Local fibrinolytic response
bull Local plasmin generation dissolves the thrombusbull Disseminated overwhelming fibrinolytic response leading to production of
FDP and D-Dimer
Bleeding
Pathophysiology of DIC - Mechanism
Systemic activation of coagulation
Intravasculardepositionof fibrin
Thrombosis of small and midsize vessels
and organ failure
Depletion of platelets and
coagulation factors
Bleeding
Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92
Pathophysiology of DIC ndash 2 Types of Clinical pictures
Chronic = non - overt DICMay be unrecognized clinically
Acute = overt DIClife threatening bleedingor multiple organ failure
Sub-Acute and Non-Overt DIC Clinical Findings
Compensated non-overt DIC Steady low level or intermittent activation
bull Compensated by increased production of coagulation components and platelets
Few or no clinical signs or multiple microvascular thrombosis sometimes not clinically obvious
Risk of decompensation leading to overt DIC
Pathophysiology of Overt DIC
Massive activation of coagulation and fibrinolysis
Does not allow for compensatory efforts
Rapid depletion of coagulation factors inhibitors and platelets
Thrombosis multiple organ failures
Bleeding complications and shock
Physiopathology of DIC ndash Overt DIC Findings
Thrombin generation
Thrombosis
Renal liver respiratory failures coma skin necrosis gangrene venous thromboembolism hypotension edema
Cytokine and kinin generation (shock)bull Tachycardia hypotension edema
Plasmin generationHemorrhage
bull Spontaneous bruising petechiae intracranial gastrointestinal and respiratory tract bleeding persistent bleeding at venipuncture sites at surgical wounds
bull Tachycardia hypotension edema
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Pathogenesis Pathways in DIC
Cytokines
TF-mediated dysfunctional impairedthrombin anticoagulant fibrinolysisgeneration mechanism due to PAI-1 deficiency
fibrin inadequateformation fibrin removal
Fibrin deposition
Inflammation
Coagulation
Stago Celebrates Lab Week 2017
NA
Stago 247 Educational Webinar Sites
wwwstago-edvantagecomUS based KOLsPACE accredited ndash all 1 hourAccessible from mobile devicesVirtual exhibit hall
wwwstagowebinarscomMostly European KOLs30 ndash 45 min including 15 min discussion
Stago Educational Apps
HaemoscoreClinical scoring algorithmsApple and AndroidTablet or phone
iHemostasisCoagulation diagramsCase studiesApple amp AndroidTablet only
BREAK
Diagnostic and Management Approach for DIC
Diagnosis of DIC
Clinical diagnosis is obvious in cases of overt DIC
Laboratory tests are necessary To makeconfirm the diagnosis To assess stage of the patient To assess the treatment efficacy
Lab Diagnosis of DIC ndash Markers of Factor Consumption
Routinescreening assays PT APTT Platelets Fibrinogen Thrombin time
Other coagulation assays Factor assays AntithrombinGeneration of Thrombin FMFSPsGeneration of Plasmin D-dimer FDPs
Important to recognize simultaneous formation of thrombin and plasmin
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122
Lab Diagnosis of DIC ndash Screening Tests
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122
Platelet count usually decreasedPT abnormal in 70 of cases (short half-life of FVII)APTT abnormal in 50 of casesThrombin time usually prolonged in overt DIC normal in non-overt DIC and no relation with syndrome severityFibrinogen low in lt 50 of cases sensitivity 22 specificity 87 overall predictive value 64 Normal fibrinogen level should not exclude DIC diagnosis (acute phase reactant initial high
fibrinogen level) repeat testing assesses progression
Screening tests not clinically specific or sensitive for DIC
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Laboratory Changes in Overt DIC
DIC Diagnostic Practices Over Time
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
British Journal of Haematology Overt DIC Score
Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
ISTH Step by Step DIC Algorithm
Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6
US Based Validation of ISTH DIC Score
When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Differential Diagnosis in DIC
aHUS atypical hemolytic uremic syndrome
HUS hemolytic uremic syndrome
HIT heparin-induced thrombocytopenia
ITP immune thrombocytopenic purpura
TTP thrombotic thrombocytopenic purpura
DIC and MAHA
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)
When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation
DIC Management Goals
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction
DIC Management and Treatment
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)
requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)
Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia
DIC Management Strategies
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant Factor Concentrate Treatment
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis
Anticoagulant Factor Concentrate Treatment Trials
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise
Markers of Thrombin amp Plasmin Generation in DIC
D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC
Cut-off value
Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen
degradation products Sensitive assay typically with cutoff adapted for DIC
D-dimer FDPs and DIC
D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC
Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80
Follow Up of DIC State of Disease
Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8
Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility
FMD-Dimer in DIC Major Differences
onset of thrombosis
days
Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8
FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)
D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)
of Abnormal Results in Patients with Confirmed and Suspected DIC
0
20
40
60
80
100
94 85 90N = 62
Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32
Positivity of Test Results ISTH Score and Disease State
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
Red bar positive for 2 points of DIC score
Pink bar positive for 1-2 points of DIC score
HT hematopoietic tumor
IF infection
SC solid cancer
Markers in Patients with or without DIC
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
HT hematopoietic tumorIF infectionSC solid cancer
Comparing an Automated FM vs Manual FSP Test
Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71
Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)
Automated (Mitsubishi) vs Automated (Stago)
In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago
Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC
Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
Non Overt DIC Overt DIC
AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC
Trends in Markers of DIC for Different Patients
Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00
Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients
Trends in Markers of DIC for Different Patients
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes
28 day outcome survival
28 day outcome death
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines
DIC Case Studies
Case Study 1 - Presentation
18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE
WBC count 77 KμL 423 ndash 907 x KμL
RBC count 17 MμL 137 ndash 175 x MμL
Hemoglobin 67 gdL 137 ndash 175 gdL
Hematocrit 195 401 ndash 510
MCV 95 fL 790 ndash 922 fL
MPV 12 fL 94 ndash 124 fL
Platelet count 9 KμL 161 ndash 347 KμL
Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0
Lymphocytes monocytes eosinophils basophils all below normal range
PT 47 sec (corrected on mixing study) 116 ndash 152 sec
APTT 75 sec (corrected on mixing study) 253 ndash 373 sec
Fibrinogen lt 76 mgdL 177 ndash 466 mgdL
D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Microscopy
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Arrow shows giant platelets in this peripheral smear Promyelocytes apparent
Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)
DIC due to TF release by APL blasts
Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases
Transfusions to replace factors along with platelets and RBCs during APL treatment
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started
Case Study 2 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L
PT 30 sec 113 ndash 146 sec
APTT 75 sec 25 ndash 34 sec
D-dimer 078 microgml FEU lt050 microgml FEU
Fibrinogen 92 mgdl 150-400 mgdl
pH 728 738 to 742
PaO2 570 mmHg 80-100 mmHg
WBC 33 times 103mm3 40-11 times 103mm3
ALT 111 IUL 0ndash34 IUL
AST 61 IUL 0ndash34 IUL
BUN 303 mgdL 08-13 mgdL
Case Study 2 ndash Lab Results
Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures
Case Study 2 ndash Diagnosis
60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior
Case Study 3 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L
PT 228 sec 113 ndash 146 sec
APTT 45 sec 25 ndash 34 sec
D-dimer 080 microgml FEU lt050 microgmL FEU
Fibrinogen 82 mgdL 150-400 mgdL
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 134 gdL 14-16 gdL
WBC 81 times 103mm3 40-11 times 103mm3
ALT 32 IUL 0ndash34 IUL
AST 28 IUL 0ndash34 IUL
BUN 09 mgdL 08-13 mgdL
Case Study 3 ndash Lab Results
Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment
Case Study 3 ndash Diagnosis and Therapy
Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91
Case Study 4 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L
PT 28 sec 113 ndash 146 sec
APTT 71 sec 25 ndash 34 sec
D-dimer 31 microgmL FEU lt050 microgml FEU
Fibrinogen 92 mgdL 150-400 mgdl
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 158 gdL 14-16 gdL
WBC 71 times 103mm3 40-11 times 103mm3
ALT 60 IUL 0ndash34 IUL
AST 47 IUL 0ndash34 IUL
BUN 38 mgdL 08-13 mgdL
Case Study 4 ndash Lab Results
Lyme disease with DICProvide antibiotics with supportive measures
Case Study 4 ndash Diagnosis
55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis
Case Study 5 ndash Presentation
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
Case Study 5 ndash Lab Results and Time Course
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
TEST RESULT REFERENCE RANGE
Platelet count 33 x 109L 150-450 x 109L
PT 215 sec 103 ndash 128 sec
APTT 44 sec 26 ndash 36 sec
D-dimer 20 microgmL FEU lt025 microgml FEU
Fibrinogen 34 mgdL 200-375 mgdl
FII FV FVIII Low Not reported (NR)
FVII FIX FX vWF Normal NR
Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)
DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic
dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR
(C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen
(D) Illustration demonstrating repair
Case Study 5 ndash Diagnosis and Treatment
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography
Case Study 6 ndash Presentation
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
Case Study 6 ndash Lab Results
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L
PT 63 sec gt control 113 ndash 146 sec
INR 658 1 ndash 125
APTT 80 sec gt control 25 ndash 34 sec
D-dimer gt200 microgmL DDU 02 microgmL DDU
Urine exam Proteinuria and hematuria 150-400 mgdl
Albumin 28 gdL NR
Hb 58 gdL NR
LDH 1196 UL NR
SGPT 144 IU NR
SGOT 88 IU NR
Bilirubin 32 mgdL NR
DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th
day postop
Case Study 6 ndash Diagnosis and Treatment
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure
Case Study 6 ndash Discussion
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Case Study 7 ndash Lab Results vs Time
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
DIC Take Home Messages
Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation
Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers
DIC
Thank you Questions
- Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
- Learning Objectives
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Wound Sealing
- The Three Steps of Hemostasis
- Vessel Wall
- Slide Number 12
- Slide Number 13
- Platelet Structure UnactivatedActivated
- Primary Hemostasis
- Primary Hemostasis Assays
- Slide Number 17
- Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
- Slide Number 19
- Coagulation factors
- Coagulation Assay Mechanisms
- Slide Number 22
- Fibrin Formation
- Slide Number 24
- Fibrinolysis Overview
- Fibrinolysis Overview
- Slide Number 27
- Fibrinolysis Releases D-dimers
- Basic Pathophysiology of DIC
- Disseminated Intravascular Coagulation (DIC)
- Purpura Fulminans with DIC Due to Meningococcal Sepsis
- Clinical Conditions Associated With DIC
- Frequency of DIC in Selected Disease States
- Underlying Diseases in DIC Patients
- Slide Number 36
- Slide Number 37
- Slide Number 38
- Slide Number 39
- Pathophysiology of DIC
- Pathogenesis of DIC in Sepsis
- Host Response in Severe Sepsis
- Organ Failure in Severe Sepsis
- Mechanism of DIC in Organ Failure
- Interaction of Inflammation and Coagulation in Sepsis
- Slide Number 47
- Diverse and Opposing Effects of Thrombin
- Coagulation and Fibrinolysis in DIC
- Mechanism of DIC
- Pathophysiology of DIC
- Pathophysiology of DIC - Mechanism
- Pathophysiology of DIC ndash 2 Types of Clinical pictures
- Sub-Acute and Non-Overt DIC Clinical Findings
- Pathophysiology of Overt DIC
- Physiopathology of DIC ndash Overt DIC Findings
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- BREAK
- Diagnostic and Management Approach for DIC
- Diagnosis of DIC
- Lab Diagnosis of DIC ndash Markers of Factor Consumption
- Lab Diagnosis of DIC ndash Screening Tests
- Slide Number 67
- Slide Number 68
- British Journal of Haematology Overt DIC Score
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- DIC Management Goals
- DIC Management and Treatment
- DIC Management Strategies
- Anticoagulant Factor Concentrate Treatment
- Anticoagulant Factor Concentrate Treatment Trials
- Markers of Thrombin amp Plasmin Generation in DIC
- D-dimer FDPs and DIC
- D-Dimer and FDPs in DIC
- Follow Up of DIC State of Disease
- FMD-Dimer in DIC Major Differences
- of Abnormal Results in Patients with Confirmed and Suspected DIC
- Slide Number 85
- Slide Number 86
- Comparing an Automated FM vs Manual FSP Test
- Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Slide Number 94
- Slide Number 95
- Slide Number 96
- Slide Number 97
- Slide Number 98
- Slide Number 99
- DIC Case Studies
- Case Study 1 - Presentation
- Case Study 1 ndash Lab Results
- Case Study 1 ndash Microscopy
- Case Study 1 ndash Diagnosis and Therapy
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Slide Number 110
- Slide Number 111
- Slide Number 112
- Slide Number 113
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
- Slide Number 124
- Slide Number 125
- DIC Take Home Messages
- Slide Number 127
- Slide Number 128
-
Platelet Structure UnactivatedActivated
GpIb-IX-V
GpIIb-IIIa
α granules (raw materials)PF4 β-TG Fibrinogen VWF Factor V and PAI-1
dense granules (energy and glue)ATP ADP SerotoninCa2+ Mg2+ P
Hillman Robert S Ault Kenneth A Rinder Henry M Hematology in Clinical Practice 4th Edition McGraw-Hill New York NY 2005
Primary Hemostasis
2) activation2nd shape changeamp release
platelet at rest 1) adhesion1st shape change
3) aggregation(not reversible)
Vasoconstriction occurs first
Platelets then aggregate on the break in the vessel wall
Primary Hemostasis AssaysRoutine Platelet count PT APTT TT
Follow-up von Willebrand Factor Antigen determination Activity Factor VIII PFA-100 Platelet aggregation studies
SpecializedSend Out Activation markers (b-TG PF4 GPV) Specialized tests for platelet function
Aim is to strengthen the platelet plug
Coagulation
Coagulation is a balancebetween pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
THROMBIN
Fibrinogen Fibrin
bull Triggering agentsbull pro-enzyme enzyme (serine-protease FIIa FVIIa FIXa FXa)bull Cofactors (FVa amp FVIIIa)
bull Serine-protease inhibitor Antithrombin (AT) bull Cofactorsinhibitors Protein C Sbull Tissue factor pathway inhibitor (TFPI)
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Coagulation Cascade Schematic
Coagulation factors
Historic name
Fibrinogen
Prothrombin
Proaccelerin
Proconvertin
Anti-hemophilic factor A
Anti-hemophilic factor B
Stuart factor
Rosenthal factor
Hageman factor
Fibrin Stabilizing Factor
Factor
I
II
V
VII
VIII
IX
X
XI
XII
XIII
Function
Substrate
Pro-enzyme
Pro-cofactor
Pro-enzyme
Pro-cofactor
Pro-enzyme
Pro-enzyme
Pro-enzyme
Pro-enzyme
Pro-enzyme
Pro-enzyme = Zymogen activation Active Enzyme
Coagulation Assay Mechanisms
aPTT Based
PT Based
PT Based
Fibrin Under Microscope
Weisel JW Structure of fibrin impact on clot stability J Thromb Haemost 2007 5 Suppl 1 116-24
Low thrombin concentration
High thrombin concentration
Fibrin Formation
Soluble FibrinPolymer
ThrombinFibrinogen
FM+ fibrinopeptides A amp B
Stabilized Fibrin clot(not soluble)
ThrombinXIII XIIIa
(Digestion of Fibrin)
Fibrinolysis
Fibrinolysis Overview
Destroys fibrin fibers
Destroys the scab (dried wound)
Maintains vessel integrity
Fibrinolysis Overview
Fibrin =cement fibers
Plasmin
Plasmin digests fibrin
t-PA
Pro Urokinase
Urokinase
PAI-1PAI-1
Plasminogen Plasmin
1st Step
2nd Step
Fibrinolysis Cascade
t-PA tissue-type plasminogen activator PAI-1 Plasminogen activator inhibitor 1 PK Prekallikrein FDP Fibrinogen degradation products AP Antiplasmin = a2AP alpha 2 Antiplasmin a2MG alpha 2 Macroglobulin
Extrinsic pathway(endothelia l cells)
Intrinsic pathway(plasma)
Fibrin clot
D-dimerFibrin degradation products
Fibrin
TAFIa
APAntiplasmin(amp a2-MG)
PK Kallikrein
XII
Fibrinolysis Releases D-dimers
D-dimer presence fibrin has been formed and digested in patients body
Normal D-dimer level no thrombosis occurred in the patient
Basic Pathophysiology of DIC
Disseminated Intravascular Coagulation (DIC)
Massive activation of coagulation leading to clots forming in multiple locations around the bodyRapid consumption of clotting factors leading to bleedingParadoxical condition leading to both clotting and bleedingA confusing disorder from both diagnostic and therapeutic standpoints Many unrelated diseases can trigger DIC Lack of uniformity in clinical manifestation Lack of uniformity in the laboratory diagnosis Lack of uniformity or consensus on management
Clinical Manifestations of DICOrgan Ischemic Hemorrhagic
Skin Pupura Fulminans Petechiae
Gangrene Echymoses
Acral cyanosis Oozing
CNS Deliriumcoma Intracranial
Infarcts Bleeding
Renal OliguriaAzotemia Hematuria
Cortical Necrosis
Cardiovascular Myocardial dysfunction
Pulmonary DyspneaHypoxia Hemorrhagic lung
Infarct
Gastrointestinal Ulcers infarcts Massive hemorrhage
Endocrine Adrenal infarcts
Purpura Fulminans with DIC Due to Meningococcal Sepsis
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Clinical Conditions Associated With DIC
Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33
Frequency of DIC in Selected Disease States
Disease Frequency
Gram-negative sepsis 30-50
Severe trauma and systemic inflammation 50-70
Metastasized tumors 15
Abruptio placentaamniotic fluid embolism 50
Severe preeclampsia 7
Giant hemangioma 25
Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92
Masao Nakagawa Modified from a research report on the incidence of disseminated intravascular coagulation (DIC) and underlying diseases in Japan Ministry of Health Labour and Welfare Research report published in Fiscal Year 1998 57-64 199 httpwwwrecomodulincomendicindexhtml Accessed Apr 21 2017
Underlying Diseases in DIC Patients
In a Japanese survey from 1997 on incidence of DIC and underlying diseases in 652 divisions and departments of university hospitals DIC occurred in 2193 patients with the number of patient with infections (including sepsis) and hematologic tumors (including leukemia) accounted for 28 and 23 respectively
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Epidemiology of DIC
Impact of DIC Status on Mortality - 1
Okamoto K Wada H Hatada T Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Frequency and hemostatic abnormalities in pre-DIC patients Thromb Res 2010 126 74-8
Patients with positivity of DIC tend to have worse mortality outcomes compared to negative patients or those with pre-DIC
Impact of DIC Status on Mortality - 2
Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4
Patients with positivity of either Overt or Non-Overt DIC tend to have worse mortality outcomes compared to negative patients
Impact of Age on Mortality in DIC Patients
Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4
Older patients with DIC (black bars) generally tend to have worse outcomes compared to non-DIC patients (grey bars)
Pathophysiology of DIC
Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33
Pathogenesis of DIC in Sepsis
Allen KS Sawheny E Kinasewitzet GT Anticoagulant modulation of inflammation in severe sepsis World J Crit Care Med 2015 4 105-15
Bacteria in sepsis infections cause release of TF from immune cells leading to coagulation activation and proinflammatory cytokines cause endothelial cell activation impairing the anticoagulation and fibrinolysis process resulting in DIC
Host Response in Severe Sepsis
Exaggerated inflammation as a result of the host response to sepsis is collateral tissue damage and cell death further resulting in release of danger molecules continuing the inflammatory process in a downward spiral
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Organ Failure in Severe Sepsis
Sepsis associated with microvascular thrombosis as a result of TF mediated coagulation activation results in release of neutrophil extracellular traps (NETs) tissue hypoperfusion and mitochondrial damage resulting in a downward spiral leading to organ failure
Angus DC van der Poll T Severe Sepsis and Septic Shock N Engl J Med 2013 369 840-51
Mechanism of DIC in Organ Failure
Underlying condition(sepsis trauma)
Cytokines
TF-mediatedactivation of coagulation
Depression of inhibitory systems
Reducesfibrinolysis
Fibrin deposition
Organ failure
Inadequate fibrin removal
Fibrinformation
Note impaired fibrinolysis in relation to the clinical need not in absolute value (FDPs are )
Levi M de Jonge E van der Poll T ten Cate H Disseminated intravascular coagulation ThrombHaemost 1999 82 695-705
Interaction of Inflammation and Coagulation in Sepsis
Binding of TF thrombin and other activation coagulation factors to PARs and fibrin to TLRs on inflammatory cells results in inflammation through release of proinflammatory cytokines and chemokines
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Mechanism of Multiple Organ Failure in DIC
Wheeler AP Bernard GR Treating Patients with Severe Sepsis N Engl J Med 1999 340207-14
Inflammatory activation and microvascular thrombosis contributes to multiple organ failure in DIC
lipopolysaccharides
cytokines
coagulation activation
mononuclear cell
tissue factor
Diverse and Opposing Effects of Thrombin
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Coagulation and Fibrinolysis in DIC
Soluble fibrin Polymer
XIIIa
D-Dimer
E
Fibrin clot
Fibrin Degradation Products
Fibrinogen Thrombin
Fibrinogen Degradation
Products
D E
Plasmin
DFM + fibrinopeptides
Soluble FM ComplexesPre-throm
boticPost-throm
botic
Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis Semin Thromb Hemost 2008 34 33-8
Mechanism of DIC
THROMBOSIS
Fibrin
Blood activationEndothelial lysisTF expression
BLEEDING
FDPs
D-Dimer
Plasmin
Pathophysiology of DIC
1st step abnormal activation of coagulation Injury of vessel wall cells venous stasis release of large quantities of
thromboplastin influx of activated cells (monocytes macrophages)
Results in an intravascular deposition of fibrin
Morbidity from disseminated microthrombosis in small and midsize vessels leading to multiple organ failure
Second step Consumption and depletion of coagulation factors inhibitors (Protein C
Protein S AT) and platelets Local fibrinolytic response
bull Local plasmin generation dissolves the thrombusbull Disseminated overwhelming fibrinolytic response leading to production of
FDP and D-Dimer
Bleeding
Pathophysiology of DIC - Mechanism
Systemic activation of coagulation
Intravasculardepositionof fibrin
Thrombosis of small and midsize vessels
and organ failure
Depletion of platelets and
coagulation factors
Bleeding
Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92
Pathophysiology of DIC ndash 2 Types of Clinical pictures
Chronic = non - overt DICMay be unrecognized clinically
Acute = overt DIClife threatening bleedingor multiple organ failure
Sub-Acute and Non-Overt DIC Clinical Findings
Compensated non-overt DIC Steady low level or intermittent activation
bull Compensated by increased production of coagulation components and platelets
Few or no clinical signs or multiple microvascular thrombosis sometimes not clinically obvious
Risk of decompensation leading to overt DIC
Pathophysiology of Overt DIC
Massive activation of coagulation and fibrinolysis
Does not allow for compensatory efforts
Rapid depletion of coagulation factors inhibitors and platelets
Thrombosis multiple organ failures
Bleeding complications and shock
Physiopathology of DIC ndash Overt DIC Findings
Thrombin generation
Thrombosis
Renal liver respiratory failures coma skin necrosis gangrene venous thromboembolism hypotension edema
Cytokine and kinin generation (shock)bull Tachycardia hypotension edema
Plasmin generationHemorrhage
bull Spontaneous bruising petechiae intracranial gastrointestinal and respiratory tract bleeding persistent bleeding at venipuncture sites at surgical wounds
bull Tachycardia hypotension edema
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Pathogenesis Pathways in DIC
Cytokines
TF-mediated dysfunctional impairedthrombin anticoagulant fibrinolysisgeneration mechanism due to PAI-1 deficiency
fibrin inadequateformation fibrin removal
Fibrin deposition
Inflammation
Coagulation
Stago Celebrates Lab Week 2017
NA
Stago 247 Educational Webinar Sites
wwwstago-edvantagecomUS based KOLsPACE accredited ndash all 1 hourAccessible from mobile devicesVirtual exhibit hall
wwwstagowebinarscomMostly European KOLs30 ndash 45 min including 15 min discussion
Stago Educational Apps
HaemoscoreClinical scoring algorithmsApple and AndroidTablet or phone
iHemostasisCoagulation diagramsCase studiesApple amp AndroidTablet only
BREAK
Diagnostic and Management Approach for DIC
Diagnosis of DIC
Clinical diagnosis is obvious in cases of overt DIC
Laboratory tests are necessary To makeconfirm the diagnosis To assess stage of the patient To assess the treatment efficacy
Lab Diagnosis of DIC ndash Markers of Factor Consumption
Routinescreening assays PT APTT Platelets Fibrinogen Thrombin time
Other coagulation assays Factor assays AntithrombinGeneration of Thrombin FMFSPsGeneration of Plasmin D-dimer FDPs
Important to recognize simultaneous formation of thrombin and plasmin
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122
Lab Diagnosis of DIC ndash Screening Tests
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122
Platelet count usually decreasedPT abnormal in 70 of cases (short half-life of FVII)APTT abnormal in 50 of casesThrombin time usually prolonged in overt DIC normal in non-overt DIC and no relation with syndrome severityFibrinogen low in lt 50 of cases sensitivity 22 specificity 87 overall predictive value 64 Normal fibrinogen level should not exclude DIC diagnosis (acute phase reactant initial high
fibrinogen level) repeat testing assesses progression
Screening tests not clinically specific or sensitive for DIC
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Laboratory Changes in Overt DIC
DIC Diagnostic Practices Over Time
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
British Journal of Haematology Overt DIC Score
Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
ISTH Step by Step DIC Algorithm
Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6
US Based Validation of ISTH DIC Score
When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Differential Diagnosis in DIC
aHUS atypical hemolytic uremic syndrome
HUS hemolytic uremic syndrome
HIT heparin-induced thrombocytopenia
ITP immune thrombocytopenic purpura
TTP thrombotic thrombocytopenic purpura
DIC and MAHA
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)
When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation
DIC Management Goals
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction
DIC Management and Treatment
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)
requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)
Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia
DIC Management Strategies
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant Factor Concentrate Treatment
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis
Anticoagulant Factor Concentrate Treatment Trials
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise
Markers of Thrombin amp Plasmin Generation in DIC
D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC
Cut-off value
Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen
degradation products Sensitive assay typically with cutoff adapted for DIC
D-dimer FDPs and DIC
D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC
Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80
Follow Up of DIC State of Disease
Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8
Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility
FMD-Dimer in DIC Major Differences
onset of thrombosis
days
Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8
FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)
D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)
of Abnormal Results in Patients with Confirmed and Suspected DIC
0
20
40
60
80
100
94 85 90N = 62
Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32
Positivity of Test Results ISTH Score and Disease State
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
Red bar positive for 2 points of DIC score
Pink bar positive for 1-2 points of DIC score
HT hematopoietic tumor
IF infection
SC solid cancer
Markers in Patients with or without DIC
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
HT hematopoietic tumorIF infectionSC solid cancer
Comparing an Automated FM vs Manual FSP Test
Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71
Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)
Automated (Mitsubishi) vs Automated (Stago)
In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago
Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC
Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
Non Overt DIC Overt DIC
AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC
Trends in Markers of DIC for Different Patients
Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00
Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients
Trends in Markers of DIC for Different Patients
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes
28 day outcome survival
28 day outcome death
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines
DIC Case Studies
Case Study 1 - Presentation
18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE
WBC count 77 KμL 423 ndash 907 x KμL
RBC count 17 MμL 137 ndash 175 x MμL
Hemoglobin 67 gdL 137 ndash 175 gdL
Hematocrit 195 401 ndash 510
MCV 95 fL 790 ndash 922 fL
MPV 12 fL 94 ndash 124 fL
Platelet count 9 KμL 161 ndash 347 KμL
Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0
Lymphocytes monocytes eosinophils basophils all below normal range
PT 47 sec (corrected on mixing study) 116 ndash 152 sec
APTT 75 sec (corrected on mixing study) 253 ndash 373 sec
Fibrinogen lt 76 mgdL 177 ndash 466 mgdL
D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Microscopy
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Arrow shows giant platelets in this peripheral smear Promyelocytes apparent
Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)
DIC due to TF release by APL blasts
Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases
Transfusions to replace factors along with platelets and RBCs during APL treatment
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started
Case Study 2 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L
PT 30 sec 113 ndash 146 sec
APTT 75 sec 25 ndash 34 sec
D-dimer 078 microgml FEU lt050 microgml FEU
Fibrinogen 92 mgdl 150-400 mgdl
pH 728 738 to 742
PaO2 570 mmHg 80-100 mmHg
WBC 33 times 103mm3 40-11 times 103mm3
ALT 111 IUL 0ndash34 IUL
AST 61 IUL 0ndash34 IUL
BUN 303 mgdL 08-13 mgdL
Case Study 2 ndash Lab Results
Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures
Case Study 2 ndash Diagnosis
60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior
Case Study 3 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L
PT 228 sec 113 ndash 146 sec
APTT 45 sec 25 ndash 34 sec
D-dimer 080 microgml FEU lt050 microgmL FEU
Fibrinogen 82 mgdL 150-400 mgdL
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 134 gdL 14-16 gdL
WBC 81 times 103mm3 40-11 times 103mm3
ALT 32 IUL 0ndash34 IUL
AST 28 IUL 0ndash34 IUL
BUN 09 mgdL 08-13 mgdL
Case Study 3 ndash Lab Results
Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment
Case Study 3 ndash Diagnosis and Therapy
Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91
Case Study 4 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L
PT 28 sec 113 ndash 146 sec
APTT 71 sec 25 ndash 34 sec
D-dimer 31 microgmL FEU lt050 microgml FEU
Fibrinogen 92 mgdL 150-400 mgdl
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 158 gdL 14-16 gdL
WBC 71 times 103mm3 40-11 times 103mm3
ALT 60 IUL 0ndash34 IUL
AST 47 IUL 0ndash34 IUL
BUN 38 mgdL 08-13 mgdL
Case Study 4 ndash Lab Results
Lyme disease with DICProvide antibiotics with supportive measures
Case Study 4 ndash Diagnosis
55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis
Case Study 5 ndash Presentation
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
Case Study 5 ndash Lab Results and Time Course
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
TEST RESULT REFERENCE RANGE
Platelet count 33 x 109L 150-450 x 109L
PT 215 sec 103 ndash 128 sec
APTT 44 sec 26 ndash 36 sec
D-dimer 20 microgmL FEU lt025 microgml FEU
Fibrinogen 34 mgdL 200-375 mgdl
FII FV FVIII Low Not reported (NR)
FVII FIX FX vWF Normal NR
Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)
DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic
dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR
(C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen
(D) Illustration demonstrating repair
Case Study 5 ndash Diagnosis and Treatment
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography
Case Study 6 ndash Presentation
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
Case Study 6 ndash Lab Results
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L
PT 63 sec gt control 113 ndash 146 sec
INR 658 1 ndash 125
APTT 80 sec gt control 25 ndash 34 sec
D-dimer gt200 microgmL DDU 02 microgmL DDU
Urine exam Proteinuria and hematuria 150-400 mgdl
Albumin 28 gdL NR
Hb 58 gdL NR
LDH 1196 UL NR
SGPT 144 IU NR
SGOT 88 IU NR
Bilirubin 32 mgdL NR
DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th
day postop
Case Study 6 ndash Diagnosis and Treatment
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure
Case Study 6 ndash Discussion
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Case Study 7 ndash Lab Results vs Time
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
DIC Take Home Messages
Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation
Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers
DIC
Thank you Questions
- Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
- Learning Objectives
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Wound Sealing
- The Three Steps of Hemostasis
- Vessel Wall
- Slide Number 12
- Slide Number 13
- Platelet Structure UnactivatedActivated
- Primary Hemostasis
- Primary Hemostasis Assays
- Slide Number 17
- Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
- Slide Number 19
- Coagulation factors
- Coagulation Assay Mechanisms
- Slide Number 22
- Fibrin Formation
- Slide Number 24
- Fibrinolysis Overview
- Fibrinolysis Overview
- Slide Number 27
- Fibrinolysis Releases D-dimers
- Basic Pathophysiology of DIC
- Disseminated Intravascular Coagulation (DIC)
- Purpura Fulminans with DIC Due to Meningococcal Sepsis
- Clinical Conditions Associated With DIC
- Frequency of DIC in Selected Disease States
- Underlying Diseases in DIC Patients
- Slide Number 36
- Slide Number 37
- Slide Number 38
- Slide Number 39
- Pathophysiology of DIC
- Pathogenesis of DIC in Sepsis
- Host Response in Severe Sepsis
- Organ Failure in Severe Sepsis
- Mechanism of DIC in Organ Failure
- Interaction of Inflammation and Coagulation in Sepsis
- Slide Number 47
- Diverse and Opposing Effects of Thrombin
- Coagulation and Fibrinolysis in DIC
- Mechanism of DIC
- Pathophysiology of DIC
- Pathophysiology of DIC - Mechanism
- Pathophysiology of DIC ndash 2 Types of Clinical pictures
- Sub-Acute and Non-Overt DIC Clinical Findings
- Pathophysiology of Overt DIC
- Physiopathology of DIC ndash Overt DIC Findings
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- BREAK
- Diagnostic and Management Approach for DIC
- Diagnosis of DIC
- Lab Diagnosis of DIC ndash Markers of Factor Consumption
- Lab Diagnosis of DIC ndash Screening Tests
- Slide Number 67
- Slide Number 68
- British Journal of Haematology Overt DIC Score
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- DIC Management Goals
- DIC Management and Treatment
- DIC Management Strategies
- Anticoagulant Factor Concentrate Treatment
- Anticoagulant Factor Concentrate Treatment Trials
- Markers of Thrombin amp Plasmin Generation in DIC
- D-dimer FDPs and DIC
- D-Dimer and FDPs in DIC
- Follow Up of DIC State of Disease
- FMD-Dimer in DIC Major Differences
- of Abnormal Results in Patients with Confirmed and Suspected DIC
- Slide Number 85
- Slide Number 86
- Comparing an Automated FM vs Manual FSP Test
- Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Slide Number 94
- Slide Number 95
- Slide Number 96
- Slide Number 97
- Slide Number 98
- Slide Number 99
- DIC Case Studies
- Case Study 1 - Presentation
- Case Study 1 ndash Lab Results
- Case Study 1 ndash Microscopy
- Case Study 1 ndash Diagnosis and Therapy
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Slide Number 110
- Slide Number 111
- Slide Number 112
- Slide Number 113
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
- Slide Number 124
- Slide Number 125
- DIC Take Home Messages
- Slide Number 127
- Slide Number 128
-
Primary Hemostasis
2) activation2nd shape changeamp release
platelet at rest 1) adhesion1st shape change
3) aggregation(not reversible)
Vasoconstriction occurs first
Platelets then aggregate on the break in the vessel wall
Primary Hemostasis AssaysRoutine Platelet count PT APTT TT
Follow-up von Willebrand Factor Antigen determination Activity Factor VIII PFA-100 Platelet aggregation studies
SpecializedSend Out Activation markers (b-TG PF4 GPV) Specialized tests for platelet function
Aim is to strengthen the platelet plug
Coagulation
Coagulation is a balancebetween pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
THROMBIN
Fibrinogen Fibrin
bull Triggering agentsbull pro-enzyme enzyme (serine-protease FIIa FVIIa FIXa FXa)bull Cofactors (FVa amp FVIIIa)
bull Serine-protease inhibitor Antithrombin (AT) bull Cofactorsinhibitors Protein C Sbull Tissue factor pathway inhibitor (TFPI)
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Coagulation Cascade Schematic
Coagulation factors
Historic name
Fibrinogen
Prothrombin
Proaccelerin
Proconvertin
Anti-hemophilic factor A
Anti-hemophilic factor B
Stuart factor
Rosenthal factor
Hageman factor
Fibrin Stabilizing Factor
Factor
I
II
V
VII
VIII
IX
X
XI
XII
XIII
Function
Substrate
Pro-enzyme
Pro-cofactor
Pro-enzyme
Pro-cofactor
Pro-enzyme
Pro-enzyme
Pro-enzyme
Pro-enzyme
Pro-enzyme
Pro-enzyme = Zymogen activation Active Enzyme
Coagulation Assay Mechanisms
aPTT Based
PT Based
PT Based
Fibrin Under Microscope
Weisel JW Structure of fibrin impact on clot stability J Thromb Haemost 2007 5 Suppl 1 116-24
Low thrombin concentration
High thrombin concentration
Fibrin Formation
Soluble FibrinPolymer
ThrombinFibrinogen
FM+ fibrinopeptides A amp B
Stabilized Fibrin clot(not soluble)
ThrombinXIII XIIIa
(Digestion of Fibrin)
Fibrinolysis
Fibrinolysis Overview
Destroys fibrin fibers
Destroys the scab (dried wound)
Maintains vessel integrity
Fibrinolysis Overview
Fibrin =cement fibers
Plasmin
Plasmin digests fibrin
t-PA
Pro Urokinase
Urokinase
PAI-1PAI-1
Plasminogen Plasmin
1st Step
2nd Step
Fibrinolysis Cascade
t-PA tissue-type plasminogen activator PAI-1 Plasminogen activator inhibitor 1 PK Prekallikrein FDP Fibrinogen degradation products AP Antiplasmin = a2AP alpha 2 Antiplasmin a2MG alpha 2 Macroglobulin
Extrinsic pathway(endothelia l cells)
Intrinsic pathway(plasma)
Fibrin clot
D-dimerFibrin degradation products
Fibrin
TAFIa
APAntiplasmin(amp a2-MG)
PK Kallikrein
XII
Fibrinolysis Releases D-dimers
D-dimer presence fibrin has been formed and digested in patients body
Normal D-dimer level no thrombosis occurred in the patient
Basic Pathophysiology of DIC
Disseminated Intravascular Coagulation (DIC)
Massive activation of coagulation leading to clots forming in multiple locations around the bodyRapid consumption of clotting factors leading to bleedingParadoxical condition leading to both clotting and bleedingA confusing disorder from both diagnostic and therapeutic standpoints Many unrelated diseases can trigger DIC Lack of uniformity in clinical manifestation Lack of uniformity in the laboratory diagnosis Lack of uniformity or consensus on management
Clinical Manifestations of DICOrgan Ischemic Hemorrhagic
Skin Pupura Fulminans Petechiae
Gangrene Echymoses
Acral cyanosis Oozing
CNS Deliriumcoma Intracranial
Infarcts Bleeding
Renal OliguriaAzotemia Hematuria
Cortical Necrosis
Cardiovascular Myocardial dysfunction
Pulmonary DyspneaHypoxia Hemorrhagic lung
Infarct
Gastrointestinal Ulcers infarcts Massive hemorrhage
Endocrine Adrenal infarcts
Purpura Fulminans with DIC Due to Meningococcal Sepsis
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Clinical Conditions Associated With DIC
Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33
Frequency of DIC in Selected Disease States
Disease Frequency
Gram-negative sepsis 30-50
Severe trauma and systemic inflammation 50-70
Metastasized tumors 15
Abruptio placentaamniotic fluid embolism 50
Severe preeclampsia 7
Giant hemangioma 25
Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92
Masao Nakagawa Modified from a research report on the incidence of disseminated intravascular coagulation (DIC) and underlying diseases in Japan Ministry of Health Labour and Welfare Research report published in Fiscal Year 1998 57-64 199 httpwwwrecomodulincomendicindexhtml Accessed Apr 21 2017
Underlying Diseases in DIC Patients
In a Japanese survey from 1997 on incidence of DIC and underlying diseases in 652 divisions and departments of university hospitals DIC occurred in 2193 patients with the number of patient with infections (including sepsis) and hematologic tumors (including leukemia) accounted for 28 and 23 respectively
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Epidemiology of DIC
Impact of DIC Status on Mortality - 1
Okamoto K Wada H Hatada T Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Frequency and hemostatic abnormalities in pre-DIC patients Thromb Res 2010 126 74-8
Patients with positivity of DIC tend to have worse mortality outcomes compared to negative patients or those with pre-DIC
Impact of DIC Status on Mortality - 2
Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4
Patients with positivity of either Overt or Non-Overt DIC tend to have worse mortality outcomes compared to negative patients
Impact of Age on Mortality in DIC Patients
Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4
Older patients with DIC (black bars) generally tend to have worse outcomes compared to non-DIC patients (grey bars)
Pathophysiology of DIC
Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33
Pathogenesis of DIC in Sepsis
Allen KS Sawheny E Kinasewitzet GT Anticoagulant modulation of inflammation in severe sepsis World J Crit Care Med 2015 4 105-15
Bacteria in sepsis infections cause release of TF from immune cells leading to coagulation activation and proinflammatory cytokines cause endothelial cell activation impairing the anticoagulation and fibrinolysis process resulting in DIC
Host Response in Severe Sepsis
Exaggerated inflammation as a result of the host response to sepsis is collateral tissue damage and cell death further resulting in release of danger molecules continuing the inflammatory process in a downward spiral
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Organ Failure in Severe Sepsis
Sepsis associated with microvascular thrombosis as a result of TF mediated coagulation activation results in release of neutrophil extracellular traps (NETs) tissue hypoperfusion and mitochondrial damage resulting in a downward spiral leading to organ failure
Angus DC van der Poll T Severe Sepsis and Septic Shock N Engl J Med 2013 369 840-51
Mechanism of DIC in Organ Failure
Underlying condition(sepsis trauma)
Cytokines
TF-mediatedactivation of coagulation
Depression of inhibitory systems
Reducesfibrinolysis
Fibrin deposition
Organ failure
Inadequate fibrin removal
Fibrinformation
Note impaired fibrinolysis in relation to the clinical need not in absolute value (FDPs are )
Levi M de Jonge E van der Poll T ten Cate H Disseminated intravascular coagulation ThrombHaemost 1999 82 695-705
Interaction of Inflammation and Coagulation in Sepsis
Binding of TF thrombin and other activation coagulation factors to PARs and fibrin to TLRs on inflammatory cells results in inflammation through release of proinflammatory cytokines and chemokines
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Mechanism of Multiple Organ Failure in DIC
Wheeler AP Bernard GR Treating Patients with Severe Sepsis N Engl J Med 1999 340207-14
Inflammatory activation and microvascular thrombosis contributes to multiple organ failure in DIC
lipopolysaccharides
cytokines
coagulation activation
mononuclear cell
tissue factor
Diverse and Opposing Effects of Thrombin
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Coagulation and Fibrinolysis in DIC
Soluble fibrin Polymer
XIIIa
D-Dimer
E
Fibrin clot
Fibrin Degradation Products
Fibrinogen Thrombin
Fibrinogen Degradation
Products
D E
Plasmin
DFM + fibrinopeptides
Soluble FM ComplexesPre-throm
boticPost-throm
botic
Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis Semin Thromb Hemost 2008 34 33-8
Mechanism of DIC
THROMBOSIS
Fibrin
Blood activationEndothelial lysisTF expression
BLEEDING
FDPs
D-Dimer
Plasmin
Pathophysiology of DIC
1st step abnormal activation of coagulation Injury of vessel wall cells venous stasis release of large quantities of
thromboplastin influx of activated cells (monocytes macrophages)
Results in an intravascular deposition of fibrin
Morbidity from disseminated microthrombosis in small and midsize vessels leading to multiple organ failure
Second step Consumption and depletion of coagulation factors inhibitors (Protein C
Protein S AT) and platelets Local fibrinolytic response
bull Local plasmin generation dissolves the thrombusbull Disseminated overwhelming fibrinolytic response leading to production of
FDP and D-Dimer
Bleeding
Pathophysiology of DIC - Mechanism
Systemic activation of coagulation
Intravasculardepositionof fibrin
Thrombosis of small and midsize vessels
and organ failure
Depletion of platelets and
coagulation factors
Bleeding
Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92
Pathophysiology of DIC ndash 2 Types of Clinical pictures
Chronic = non - overt DICMay be unrecognized clinically
Acute = overt DIClife threatening bleedingor multiple organ failure
Sub-Acute and Non-Overt DIC Clinical Findings
Compensated non-overt DIC Steady low level or intermittent activation
bull Compensated by increased production of coagulation components and platelets
Few or no clinical signs or multiple microvascular thrombosis sometimes not clinically obvious
Risk of decompensation leading to overt DIC
Pathophysiology of Overt DIC
Massive activation of coagulation and fibrinolysis
Does not allow for compensatory efforts
Rapid depletion of coagulation factors inhibitors and platelets
Thrombosis multiple organ failures
Bleeding complications and shock
Physiopathology of DIC ndash Overt DIC Findings
Thrombin generation
Thrombosis
Renal liver respiratory failures coma skin necrosis gangrene venous thromboembolism hypotension edema
Cytokine and kinin generation (shock)bull Tachycardia hypotension edema
Plasmin generationHemorrhage
bull Spontaneous bruising petechiae intracranial gastrointestinal and respiratory tract bleeding persistent bleeding at venipuncture sites at surgical wounds
bull Tachycardia hypotension edema
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Pathogenesis Pathways in DIC
Cytokines
TF-mediated dysfunctional impairedthrombin anticoagulant fibrinolysisgeneration mechanism due to PAI-1 deficiency
fibrin inadequateformation fibrin removal
Fibrin deposition
Inflammation
Coagulation
Stago Celebrates Lab Week 2017
NA
Stago 247 Educational Webinar Sites
wwwstago-edvantagecomUS based KOLsPACE accredited ndash all 1 hourAccessible from mobile devicesVirtual exhibit hall
wwwstagowebinarscomMostly European KOLs30 ndash 45 min including 15 min discussion
Stago Educational Apps
HaemoscoreClinical scoring algorithmsApple and AndroidTablet or phone
iHemostasisCoagulation diagramsCase studiesApple amp AndroidTablet only
BREAK
Diagnostic and Management Approach for DIC
Diagnosis of DIC
Clinical diagnosis is obvious in cases of overt DIC
Laboratory tests are necessary To makeconfirm the diagnosis To assess stage of the patient To assess the treatment efficacy
Lab Diagnosis of DIC ndash Markers of Factor Consumption
Routinescreening assays PT APTT Platelets Fibrinogen Thrombin time
Other coagulation assays Factor assays AntithrombinGeneration of Thrombin FMFSPsGeneration of Plasmin D-dimer FDPs
Important to recognize simultaneous formation of thrombin and plasmin
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122
Lab Diagnosis of DIC ndash Screening Tests
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122
Platelet count usually decreasedPT abnormal in 70 of cases (short half-life of FVII)APTT abnormal in 50 of casesThrombin time usually prolonged in overt DIC normal in non-overt DIC and no relation with syndrome severityFibrinogen low in lt 50 of cases sensitivity 22 specificity 87 overall predictive value 64 Normal fibrinogen level should not exclude DIC diagnosis (acute phase reactant initial high
fibrinogen level) repeat testing assesses progression
Screening tests not clinically specific or sensitive for DIC
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Laboratory Changes in Overt DIC
DIC Diagnostic Practices Over Time
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
British Journal of Haematology Overt DIC Score
Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
ISTH Step by Step DIC Algorithm
Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6
US Based Validation of ISTH DIC Score
When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Differential Diagnosis in DIC
aHUS atypical hemolytic uremic syndrome
HUS hemolytic uremic syndrome
HIT heparin-induced thrombocytopenia
ITP immune thrombocytopenic purpura
TTP thrombotic thrombocytopenic purpura
DIC and MAHA
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)
When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation
DIC Management Goals
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction
DIC Management and Treatment
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)
requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)
Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia
DIC Management Strategies
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant Factor Concentrate Treatment
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis
Anticoagulant Factor Concentrate Treatment Trials
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise
Markers of Thrombin amp Plasmin Generation in DIC
D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC
Cut-off value
Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen
degradation products Sensitive assay typically with cutoff adapted for DIC
D-dimer FDPs and DIC
D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC
Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80
Follow Up of DIC State of Disease
Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8
Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility
FMD-Dimer in DIC Major Differences
onset of thrombosis
days
Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8
FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)
D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)
of Abnormal Results in Patients with Confirmed and Suspected DIC
0
20
40
60
80
100
94 85 90N = 62
Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32
Positivity of Test Results ISTH Score and Disease State
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
Red bar positive for 2 points of DIC score
Pink bar positive for 1-2 points of DIC score
HT hematopoietic tumor
IF infection
SC solid cancer
Markers in Patients with or without DIC
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
HT hematopoietic tumorIF infectionSC solid cancer
Comparing an Automated FM vs Manual FSP Test
Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71
Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)
Automated (Mitsubishi) vs Automated (Stago)
In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago
Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC
Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
Non Overt DIC Overt DIC
AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC
Trends in Markers of DIC for Different Patients
Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00
Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients
Trends in Markers of DIC for Different Patients
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes
28 day outcome survival
28 day outcome death
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines
DIC Case Studies
Case Study 1 - Presentation
18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE
WBC count 77 KμL 423 ndash 907 x KμL
RBC count 17 MμL 137 ndash 175 x MμL
Hemoglobin 67 gdL 137 ndash 175 gdL
Hematocrit 195 401 ndash 510
MCV 95 fL 790 ndash 922 fL
MPV 12 fL 94 ndash 124 fL
Platelet count 9 KμL 161 ndash 347 KμL
Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0
Lymphocytes monocytes eosinophils basophils all below normal range
PT 47 sec (corrected on mixing study) 116 ndash 152 sec
APTT 75 sec (corrected on mixing study) 253 ndash 373 sec
Fibrinogen lt 76 mgdL 177 ndash 466 mgdL
D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Microscopy
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Arrow shows giant platelets in this peripheral smear Promyelocytes apparent
Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)
DIC due to TF release by APL blasts
Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases
Transfusions to replace factors along with platelets and RBCs during APL treatment
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started
Case Study 2 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L
PT 30 sec 113 ndash 146 sec
APTT 75 sec 25 ndash 34 sec
D-dimer 078 microgml FEU lt050 microgml FEU
Fibrinogen 92 mgdl 150-400 mgdl
pH 728 738 to 742
PaO2 570 mmHg 80-100 mmHg
WBC 33 times 103mm3 40-11 times 103mm3
ALT 111 IUL 0ndash34 IUL
AST 61 IUL 0ndash34 IUL
BUN 303 mgdL 08-13 mgdL
Case Study 2 ndash Lab Results
Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures
Case Study 2 ndash Diagnosis
60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior
Case Study 3 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L
PT 228 sec 113 ndash 146 sec
APTT 45 sec 25 ndash 34 sec
D-dimer 080 microgml FEU lt050 microgmL FEU
Fibrinogen 82 mgdL 150-400 mgdL
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 134 gdL 14-16 gdL
WBC 81 times 103mm3 40-11 times 103mm3
ALT 32 IUL 0ndash34 IUL
AST 28 IUL 0ndash34 IUL
BUN 09 mgdL 08-13 mgdL
Case Study 3 ndash Lab Results
Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment
Case Study 3 ndash Diagnosis and Therapy
Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91
Case Study 4 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L
PT 28 sec 113 ndash 146 sec
APTT 71 sec 25 ndash 34 sec
D-dimer 31 microgmL FEU lt050 microgml FEU
Fibrinogen 92 mgdL 150-400 mgdl
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 158 gdL 14-16 gdL
WBC 71 times 103mm3 40-11 times 103mm3
ALT 60 IUL 0ndash34 IUL
AST 47 IUL 0ndash34 IUL
BUN 38 mgdL 08-13 mgdL
Case Study 4 ndash Lab Results
Lyme disease with DICProvide antibiotics with supportive measures
Case Study 4 ndash Diagnosis
55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis
Case Study 5 ndash Presentation
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
Case Study 5 ndash Lab Results and Time Course
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
TEST RESULT REFERENCE RANGE
Platelet count 33 x 109L 150-450 x 109L
PT 215 sec 103 ndash 128 sec
APTT 44 sec 26 ndash 36 sec
D-dimer 20 microgmL FEU lt025 microgml FEU
Fibrinogen 34 mgdL 200-375 mgdl
FII FV FVIII Low Not reported (NR)
FVII FIX FX vWF Normal NR
Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)
DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic
dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR
(C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen
(D) Illustration demonstrating repair
Case Study 5 ndash Diagnosis and Treatment
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography
Case Study 6 ndash Presentation
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
Case Study 6 ndash Lab Results
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L
PT 63 sec gt control 113 ndash 146 sec
INR 658 1 ndash 125
APTT 80 sec gt control 25 ndash 34 sec
D-dimer gt200 microgmL DDU 02 microgmL DDU
Urine exam Proteinuria and hematuria 150-400 mgdl
Albumin 28 gdL NR
Hb 58 gdL NR
LDH 1196 UL NR
SGPT 144 IU NR
SGOT 88 IU NR
Bilirubin 32 mgdL NR
DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th
day postop
Case Study 6 ndash Diagnosis and Treatment
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure
Case Study 6 ndash Discussion
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Case Study 7 ndash Lab Results vs Time
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
DIC Take Home Messages
Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation
Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers
DIC
Thank you Questions
- Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
- Learning Objectives
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Wound Sealing
- The Three Steps of Hemostasis
- Vessel Wall
- Slide Number 12
- Slide Number 13
- Platelet Structure UnactivatedActivated
- Primary Hemostasis
- Primary Hemostasis Assays
- Slide Number 17
- Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
- Slide Number 19
- Coagulation factors
- Coagulation Assay Mechanisms
- Slide Number 22
- Fibrin Formation
- Slide Number 24
- Fibrinolysis Overview
- Fibrinolysis Overview
- Slide Number 27
- Fibrinolysis Releases D-dimers
- Basic Pathophysiology of DIC
- Disseminated Intravascular Coagulation (DIC)
- Purpura Fulminans with DIC Due to Meningococcal Sepsis
- Clinical Conditions Associated With DIC
- Frequency of DIC in Selected Disease States
- Underlying Diseases in DIC Patients
- Slide Number 36
- Slide Number 37
- Slide Number 38
- Slide Number 39
- Pathophysiology of DIC
- Pathogenesis of DIC in Sepsis
- Host Response in Severe Sepsis
- Organ Failure in Severe Sepsis
- Mechanism of DIC in Organ Failure
- Interaction of Inflammation and Coagulation in Sepsis
- Slide Number 47
- Diverse and Opposing Effects of Thrombin
- Coagulation and Fibrinolysis in DIC
- Mechanism of DIC
- Pathophysiology of DIC
- Pathophysiology of DIC - Mechanism
- Pathophysiology of DIC ndash 2 Types of Clinical pictures
- Sub-Acute and Non-Overt DIC Clinical Findings
- Pathophysiology of Overt DIC
- Physiopathology of DIC ndash Overt DIC Findings
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- BREAK
- Diagnostic and Management Approach for DIC
- Diagnosis of DIC
- Lab Diagnosis of DIC ndash Markers of Factor Consumption
- Lab Diagnosis of DIC ndash Screening Tests
- Slide Number 67
- Slide Number 68
- British Journal of Haematology Overt DIC Score
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- DIC Management Goals
- DIC Management and Treatment
- DIC Management Strategies
- Anticoagulant Factor Concentrate Treatment
- Anticoagulant Factor Concentrate Treatment Trials
- Markers of Thrombin amp Plasmin Generation in DIC
- D-dimer FDPs and DIC
- D-Dimer and FDPs in DIC
- Follow Up of DIC State of Disease
- FMD-Dimer in DIC Major Differences
- of Abnormal Results in Patients with Confirmed and Suspected DIC
- Slide Number 85
- Slide Number 86
- Comparing an Automated FM vs Manual FSP Test
- Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Slide Number 94
- Slide Number 95
- Slide Number 96
- Slide Number 97
- Slide Number 98
- Slide Number 99
- DIC Case Studies
- Case Study 1 - Presentation
- Case Study 1 ndash Lab Results
- Case Study 1 ndash Microscopy
- Case Study 1 ndash Diagnosis and Therapy
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Slide Number 110
- Slide Number 111
- Slide Number 112
- Slide Number 113
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
- Slide Number 124
- Slide Number 125
- DIC Take Home Messages
- Slide Number 127
- Slide Number 128
-
Primary Hemostasis AssaysRoutine Platelet count PT APTT TT
Follow-up von Willebrand Factor Antigen determination Activity Factor VIII PFA-100 Platelet aggregation studies
SpecializedSend Out Activation markers (b-TG PF4 GPV) Specialized tests for platelet function
Aim is to strengthen the platelet plug
Coagulation
Coagulation is a balancebetween pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
THROMBIN
Fibrinogen Fibrin
bull Triggering agentsbull pro-enzyme enzyme (serine-protease FIIa FVIIa FIXa FXa)bull Cofactors (FVa amp FVIIIa)
bull Serine-protease inhibitor Antithrombin (AT) bull Cofactorsinhibitors Protein C Sbull Tissue factor pathway inhibitor (TFPI)
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Coagulation Cascade Schematic
Coagulation factors
Historic name
Fibrinogen
Prothrombin
Proaccelerin
Proconvertin
Anti-hemophilic factor A
Anti-hemophilic factor B
Stuart factor
Rosenthal factor
Hageman factor
Fibrin Stabilizing Factor
Factor
I
II
V
VII
VIII
IX
X
XI
XII
XIII
Function
Substrate
Pro-enzyme
Pro-cofactor
Pro-enzyme
Pro-cofactor
Pro-enzyme
Pro-enzyme
Pro-enzyme
Pro-enzyme
Pro-enzyme
Pro-enzyme = Zymogen activation Active Enzyme
Coagulation Assay Mechanisms
aPTT Based
PT Based
PT Based
Fibrin Under Microscope
Weisel JW Structure of fibrin impact on clot stability J Thromb Haemost 2007 5 Suppl 1 116-24
Low thrombin concentration
High thrombin concentration
Fibrin Formation
Soluble FibrinPolymer
ThrombinFibrinogen
FM+ fibrinopeptides A amp B
Stabilized Fibrin clot(not soluble)
ThrombinXIII XIIIa
(Digestion of Fibrin)
Fibrinolysis
Fibrinolysis Overview
Destroys fibrin fibers
Destroys the scab (dried wound)
Maintains vessel integrity
Fibrinolysis Overview
Fibrin =cement fibers
Plasmin
Plasmin digests fibrin
t-PA
Pro Urokinase
Urokinase
PAI-1PAI-1
Plasminogen Plasmin
1st Step
2nd Step
Fibrinolysis Cascade
t-PA tissue-type plasminogen activator PAI-1 Plasminogen activator inhibitor 1 PK Prekallikrein FDP Fibrinogen degradation products AP Antiplasmin = a2AP alpha 2 Antiplasmin a2MG alpha 2 Macroglobulin
Extrinsic pathway(endothelia l cells)
Intrinsic pathway(plasma)
Fibrin clot
D-dimerFibrin degradation products
Fibrin
TAFIa
APAntiplasmin(amp a2-MG)
PK Kallikrein
XII
Fibrinolysis Releases D-dimers
D-dimer presence fibrin has been formed and digested in patients body
Normal D-dimer level no thrombosis occurred in the patient
Basic Pathophysiology of DIC
Disseminated Intravascular Coagulation (DIC)
Massive activation of coagulation leading to clots forming in multiple locations around the bodyRapid consumption of clotting factors leading to bleedingParadoxical condition leading to both clotting and bleedingA confusing disorder from both diagnostic and therapeutic standpoints Many unrelated diseases can trigger DIC Lack of uniformity in clinical manifestation Lack of uniformity in the laboratory diagnosis Lack of uniformity or consensus on management
Clinical Manifestations of DICOrgan Ischemic Hemorrhagic
Skin Pupura Fulminans Petechiae
Gangrene Echymoses
Acral cyanosis Oozing
CNS Deliriumcoma Intracranial
Infarcts Bleeding
Renal OliguriaAzotemia Hematuria
Cortical Necrosis
Cardiovascular Myocardial dysfunction
Pulmonary DyspneaHypoxia Hemorrhagic lung
Infarct
Gastrointestinal Ulcers infarcts Massive hemorrhage
Endocrine Adrenal infarcts
Purpura Fulminans with DIC Due to Meningococcal Sepsis
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Clinical Conditions Associated With DIC
Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33
Frequency of DIC in Selected Disease States
Disease Frequency
Gram-negative sepsis 30-50
Severe trauma and systemic inflammation 50-70
Metastasized tumors 15
Abruptio placentaamniotic fluid embolism 50
Severe preeclampsia 7
Giant hemangioma 25
Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92
Masao Nakagawa Modified from a research report on the incidence of disseminated intravascular coagulation (DIC) and underlying diseases in Japan Ministry of Health Labour and Welfare Research report published in Fiscal Year 1998 57-64 199 httpwwwrecomodulincomendicindexhtml Accessed Apr 21 2017
Underlying Diseases in DIC Patients
In a Japanese survey from 1997 on incidence of DIC and underlying diseases in 652 divisions and departments of university hospitals DIC occurred in 2193 patients with the number of patient with infections (including sepsis) and hematologic tumors (including leukemia) accounted for 28 and 23 respectively
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Epidemiology of DIC
Impact of DIC Status on Mortality - 1
Okamoto K Wada H Hatada T Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Frequency and hemostatic abnormalities in pre-DIC patients Thromb Res 2010 126 74-8
Patients with positivity of DIC tend to have worse mortality outcomes compared to negative patients or those with pre-DIC
Impact of DIC Status on Mortality - 2
Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4
Patients with positivity of either Overt or Non-Overt DIC tend to have worse mortality outcomes compared to negative patients
Impact of Age on Mortality in DIC Patients
Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4
Older patients with DIC (black bars) generally tend to have worse outcomes compared to non-DIC patients (grey bars)
Pathophysiology of DIC
Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33
Pathogenesis of DIC in Sepsis
Allen KS Sawheny E Kinasewitzet GT Anticoagulant modulation of inflammation in severe sepsis World J Crit Care Med 2015 4 105-15
Bacteria in sepsis infections cause release of TF from immune cells leading to coagulation activation and proinflammatory cytokines cause endothelial cell activation impairing the anticoagulation and fibrinolysis process resulting in DIC
Host Response in Severe Sepsis
Exaggerated inflammation as a result of the host response to sepsis is collateral tissue damage and cell death further resulting in release of danger molecules continuing the inflammatory process in a downward spiral
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Organ Failure in Severe Sepsis
Sepsis associated with microvascular thrombosis as a result of TF mediated coagulation activation results in release of neutrophil extracellular traps (NETs) tissue hypoperfusion and mitochondrial damage resulting in a downward spiral leading to organ failure
Angus DC van der Poll T Severe Sepsis and Septic Shock N Engl J Med 2013 369 840-51
Mechanism of DIC in Organ Failure
Underlying condition(sepsis trauma)
Cytokines
TF-mediatedactivation of coagulation
Depression of inhibitory systems
Reducesfibrinolysis
Fibrin deposition
Organ failure
Inadequate fibrin removal
Fibrinformation
Note impaired fibrinolysis in relation to the clinical need not in absolute value (FDPs are )
Levi M de Jonge E van der Poll T ten Cate H Disseminated intravascular coagulation ThrombHaemost 1999 82 695-705
Interaction of Inflammation and Coagulation in Sepsis
Binding of TF thrombin and other activation coagulation factors to PARs and fibrin to TLRs on inflammatory cells results in inflammation through release of proinflammatory cytokines and chemokines
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Mechanism of Multiple Organ Failure in DIC
Wheeler AP Bernard GR Treating Patients with Severe Sepsis N Engl J Med 1999 340207-14
Inflammatory activation and microvascular thrombosis contributes to multiple organ failure in DIC
lipopolysaccharides
cytokines
coagulation activation
mononuclear cell
tissue factor
Diverse and Opposing Effects of Thrombin
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Coagulation and Fibrinolysis in DIC
Soluble fibrin Polymer
XIIIa
D-Dimer
E
Fibrin clot
Fibrin Degradation Products
Fibrinogen Thrombin
Fibrinogen Degradation
Products
D E
Plasmin
DFM + fibrinopeptides
Soluble FM ComplexesPre-throm
boticPost-throm
botic
Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis Semin Thromb Hemost 2008 34 33-8
Mechanism of DIC
THROMBOSIS
Fibrin
Blood activationEndothelial lysisTF expression
BLEEDING
FDPs
D-Dimer
Plasmin
Pathophysiology of DIC
1st step abnormal activation of coagulation Injury of vessel wall cells venous stasis release of large quantities of
thromboplastin influx of activated cells (monocytes macrophages)
Results in an intravascular deposition of fibrin
Morbidity from disseminated microthrombosis in small and midsize vessels leading to multiple organ failure
Second step Consumption and depletion of coagulation factors inhibitors (Protein C
Protein S AT) and platelets Local fibrinolytic response
bull Local plasmin generation dissolves the thrombusbull Disseminated overwhelming fibrinolytic response leading to production of
FDP and D-Dimer
Bleeding
Pathophysiology of DIC - Mechanism
Systemic activation of coagulation
Intravasculardepositionof fibrin
Thrombosis of small and midsize vessels
and organ failure
Depletion of platelets and
coagulation factors
Bleeding
Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92
Pathophysiology of DIC ndash 2 Types of Clinical pictures
Chronic = non - overt DICMay be unrecognized clinically
Acute = overt DIClife threatening bleedingor multiple organ failure
Sub-Acute and Non-Overt DIC Clinical Findings
Compensated non-overt DIC Steady low level or intermittent activation
bull Compensated by increased production of coagulation components and platelets
Few or no clinical signs or multiple microvascular thrombosis sometimes not clinically obvious
Risk of decompensation leading to overt DIC
Pathophysiology of Overt DIC
Massive activation of coagulation and fibrinolysis
Does not allow for compensatory efforts
Rapid depletion of coagulation factors inhibitors and platelets
Thrombosis multiple organ failures
Bleeding complications and shock
Physiopathology of DIC ndash Overt DIC Findings
Thrombin generation
Thrombosis
Renal liver respiratory failures coma skin necrosis gangrene venous thromboembolism hypotension edema
Cytokine and kinin generation (shock)bull Tachycardia hypotension edema
Plasmin generationHemorrhage
bull Spontaneous bruising petechiae intracranial gastrointestinal and respiratory tract bleeding persistent bleeding at venipuncture sites at surgical wounds
bull Tachycardia hypotension edema
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Pathogenesis Pathways in DIC
Cytokines
TF-mediated dysfunctional impairedthrombin anticoagulant fibrinolysisgeneration mechanism due to PAI-1 deficiency
fibrin inadequateformation fibrin removal
Fibrin deposition
Inflammation
Coagulation
Stago Celebrates Lab Week 2017
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Stago 247 Educational Webinar Sites
wwwstago-edvantagecomUS based KOLsPACE accredited ndash all 1 hourAccessible from mobile devicesVirtual exhibit hall
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HaemoscoreClinical scoring algorithmsApple and AndroidTablet or phone
iHemostasisCoagulation diagramsCase studiesApple amp AndroidTablet only
BREAK
Diagnostic and Management Approach for DIC
Diagnosis of DIC
Clinical diagnosis is obvious in cases of overt DIC
Laboratory tests are necessary To makeconfirm the diagnosis To assess stage of the patient To assess the treatment efficacy
Lab Diagnosis of DIC ndash Markers of Factor Consumption
Routinescreening assays PT APTT Platelets Fibrinogen Thrombin time
Other coagulation assays Factor assays AntithrombinGeneration of Thrombin FMFSPsGeneration of Plasmin D-dimer FDPs
Important to recognize simultaneous formation of thrombin and plasmin
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122
Lab Diagnosis of DIC ndash Screening Tests
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122
Platelet count usually decreasedPT abnormal in 70 of cases (short half-life of FVII)APTT abnormal in 50 of casesThrombin time usually prolonged in overt DIC normal in non-overt DIC and no relation with syndrome severityFibrinogen low in lt 50 of cases sensitivity 22 specificity 87 overall predictive value 64 Normal fibrinogen level should not exclude DIC diagnosis (acute phase reactant initial high
fibrinogen level) repeat testing assesses progression
Screening tests not clinically specific or sensitive for DIC
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Laboratory Changes in Overt DIC
DIC Diagnostic Practices Over Time
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
British Journal of Haematology Overt DIC Score
Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
ISTH Step by Step DIC Algorithm
Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6
US Based Validation of ISTH DIC Score
When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Differential Diagnosis in DIC
aHUS atypical hemolytic uremic syndrome
HUS hemolytic uremic syndrome
HIT heparin-induced thrombocytopenia
ITP immune thrombocytopenic purpura
TTP thrombotic thrombocytopenic purpura
DIC and MAHA
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)
When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation
DIC Management Goals
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction
DIC Management and Treatment
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)
requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)
Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia
DIC Management Strategies
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant Factor Concentrate Treatment
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis
Anticoagulant Factor Concentrate Treatment Trials
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise
Markers of Thrombin amp Plasmin Generation in DIC
D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC
Cut-off value
Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen
degradation products Sensitive assay typically with cutoff adapted for DIC
D-dimer FDPs and DIC
D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC
Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80
Follow Up of DIC State of Disease
Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8
Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility
FMD-Dimer in DIC Major Differences
onset of thrombosis
days
Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8
FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)
D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)
of Abnormal Results in Patients with Confirmed and Suspected DIC
0
20
40
60
80
100
94 85 90N = 62
Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32
Positivity of Test Results ISTH Score and Disease State
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
Red bar positive for 2 points of DIC score
Pink bar positive for 1-2 points of DIC score
HT hematopoietic tumor
IF infection
SC solid cancer
Markers in Patients with or without DIC
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
HT hematopoietic tumorIF infectionSC solid cancer
Comparing an Automated FM vs Manual FSP Test
Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71
Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)
Automated (Mitsubishi) vs Automated (Stago)
In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago
Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC
Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
Non Overt DIC Overt DIC
AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC
Trends in Markers of DIC for Different Patients
Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00
Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients
Trends in Markers of DIC for Different Patients
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes
28 day outcome survival
28 day outcome death
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines
DIC Case Studies
Case Study 1 - Presentation
18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE
WBC count 77 KμL 423 ndash 907 x KμL
RBC count 17 MμL 137 ndash 175 x MμL
Hemoglobin 67 gdL 137 ndash 175 gdL
Hematocrit 195 401 ndash 510
MCV 95 fL 790 ndash 922 fL
MPV 12 fL 94 ndash 124 fL
Platelet count 9 KμL 161 ndash 347 KμL
Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0
Lymphocytes monocytes eosinophils basophils all below normal range
PT 47 sec (corrected on mixing study) 116 ndash 152 sec
APTT 75 sec (corrected on mixing study) 253 ndash 373 sec
Fibrinogen lt 76 mgdL 177 ndash 466 mgdL
D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Microscopy
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Arrow shows giant platelets in this peripheral smear Promyelocytes apparent
Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)
DIC due to TF release by APL blasts
Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases
Transfusions to replace factors along with platelets and RBCs during APL treatment
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started
Case Study 2 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L
PT 30 sec 113 ndash 146 sec
APTT 75 sec 25 ndash 34 sec
D-dimer 078 microgml FEU lt050 microgml FEU
Fibrinogen 92 mgdl 150-400 mgdl
pH 728 738 to 742
PaO2 570 mmHg 80-100 mmHg
WBC 33 times 103mm3 40-11 times 103mm3
ALT 111 IUL 0ndash34 IUL
AST 61 IUL 0ndash34 IUL
BUN 303 mgdL 08-13 mgdL
Case Study 2 ndash Lab Results
Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures
Case Study 2 ndash Diagnosis
60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior
Case Study 3 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L
PT 228 sec 113 ndash 146 sec
APTT 45 sec 25 ndash 34 sec
D-dimer 080 microgml FEU lt050 microgmL FEU
Fibrinogen 82 mgdL 150-400 mgdL
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 134 gdL 14-16 gdL
WBC 81 times 103mm3 40-11 times 103mm3
ALT 32 IUL 0ndash34 IUL
AST 28 IUL 0ndash34 IUL
BUN 09 mgdL 08-13 mgdL
Case Study 3 ndash Lab Results
Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment
Case Study 3 ndash Diagnosis and Therapy
Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91
Case Study 4 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L
PT 28 sec 113 ndash 146 sec
APTT 71 sec 25 ndash 34 sec
D-dimer 31 microgmL FEU lt050 microgml FEU
Fibrinogen 92 mgdL 150-400 mgdl
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 158 gdL 14-16 gdL
WBC 71 times 103mm3 40-11 times 103mm3
ALT 60 IUL 0ndash34 IUL
AST 47 IUL 0ndash34 IUL
BUN 38 mgdL 08-13 mgdL
Case Study 4 ndash Lab Results
Lyme disease with DICProvide antibiotics with supportive measures
Case Study 4 ndash Diagnosis
55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis
Case Study 5 ndash Presentation
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
Case Study 5 ndash Lab Results and Time Course
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
TEST RESULT REFERENCE RANGE
Platelet count 33 x 109L 150-450 x 109L
PT 215 sec 103 ndash 128 sec
APTT 44 sec 26 ndash 36 sec
D-dimer 20 microgmL FEU lt025 microgml FEU
Fibrinogen 34 mgdL 200-375 mgdl
FII FV FVIII Low Not reported (NR)
FVII FIX FX vWF Normal NR
Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)
DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic
dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR
(C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen
(D) Illustration demonstrating repair
Case Study 5 ndash Diagnosis and Treatment
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography
Case Study 6 ndash Presentation
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
Case Study 6 ndash Lab Results
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L
PT 63 sec gt control 113 ndash 146 sec
INR 658 1 ndash 125
APTT 80 sec gt control 25 ndash 34 sec
D-dimer gt200 microgmL DDU 02 microgmL DDU
Urine exam Proteinuria and hematuria 150-400 mgdl
Albumin 28 gdL NR
Hb 58 gdL NR
LDH 1196 UL NR
SGPT 144 IU NR
SGOT 88 IU NR
Bilirubin 32 mgdL NR
DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th
day postop
Case Study 6 ndash Diagnosis and Treatment
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure
Case Study 6 ndash Discussion
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Case Study 7 ndash Lab Results vs Time
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
DIC Take Home Messages
Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation
Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers
DIC
Thank you Questions
- Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
- Learning Objectives
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Wound Sealing
- The Three Steps of Hemostasis
- Vessel Wall
- Slide Number 12
- Slide Number 13
- Platelet Structure UnactivatedActivated
- Primary Hemostasis
- Primary Hemostasis Assays
- Slide Number 17
- Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
- Slide Number 19
- Coagulation factors
- Coagulation Assay Mechanisms
- Slide Number 22
- Fibrin Formation
- Slide Number 24
- Fibrinolysis Overview
- Fibrinolysis Overview
- Slide Number 27
- Fibrinolysis Releases D-dimers
- Basic Pathophysiology of DIC
- Disseminated Intravascular Coagulation (DIC)
- Purpura Fulminans with DIC Due to Meningococcal Sepsis
- Clinical Conditions Associated With DIC
- Frequency of DIC in Selected Disease States
- Underlying Diseases in DIC Patients
- Slide Number 36
- Slide Number 37
- Slide Number 38
- Slide Number 39
- Pathophysiology of DIC
- Pathogenesis of DIC in Sepsis
- Host Response in Severe Sepsis
- Organ Failure in Severe Sepsis
- Mechanism of DIC in Organ Failure
- Interaction of Inflammation and Coagulation in Sepsis
- Slide Number 47
- Diverse and Opposing Effects of Thrombin
- Coagulation and Fibrinolysis in DIC
- Mechanism of DIC
- Pathophysiology of DIC
- Pathophysiology of DIC - Mechanism
- Pathophysiology of DIC ndash 2 Types of Clinical pictures
- Sub-Acute and Non-Overt DIC Clinical Findings
- Pathophysiology of Overt DIC
- Physiopathology of DIC ndash Overt DIC Findings
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- BREAK
- Diagnostic and Management Approach for DIC
- Diagnosis of DIC
- Lab Diagnosis of DIC ndash Markers of Factor Consumption
- Lab Diagnosis of DIC ndash Screening Tests
- Slide Number 67
- Slide Number 68
- British Journal of Haematology Overt DIC Score
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- DIC Management Goals
- DIC Management and Treatment
- DIC Management Strategies
- Anticoagulant Factor Concentrate Treatment
- Anticoagulant Factor Concentrate Treatment Trials
- Markers of Thrombin amp Plasmin Generation in DIC
- D-dimer FDPs and DIC
- D-Dimer and FDPs in DIC
- Follow Up of DIC State of Disease
- FMD-Dimer in DIC Major Differences
- of Abnormal Results in Patients with Confirmed and Suspected DIC
- Slide Number 85
- Slide Number 86
- Comparing an Automated FM vs Manual FSP Test
- Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Slide Number 94
- Slide Number 95
- Slide Number 96
- Slide Number 97
- Slide Number 98
- Slide Number 99
- DIC Case Studies
- Case Study 1 - Presentation
- Case Study 1 ndash Lab Results
- Case Study 1 ndash Microscopy
- Case Study 1 ndash Diagnosis and Therapy
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Slide Number 110
- Slide Number 111
- Slide Number 112
- Slide Number 113
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
- Slide Number 124
- Slide Number 125
- DIC Take Home Messages
- Slide Number 127
- Slide Number 128
-
Aim is to strengthen the platelet plug
Coagulation
Coagulation is a balancebetween pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
THROMBIN
Fibrinogen Fibrin
bull Triggering agentsbull pro-enzyme enzyme (serine-protease FIIa FVIIa FIXa FXa)bull Cofactors (FVa amp FVIIIa)
bull Serine-protease inhibitor Antithrombin (AT) bull Cofactorsinhibitors Protein C Sbull Tissue factor pathway inhibitor (TFPI)
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Coagulation Cascade Schematic
Coagulation factors
Historic name
Fibrinogen
Prothrombin
Proaccelerin
Proconvertin
Anti-hemophilic factor A
Anti-hemophilic factor B
Stuart factor
Rosenthal factor
Hageman factor
Fibrin Stabilizing Factor
Factor
I
II
V
VII
VIII
IX
X
XI
XII
XIII
Function
Substrate
Pro-enzyme
Pro-cofactor
Pro-enzyme
Pro-cofactor
Pro-enzyme
Pro-enzyme
Pro-enzyme
Pro-enzyme
Pro-enzyme
Pro-enzyme = Zymogen activation Active Enzyme
Coagulation Assay Mechanisms
aPTT Based
PT Based
PT Based
Fibrin Under Microscope
Weisel JW Structure of fibrin impact on clot stability J Thromb Haemost 2007 5 Suppl 1 116-24
Low thrombin concentration
High thrombin concentration
Fibrin Formation
Soluble FibrinPolymer
ThrombinFibrinogen
FM+ fibrinopeptides A amp B
Stabilized Fibrin clot(not soluble)
ThrombinXIII XIIIa
(Digestion of Fibrin)
Fibrinolysis
Fibrinolysis Overview
Destroys fibrin fibers
Destroys the scab (dried wound)
Maintains vessel integrity
Fibrinolysis Overview
Fibrin =cement fibers
Plasmin
Plasmin digests fibrin
t-PA
Pro Urokinase
Urokinase
PAI-1PAI-1
Plasminogen Plasmin
1st Step
2nd Step
Fibrinolysis Cascade
t-PA tissue-type plasminogen activator PAI-1 Plasminogen activator inhibitor 1 PK Prekallikrein FDP Fibrinogen degradation products AP Antiplasmin = a2AP alpha 2 Antiplasmin a2MG alpha 2 Macroglobulin
Extrinsic pathway(endothelia l cells)
Intrinsic pathway(plasma)
Fibrin clot
D-dimerFibrin degradation products
Fibrin
TAFIa
APAntiplasmin(amp a2-MG)
PK Kallikrein
XII
Fibrinolysis Releases D-dimers
D-dimer presence fibrin has been formed and digested in patients body
Normal D-dimer level no thrombosis occurred in the patient
Basic Pathophysiology of DIC
Disseminated Intravascular Coagulation (DIC)
Massive activation of coagulation leading to clots forming in multiple locations around the bodyRapid consumption of clotting factors leading to bleedingParadoxical condition leading to both clotting and bleedingA confusing disorder from both diagnostic and therapeutic standpoints Many unrelated diseases can trigger DIC Lack of uniformity in clinical manifestation Lack of uniformity in the laboratory diagnosis Lack of uniformity or consensus on management
Clinical Manifestations of DICOrgan Ischemic Hemorrhagic
Skin Pupura Fulminans Petechiae
Gangrene Echymoses
Acral cyanosis Oozing
CNS Deliriumcoma Intracranial
Infarcts Bleeding
Renal OliguriaAzotemia Hematuria
Cortical Necrosis
Cardiovascular Myocardial dysfunction
Pulmonary DyspneaHypoxia Hemorrhagic lung
Infarct
Gastrointestinal Ulcers infarcts Massive hemorrhage
Endocrine Adrenal infarcts
Purpura Fulminans with DIC Due to Meningococcal Sepsis
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Clinical Conditions Associated With DIC
Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33
Frequency of DIC in Selected Disease States
Disease Frequency
Gram-negative sepsis 30-50
Severe trauma and systemic inflammation 50-70
Metastasized tumors 15
Abruptio placentaamniotic fluid embolism 50
Severe preeclampsia 7
Giant hemangioma 25
Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92
Masao Nakagawa Modified from a research report on the incidence of disseminated intravascular coagulation (DIC) and underlying diseases in Japan Ministry of Health Labour and Welfare Research report published in Fiscal Year 1998 57-64 199 httpwwwrecomodulincomendicindexhtml Accessed Apr 21 2017
Underlying Diseases in DIC Patients
In a Japanese survey from 1997 on incidence of DIC and underlying diseases in 652 divisions and departments of university hospitals DIC occurred in 2193 patients with the number of patient with infections (including sepsis) and hematologic tumors (including leukemia) accounted for 28 and 23 respectively
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Epidemiology of DIC
Impact of DIC Status on Mortality - 1
Okamoto K Wada H Hatada T Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Frequency and hemostatic abnormalities in pre-DIC patients Thromb Res 2010 126 74-8
Patients with positivity of DIC tend to have worse mortality outcomes compared to negative patients or those with pre-DIC
Impact of DIC Status on Mortality - 2
Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4
Patients with positivity of either Overt or Non-Overt DIC tend to have worse mortality outcomes compared to negative patients
Impact of Age on Mortality in DIC Patients
Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4
Older patients with DIC (black bars) generally tend to have worse outcomes compared to non-DIC patients (grey bars)
Pathophysiology of DIC
Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33
Pathogenesis of DIC in Sepsis
Allen KS Sawheny E Kinasewitzet GT Anticoagulant modulation of inflammation in severe sepsis World J Crit Care Med 2015 4 105-15
Bacteria in sepsis infections cause release of TF from immune cells leading to coagulation activation and proinflammatory cytokines cause endothelial cell activation impairing the anticoagulation and fibrinolysis process resulting in DIC
Host Response in Severe Sepsis
Exaggerated inflammation as a result of the host response to sepsis is collateral tissue damage and cell death further resulting in release of danger molecules continuing the inflammatory process in a downward spiral
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Organ Failure in Severe Sepsis
Sepsis associated with microvascular thrombosis as a result of TF mediated coagulation activation results in release of neutrophil extracellular traps (NETs) tissue hypoperfusion and mitochondrial damage resulting in a downward spiral leading to organ failure
Angus DC van der Poll T Severe Sepsis and Septic Shock N Engl J Med 2013 369 840-51
Mechanism of DIC in Organ Failure
Underlying condition(sepsis trauma)
Cytokines
TF-mediatedactivation of coagulation
Depression of inhibitory systems
Reducesfibrinolysis
Fibrin deposition
Organ failure
Inadequate fibrin removal
Fibrinformation
Note impaired fibrinolysis in relation to the clinical need not in absolute value (FDPs are )
Levi M de Jonge E van der Poll T ten Cate H Disseminated intravascular coagulation ThrombHaemost 1999 82 695-705
Interaction of Inflammation and Coagulation in Sepsis
Binding of TF thrombin and other activation coagulation factors to PARs and fibrin to TLRs on inflammatory cells results in inflammation through release of proinflammatory cytokines and chemokines
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Mechanism of Multiple Organ Failure in DIC
Wheeler AP Bernard GR Treating Patients with Severe Sepsis N Engl J Med 1999 340207-14
Inflammatory activation and microvascular thrombosis contributes to multiple organ failure in DIC
lipopolysaccharides
cytokines
coagulation activation
mononuclear cell
tissue factor
Diverse and Opposing Effects of Thrombin
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Coagulation and Fibrinolysis in DIC
Soluble fibrin Polymer
XIIIa
D-Dimer
E
Fibrin clot
Fibrin Degradation Products
Fibrinogen Thrombin
Fibrinogen Degradation
Products
D E
Plasmin
DFM + fibrinopeptides
Soluble FM ComplexesPre-throm
boticPost-throm
botic
Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis Semin Thromb Hemost 2008 34 33-8
Mechanism of DIC
THROMBOSIS
Fibrin
Blood activationEndothelial lysisTF expression
BLEEDING
FDPs
D-Dimer
Plasmin
Pathophysiology of DIC
1st step abnormal activation of coagulation Injury of vessel wall cells venous stasis release of large quantities of
thromboplastin influx of activated cells (monocytes macrophages)
Results in an intravascular deposition of fibrin
Morbidity from disseminated microthrombosis in small and midsize vessels leading to multiple organ failure
Second step Consumption and depletion of coagulation factors inhibitors (Protein C
Protein S AT) and platelets Local fibrinolytic response
bull Local plasmin generation dissolves the thrombusbull Disseminated overwhelming fibrinolytic response leading to production of
FDP and D-Dimer
Bleeding
Pathophysiology of DIC - Mechanism
Systemic activation of coagulation
Intravasculardepositionof fibrin
Thrombosis of small and midsize vessels
and organ failure
Depletion of platelets and
coagulation factors
Bleeding
Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92
Pathophysiology of DIC ndash 2 Types of Clinical pictures
Chronic = non - overt DICMay be unrecognized clinically
Acute = overt DIClife threatening bleedingor multiple organ failure
Sub-Acute and Non-Overt DIC Clinical Findings
Compensated non-overt DIC Steady low level or intermittent activation
bull Compensated by increased production of coagulation components and platelets
Few or no clinical signs or multiple microvascular thrombosis sometimes not clinically obvious
Risk of decompensation leading to overt DIC
Pathophysiology of Overt DIC
Massive activation of coagulation and fibrinolysis
Does not allow for compensatory efforts
Rapid depletion of coagulation factors inhibitors and platelets
Thrombosis multiple organ failures
Bleeding complications and shock
Physiopathology of DIC ndash Overt DIC Findings
Thrombin generation
Thrombosis
Renal liver respiratory failures coma skin necrosis gangrene venous thromboembolism hypotension edema
Cytokine and kinin generation (shock)bull Tachycardia hypotension edema
Plasmin generationHemorrhage
bull Spontaneous bruising petechiae intracranial gastrointestinal and respiratory tract bleeding persistent bleeding at venipuncture sites at surgical wounds
bull Tachycardia hypotension edema
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Pathogenesis Pathways in DIC
Cytokines
TF-mediated dysfunctional impairedthrombin anticoagulant fibrinolysisgeneration mechanism due to PAI-1 deficiency
fibrin inadequateformation fibrin removal
Fibrin deposition
Inflammation
Coagulation
Stago Celebrates Lab Week 2017
NA
Stago 247 Educational Webinar Sites
wwwstago-edvantagecomUS based KOLsPACE accredited ndash all 1 hourAccessible from mobile devicesVirtual exhibit hall
wwwstagowebinarscomMostly European KOLs30 ndash 45 min including 15 min discussion
Stago Educational Apps
HaemoscoreClinical scoring algorithmsApple and AndroidTablet or phone
iHemostasisCoagulation diagramsCase studiesApple amp AndroidTablet only
BREAK
Diagnostic and Management Approach for DIC
Diagnosis of DIC
Clinical diagnosis is obvious in cases of overt DIC
Laboratory tests are necessary To makeconfirm the diagnosis To assess stage of the patient To assess the treatment efficacy
Lab Diagnosis of DIC ndash Markers of Factor Consumption
Routinescreening assays PT APTT Platelets Fibrinogen Thrombin time
Other coagulation assays Factor assays AntithrombinGeneration of Thrombin FMFSPsGeneration of Plasmin D-dimer FDPs
Important to recognize simultaneous formation of thrombin and plasmin
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122
Lab Diagnosis of DIC ndash Screening Tests
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122
Platelet count usually decreasedPT abnormal in 70 of cases (short half-life of FVII)APTT abnormal in 50 of casesThrombin time usually prolonged in overt DIC normal in non-overt DIC and no relation with syndrome severityFibrinogen low in lt 50 of cases sensitivity 22 specificity 87 overall predictive value 64 Normal fibrinogen level should not exclude DIC diagnosis (acute phase reactant initial high
fibrinogen level) repeat testing assesses progression
Screening tests not clinically specific or sensitive for DIC
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Laboratory Changes in Overt DIC
DIC Diagnostic Practices Over Time
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
British Journal of Haematology Overt DIC Score
Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
ISTH Step by Step DIC Algorithm
Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6
US Based Validation of ISTH DIC Score
When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Differential Diagnosis in DIC
aHUS atypical hemolytic uremic syndrome
HUS hemolytic uremic syndrome
HIT heparin-induced thrombocytopenia
ITP immune thrombocytopenic purpura
TTP thrombotic thrombocytopenic purpura
DIC and MAHA
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)
When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation
DIC Management Goals
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction
DIC Management and Treatment
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)
requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)
Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia
DIC Management Strategies
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant Factor Concentrate Treatment
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis
Anticoagulant Factor Concentrate Treatment Trials
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise
Markers of Thrombin amp Plasmin Generation in DIC
D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC
Cut-off value
Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen
degradation products Sensitive assay typically with cutoff adapted for DIC
D-dimer FDPs and DIC
D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC
Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80
Follow Up of DIC State of Disease
Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8
Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility
FMD-Dimer in DIC Major Differences
onset of thrombosis
days
Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8
FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)
D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)
of Abnormal Results in Patients with Confirmed and Suspected DIC
0
20
40
60
80
100
94 85 90N = 62
Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32
Positivity of Test Results ISTH Score and Disease State
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
Red bar positive for 2 points of DIC score
Pink bar positive for 1-2 points of DIC score
HT hematopoietic tumor
IF infection
SC solid cancer
Markers in Patients with or without DIC
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
HT hematopoietic tumorIF infectionSC solid cancer
Comparing an Automated FM vs Manual FSP Test
Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71
Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)
Automated (Mitsubishi) vs Automated (Stago)
In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago
Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC
Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
Non Overt DIC Overt DIC
AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC
Trends in Markers of DIC for Different Patients
Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00
Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients
Trends in Markers of DIC for Different Patients
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes
28 day outcome survival
28 day outcome death
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines
DIC Case Studies
Case Study 1 - Presentation
18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE
WBC count 77 KμL 423 ndash 907 x KμL
RBC count 17 MμL 137 ndash 175 x MμL
Hemoglobin 67 gdL 137 ndash 175 gdL
Hematocrit 195 401 ndash 510
MCV 95 fL 790 ndash 922 fL
MPV 12 fL 94 ndash 124 fL
Platelet count 9 KμL 161 ndash 347 KμL
Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0
Lymphocytes monocytes eosinophils basophils all below normal range
PT 47 sec (corrected on mixing study) 116 ndash 152 sec
APTT 75 sec (corrected on mixing study) 253 ndash 373 sec
Fibrinogen lt 76 mgdL 177 ndash 466 mgdL
D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Microscopy
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Arrow shows giant platelets in this peripheral smear Promyelocytes apparent
Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)
DIC due to TF release by APL blasts
Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases
Transfusions to replace factors along with platelets and RBCs during APL treatment
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started
Case Study 2 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L
PT 30 sec 113 ndash 146 sec
APTT 75 sec 25 ndash 34 sec
D-dimer 078 microgml FEU lt050 microgml FEU
Fibrinogen 92 mgdl 150-400 mgdl
pH 728 738 to 742
PaO2 570 mmHg 80-100 mmHg
WBC 33 times 103mm3 40-11 times 103mm3
ALT 111 IUL 0ndash34 IUL
AST 61 IUL 0ndash34 IUL
BUN 303 mgdL 08-13 mgdL
Case Study 2 ndash Lab Results
Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures
Case Study 2 ndash Diagnosis
60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior
Case Study 3 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L
PT 228 sec 113 ndash 146 sec
APTT 45 sec 25 ndash 34 sec
D-dimer 080 microgml FEU lt050 microgmL FEU
Fibrinogen 82 mgdL 150-400 mgdL
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 134 gdL 14-16 gdL
WBC 81 times 103mm3 40-11 times 103mm3
ALT 32 IUL 0ndash34 IUL
AST 28 IUL 0ndash34 IUL
BUN 09 mgdL 08-13 mgdL
Case Study 3 ndash Lab Results
Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment
Case Study 3 ndash Diagnosis and Therapy
Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91
Case Study 4 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L
PT 28 sec 113 ndash 146 sec
APTT 71 sec 25 ndash 34 sec
D-dimer 31 microgmL FEU lt050 microgml FEU
Fibrinogen 92 mgdL 150-400 mgdl
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 158 gdL 14-16 gdL
WBC 71 times 103mm3 40-11 times 103mm3
ALT 60 IUL 0ndash34 IUL
AST 47 IUL 0ndash34 IUL
BUN 38 mgdL 08-13 mgdL
Case Study 4 ndash Lab Results
Lyme disease with DICProvide antibiotics with supportive measures
Case Study 4 ndash Diagnosis
55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis
Case Study 5 ndash Presentation
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
Case Study 5 ndash Lab Results and Time Course
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
TEST RESULT REFERENCE RANGE
Platelet count 33 x 109L 150-450 x 109L
PT 215 sec 103 ndash 128 sec
APTT 44 sec 26 ndash 36 sec
D-dimer 20 microgmL FEU lt025 microgml FEU
Fibrinogen 34 mgdL 200-375 mgdl
FII FV FVIII Low Not reported (NR)
FVII FIX FX vWF Normal NR
Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)
DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic
dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR
(C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen
(D) Illustration demonstrating repair
Case Study 5 ndash Diagnosis and Treatment
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography
Case Study 6 ndash Presentation
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
Case Study 6 ndash Lab Results
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L
PT 63 sec gt control 113 ndash 146 sec
INR 658 1 ndash 125
APTT 80 sec gt control 25 ndash 34 sec
D-dimer gt200 microgmL DDU 02 microgmL DDU
Urine exam Proteinuria and hematuria 150-400 mgdl
Albumin 28 gdL NR
Hb 58 gdL NR
LDH 1196 UL NR
SGPT 144 IU NR
SGOT 88 IU NR
Bilirubin 32 mgdL NR
DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th
day postop
Case Study 6 ndash Diagnosis and Treatment
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure
Case Study 6 ndash Discussion
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Case Study 7 ndash Lab Results vs Time
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
DIC Take Home Messages
Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation
Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers
DIC
Thank you Questions
- Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
- Learning Objectives
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Wound Sealing
- The Three Steps of Hemostasis
- Vessel Wall
- Slide Number 12
- Slide Number 13
- Platelet Structure UnactivatedActivated
- Primary Hemostasis
- Primary Hemostasis Assays
- Slide Number 17
- Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
- Slide Number 19
- Coagulation factors
- Coagulation Assay Mechanisms
- Slide Number 22
- Fibrin Formation
- Slide Number 24
- Fibrinolysis Overview
- Fibrinolysis Overview
- Slide Number 27
- Fibrinolysis Releases D-dimers
- Basic Pathophysiology of DIC
- Disseminated Intravascular Coagulation (DIC)
- Purpura Fulminans with DIC Due to Meningococcal Sepsis
- Clinical Conditions Associated With DIC
- Frequency of DIC in Selected Disease States
- Underlying Diseases in DIC Patients
- Slide Number 36
- Slide Number 37
- Slide Number 38
- Slide Number 39
- Pathophysiology of DIC
- Pathogenesis of DIC in Sepsis
- Host Response in Severe Sepsis
- Organ Failure in Severe Sepsis
- Mechanism of DIC in Organ Failure
- Interaction of Inflammation and Coagulation in Sepsis
- Slide Number 47
- Diverse and Opposing Effects of Thrombin
- Coagulation and Fibrinolysis in DIC
- Mechanism of DIC
- Pathophysiology of DIC
- Pathophysiology of DIC - Mechanism
- Pathophysiology of DIC ndash 2 Types of Clinical pictures
- Sub-Acute and Non-Overt DIC Clinical Findings
- Pathophysiology of Overt DIC
- Physiopathology of DIC ndash Overt DIC Findings
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- BREAK
- Diagnostic and Management Approach for DIC
- Diagnosis of DIC
- Lab Diagnosis of DIC ndash Markers of Factor Consumption
- Lab Diagnosis of DIC ndash Screening Tests
- Slide Number 67
- Slide Number 68
- British Journal of Haematology Overt DIC Score
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- DIC Management Goals
- DIC Management and Treatment
- DIC Management Strategies
- Anticoagulant Factor Concentrate Treatment
- Anticoagulant Factor Concentrate Treatment Trials
- Markers of Thrombin amp Plasmin Generation in DIC
- D-dimer FDPs and DIC
- D-Dimer and FDPs in DIC
- Follow Up of DIC State of Disease
- FMD-Dimer in DIC Major Differences
- of Abnormal Results in Patients with Confirmed and Suspected DIC
- Slide Number 85
- Slide Number 86
- Comparing an Automated FM vs Manual FSP Test
- Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Slide Number 94
- Slide Number 95
- Slide Number 96
- Slide Number 97
- Slide Number 98
- Slide Number 99
- DIC Case Studies
- Case Study 1 - Presentation
- Case Study 1 ndash Lab Results
- Case Study 1 ndash Microscopy
- Case Study 1 ndash Diagnosis and Therapy
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Slide Number 110
- Slide Number 111
- Slide Number 112
- Slide Number 113
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
- Slide Number 124
- Slide Number 125
- DIC Take Home Messages
- Slide Number 127
- Slide Number 128
-
Coagulation is a balancebetween pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
THROMBIN
Fibrinogen Fibrin
bull Triggering agentsbull pro-enzyme enzyme (serine-protease FIIa FVIIa FIXa FXa)bull Cofactors (FVa amp FVIIIa)
bull Serine-protease inhibitor Antithrombin (AT) bull Cofactorsinhibitors Protein C Sbull Tissue factor pathway inhibitor (TFPI)
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Coagulation Cascade Schematic
Coagulation factors
Historic name
Fibrinogen
Prothrombin
Proaccelerin
Proconvertin
Anti-hemophilic factor A
Anti-hemophilic factor B
Stuart factor
Rosenthal factor
Hageman factor
Fibrin Stabilizing Factor
Factor
I
II
V
VII
VIII
IX
X
XI
XII
XIII
Function
Substrate
Pro-enzyme
Pro-cofactor
Pro-enzyme
Pro-cofactor
Pro-enzyme
Pro-enzyme
Pro-enzyme
Pro-enzyme
Pro-enzyme
Pro-enzyme = Zymogen activation Active Enzyme
Coagulation Assay Mechanisms
aPTT Based
PT Based
PT Based
Fibrin Under Microscope
Weisel JW Structure of fibrin impact on clot stability J Thromb Haemost 2007 5 Suppl 1 116-24
Low thrombin concentration
High thrombin concentration
Fibrin Formation
Soluble FibrinPolymer
ThrombinFibrinogen
FM+ fibrinopeptides A amp B
Stabilized Fibrin clot(not soluble)
ThrombinXIII XIIIa
(Digestion of Fibrin)
Fibrinolysis
Fibrinolysis Overview
Destroys fibrin fibers
Destroys the scab (dried wound)
Maintains vessel integrity
Fibrinolysis Overview
Fibrin =cement fibers
Plasmin
Plasmin digests fibrin
t-PA
Pro Urokinase
Urokinase
PAI-1PAI-1
Plasminogen Plasmin
1st Step
2nd Step
Fibrinolysis Cascade
t-PA tissue-type plasminogen activator PAI-1 Plasminogen activator inhibitor 1 PK Prekallikrein FDP Fibrinogen degradation products AP Antiplasmin = a2AP alpha 2 Antiplasmin a2MG alpha 2 Macroglobulin
Extrinsic pathway(endothelia l cells)
Intrinsic pathway(plasma)
Fibrin clot
D-dimerFibrin degradation products
Fibrin
TAFIa
APAntiplasmin(amp a2-MG)
PK Kallikrein
XII
Fibrinolysis Releases D-dimers
D-dimer presence fibrin has been formed and digested in patients body
Normal D-dimer level no thrombosis occurred in the patient
Basic Pathophysiology of DIC
Disseminated Intravascular Coagulation (DIC)
Massive activation of coagulation leading to clots forming in multiple locations around the bodyRapid consumption of clotting factors leading to bleedingParadoxical condition leading to both clotting and bleedingA confusing disorder from both diagnostic and therapeutic standpoints Many unrelated diseases can trigger DIC Lack of uniformity in clinical manifestation Lack of uniformity in the laboratory diagnosis Lack of uniformity or consensus on management
Clinical Manifestations of DICOrgan Ischemic Hemorrhagic
Skin Pupura Fulminans Petechiae
Gangrene Echymoses
Acral cyanosis Oozing
CNS Deliriumcoma Intracranial
Infarcts Bleeding
Renal OliguriaAzotemia Hematuria
Cortical Necrosis
Cardiovascular Myocardial dysfunction
Pulmonary DyspneaHypoxia Hemorrhagic lung
Infarct
Gastrointestinal Ulcers infarcts Massive hemorrhage
Endocrine Adrenal infarcts
Purpura Fulminans with DIC Due to Meningococcal Sepsis
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Clinical Conditions Associated With DIC
Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33
Frequency of DIC in Selected Disease States
Disease Frequency
Gram-negative sepsis 30-50
Severe trauma and systemic inflammation 50-70
Metastasized tumors 15
Abruptio placentaamniotic fluid embolism 50
Severe preeclampsia 7
Giant hemangioma 25
Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92
Masao Nakagawa Modified from a research report on the incidence of disseminated intravascular coagulation (DIC) and underlying diseases in Japan Ministry of Health Labour and Welfare Research report published in Fiscal Year 1998 57-64 199 httpwwwrecomodulincomendicindexhtml Accessed Apr 21 2017
Underlying Diseases in DIC Patients
In a Japanese survey from 1997 on incidence of DIC and underlying diseases in 652 divisions and departments of university hospitals DIC occurred in 2193 patients with the number of patient with infections (including sepsis) and hematologic tumors (including leukemia) accounted for 28 and 23 respectively
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Epidemiology of DIC
Impact of DIC Status on Mortality - 1
Okamoto K Wada H Hatada T Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Frequency and hemostatic abnormalities in pre-DIC patients Thromb Res 2010 126 74-8
Patients with positivity of DIC tend to have worse mortality outcomes compared to negative patients or those with pre-DIC
Impact of DIC Status on Mortality - 2
Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4
Patients with positivity of either Overt or Non-Overt DIC tend to have worse mortality outcomes compared to negative patients
Impact of Age on Mortality in DIC Patients
Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4
Older patients with DIC (black bars) generally tend to have worse outcomes compared to non-DIC patients (grey bars)
Pathophysiology of DIC
Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33
Pathogenesis of DIC in Sepsis
Allen KS Sawheny E Kinasewitzet GT Anticoagulant modulation of inflammation in severe sepsis World J Crit Care Med 2015 4 105-15
Bacteria in sepsis infections cause release of TF from immune cells leading to coagulation activation and proinflammatory cytokines cause endothelial cell activation impairing the anticoagulation and fibrinolysis process resulting in DIC
Host Response in Severe Sepsis
Exaggerated inflammation as a result of the host response to sepsis is collateral tissue damage and cell death further resulting in release of danger molecules continuing the inflammatory process in a downward spiral
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Organ Failure in Severe Sepsis
Sepsis associated with microvascular thrombosis as a result of TF mediated coagulation activation results in release of neutrophil extracellular traps (NETs) tissue hypoperfusion and mitochondrial damage resulting in a downward spiral leading to organ failure
Angus DC van der Poll T Severe Sepsis and Septic Shock N Engl J Med 2013 369 840-51
Mechanism of DIC in Organ Failure
Underlying condition(sepsis trauma)
Cytokines
TF-mediatedactivation of coagulation
Depression of inhibitory systems
Reducesfibrinolysis
Fibrin deposition
Organ failure
Inadequate fibrin removal
Fibrinformation
Note impaired fibrinolysis in relation to the clinical need not in absolute value (FDPs are )
Levi M de Jonge E van der Poll T ten Cate H Disseminated intravascular coagulation ThrombHaemost 1999 82 695-705
Interaction of Inflammation and Coagulation in Sepsis
Binding of TF thrombin and other activation coagulation factors to PARs and fibrin to TLRs on inflammatory cells results in inflammation through release of proinflammatory cytokines and chemokines
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Mechanism of Multiple Organ Failure in DIC
Wheeler AP Bernard GR Treating Patients with Severe Sepsis N Engl J Med 1999 340207-14
Inflammatory activation and microvascular thrombosis contributes to multiple organ failure in DIC
lipopolysaccharides
cytokines
coagulation activation
mononuclear cell
tissue factor
Diverse and Opposing Effects of Thrombin
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Coagulation and Fibrinolysis in DIC
Soluble fibrin Polymer
XIIIa
D-Dimer
E
Fibrin clot
Fibrin Degradation Products
Fibrinogen Thrombin
Fibrinogen Degradation
Products
D E
Plasmin
DFM + fibrinopeptides
Soluble FM ComplexesPre-throm
boticPost-throm
botic
Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis Semin Thromb Hemost 2008 34 33-8
Mechanism of DIC
THROMBOSIS
Fibrin
Blood activationEndothelial lysisTF expression
BLEEDING
FDPs
D-Dimer
Plasmin
Pathophysiology of DIC
1st step abnormal activation of coagulation Injury of vessel wall cells venous stasis release of large quantities of
thromboplastin influx of activated cells (monocytes macrophages)
Results in an intravascular deposition of fibrin
Morbidity from disseminated microthrombosis in small and midsize vessels leading to multiple organ failure
Second step Consumption and depletion of coagulation factors inhibitors (Protein C
Protein S AT) and platelets Local fibrinolytic response
bull Local plasmin generation dissolves the thrombusbull Disseminated overwhelming fibrinolytic response leading to production of
FDP and D-Dimer
Bleeding
Pathophysiology of DIC - Mechanism
Systemic activation of coagulation
Intravasculardepositionof fibrin
Thrombosis of small and midsize vessels
and organ failure
Depletion of platelets and
coagulation factors
Bleeding
Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92
Pathophysiology of DIC ndash 2 Types of Clinical pictures
Chronic = non - overt DICMay be unrecognized clinically
Acute = overt DIClife threatening bleedingor multiple organ failure
Sub-Acute and Non-Overt DIC Clinical Findings
Compensated non-overt DIC Steady low level or intermittent activation
bull Compensated by increased production of coagulation components and platelets
Few or no clinical signs or multiple microvascular thrombosis sometimes not clinically obvious
Risk of decompensation leading to overt DIC
Pathophysiology of Overt DIC
Massive activation of coagulation and fibrinolysis
Does not allow for compensatory efforts
Rapid depletion of coagulation factors inhibitors and platelets
Thrombosis multiple organ failures
Bleeding complications and shock
Physiopathology of DIC ndash Overt DIC Findings
Thrombin generation
Thrombosis
Renal liver respiratory failures coma skin necrosis gangrene venous thromboembolism hypotension edema
Cytokine and kinin generation (shock)bull Tachycardia hypotension edema
Plasmin generationHemorrhage
bull Spontaneous bruising petechiae intracranial gastrointestinal and respiratory tract bleeding persistent bleeding at venipuncture sites at surgical wounds
bull Tachycardia hypotension edema
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Pathogenesis Pathways in DIC
Cytokines
TF-mediated dysfunctional impairedthrombin anticoagulant fibrinolysisgeneration mechanism due to PAI-1 deficiency
fibrin inadequateformation fibrin removal
Fibrin deposition
Inflammation
Coagulation
Stago Celebrates Lab Week 2017
NA
Stago 247 Educational Webinar Sites
wwwstago-edvantagecomUS based KOLsPACE accredited ndash all 1 hourAccessible from mobile devicesVirtual exhibit hall
wwwstagowebinarscomMostly European KOLs30 ndash 45 min including 15 min discussion
Stago Educational Apps
HaemoscoreClinical scoring algorithmsApple and AndroidTablet or phone
iHemostasisCoagulation diagramsCase studiesApple amp AndroidTablet only
BREAK
Diagnostic and Management Approach for DIC
Diagnosis of DIC
Clinical diagnosis is obvious in cases of overt DIC
Laboratory tests are necessary To makeconfirm the diagnosis To assess stage of the patient To assess the treatment efficacy
Lab Diagnosis of DIC ndash Markers of Factor Consumption
Routinescreening assays PT APTT Platelets Fibrinogen Thrombin time
Other coagulation assays Factor assays AntithrombinGeneration of Thrombin FMFSPsGeneration of Plasmin D-dimer FDPs
Important to recognize simultaneous formation of thrombin and plasmin
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122
Lab Diagnosis of DIC ndash Screening Tests
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122
Platelet count usually decreasedPT abnormal in 70 of cases (short half-life of FVII)APTT abnormal in 50 of casesThrombin time usually prolonged in overt DIC normal in non-overt DIC and no relation with syndrome severityFibrinogen low in lt 50 of cases sensitivity 22 specificity 87 overall predictive value 64 Normal fibrinogen level should not exclude DIC diagnosis (acute phase reactant initial high
fibrinogen level) repeat testing assesses progression
Screening tests not clinically specific or sensitive for DIC
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Laboratory Changes in Overt DIC
DIC Diagnostic Practices Over Time
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
British Journal of Haematology Overt DIC Score
Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
ISTH Step by Step DIC Algorithm
Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6
US Based Validation of ISTH DIC Score
When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Differential Diagnosis in DIC
aHUS atypical hemolytic uremic syndrome
HUS hemolytic uremic syndrome
HIT heparin-induced thrombocytopenia
ITP immune thrombocytopenic purpura
TTP thrombotic thrombocytopenic purpura
DIC and MAHA
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)
When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation
DIC Management Goals
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction
DIC Management and Treatment
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)
requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)
Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia
DIC Management Strategies
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant Factor Concentrate Treatment
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis
Anticoagulant Factor Concentrate Treatment Trials
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise
Markers of Thrombin amp Plasmin Generation in DIC
D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC
Cut-off value
Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen
degradation products Sensitive assay typically with cutoff adapted for DIC
D-dimer FDPs and DIC
D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC
Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80
Follow Up of DIC State of Disease
Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8
Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility
FMD-Dimer in DIC Major Differences
onset of thrombosis
days
Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8
FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)
D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)
of Abnormal Results in Patients with Confirmed and Suspected DIC
0
20
40
60
80
100
94 85 90N = 62
Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32
Positivity of Test Results ISTH Score and Disease State
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
Red bar positive for 2 points of DIC score
Pink bar positive for 1-2 points of DIC score
HT hematopoietic tumor
IF infection
SC solid cancer
Markers in Patients with or without DIC
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
HT hematopoietic tumorIF infectionSC solid cancer
Comparing an Automated FM vs Manual FSP Test
Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71
Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)
Automated (Mitsubishi) vs Automated (Stago)
In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago
Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC
Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
Non Overt DIC Overt DIC
AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC
Trends in Markers of DIC for Different Patients
Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00
Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients
Trends in Markers of DIC for Different Patients
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes
28 day outcome survival
28 day outcome death
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines
DIC Case Studies
Case Study 1 - Presentation
18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE
WBC count 77 KμL 423 ndash 907 x KμL
RBC count 17 MμL 137 ndash 175 x MμL
Hemoglobin 67 gdL 137 ndash 175 gdL
Hematocrit 195 401 ndash 510
MCV 95 fL 790 ndash 922 fL
MPV 12 fL 94 ndash 124 fL
Platelet count 9 KμL 161 ndash 347 KμL
Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0
Lymphocytes monocytes eosinophils basophils all below normal range
PT 47 sec (corrected on mixing study) 116 ndash 152 sec
APTT 75 sec (corrected on mixing study) 253 ndash 373 sec
Fibrinogen lt 76 mgdL 177 ndash 466 mgdL
D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Microscopy
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Arrow shows giant platelets in this peripheral smear Promyelocytes apparent
Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)
DIC due to TF release by APL blasts
Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases
Transfusions to replace factors along with platelets and RBCs during APL treatment
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started
Case Study 2 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L
PT 30 sec 113 ndash 146 sec
APTT 75 sec 25 ndash 34 sec
D-dimer 078 microgml FEU lt050 microgml FEU
Fibrinogen 92 mgdl 150-400 mgdl
pH 728 738 to 742
PaO2 570 mmHg 80-100 mmHg
WBC 33 times 103mm3 40-11 times 103mm3
ALT 111 IUL 0ndash34 IUL
AST 61 IUL 0ndash34 IUL
BUN 303 mgdL 08-13 mgdL
Case Study 2 ndash Lab Results
Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures
Case Study 2 ndash Diagnosis
60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior
Case Study 3 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L
PT 228 sec 113 ndash 146 sec
APTT 45 sec 25 ndash 34 sec
D-dimer 080 microgml FEU lt050 microgmL FEU
Fibrinogen 82 mgdL 150-400 mgdL
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 134 gdL 14-16 gdL
WBC 81 times 103mm3 40-11 times 103mm3
ALT 32 IUL 0ndash34 IUL
AST 28 IUL 0ndash34 IUL
BUN 09 mgdL 08-13 mgdL
Case Study 3 ndash Lab Results
Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment
Case Study 3 ndash Diagnosis and Therapy
Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91
Case Study 4 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L
PT 28 sec 113 ndash 146 sec
APTT 71 sec 25 ndash 34 sec
D-dimer 31 microgmL FEU lt050 microgml FEU
Fibrinogen 92 mgdL 150-400 mgdl
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 158 gdL 14-16 gdL
WBC 71 times 103mm3 40-11 times 103mm3
ALT 60 IUL 0ndash34 IUL
AST 47 IUL 0ndash34 IUL
BUN 38 mgdL 08-13 mgdL
Case Study 4 ndash Lab Results
Lyme disease with DICProvide antibiotics with supportive measures
Case Study 4 ndash Diagnosis
55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis
Case Study 5 ndash Presentation
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
Case Study 5 ndash Lab Results and Time Course
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
TEST RESULT REFERENCE RANGE
Platelet count 33 x 109L 150-450 x 109L
PT 215 sec 103 ndash 128 sec
APTT 44 sec 26 ndash 36 sec
D-dimer 20 microgmL FEU lt025 microgml FEU
Fibrinogen 34 mgdL 200-375 mgdl
FII FV FVIII Low Not reported (NR)
FVII FIX FX vWF Normal NR
Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)
DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic
dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR
(C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen
(D) Illustration demonstrating repair
Case Study 5 ndash Diagnosis and Treatment
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography
Case Study 6 ndash Presentation
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
Case Study 6 ndash Lab Results
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L
PT 63 sec gt control 113 ndash 146 sec
INR 658 1 ndash 125
APTT 80 sec gt control 25 ndash 34 sec
D-dimer gt200 microgmL DDU 02 microgmL DDU
Urine exam Proteinuria and hematuria 150-400 mgdl
Albumin 28 gdL NR
Hb 58 gdL NR
LDH 1196 UL NR
SGPT 144 IU NR
SGOT 88 IU NR
Bilirubin 32 mgdL NR
DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th
day postop
Case Study 6 ndash Diagnosis and Treatment
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure
Case Study 6 ndash Discussion
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Case Study 7 ndash Lab Results vs Time
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
DIC Take Home Messages
Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation
Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers
DIC
Thank you Questions
- Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
- Learning Objectives
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Wound Sealing
- The Three Steps of Hemostasis
- Vessel Wall
- Slide Number 12
- Slide Number 13
- Platelet Structure UnactivatedActivated
- Primary Hemostasis
- Primary Hemostasis Assays
- Slide Number 17
- Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
- Slide Number 19
- Coagulation factors
- Coagulation Assay Mechanisms
- Slide Number 22
- Fibrin Formation
- Slide Number 24
- Fibrinolysis Overview
- Fibrinolysis Overview
- Slide Number 27
- Fibrinolysis Releases D-dimers
- Basic Pathophysiology of DIC
- Disseminated Intravascular Coagulation (DIC)
- Purpura Fulminans with DIC Due to Meningococcal Sepsis
- Clinical Conditions Associated With DIC
- Frequency of DIC in Selected Disease States
- Underlying Diseases in DIC Patients
- Slide Number 36
- Slide Number 37
- Slide Number 38
- Slide Number 39
- Pathophysiology of DIC
- Pathogenesis of DIC in Sepsis
- Host Response in Severe Sepsis
- Organ Failure in Severe Sepsis
- Mechanism of DIC in Organ Failure
- Interaction of Inflammation and Coagulation in Sepsis
- Slide Number 47
- Diverse and Opposing Effects of Thrombin
- Coagulation and Fibrinolysis in DIC
- Mechanism of DIC
- Pathophysiology of DIC
- Pathophysiology of DIC - Mechanism
- Pathophysiology of DIC ndash 2 Types of Clinical pictures
- Sub-Acute and Non-Overt DIC Clinical Findings
- Pathophysiology of Overt DIC
- Physiopathology of DIC ndash Overt DIC Findings
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- BREAK
- Diagnostic and Management Approach for DIC
- Diagnosis of DIC
- Lab Diagnosis of DIC ndash Markers of Factor Consumption
- Lab Diagnosis of DIC ndash Screening Tests
- Slide Number 67
- Slide Number 68
- British Journal of Haematology Overt DIC Score
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- DIC Management Goals
- DIC Management and Treatment
- DIC Management Strategies
- Anticoagulant Factor Concentrate Treatment
- Anticoagulant Factor Concentrate Treatment Trials
- Markers of Thrombin amp Plasmin Generation in DIC
- D-dimer FDPs and DIC
- D-Dimer and FDPs in DIC
- Follow Up of DIC State of Disease
- FMD-Dimer in DIC Major Differences
- of Abnormal Results in Patients with Confirmed and Suspected DIC
- Slide Number 85
- Slide Number 86
- Comparing an Automated FM vs Manual FSP Test
- Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Slide Number 94
- Slide Number 95
- Slide Number 96
- Slide Number 97
- Slide Number 98
- Slide Number 99
- DIC Case Studies
- Case Study 1 - Presentation
- Case Study 1 ndash Lab Results
- Case Study 1 ndash Microscopy
- Case Study 1 ndash Diagnosis and Therapy
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Slide Number 110
- Slide Number 111
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Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Coagulation Cascade Schematic
Coagulation factors
Historic name
Fibrinogen
Prothrombin
Proaccelerin
Proconvertin
Anti-hemophilic factor A
Anti-hemophilic factor B
Stuart factor
Rosenthal factor
Hageman factor
Fibrin Stabilizing Factor
Factor
I
II
V
VII
VIII
IX
X
XI
XII
XIII
Function
Substrate
Pro-enzyme
Pro-cofactor
Pro-enzyme
Pro-cofactor
Pro-enzyme
Pro-enzyme
Pro-enzyme
Pro-enzyme
Pro-enzyme
Pro-enzyme = Zymogen activation Active Enzyme
Coagulation Assay Mechanisms
aPTT Based
PT Based
PT Based
Fibrin Under Microscope
Weisel JW Structure of fibrin impact on clot stability J Thromb Haemost 2007 5 Suppl 1 116-24
Low thrombin concentration
High thrombin concentration
Fibrin Formation
Soluble FibrinPolymer
ThrombinFibrinogen
FM+ fibrinopeptides A amp B
Stabilized Fibrin clot(not soluble)
ThrombinXIII XIIIa
(Digestion of Fibrin)
Fibrinolysis
Fibrinolysis Overview
Destroys fibrin fibers
Destroys the scab (dried wound)
Maintains vessel integrity
Fibrinolysis Overview
Fibrin =cement fibers
Plasmin
Plasmin digests fibrin
t-PA
Pro Urokinase
Urokinase
PAI-1PAI-1
Plasminogen Plasmin
1st Step
2nd Step
Fibrinolysis Cascade
t-PA tissue-type plasminogen activator PAI-1 Plasminogen activator inhibitor 1 PK Prekallikrein FDP Fibrinogen degradation products AP Antiplasmin = a2AP alpha 2 Antiplasmin a2MG alpha 2 Macroglobulin
Extrinsic pathway(endothelia l cells)
Intrinsic pathway(plasma)
Fibrin clot
D-dimerFibrin degradation products
Fibrin
TAFIa
APAntiplasmin(amp a2-MG)
PK Kallikrein
XII
Fibrinolysis Releases D-dimers
D-dimer presence fibrin has been formed and digested in patients body
Normal D-dimer level no thrombosis occurred in the patient
Basic Pathophysiology of DIC
Disseminated Intravascular Coagulation (DIC)
Massive activation of coagulation leading to clots forming in multiple locations around the bodyRapid consumption of clotting factors leading to bleedingParadoxical condition leading to both clotting and bleedingA confusing disorder from both diagnostic and therapeutic standpoints Many unrelated diseases can trigger DIC Lack of uniformity in clinical manifestation Lack of uniformity in the laboratory diagnosis Lack of uniformity or consensus on management
Clinical Manifestations of DICOrgan Ischemic Hemorrhagic
Skin Pupura Fulminans Petechiae
Gangrene Echymoses
Acral cyanosis Oozing
CNS Deliriumcoma Intracranial
Infarcts Bleeding
Renal OliguriaAzotemia Hematuria
Cortical Necrosis
Cardiovascular Myocardial dysfunction
Pulmonary DyspneaHypoxia Hemorrhagic lung
Infarct
Gastrointestinal Ulcers infarcts Massive hemorrhage
Endocrine Adrenal infarcts
Purpura Fulminans with DIC Due to Meningococcal Sepsis
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Clinical Conditions Associated With DIC
Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33
Frequency of DIC in Selected Disease States
Disease Frequency
Gram-negative sepsis 30-50
Severe trauma and systemic inflammation 50-70
Metastasized tumors 15
Abruptio placentaamniotic fluid embolism 50
Severe preeclampsia 7
Giant hemangioma 25
Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92
Masao Nakagawa Modified from a research report on the incidence of disseminated intravascular coagulation (DIC) and underlying diseases in Japan Ministry of Health Labour and Welfare Research report published in Fiscal Year 1998 57-64 199 httpwwwrecomodulincomendicindexhtml Accessed Apr 21 2017
Underlying Diseases in DIC Patients
In a Japanese survey from 1997 on incidence of DIC and underlying diseases in 652 divisions and departments of university hospitals DIC occurred in 2193 patients with the number of patient with infections (including sepsis) and hematologic tumors (including leukemia) accounted for 28 and 23 respectively
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Epidemiology of DIC
Impact of DIC Status on Mortality - 1
Okamoto K Wada H Hatada T Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Frequency and hemostatic abnormalities in pre-DIC patients Thromb Res 2010 126 74-8
Patients with positivity of DIC tend to have worse mortality outcomes compared to negative patients or those with pre-DIC
Impact of DIC Status on Mortality - 2
Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4
Patients with positivity of either Overt or Non-Overt DIC tend to have worse mortality outcomes compared to negative patients
Impact of Age on Mortality in DIC Patients
Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4
Older patients with DIC (black bars) generally tend to have worse outcomes compared to non-DIC patients (grey bars)
Pathophysiology of DIC
Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33
Pathogenesis of DIC in Sepsis
Allen KS Sawheny E Kinasewitzet GT Anticoagulant modulation of inflammation in severe sepsis World J Crit Care Med 2015 4 105-15
Bacteria in sepsis infections cause release of TF from immune cells leading to coagulation activation and proinflammatory cytokines cause endothelial cell activation impairing the anticoagulation and fibrinolysis process resulting in DIC
Host Response in Severe Sepsis
Exaggerated inflammation as a result of the host response to sepsis is collateral tissue damage and cell death further resulting in release of danger molecules continuing the inflammatory process in a downward spiral
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Organ Failure in Severe Sepsis
Sepsis associated with microvascular thrombosis as a result of TF mediated coagulation activation results in release of neutrophil extracellular traps (NETs) tissue hypoperfusion and mitochondrial damage resulting in a downward spiral leading to organ failure
Angus DC van der Poll T Severe Sepsis and Septic Shock N Engl J Med 2013 369 840-51
Mechanism of DIC in Organ Failure
Underlying condition(sepsis trauma)
Cytokines
TF-mediatedactivation of coagulation
Depression of inhibitory systems
Reducesfibrinolysis
Fibrin deposition
Organ failure
Inadequate fibrin removal
Fibrinformation
Note impaired fibrinolysis in relation to the clinical need not in absolute value (FDPs are )
Levi M de Jonge E van der Poll T ten Cate H Disseminated intravascular coagulation ThrombHaemost 1999 82 695-705
Interaction of Inflammation and Coagulation in Sepsis
Binding of TF thrombin and other activation coagulation factors to PARs and fibrin to TLRs on inflammatory cells results in inflammation through release of proinflammatory cytokines and chemokines
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Mechanism of Multiple Organ Failure in DIC
Wheeler AP Bernard GR Treating Patients with Severe Sepsis N Engl J Med 1999 340207-14
Inflammatory activation and microvascular thrombosis contributes to multiple organ failure in DIC
lipopolysaccharides
cytokines
coagulation activation
mononuclear cell
tissue factor
Diverse and Opposing Effects of Thrombin
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Coagulation and Fibrinolysis in DIC
Soluble fibrin Polymer
XIIIa
D-Dimer
E
Fibrin clot
Fibrin Degradation Products
Fibrinogen Thrombin
Fibrinogen Degradation
Products
D E
Plasmin
DFM + fibrinopeptides
Soluble FM ComplexesPre-throm
boticPost-throm
botic
Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis Semin Thromb Hemost 2008 34 33-8
Mechanism of DIC
THROMBOSIS
Fibrin
Blood activationEndothelial lysisTF expression
BLEEDING
FDPs
D-Dimer
Plasmin
Pathophysiology of DIC
1st step abnormal activation of coagulation Injury of vessel wall cells venous stasis release of large quantities of
thromboplastin influx of activated cells (monocytes macrophages)
Results in an intravascular deposition of fibrin
Morbidity from disseminated microthrombosis in small and midsize vessels leading to multiple organ failure
Second step Consumption and depletion of coagulation factors inhibitors (Protein C
Protein S AT) and platelets Local fibrinolytic response
bull Local plasmin generation dissolves the thrombusbull Disseminated overwhelming fibrinolytic response leading to production of
FDP and D-Dimer
Bleeding
Pathophysiology of DIC - Mechanism
Systemic activation of coagulation
Intravasculardepositionof fibrin
Thrombosis of small and midsize vessels
and organ failure
Depletion of platelets and
coagulation factors
Bleeding
Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92
Pathophysiology of DIC ndash 2 Types of Clinical pictures
Chronic = non - overt DICMay be unrecognized clinically
Acute = overt DIClife threatening bleedingor multiple organ failure
Sub-Acute and Non-Overt DIC Clinical Findings
Compensated non-overt DIC Steady low level or intermittent activation
bull Compensated by increased production of coagulation components and platelets
Few or no clinical signs or multiple microvascular thrombosis sometimes not clinically obvious
Risk of decompensation leading to overt DIC
Pathophysiology of Overt DIC
Massive activation of coagulation and fibrinolysis
Does not allow for compensatory efforts
Rapid depletion of coagulation factors inhibitors and platelets
Thrombosis multiple organ failures
Bleeding complications and shock
Physiopathology of DIC ndash Overt DIC Findings
Thrombin generation
Thrombosis
Renal liver respiratory failures coma skin necrosis gangrene venous thromboembolism hypotension edema
Cytokine and kinin generation (shock)bull Tachycardia hypotension edema
Plasmin generationHemorrhage
bull Spontaneous bruising petechiae intracranial gastrointestinal and respiratory tract bleeding persistent bleeding at venipuncture sites at surgical wounds
bull Tachycardia hypotension edema
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Pathogenesis Pathways in DIC
Cytokines
TF-mediated dysfunctional impairedthrombin anticoagulant fibrinolysisgeneration mechanism due to PAI-1 deficiency
fibrin inadequateformation fibrin removal
Fibrin deposition
Inflammation
Coagulation
Stago Celebrates Lab Week 2017
NA
Stago 247 Educational Webinar Sites
wwwstago-edvantagecomUS based KOLsPACE accredited ndash all 1 hourAccessible from mobile devicesVirtual exhibit hall
wwwstagowebinarscomMostly European KOLs30 ndash 45 min including 15 min discussion
Stago Educational Apps
HaemoscoreClinical scoring algorithmsApple and AndroidTablet or phone
iHemostasisCoagulation diagramsCase studiesApple amp AndroidTablet only
BREAK
Diagnostic and Management Approach for DIC
Diagnosis of DIC
Clinical diagnosis is obvious in cases of overt DIC
Laboratory tests are necessary To makeconfirm the diagnosis To assess stage of the patient To assess the treatment efficacy
Lab Diagnosis of DIC ndash Markers of Factor Consumption
Routinescreening assays PT APTT Platelets Fibrinogen Thrombin time
Other coagulation assays Factor assays AntithrombinGeneration of Thrombin FMFSPsGeneration of Plasmin D-dimer FDPs
Important to recognize simultaneous formation of thrombin and plasmin
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122
Lab Diagnosis of DIC ndash Screening Tests
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122
Platelet count usually decreasedPT abnormal in 70 of cases (short half-life of FVII)APTT abnormal in 50 of casesThrombin time usually prolonged in overt DIC normal in non-overt DIC and no relation with syndrome severityFibrinogen low in lt 50 of cases sensitivity 22 specificity 87 overall predictive value 64 Normal fibrinogen level should not exclude DIC diagnosis (acute phase reactant initial high
fibrinogen level) repeat testing assesses progression
Screening tests not clinically specific or sensitive for DIC
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Laboratory Changes in Overt DIC
DIC Diagnostic Practices Over Time
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
British Journal of Haematology Overt DIC Score
Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
ISTH Step by Step DIC Algorithm
Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6
US Based Validation of ISTH DIC Score
When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Differential Diagnosis in DIC
aHUS atypical hemolytic uremic syndrome
HUS hemolytic uremic syndrome
HIT heparin-induced thrombocytopenia
ITP immune thrombocytopenic purpura
TTP thrombotic thrombocytopenic purpura
DIC and MAHA
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)
When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation
DIC Management Goals
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction
DIC Management and Treatment
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)
requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)
Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia
DIC Management Strategies
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant Factor Concentrate Treatment
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis
Anticoagulant Factor Concentrate Treatment Trials
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise
Markers of Thrombin amp Plasmin Generation in DIC
D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC
Cut-off value
Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen
degradation products Sensitive assay typically with cutoff adapted for DIC
D-dimer FDPs and DIC
D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC
Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80
Follow Up of DIC State of Disease
Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8
Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility
FMD-Dimer in DIC Major Differences
onset of thrombosis
days
Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8
FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)
D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)
of Abnormal Results in Patients with Confirmed and Suspected DIC
0
20
40
60
80
100
94 85 90N = 62
Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32
Positivity of Test Results ISTH Score and Disease State
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
Red bar positive for 2 points of DIC score
Pink bar positive for 1-2 points of DIC score
HT hematopoietic tumor
IF infection
SC solid cancer
Markers in Patients with or without DIC
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
HT hematopoietic tumorIF infectionSC solid cancer
Comparing an Automated FM vs Manual FSP Test
Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71
Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)
Automated (Mitsubishi) vs Automated (Stago)
In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago
Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC
Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
Non Overt DIC Overt DIC
AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC
Trends in Markers of DIC for Different Patients
Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00
Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients
Trends in Markers of DIC for Different Patients
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes
28 day outcome survival
28 day outcome death
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines
DIC Case Studies
Case Study 1 - Presentation
18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE
WBC count 77 KμL 423 ndash 907 x KμL
RBC count 17 MμL 137 ndash 175 x MμL
Hemoglobin 67 gdL 137 ndash 175 gdL
Hematocrit 195 401 ndash 510
MCV 95 fL 790 ndash 922 fL
MPV 12 fL 94 ndash 124 fL
Platelet count 9 KμL 161 ndash 347 KμL
Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0
Lymphocytes monocytes eosinophils basophils all below normal range
PT 47 sec (corrected on mixing study) 116 ndash 152 sec
APTT 75 sec (corrected on mixing study) 253 ndash 373 sec
Fibrinogen lt 76 mgdL 177 ndash 466 mgdL
D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Microscopy
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Arrow shows giant platelets in this peripheral smear Promyelocytes apparent
Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)
DIC due to TF release by APL blasts
Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases
Transfusions to replace factors along with platelets and RBCs during APL treatment
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started
Case Study 2 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L
PT 30 sec 113 ndash 146 sec
APTT 75 sec 25 ndash 34 sec
D-dimer 078 microgml FEU lt050 microgml FEU
Fibrinogen 92 mgdl 150-400 mgdl
pH 728 738 to 742
PaO2 570 mmHg 80-100 mmHg
WBC 33 times 103mm3 40-11 times 103mm3
ALT 111 IUL 0ndash34 IUL
AST 61 IUL 0ndash34 IUL
BUN 303 mgdL 08-13 mgdL
Case Study 2 ndash Lab Results
Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures
Case Study 2 ndash Diagnosis
60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior
Case Study 3 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L
PT 228 sec 113 ndash 146 sec
APTT 45 sec 25 ndash 34 sec
D-dimer 080 microgml FEU lt050 microgmL FEU
Fibrinogen 82 mgdL 150-400 mgdL
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 134 gdL 14-16 gdL
WBC 81 times 103mm3 40-11 times 103mm3
ALT 32 IUL 0ndash34 IUL
AST 28 IUL 0ndash34 IUL
BUN 09 mgdL 08-13 mgdL
Case Study 3 ndash Lab Results
Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment
Case Study 3 ndash Diagnosis and Therapy
Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91
Case Study 4 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L
PT 28 sec 113 ndash 146 sec
APTT 71 sec 25 ndash 34 sec
D-dimer 31 microgmL FEU lt050 microgml FEU
Fibrinogen 92 mgdL 150-400 mgdl
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 158 gdL 14-16 gdL
WBC 71 times 103mm3 40-11 times 103mm3
ALT 60 IUL 0ndash34 IUL
AST 47 IUL 0ndash34 IUL
BUN 38 mgdL 08-13 mgdL
Case Study 4 ndash Lab Results
Lyme disease with DICProvide antibiotics with supportive measures
Case Study 4 ndash Diagnosis
55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis
Case Study 5 ndash Presentation
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
Case Study 5 ndash Lab Results and Time Course
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
TEST RESULT REFERENCE RANGE
Platelet count 33 x 109L 150-450 x 109L
PT 215 sec 103 ndash 128 sec
APTT 44 sec 26 ndash 36 sec
D-dimer 20 microgmL FEU lt025 microgml FEU
Fibrinogen 34 mgdL 200-375 mgdl
FII FV FVIII Low Not reported (NR)
FVII FIX FX vWF Normal NR
Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)
DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic
dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR
(C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen
(D) Illustration demonstrating repair
Case Study 5 ndash Diagnosis and Treatment
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography
Case Study 6 ndash Presentation
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
Case Study 6 ndash Lab Results
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L
PT 63 sec gt control 113 ndash 146 sec
INR 658 1 ndash 125
APTT 80 sec gt control 25 ndash 34 sec
D-dimer gt200 microgmL DDU 02 microgmL DDU
Urine exam Proteinuria and hematuria 150-400 mgdl
Albumin 28 gdL NR
Hb 58 gdL NR
LDH 1196 UL NR
SGPT 144 IU NR
SGOT 88 IU NR
Bilirubin 32 mgdL NR
DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th
day postop
Case Study 6 ndash Diagnosis and Treatment
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure
Case Study 6 ndash Discussion
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Case Study 7 ndash Lab Results vs Time
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
DIC Take Home Messages
Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation
Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers
DIC
Thank you Questions
- Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
- Learning Objectives
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Wound Sealing
- The Three Steps of Hemostasis
- Vessel Wall
- Slide Number 12
- Slide Number 13
- Platelet Structure UnactivatedActivated
- Primary Hemostasis
- Primary Hemostasis Assays
- Slide Number 17
- Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
- Slide Number 19
- Coagulation factors
- Coagulation Assay Mechanisms
- Slide Number 22
- Fibrin Formation
- Slide Number 24
- Fibrinolysis Overview
- Fibrinolysis Overview
- Slide Number 27
- Fibrinolysis Releases D-dimers
- Basic Pathophysiology of DIC
- Disseminated Intravascular Coagulation (DIC)
- Purpura Fulminans with DIC Due to Meningococcal Sepsis
- Clinical Conditions Associated With DIC
- Frequency of DIC in Selected Disease States
- Underlying Diseases in DIC Patients
- Slide Number 36
- Slide Number 37
- Slide Number 38
- Slide Number 39
- Pathophysiology of DIC
- Pathogenesis of DIC in Sepsis
- Host Response in Severe Sepsis
- Organ Failure in Severe Sepsis
- Mechanism of DIC in Organ Failure
- Interaction of Inflammation and Coagulation in Sepsis
- Slide Number 47
- Diverse and Opposing Effects of Thrombin
- Coagulation and Fibrinolysis in DIC
- Mechanism of DIC
- Pathophysiology of DIC
- Pathophysiology of DIC - Mechanism
- Pathophysiology of DIC ndash 2 Types of Clinical pictures
- Sub-Acute and Non-Overt DIC Clinical Findings
- Pathophysiology of Overt DIC
- Physiopathology of DIC ndash Overt DIC Findings
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- BREAK
- Diagnostic and Management Approach for DIC
- Diagnosis of DIC
- Lab Diagnosis of DIC ndash Markers of Factor Consumption
- Lab Diagnosis of DIC ndash Screening Tests
- Slide Number 67
- Slide Number 68
- British Journal of Haematology Overt DIC Score
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- DIC Management Goals
- DIC Management and Treatment
- DIC Management Strategies
- Anticoagulant Factor Concentrate Treatment
- Anticoagulant Factor Concentrate Treatment Trials
- Markers of Thrombin amp Plasmin Generation in DIC
- D-dimer FDPs and DIC
- D-Dimer and FDPs in DIC
- Follow Up of DIC State of Disease
- FMD-Dimer in DIC Major Differences
- of Abnormal Results in Patients with Confirmed and Suspected DIC
- Slide Number 85
- Slide Number 86
- Comparing an Automated FM vs Manual FSP Test
- Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Slide Number 94
- Slide Number 95
- Slide Number 96
- Slide Number 97
- Slide Number 98
- Slide Number 99
- DIC Case Studies
- Case Study 1 - Presentation
- Case Study 1 ndash Lab Results
- Case Study 1 ndash Microscopy
- Case Study 1 ndash Diagnosis and Therapy
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Slide Number 110
- Slide Number 111
- Slide Number 112
- Slide Number 113
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
- Slide Number 124
- Slide Number 125
- DIC Take Home Messages
- Slide Number 127
- Slide Number 128
-
Coagulation factors
Historic name
Fibrinogen
Prothrombin
Proaccelerin
Proconvertin
Anti-hemophilic factor A
Anti-hemophilic factor B
Stuart factor
Rosenthal factor
Hageman factor
Fibrin Stabilizing Factor
Factor
I
II
V
VII
VIII
IX
X
XI
XII
XIII
Function
Substrate
Pro-enzyme
Pro-cofactor
Pro-enzyme
Pro-cofactor
Pro-enzyme
Pro-enzyme
Pro-enzyme
Pro-enzyme
Pro-enzyme
Pro-enzyme = Zymogen activation Active Enzyme
Coagulation Assay Mechanisms
aPTT Based
PT Based
PT Based
Fibrin Under Microscope
Weisel JW Structure of fibrin impact on clot stability J Thromb Haemost 2007 5 Suppl 1 116-24
Low thrombin concentration
High thrombin concentration
Fibrin Formation
Soluble FibrinPolymer
ThrombinFibrinogen
FM+ fibrinopeptides A amp B
Stabilized Fibrin clot(not soluble)
ThrombinXIII XIIIa
(Digestion of Fibrin)
Fibrinolysis
Fibrinolysis Overview
Destroys fibrin fibers
Destroys the scab (dried wound)
Maintains vessel integrity
Fibrinolysis Overview
Fibrin =cement fibers
Plasmin
Plasmin digests fibrin
t-PA
Pro Urokinase
Urokinase
PAI-1PAI-1
Plasminogen Plasmin
1st Step
2nd Step
Fibrinolysis Cascade
t-PA tissue-type plasminogen activator PAI-1 Plasminogen activator inhibitor 1 PK Prekallikrein FDP Fibrinogen degradation products AP Antiplasmin = a2AP alpha 2 Antiplasmin a2MG alpha 2 Macroglobulin
Extrinsic pathway(endothelia l cells)
Intrinsic pathway(plasma)
Fibrin clot
D-dimerFibrin degradation products
Fibrin
TAFIa
APAntiplasmin(amp a2-MG)
PK Kallikrein
XII
Fibrinolysis Releases D-dimers
D-dimer presence fibrin has been formed and digested in patients body
Normal D-dimer level no thrombosis occurred in the patient
Basic Pathophysiology of DIC
Disseminated Intravascular Coagulation (DIC)
Massive activation of coagulation leading to clots forming in multiple locations around the bodyRapid consumption of clotting factors leading to bleedingParadoxical condition leading to both clotting and bleedingA confusing disorder from both diagnostic and therapeutic standpoints Many unrelated diseases can trigger DIC Lack of uniformity in clinical manifestation Lack of uniformity in the laboratory diagnosis Lack of uniformity or consensus on management
Clinical Manifestations of DICOrgan Ischemic Hemorrhagic
Skin Pupura Fulminans Petechiae
Gangrene Echymoses
Acral cyanosis Oozing
CNS Deliriumcoma Intracranial
Infarcts Bleeding
Renal OliguriaAzotemia Hematuria
Cortical Necrosis
Cardiovascular Myocardial dysfunction
Pulmonary DyspneaHypoxia Hemorrhagic lung
Infarct
Gastrointestinal Ulcers infarcts Massive hemorrhage
Endocrine Adrenal infarcts
Purpura Fulminans with DIC Due to Meningococcal Sepsis
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Clinical Conditions Associated With DIC
Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33
Frequency of DIC in Selected Disease States
Disease Frequency
Gram-negative sepsis 30-50
Severe trauma and systemic inflammation 50-70
Metastasized tumors 15
Abruptio placentaamniotic fluid embolism 50
Severe preeclampsia 7
Giant hemangioma 25
Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92
Masao Nakagawa Modified from a research report on the incidence of disseminated intravascular coagulation (DIC) and underlying diseases in Japan Ministry of Health Labour and Welfare Research report published in Fiscal Year 1998 57-64 199 httpwwwrecomodulincomendicindexhtml Accessed Apr 21 2017
Underlying Diseases in DIC Patients
In a Japanese survey from 1997 on incidence of DIC and underlying diseases in 652 divisions and departments of university hospitals DIC occurred in 2193 patients with the number of patient with infections (including sepsis) and hematologic tumors (including leukemia) accounted for 28 and 23 respectively
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Epidemiology of DIC
Impact of DIC Status on Mortality - 1
Okamoto K Wada H Hatada T Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Frequency and hemostatic abnormalities in pre-DIC patients Thromb Res 2010 126 74-8
Patients with positivity of DIC tend to have worse mortality outcomes compared to negative patients or those with pre-DIC
Impact of DIC Status on Mortality - 2
Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4
Patients with positivity of either Overt or Non-Overt DIC tend to have worse mortality outcomes compared to negative patients
Impact of Age on Mortality in DIC Patients
Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4
Older patients with DIC (black bars) generally tend to have worse outcomes compared to non-DIC patients (grey bars)
Pathophysiology of DIC
Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33
Pathogenesis of DIC in Sepsis
Allen KS Sawheny E Kinasewitzet GT Anticoagulant modulation of inflammation in severe sepsis World J Crit Care Med 2015 4 105-15
Bacteria in sepsis infections cause release of TF from immune cells leading to coagulation activation and proinflammatory cytokines cause endothelial cell activation impairing the anticoagulation and fibrinolysis process resulting in DIC
Host Response in Severe Sepsis
Exaggerated inflammation as a result of the host response to sepsis is collateral tissue damage and cell death further resulting in release of danger molecules continuing the inflammatory process in a downward spiral
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Organ Failure in Severe Sepsis
Sepsis associated with microvascular thrombosis as a result of TF mediated coagulation activation results in release of neutrophil extracellular traps (NETs) tissue hypoperfusion and mitochondrial damage resulting in a downward spiral leading to organ failure
Angus DC van der Poll T Severe Sepsis and Septic Shock N Engl J Med 2013 369 840-51
Mechanism of DIC in Organ Failure
Underlying condition(sepsis trauma)
Cytokines
TF-mediatedactivation of coagulation
Depression of inhibitory systems
Reducesfibrinolysis
Fibrin deposition
Organ failure
Inadequate fibrin removal
Fibrinformation
Note impaired fibrinolysis in relation to the clinical need not in absolute value (FDPs are )
Levi M de Jonge E van der Poll T ten Cate H Disseminated intravascular coagulation ThrombHaemost 1999 82 695-705
Interaction of Inflammation and Coagulation in Sepsis
Binding of TF thrombin and other activation coagulation factors to PARs and fibrin to TLRs on inflammatory cells results in inflammation through release of proinflammatory cytokines and chemokines
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Mechanism of Multiple Organ Failure in DIC
Wheeler AP Bernard GR Treating Patients with Severe Sepsis N Engl J Med 1999 340207-14
Inflammatory activation and microvascular thrombosis contributes to multiple organ failure in DIC
lipopolysaccharides
cytokines
coagulation activation
mononuclear cell
tissue factor
Diverse and Opposing Effects of Thrombin
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Coagulation and Fibrinolysis in DIC
Soluble fibrin Polymer
XIIIa
D-Dimer
E
Fibrin clot
Fibrin Degradation Products
Fibrinogen Thrombin
Fibrinogen Degradation
Products
D E
Plasmin
DFM + fibrinopeptides
Soluble FM ComplexesPre-throm
boticPost-throm
botic
Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis Semin Thromb Hemost 2008 34 33-8
Mechanism of DIC
THROMBOSIS
Fibrin
Blood activationEndothelial lysisTF expression
BLEEDING
FDPs
D-Dimer
Plasmin
Pathophysiology of DIC
1st step abnormal activation of coagulation Injury of vessel wall cells venous stasis release of large quantities of
thromboplastin influx of activated cells (monocytes macrophages)
Results in an intravascular deposition of fibrin
Morbidity from disseminated microthrombosis in small and midsize vessels leading to multiple organ failure
Second step Consumption and depletion of coagulation factors inhibitors (Protein C
Protein S AT) and platelets Local fibrinolytic response
bull Local plasmin generation dissolves the thrombusbull Disseminated overwhelming fibrinolytic response leading to production of
FDP and D-Dimer
Bleeding
Pathophysiology of DIC - Mechanism
Systemic activation of coagulation
Intravasculardepositionof fibrin
Thrombosis of small and midsize vessels
and organ failure
Depletion of platelets and
coagulation factors
Bleeding
Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92
Pathophysiology of DIC ndash 2 Types of Clinical pictures
Chronic = non - overt DICMay be unrecognized clinically
Acute = overt DIClife threatening bleedingor multiple organ failure
Sub-Acute and Non-Overt DIC Clinical Findings
Compensated non-overt DIC Steady low level or intermittent activation
bull Compensated by increased production of coagulation components and platelets
Few or no clinical signs or multiple microvascular thrombosis sometimes not clinically obvious
Risk of decompensation leading to overt DIC
Pathophysiology of Overt DIC
Massive activation of coagulation and fibrinolysis
Does not allow for compensatory efforts
Rapid depletion of coagulation factors inhibitors and platelets
Thrombosis multiple organ failures
Bleeding complications and shock
Physiopathology of DIC ndash Overt DIC Findings
Thrombin generation
Thrombosis
Renal liver respiratory failures coma skin necrosis gangrene venous thromboembolism hypotension edema
Cytokine and kinin generation (shock)bull Tachycardia hypotension edema
Plasmin generationHemorrhage
bull Spontaneous bruising petechiae intracranial gastrointestinal and respiratory tract bleeding persistent bleeding at venipuncture sites at surgical wounds
bull Tachycardia hypotension edema
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Pathogenesis Pathways in DIC
Cytokines
TF-mediated dysfunctional impairedthrombin anticoagulant fibrinolysisgeneration mechanism due to PAI-1 deficiency
fibrin inadequateformation fibrin removal
Fibrin deposition
Inflammation
Coagulation
Stago Celebrates Lab Week 2017
NA
Stago 247 Educational Webinar Sites
wwwstago-edvantagecomUS based KOLsPACE accredited ndash all 1 hourAccessible from mobile devicesVirtual exhibit hall
wwwstagowebinarscomMostly European KOLs30 ndash 45 min including 15 min discussion
Stago Educational Apps
HaemoscoreClinical scoring algorithmsApple and AndroidTablet or phone
iHemostasisCoagulation diagramsCase studiesApple amp AndroidTablet only
BREAK
Diagnostic and Management Approach for DIC
Diagnosis of DIC
Clinical diagnosis is obvious in cases of overt DIC
Laboratory tests are necessary To makeconfirm the diagnosis To assess stage of the patient To assess the treatment efficacy
Lab Diagnosis of DIC ndash Markers of Factor Consumption
Routinescreening assays PT APTT Platelets Fibrinogen Thrombin time
Other coagulation assays Factor assays AntithrombinGeneration of Thrombin FMFSPsGeneration of Plasmin D-dimer FDPs
Important to recognize simultaneous formation of thrombin and plasmin
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122
Lab Diagnosis of DIC ndash Screening Tests
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122
Platelet count usually decreasedPT abnormal in 70 of cases (short half-life of FVII)APTT abnormal in 50 of casesThrombin time usually prolonged in overt DIC normal in non-overt DIC and no relation with syndrome severityFibrinogen low in lt 50 of cases sensitivity 22 specificity 87 overall predictive value 64 Normal fibrinogen level should not exclude DIC diagnosis (acute phase reactant initial high
fibrinogen level) repeat testing assesses progression
Screening tests not clinically specific or sensitive for DIC
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Laboratory Changes in Overt DIC
DIC Diagnostic Practices Over Time
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
British Journal of Haematology Overt DIC Score
Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
ISTH Step by Step DIC Algorithm
Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6
US Based Validation of ISTH DIC Score
When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Differential Diagnosis in DIC
aHUS atypical hemolytic uremic syndrome
HUS hemolytic uremic syndrome
HIT heparin-induced thrombocytopenia
ITP immune thrombocytopenic purpura
TTP thrombotic thrombocytopenic purpura
DIC and MAHA
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)
When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation
DIC Management Goals
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction
DIC Management and Treatment
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)
requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)
Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia
DIC Management Strategies
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant Factor Concentrate Treatment
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis
Anticoagulant Factor Concentrate Treatment Trials
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise
Markers of Thrombin amp Plasmin Generation in DIC
D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC
Cut-off value
Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen
degradation products Sensitive assay typically with cutoff adapted for DIC
D-dimer FDPs and DIC
D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC
Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80
Follow Up of DIC State of Disease
Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8
Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility
FMD-Dimer in DIC Major Differences
onset of thrombosis
days
Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8
FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)
D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)
of Abnormal Results in Patients with Confirmed and Suspected DIC
0
20
40
60
80
100
94 85 90N = 62
Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32
Positivity of Test Results ISTH Score and Disease State
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
Red bar positive for 2 points of DIC score
Pink bar positive for 1-2 points of DIC score
HT hematopoietic tumor
IF infection
SC solid cancer
Markers in Patients with or without DIC
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
HT hematopoietic tumorIF infectionSC solid cancer
Comparing an Automated FM vs Manual FSP Test
Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71
Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)
Automated (Mitsubishi) vs Automated (Stago)
In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago
Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC
Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
Non Overt DIC Overt DIC
AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC
Trends in Markers of DIC for Different Patients
Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00
Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients
Trends in Markers of DIC for Different Patients
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes
28 day outcome survival
28 day outcome death
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines
DIC Case Studies
Case Study 1 - Presentation
18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE
WBC count 77 KμL 423 ndash 907 x KμL
RBC count 17 MμL 137 ndash 175 x MμL
Hemoglobin 67 gdL 137 ndash 175 gdL
Hematocrit 195 401 ndash 510
MCV 95 fL 790 ndash 922 fL
MPV 12 fL 94 ndash 124 fL
Platelet count 9 KμL 161 ndash 347 KμL
Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0
Lymphocytes monocytes eosinophils basophils all below normal range
PT 47 sec (corrected on mixing study) 116 ndash 152 sec
APTT 75 sec (corrected on mixing study) 253 ndash 373 sec
Fibrinogen lt 76 mgdL 177 ndash 466 mgdL
D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Microscopy
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Arrow shows giant platelets in this peripheral smear Promyelocytes apparent
Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)
DIC due to TF release by APL blasts
Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases
Transfusions to replace factors along with platelets and RBCs during APL treatment
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started
Case Study 2 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L
PT 30 sec 113 ndash 146 sec
APTT 75 sec 25 ndash 34 sec
D-dimer 078 microgml FEU lt050 microgml FEU
Fibrinogen 92 mgdl 150-400 mgdl
pH 728 738 to 742
PaO2 570 mmHg 80-100 mmHg
WBC 33 times 103mm3 40-11 times 103mm3
ALT 111 IUL 0ndash34 IUL
AST 61 IUL 0ndash34 IUL
BUN 303 mgdL 08-13 mgdL
Case Study 2 ndash Lab Results
Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures
Case Study 2 ndash Diagnosis
60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior
Case Study 3 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L
PT 228 sec 113 ndash 146 sec
APTT 45 sec 25 ndash 34 sec
D-dimer 080 microgml FEU lt050 microgmL FEU
Fibrinogen 82 mgdL 150-400 mgdL
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 134 gdL 14-16 gdL
WBC 81 times 103mm3 40-11 times 103mm3
ALT 32 IUL 0ndash34 IUL
AST 28 IUL 0ndash34 IUL
BUN 09 mgdL 08-13 mgdL
Case Study 3 ndash Lab Results
Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment
Case Study 3 ndash Diagnosis and Therapy
Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91
Case Study 4 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L
PT 28 sec 113 ndash 146 sec
APTT 71 sec 25 ndash 34 sec
D-dimer 31 microgmL FEU lt050 microgml FEU
Fibrinogen 92 mgdL 150-400 mgdl
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 158 gdL 14-16 gdL
WBC 71 times 103mm3 40-11 times 103mm3
ALT 60 IUL 0ndash34 IUL
AST 47 IUL 0ndash34 IUL
BUN 38 mgdL 08-13 mgdL
Case Study 4 ndash Lab Results
Lyme disease with DICProvide antibiotics with supportive measures
Case Study 4 ndash Diagnosis
55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis
Case Study 5 ndash Presentation
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
Case Study 5 ndash Lab Results and Time Course
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
TEST RESULT REFERENCE RANGE
Platelet count 33 x 109L 150-450 x 109L
PT 215 sec 103 ndash 128 sec
APTT 44 sec 26 ndash 36 sec
D-dimer 20 microgmL FEU lt025 microgml FEU
Fibrinogen 34 mgdL 200-375 mgdl
FII FV FVIII Low Not reported (NR)
FVII FIX FX vWF Normal NR
Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)
DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic
dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR
(C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen
(D) Illustration demonstrating repair
Case Study 5 ndash Diagnosis and Treatment
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography
Case Study 6 ndash Presentation
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
Case Study 6 ndash Lab Results
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L
PT 63 sec gt control 113 ndash 146 sec
INR 658 1 ndash 125
APTT 80 sec gt control 25 ndash 34 sec
D-dimer gt200 microgmL DDU 02 microgmL DDU
Urine exam Proteinuria and hematuria 150-400 mgdl
Albumin 28 gdL NR
Hb 58 gdL NR
LDH 1196 UL NR
SGPT 144 IU NR
SGOT 88 IU NR
Bilirubin 32 mgdL NR
DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th
day postop
Case Study 6 ndash Diagnosis and Treatment
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure
Case Study 6 ndash Discussion
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Case Study 7 ndash Lab Results vs Time
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
DIC Take Home Messages
Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation
Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers
DIC
Thank you Questions
- Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
- Learning Objectives
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Wound Sealing
- The Three Steps of Hemostasis
- Vessel Wall
- Slide Number 12
- Slide Number 13
- Platelet Structure UnactivatedActivated
- Primary Hemostasis
- Primary Hemostasis Assays
- Slide Number 17
- Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
- Slide Number 19
- Coagulation factors
- Coagulation Assay Mechanisms
- Slide Number 22
- Fibrin Formation
- Slide Number 24
- Fibrinolysis Overview
- Fibrinolysis Overview
- Slide Number 27
- Fibrinolysis Releases D-dimers
- Basic Pathophysiology of DIC
- Disseminated Intravascular Coagulation (DIC)
- Purpura Fulminans with DIC Due to Meningococcal Sepsis
- Clinical Conditions Associated With DIC
- Frequency of DIC in Selected Disease States
- Underlying Diseases in DIC Patients
- Slide Number 36
- Slide Number 37
- Slide Number 38
- Slide Number 39
- Pathophysiology of DIC
- Pathogenesis of DIC in Sepsis
- Host Response in Severe Sepsis
- Organ Failure in Severe Sepsis
- Mechanism of DIC in Organ Failure
- Interaction of Inflammation and Coagulation in Sepsis
- Slide Number 47
- Diverse and Opposing Effects of Thrombin
- Coagulation and Fibrinolysis in DIC
- Mechanism of DIC
- Pathophysiology of DIC
- Pathophysiology of DIC - Mechanism
- Pathophysiology of DIC ndash 2 Types of Clinical pictures
- Sub-Acute and Non-Overt DIC Clinical Findings
- Pathophysiology of Overt DIC
- Physiopathology of DIC ndash Overt DIC Findings
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- BREAK
- Diagnostic and Management Approach for DIC
- Diagnosis of DIC
- Lab Diagnosis of DIC ndash Markers of Factor Consumption
- Lab Diagnosis of DIC ndash Screening Tests
- Slide Number 67
- Slide Number 68
- British Journal of Haematology Overt DIC Score
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- DIC Management Goals
- DIC Management and Treatment
- DIC Management Strategies
- Anticoagulant Factor Concentrate Treatment
- Anticoagulant Factor Concentrate Treatment Trials
- Markers of Thrombin amp Plasmin Generation in DIC
- D-dimer FDPs and DIC
- D-Dimer and FDPs in DIC
- Follow Up of DIC State of Disease
- FMD-Dimer in DIC Major Differences
- of Abnormal Results in Patients with Confirmed and Suspected DIC
- Slide Number 85
- Slide Number 86
- Comparing an Automated FM vs Manual FSP Test
- Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Slide Number 94
- Slide Number 95
- Slide Number 96
- Slide Number 97
- Slide Number 98
- Slide Number 99
- DIC Case Studies
- Case Study 1 - Presentation
- Case Study 1 ndash Lab Results
- Case Study 1 ndash Microscopy
- Case Study 1 ndash Diagnosis and Therapy
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Slide Number 110
- Slide Number 111
- Slide Number 112
- Slide Number 113
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
- Slide Number 124
- Slide Number 125
- DIC Take Home Messages
- Slide Number 127
- Slide Number 128
-
Coagulation Assay Mechanisms
aPTT Based
PT Based
PT Based
Fibrin Under Microscope
Weisel JW Structure of fibrin impact on clot stability J Thromb Haemost 2007 5 Suppl 1 116-24
Low thrombin concentration
High thrombin concentration
Fibrin Formation
Soluble FibrinPolymer
ThrombinFibrinogen
FM+ fibrinopeptides A amp B
Stabilized Fibrin clot(not soluble)
ThrombinXIII XIIIa
(Digestion of Fibrin)
Fibrinolysis
Fibrinolysis Overview
Destroys fibrin fibers
Destroys the scab (dried wound)
Maintains vessel integrity
Fibrinolysis Overview
Fibrin =cement fibers
Plasmin
Plasmin digests fibrin
t-PA
Pro Urokinase
Urokinase
PAI-1PAI-1
Plasminogen Plasmin
1st Step
2nd Step
Fibrinolysis Cascade
t-PA tissue-type plasminogen activator PAI-1 Plasminogen activator inhibitor 1 PK Prekallikrein FDP Fibrinogen degradation products AP Antiplasmin = a2AP alpha 2 Antiplasmin a2MG alpha 2 Macroglobulin
Extrinsic pathway(endothelia l cells)
Intrinsic pathway(plasma)
Fibrin clot
D-dimerFibrin degradation products
Fibrin
TAFIa
APAntiplasmin(amp a2-MG)
PK Kallikrein
XII
Fibrinolysis Releases D-dimers
D-dimer presence fibrin has been formed and digested in patients body
Normal D-dimer level no thrombosis occurred in the patient
Basic Pathophysiology of DIC
Disseminated Intravascular Coagulation (DIC)
Massive activation of coagulation leading to clots forming in multiple locations around the bodyRapid consumption of clotting factors leading to bleedingParadoxical condition leading to both clotting and bleedingA confusing disorder from both diagnostic and therapeutic standpoints Many unrelated diseases can trigger DIC Lack of uniformity in clinical manifestation Lack of uniformity in the laboratory diagnosis Lack of uniformity or consensus on management
Clinical Manifestations of DICOrgan Ischemic Hemorrhagic
Skin Pupura Fulminans Petechiae
Gangrene Echymoses
Acral cyanosis Oozing
CNS Deliriumcoma Intracranial
Infarcts Bleeding
Renal OliguriaAzotemia Hematuria
Cortical Necrosis
Cardiovascular Myocardial dysfunction
Pulmonary DyspneaHypoxia Hemorrhagic lung
Infarct
Gastrointestinal Ulcers infarcts Massive hemorrhage
Endocrine Adrenal infarcts
Purpura Fulminans with DIC Due to Meningococcal Sepsis
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Clinical Conditions Associated With DIC
Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33
Frequency of DIC in Selected Disease States
Disease Frequency
Gram-negative sepsis 30-50
Severe trauma and systemic inflammation 50-70
Metastasized tumors 15
Abruptio placentaamniotic fluid embolism 50
Severe preeclampsia 7
Giant hemangioma 25
Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92
Masao Nakagawa Modified from a research report on the incidence of disseminated intravascular coagulation (DIC) and underlying diseases in Japan Ministry of Health Labour and Welfare Research report published in Fiscal Year 1998 57-64 199 httpwwwrecomodulincomendicindexhtml Accessed Apr 21 2017
Underlying Diseases in DIC Patients
In a Japanese survey from 1997 on incidence of DIC and underlying diseases in 652 divisions and departments of university hospitals DIC occurred in 2193 patients with the number of patient with infections (including sepsis) and hematologic tumors (including leukemia) accounted for 28 and 23 respectively
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Epidemiology of DIC
Impact of DIC Status on Mortality - 1
Okamoto K Wada H Hatada T Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Frequency and hemostatic abnormalities in pre-DIC patients Thromb Res 2010 126 74-8
Patients with positivity of DIC tend to have worse mortality outcomes compared to negative patients or those with pre-DIC
Impact of DIC Status on Mortality - 2
Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4
Patients with positivity of either Overt or Non-Overt DIC tend to have worse mortality outcomes compared to negative patients
Impact of Age on Mortality in DIC Patients
Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4
Older patients with DIC (black bars) generally tend to have worse outcomes compared to non-DIC patients (grey bars)
Pathophysiology of DIC
Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33
Pathogenesis of DIC in Sepsis
Allen KS Sawheny E Kinasewitzet GT Anticoagulant modulation of inflammation in severe sepsis World J Crit Care Med 2015 4 105-15
Bacteria in sepsis infections cause release of TF from immune cells leading to coagulation activation and proinflammatory cytokines cause endothelial cell activation impairing the anticoagulation and fibrinolysis process resulting in DIC
Host Response in Severe Sepsis
Exaggerated inflammation as a result of the host response to sepsis is collateral tissue damage and cell death further resulting in release of danger molecules continuing the inflammatory process in a downward spiral
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Organ Failure in Severe Sepsis
Sepsis associated with microvascular thrombosis as a result of TF mediated coagulation activation results in release of neutrophil extracellular traps (NETs) tissue hypoperfusion and mitochondrial damage resulting in a downward spiral leading to organ failure
Angus DC van der Poll T Severe Sepsis and Septic Shock N Engl J Med 2013 369 840-51
Mechanism of DIC in Organ Failure
Underlying condition(sepsis trauma)
Cytokines
TF-mediatedactivation of coagulation
Depression of inhibitory systems
Reducesfibrinolysis
Fibrin deposition
Organ failure
Inadequate fibrin removal
Fibrinformation
Note impaired fibrinolysis in relation to the clinical need not in absolute value (FDPs are )
Levi M de Jonge E van der Poll T ten Cate H Disseminated intravascular coagulation ThrombHaemost 1999 82 695-705
Interaction of Inflammation and Coagulation in Sepsis
Binding of TF thrombin and other activation coagulation factors to PARs and fibrin to TLRs on inflammatory cells results in inflammation through release of proinflammatory cytokines and chemokines
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Mechanism of Multiple Organ Failure in DIC
Wheeler AP Bernard GR Treating Patients with Severe Sepsis N Engl J Med 1999 340207-14
Inflammatory activation and microvascular thrombosis contributes to multiple organ failure in DIC
lipopolysaccharides
cytokines
coagulation activation
mononuclear cell
tissue factor
Diverse and Opposing Effects of Thrombin
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Coagulation and Fibrinolysis in DIC
Soluble fibrin Polymer
XIIIa
D-Dimer
E
Fibrin clot
Fibrin Degradation Products
Fibrinogen Thrombin
Fibrinogen Degradation
Products
D E
Plasmin
DFM + fibrinopeptides
Soluble FM ComplexesPre-throm
boticPost-throm
botic
Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis Semin Thromb Hemost 2008 34 33-8
Mechanism of DIC
THROMBOSIS
Fibrin
Blood activationEndothelial lysisTF expression
BLEEDING
FDPs
D-Dimer
Plasmin
Pathophysiology of DIC
1st step abnormal activation of coagulation Injury of vessel wall cells venous stasis release of large quantities of
thromboplastin influx of activated cells (monocytes macrophages)
Results in an intravascular deposition of fibrin
Morbidity from disseminated microthrombosis in small and midsize vessels leading to multiple organ failure
Second step Consumption and depletion of coagulation factors inhibitors (Protein C
Protein S AT) and platelets Local fibrinolytic response
bull Local plasmin generation dissolves the thrombusbull Disseminated overwhelming fibrinolytic response leading to production of
FDP and D-Dimer
Bleeding
Pathophysiology of DIC - Mechanism
Systemic activation of coagulation
Intravasculardepositionof fibrin
Thrombosis of small and midsize vessels
and organ failure
Depletion of platelets and
coagulation factors
Bleeding
Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92
Pathophysiology of DIC ndash 2 Types of Clinical pictures
Chronic = non - overt DICMay be unrecognized clinically
Acute = overt DIClife threatening bleedingor multiple organ failure
Sub-Acute and Non-Overt DIC Clinical Findings
Compensated non-overt DIC Steady low level or intermittent activation
bull Compensated by increased production of coagulation components and platelets
Few or no clinical signs or multiple microvascular thrombosis sometimes not clinically obvious
Risk of decompensation leading to overt DIC
Pathophysiology of Overt DIC
Massive activation of coagulation and fibrinolysis
Does not allow for compensatory efforts
Rapid depletion of coagulation factors inhibitors and platelets
Thrombosis multiple organ failures
Bleeding complications and shock
Physiopathology of DIC ndash Overt DIC Findings
Thrombin generation
Thrombosis
Renal liver respiratory failures coma skin necrosis gangrene venous thromboembolism hypotension edema
Cytokine and kinin generation (shock)bull Tachycardia hypotension edema
Plasmin generationHemorrhage
bull Spontaneous bruising petechiae intracranial gastrointestinal and respiratory tract bleeding persistent bleeding at venipuncture sites at surgical wounds
bull Tachycardia hypotension edema
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Pathogenesis Pathways in DIC
Cytokines
TF-mediated dysfunctional impairedthrombin anticoagulant fibrinolysisgeneration mechanism due to PAI-1 deficiency
fibrin inadequateformation fibrin removal
Fibrin deposition
Inflammation
Coagulation
Stago Celebrates Lab Week 2017
NA
Stago 247 Educational Webinar Sites
wwwstago-edvantagecomUS based KOLsPACE accredited ndash all 1 hourAccessible from mobile devicesVirtual exhibit hall
wwwstagowebinarscomMostly European KOLs30 ndash 45 min including 15 min discussion
Stago Educational Apps
HaemoscoreClinical scoring algorithmsApple and AndroidTablet or phone
iHemostasisCoagulation diagramsCase studiesApple amp AndroidTablet only
BREAK
Diagnostic and Management Approach for DIC
Diagnosis of DIC
Clinical diagnosis is obvious in cases of overt DIC
Laboratory tests are necessary To makeconfirm the diagnosis To assess stage of the patient To assess the treatment efficacy
Lab Diagnosis of DIC ndash Markers of Factor Consumption
Routinescreening assays PT APTT Platelets Fibrinogen Thrombin time
Other coagulation assays Factor assays AntithrombinGeneration of Thrombin FMFSPsGeneration of Plasmin D-dimer FDPs
Important to recognize simultaneous formation of thrombin and plasmin
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122
Lab Diagnosis of DIC ndash Screening Tests
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122
Platelet count usually decreasedPT abnormal in 70 of cases (short half-life of FVII)APTT abnormal in 50 of casesThrombin time usually prolonged in overt DIC normal in non-overt DIC and no relation with syndrome severityFibrinogen low in lt 50 of cases sensitivity 22 specificity 87 overall predictive value 64 Normal fibrinogen level should not exclude DIC diagnosis (acute phase reactant initial high
fibrinogen level) repeat testing assesses progression
Screening tests not clinically specific or sensitive for DIC
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Laboratory Changes in Overt DIC
DIC Diagnostic Practices Over Time
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
British Journal of Haematology Overt DIC Score
Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
ISTH Step by Step DIC Algorithm
Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6
US Based Validation of ISTH DIC Score
When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Differential Diagnosis in DIC
aHUS atypical hemolytic uremic syndrome
HUS hemolytic uremic syndrome
HIT heparin-induced thrombocytopenia
ITP immune thrombocytopenic purpura
TTP thrombotic thrombocytopenic purpura
DIC and MAHA
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)
When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation
DIC Management Goals
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction
DIC Management and Treatment
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)
requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)
Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia
DIC Management Strategies
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant Factor Concentrate Treatment
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis
Anticoagulant Factor Concentrate Treatment Trials
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise
Markers of Thrombin amp Plasmin Generation in DIC
D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC
Cut-off value
Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen
degradation products Sensitive assay typically with cutoff adapted for DIC
D-dimer FDPs and DIC
D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC
Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80
Follow Up of DIC State of Disease
Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8
Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility
FMD-Dimer in DIC Major Differences
onset of thrombosis
days
Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8
FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)
D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)
of Abnormal Results in Patients with Confirmed and Suspected DIC
0
20
40
60
80
100
94 85 90N = 62
Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32
Positivity of Test Results ISTH Score and Disease State
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
Red bar positive for 2 points of DIC score
Pink bar positive for 1-2 points of DIC score
HT hematopoietic tumor
IF infection
SC solid cancer
Markers in Patients with or without DIC
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
HT hematopoietic tumorIF infectionSC solid cancer
Comparing an Automated FM vs Manual FSP Test
Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71
Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)
Automated (Mitsubishi) vs Automated (Stago)
In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago
Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC
Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
Non Overt DIC Overt DIC
AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC
Trends in Markers of DIC for Different Patients
Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00
Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients
Trends in Markers of DIC for Different Patients
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes
28 day outcome survival
28 day outcome death
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines
DIC Case Studies
Case Study 1 - Presentation
18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE
WBC count 77 KμL 423 ndash 907 x KμL
RBC count 17 MμL 137 ndash 175 x MμL
Hemoglobin 67 gdL 137 ndash 175 gdL
Hematocrit 195 401 ndash 510
MCV 95 fL 790 ndash 922 fL
MPV 12 fL 94 ndash 124 fL
Platelet count 9 KμL 161 ndash 347 KμL
Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0
Lymphocytes monocytes eosinophils basophils all below normal range
PT 47 sec (corrected on mixing study) 116 ndash 152 sec
APTT 75 sec (corrected on mixing study) 253 ndash 373 sec
Fibrinogen lt 76 mgdL 177 ndash 466 mgdL
D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Microscopy
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Arrow shows giant platelets in this peripheral smear Promyelocytes apparent
Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)
DIC due to TF release by APL blasts
Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases
Transfusions to replace factors along with platelets and RBCs during APL treatment
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started
Case Study 2 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L
PT 30 sec 113 ndash 146 sec
APTT 75 sec 25 ndash 34 sec
D-dimer 078 microgml FEU lt050 microgml FEU
Fibrinogen 92 mgdl 150-400 mgdl
pH 728 738 to 742
PaO2 570 mmHg 80-100 mmHg
WBC 33 times 103mm3 40-11 times 103mm3
ALT 111 IUL 0ndash34 IUL
AST 61 IUL 0ndash34 IUL
BUN 303 mgdL 08-13 mgdL
Case Study 2 ndash Lab Results
Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures
Case Study 2 ndash Diagnosis
60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior
Case Study 3 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L
PT 228 sec 113 ndash 146 sec
APTT 45 sec 25 ndash 34 sec
D-dimer 080 microgml FEU lt050 microgmL FEU
Fibrinogen 82 mgdL 150-400 mgdL
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 134 gdL 14-16 gdL
WBC 81 times 103mm3 40-11 times 103mm3
ALT 32 IUL 0ndash34 IUL
AST 28 IUL 0ndash34 IUL
BUN 09 mgdL 08-13 mgdL
Case Study 3 ndash Lab Results
Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment
Case Study 3 ndash Diagnosis and Therapy
Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91
Case Study 4 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L
PT 28 sec 113 ndash 146 sec
APTT 71 sec 25 ndash 34 sec
D-dimer 31 microgmL FEU lt050 microgml FEU
Fibrinogen 92 mgdL 150-400 mgdl
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 158 gdL 14-16 gdL
WBC 71 times 103mm3 40-11 times 103mm3
ALT 60 IUL 0ndash34 IUL
AST 47 IUL 0ndash34 IUL
BUN 38 mgdL 08-13 mgdL
Case Study 4 ndash Lab Results
Lyme disease with DICProvide antibiotics with supportive measures
Case Study 4 ndash Diagnosis
55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis
Case Study 5 ndash Presentation
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
Case Study 5 ndash Lab Results and Time Course
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
TEST RESULT REFERENCE RANGE
Platelet count 33 x 109L 150-450 x 109L
PT 215 sec 103 ndash 128 sec
APTT 44 sec 26 ndash 36 sec
D-dimer 20 microgmL FEU lt025 microgml FEU
Fibrinogen 34 mgdL 200-375 mgdl
FII FV FVIII Low Not reported (NR)
FVII FIX FX vWF Normal NR
Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)
DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic
dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR
(C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen
(D) Illustration demonstrating repair
Case Study 5 ndash Diagnosis and Treatment
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography
Case Study 6 ndash Presentation
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
Case Study 6 ndash Lab Results
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L
PT 63 sec gt control 113 ndash 146 sec
INR 658 1 ndash 125
APTT 80 sec gt control 25 ndash 34 sec
D-dimer gt200 microgmL DDU 02 microgmL DDU
Urine exam Proteinuria and hematuria 150-400 mgdl
Albumin 28 gdL NR
Hb 58 gdL NR
LDH 1196 UL NR
SGPT 144 IU NR
SGOT 88 IU NR
Bilirubin 32 mgdL NR
DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th
day postop
Case Study 6 ndash Diagnosis and Treatment
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure
Case Study 6 ndash Discussion
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Case Study 7 ndash Lab Results vs Time
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
DIC Take Home Messages
Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation
Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers
DIC
Thank you Questions
- Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
- Learning Objectives
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Wound Sealing
- The Three Steps of Hemostasis
- Vessel Wall
- Slide Number 12
- Slide Number 13
- Platelet Structure UnactivatedActivated
- Primary Hemostasis
- Primary Hemostasis Assays
- Slide Number 17
- Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
- Slide Number 19
- Coagulation factors
- Coagulation Assay Mechanisms
- Slide Number 22
- Fibrin Formation
- Slide Number 24
- Fibrinolysis Overview
- Fibrinolysis Overview
- Slide Number 27
- Fibrinolysis Releases D-dimers
- Basic Pathophysiology of DIC
- Disseminated Intravascular Coagulation (DIC)
- Purpura Fulminans with DIC Due to Meningococcal Sepsis
- Clinical Conditions Associated With DIC
- Frequency of DIC in Selected Disease States
- Underlying Diseases in DIC Patients
- Slide Number 36
- Slide Number 37
- Slide Number 38
- Slide Number 39
- Pathophysiology of DIC
- Pathogenesis of DIC in Sepsis
- Host Response in Severe Sepsis
- Organ Failure in Severe Sepsis
- Mechanism of DIC in Organ Failure
- Interaction of Inflammation and Coagulation in Sepsis
- Slide Number 47
- Diverse and Opposing Effects of Thrombin
- Coagulation and Fibrinolysis in DIC
- Mechanism of DIC
- Pathophysiology of DIC
- Pathophysiology of DIC - Mechanism
- Pathophysiology of DIC ndash 2 Types of Clinical pictures
- Sub-Acute and Non-Overt DIC Clinical Findings
- Pathophysiology of Overt DIC
- Physiopathology of DIC ndash Overt DIC Findings
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- BREAK
- Diagnostic and Management Approach for DIC
- Diagnosis of DIC
- Lab Diagnosis of DIC ndash Markers of Factor Consumption
- Lab Diagnosis of DIC ndash Screening Tests
- Slide Number 67
- Slide Number 68
- British Journal of Haematology Overt DIC Score
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- DIC Management Goals
- DIC Management and Treatment
- DIC Management Strategies
- Anticoagulant Factor Concentrate Treatment
- Anticoagulant Factor Concentrate Treatment Trials
- Markers of Thrombin amp Plasmin Generation in DIC
- D-dimer FDPs and DIC
- D-Dimer and FDPs in DIC
- Follow Up of DIC State of Disease
- FMD-Dimer in DIC Major Differences
- of Abnormal Results in Patients with Confirmed and Suspected DIC
- Slide Number 85
- Slide Number 86
- Comparing an Automated FM vs Manual FSP Test
- Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Slide Number 94
- Slide Number 95
- Slide Number 96
- Slide Number 97
- Slide Number 98
- Slide Number 99
- DIC Case Studies
- Case Study 1 - Presentation
- Case Study 1 ndash Lab Results
- Case Study 1 ndash Microscopy
- Case Study 1 ndash Diagnosis and Therapy
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Slide Number 110
- Slide Number 111
- Slide Number 112
- Slide Number 113
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
- Slide Number 124
- Slide Number 125
- DIC Take Home Messages
- Slide Number 127
- Slide Number 128
-
Fibrin Under Microscope
Weisel JW Structure of fibrin impact on clot stability J Thromb Haemost 2007 5 Suppl 1 116-24
Low thrombin concentration
High thrombin concentration
Fibrin Formation
Soluble FibrinPolymer
ThrombinFibrinogen
FM+ fibrinopeptides A amp B
Stabilized Fibrin clot(not soluble)
ThrombinXIII XIIIa
(Digestion of Fibrin)
Fibrinolysis
Fibrinolysis Overview
Destroys fibrin fibers
Destroys the scab (dried wound)
Maintains vessel integrity
Fibrinolysis Overview
Fibrin =cement fibers
Plasmin
Plasmin digests fibrin
t-PA
Pro Urokinase
Urokinase
PAI-1PAI-1
Plasminogen Plasmin
1st Step
2nd Step
Fibrinolysis Cascade
t-PA tissue-type plasminogen activator PAI-1 Plasminogen activator inhibitor 1 PK Prekallikrein FDP Fibrinogen degradation products AP Antiplasmin = a2AP alpha 2 Antiplasmin a2MG alpha 2 Macroglobulin
Extrinsic pathway(endothelia l cells)
Intrinsic pathway(plasma)
Fibrin clot
D-dimerFibrin degradation products
Fibrin
TAFIa
APAntiplasmin(amp a2-MG)
PK Kallikrein
XII
Fibrinolysis Releases D-dimers
D-dimer presence fibrin has been formed and digested in patients body
Normal D-dimer level no thrombosis occurred in the patient
Basic Pathophysiology of DIC
Disseminated Intravascular Coagulation (DIC)
Massive activation of coagulation leading to clots forming in multiple locations around the bodyRapid consumption of clotting factors leading to bleedingParadoxical condition leading to both clotting and bleedingA confusing disorder from both diagnostic and therapeutic standpoints Many unrelated diseases can trigger DIC Lack of uniformity in clinical manifestation Lack of uniformity in the laboratory diagnosis Lack of uniformity or consensus on management
Clinical Manifestations of DICOrgan Ischemic Hemorrhagic
Skin Pupura Fulminans Petechiae
Gangrene Echymoses
Acral cyanosis Oozing
CNS Deliriumcoma Intracranial
Infarcts Bleeding
Renal OliguriaAzotemia Hematuria
Cortical Necrosis
Cardiovascular Myocardial dysfunction
Pulmonary DyspneaHypoxia Hemorrhagic lung
Infarct
Gastrointestinal Ulcers infarcts Massive hemorrhage
Endocrine Adrenal infarcts
Purpura Fulminans with DIC Due to Meningococcal Sepsis
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Clinical Conditions Associated With DIC
Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33
Frequency of DIC in Selected Disease States
Disease Frequency
Gram-negative sepsis 30-50
Severe trauma and systemic inflammation 50-70
Metastasized tumors 15
Abruptio placentaamniotic fluid embolism 50
Severe preeclampsia 7
Giant hemangioma 25
Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92
Masao Nakagawa Modified from a research report on the incidence of disseminated intravascular coagulation (DIC) and underlying diseases in Japan Ministry of Health Labour and Welfare Research report published in Fiscal Year 1998 57-64 199 httpwwwrecomodulincomendicindexhtml Accessed Apr 21 2017
Underlying Diseases in DIC Patients
In a Japanese survey from 1997 on incidence of DIC and underlying diseases in 652 divisions and departments of university hospitals DIC occurred in 2193 patients with the number of patient with infections (including sepsis) and hematologic tumors (including leukemia) accounted for 28 and 23 respectively
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Epidemiology of DIC
Impact of DIC Status on Mortality - 1
Okamoto K Wada H Hatada T Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Frequency and hemostatic abnormalities in pre-DIC patients Thromb Res 2010 126 74-8
Patients with positivity of DIC tend to have worse mortality outcomes compared to negative patients or those with pre-DIC
Impact of DIC Status on Mortality - 2
Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4
Patients with positivity of either Overt or Non-Overt DIC tend to have worse mortality outcomes compared to negative patients
Impact of Age on Mortality in DIC Patients
Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4
Older patients with DIC (black bars) generally tend to have worse outcomes compared to non-DIC patients (grey bars)
Pathophysiology of DIC
Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33
Pathogenesis of DIC in Sepsis
Allen KS Sawheny E Kinasewitzet GT Anticoagulant modulation of inflammation in severe sepsis World J Crit Care Med 2015 4 105-15
Bacteria in sepsis infections cause release of TF from immune cells leading to coagulation activation and proinflammatory cytokines cause endothelial cell activation impairing the anticoagulation and fibrinolysis process resulting in DIC
Host Response in Severe Sepsis
Exaggerated inflammation as a result of the host response to sepsis is collateral tissue damage and cell death further resulting in release of danger molecules continuing the inflammatory process in a downward spiral
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Organ Failure in Severe Sepsis
Sepsis associated with microvascular thrombosis as a result of TF mediated coagulation activation results in release of neutrophil extracellular traps (NETs) tissue hypoperfusion and mitochondrial damage resulting in a downward spiral leading to organ failure
Angus DC van der Poll T Severe Sepsis and Septic Shock N Engl J Med 2013 369 840-51
Mechanism of DIC in Organ Failure
Underlying condition(sepsis trauma)
Cytokines
TF-mediatedactivation of coagulation
Depression of inhibitory systems
Reducesfibrinolysis
Fibrin deposition
Organ failure
Inadequate fibrin removal
Fibrinformation
Note impaired fibrinolysis in relation to the clinical need not in absolute value (FDPs are )
Levi M de Jonge E van der Poll T ten Cate H Disseminated intravascular coagulation ThrombHaemost 1999 82 695-705
Interaction of Inflammation and Coagulation in Sepsis
Binding of TF thrombin and other activation coagulation factors to PARs and fibrin to TLRs on inflammatory cells results in inflammation through release of proinflammatory cytokines and chemokines
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Mechanism of Multiple Organ Failure in DIC
Wheeler AP Bernard GR Treating Patients with Severe Sepsis N Engl J Med 1999 340207-14
Inflammatory activation and microvascular thrombosis contributes to multiple organ failure in DIC
lipopolysaccharides
cytokines
coagulation activation
mononuclear cell
tissue factor
Diverse and Opposing Effects of Thrombin
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Coagulation and Fibrinolysis in DIC
Soluble fibrin Polymer
XIIIa
D-Dimer
E
Fibrin clot
Fibrin Degradation Products
Fibrinogen Thrombin
Fibrinogen Degradation
Products
D E
Plasmin
DFM + fibrinopeptides
Soluble FM ComplexesPre-throm
boticPost-throm
botic
Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis Semin Thromb Hemost 2008 34 33-8
Mechanism of DIC
THROMBOSIS
Fibrin
Blood activationEndothelial lysisTF expression
BLEEDING
FDPs
D-Dimer
Plasmin
Pathophysiology of DIC
1st step abnormal activation of coagulation Injury of vessel wall cells venous stasis release of large quantities of
thromboplastin influx of activated cells (monocytes macrophages)
Results in an intravascular deposition of fibrin
Morbidity from disseminated microthrombosis in small and midsize vessels leading to multiple organ failure
Second step Consumption and depletion of coagulation factors inhibitors (Protein C
Protein S AT) and platelets Local fibrinolytic response
bull Local plasmin generation dissolves the thrombusbull Disseminated overwhelming fibrinolytic response leading to production of
FDP and D-Dimer
Bleeding
Pathophysiology of DIC - Mechanism
Systemic activation of coagulation
Intravasculardepositionof fibrin
Thrombosis of small and midsize vessels
and organ failure
Depletion of platelets and
coagulation factors
Bleeding
Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92
Pathophysiology of DIC ndash 2 Types of Clinical pictures
Chronic = non - overt DICMay be unrecognized clinically
Acute = overt DIClife threatening bleedingor multiple organ failure
Sub-Acute and Non-Overt DIC Clinical Findings
Compensated non-overt DIC Steady low level or intermittent activation
bull Compensated by increased production of coagulation components and platelets
Few or no clinical signs or multiple microvascular thrombosis sometimes not clinically obvious
Risk of decompensation leading to overt DIC
Pathophysiology of Overt DIC
Massive activation of coagulation and fibrinolysis
Does not allow for compensatory efforts
Rapid depletion of coagulation factors inhibitors and platelets
Thrombosis multiple organ failures
Bleeding complications and shock
Physiopathology of DIC ndash Overt DIC Findings
Thrombin generation
Thrombosis
Renal liver respiratory failures coma skin necrosis gangrene venous thromboembolism hypotension edema
Cytokine and kinin generation (shock)bull Tachycardia hypotension edema
Plasmin generationHemorrhage
bull Spontaneous bruising petechiae intracranial gastrointestinal and respiratory tract bleeding persistent bleeding at venipuncture sites at surgical wounds
bull Tachycardia hypotension edema
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Pathogenesis Pathways in DIC
Cytokines
TF-mediated dysfunctional impairedthrombin anticoagulant fibrinolysisgeneration mechanism due to PAI-1 deficiency
fibrin inadequateformation fibrin removal
Fibrin deposition
Inflammation
Coagulation
Stago Celebrates Lab Week 2017
NA
Stago 247 Educational Webinar Sites
wwwstago-edvantagecomUS based KOLsPACE accredited ndash all 1 hourAccessible from mobile devicesVirtual exhibit hall
wwwstagowebinarscomMostly European KOLs30 ndash 45 min including 15 min discussion
Stago Educational Apps
HaemoscoreClinical scoring algorithmsApple and AndroidTablet or phone
iHemostasisCoagulation diagramsCase studiesApple amp AndroidTablet only
BREAK
Diagnostic and Management Approach for DIC
Diagnosis of DIC
Clinical diagnosis is obvious in cases of overt DIC
Laboratory tests are necessary To makeconfirm the diagnosis To assess stage of the patient To assess the treatment efficacy
Lab Diagnosis of DIC ndash Markers of Factor Consumption
Routinescreening assays PT APTT Platelets Fibrinogen Thrombin time
Other coagulation assays Factor assays AntithrombinGeneration of Thrombin FMFSPsGeneration of Plasmin D-dimer FDPs
Important to recognize simultaneous formation of thrombin and plasmin
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122
Lab Diagnosis of DIC ndash Screening Tests
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122
Platelet count usually decreasedPT abnormal in 70 of cases (short half-life of FVII)APTT abnormal in 50 of casesThrombin time usually prolonged in overt DIC normal in non-overt DIC and no relation with syndrome severityFibrinogen low in lt 50 of cases sensitivity 22 specificity 87 overall predictive value 64 Normal fibrinogen level should not exclude DIC diagnosis (acute phase reactant initial high
fibrinogen level) repeat testing assesses progression
Screening tests not clinically specific or sensitive for DIC
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Laboratory Changes in Overt DIC
DIC Diagnostic Practices Over Time
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
British Journal of Haematology Overt DIC Score
Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
ISTH Step by Step DIC Algorithm
Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6
US Based Validation of ISTH DIC Score
When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Differential Diagnosis in DIC
aHUS atypical hemolytic uremic syndrome
HUS hemolytic uremic syndrome
HIT heparin-induced thrombocytopenia
ITP immune thrombocytopenic purpura
TTP thrombotic thrombocytopenic purpura
DIC and MAHA
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)
When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation
DIC Management Goals
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction
DIC Management and Treatment
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)
requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)
Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia
DIC Management Strategies
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant Factor Concentrate Treatment
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis
Anticoagulant Factor Concentrate Treatment Trials
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise
Markers of Thrombin amp Plasmin Generation in DIC
D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC
Cut-off value
Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen
degradation products Sensitive assay typically with cutoff adapted for DIC
D-dimer FDPs and DIC
D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC
Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80
Follow Up of DIC State of Disease
Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8
Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility
FMD-Dimer in DIC Major Differences
onset of thrombosis
days
Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8
FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)
D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)
of Abnormal Results in Patients with Confirmed and Suspected DIC
0
20
40
60
80
100
94 85 90N = 62
Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32
Positivity of Test Results ISTH Score and Disease State
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
Red bar positive for 2 points of DIC score
Pink bar positive for 1-2 points of DIC score
HT hematopoietic tumor
IF infection
SC solid cancer
Markers in Patients with or without DIC
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
HT hematopoietic tumorIF infectionSC solid cancer
Comparing an Automated FM vs Manual FSP Test
Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71
Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)
Automated (Mitsubishi) vs Automated (Stago)
In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago
Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC
Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
Non Overt DIC Overt DIC
AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC
Trends in Markers of DIC for Different Patients
Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00
Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients
Trends in Markers of DIC for Different Patients
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes
28 day outcome survival
28 day outcome death
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines
DIC Case Studies
Case Study 1 - Presentation
18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE
WBC count 77 KμL 423 ndash 907 x KμL
RBC count 17 MμL 137 ndash 175 x MμL
Hemoglobin 67 gdL 137 ndash 175 gdL
Hematocrit 195 401 ndash 510
MCV 95 fL 790 ndash 922 fL
MPV 12 fL 94 ndash 124 fL
Platelet count 9 KμL 161 ndash 347 KμL
Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0
Lymphocytes monocytes eosinophils basophils all below normal range
PT 47 sec (corrected on mixing study) 116 ndash 152 sec
APTT 75 sec (corrected on mixing study) 253 ndash 373 sec
Fibrinogen lt 76 mgdL 177 ndash 466 mgdL
D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Microscopy
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Arrow shows giant platelets in this peripheral smear Promyelocytes apparent
Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)
DIC due to TF release by APL blasts
Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases
Transfusions to replace factors along with platelets and RBCs during APL treatment
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started
Case Study 2 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L
PT 30 sec 113 ndash 146 sec
APTT 75 sec 25 ndash 34 sec
D-dimer 078 microgml FEU lt050 microgml FEU
Fibrinogen 92 mgdl 150-400 mgdl
pH 728 738 to 742
PaO2 570 mmHg 80-100 mmHg
WBC 33 times 103mm3 40-11 times 103mm3
ALT 111 IUL 0ndash34 IUL
AST 61 IUL 0ndash34 IUL
BUN 303 mgdL 08-13 mgdL
Case Study 2 ndash Lab Results
Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures
Case Study 2 ndash Diagnosis
60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior
Case Study 3 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L
PT 228 sec 113 ndash 146 sec
APTT 45 sec 25 ndash 34 sec
D-dimer 080 microgml FEU lt050 microgmL FEU
Fibrinogen 82 mgdL 150-400 mgdL
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 134 gdL 14-16 gdL
WBC 81 times 103mm3 40-11 times 103mm3
ALT 32 IUL 0ndash34 IUL
AST 28 IUL 0ndash34 IUL
BUN 09 mgdL 08-13 mgdL
Case Study 3 ndash Lab Results
Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment
Case Study 3 ndash Diagnosis and Therapy
Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91
Case Study 4 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L
PT 28 sec 113 ndash 146 sec
APTT 71 sec 25 ndash 34 sec
D-dimer 31 microgmL FEU lt050 microgml FEU
Fibrinogen 92 mgdL 150-400 mgdl
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 158 gdL 14-16 gdL
WBC 71 times 103mm3 40-11 times 103mm3
ALT 60 IUL 0ndash34 IUL
AST 47 IUL 0ndash34 IUL
BUN 38 mgdL 08-13 mgdL
Case Study 4 ndash Lab Results
Lyme disease with DICProvide antibiotics with supportive measures
Case Study 4 ndash Diagnosis
55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis
Case Study 5 ndash Presentation
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
Case Study 5 ndash Lab Results and Time Course
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
TEST RESULT REFERENCE RANGE
Platelet count 33 x 109L 150-450 x 109L
PT 215 sec 103 ndash 128 sec
APTT 44 sec 26 ndash 36 sec
D-dimer 20 microgmL FEU lt025 microgml FEU
Fibrinogen 34 mgdL 200-375 mgdl
FII FV FVIII Low Not reported (NR)
FVII FIX FX vWF Normal NR
Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)
DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic
dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR
(C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen
(D) Illustration demonstrating repair
Case Study 5 ndash Diagnosis and Treatment
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography
Case Study 6 ndash Presentation
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
Case Study 6 ndash Lab Results
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L
PT 63 sec gt control 113 ndash 146 sec
INR 658 1 ndash 125
APTT 80 sec gt control 25 ndash 34 sec
D-dimer gt200 microgmL DDU 02 microgmL DDU
Urine exam Proteinuria and hematuria 150-400 mgdl
Albumin 28 gdL NR
Hb 58 gdL NR
LDH 1196 UL NR
SGPT 144 IU NR
SGOT 88 IU NR
Bilirubin 32 mgdL NR
DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th
day postop
Case Study 6 ndash Diagnosis and Treatment
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure
Case Study 6 ndash Discussion
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Case Study 7 ndash Lab Results vs Time
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
DIC Take Home Messages
Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation
Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers
DIC
Thank you Questions
- Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
- Learning Objectives
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Wound Sealing
- The Three Steps of Hemostasis
- Vessel Wall
- Slide Number 12
- Slide Number 13
- Platelet Structure UnactivatedActivated
- Primary Hemostasis
- Primary Hemostasis Assays
- Slide Number 17
- Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
- Slide Number 19
- Coagulation factors
- Coagulation Assay Mechanisms
- Slide Number 22
- Fibrin Formation
- Slide Number 24
- Fibrinolysis Overview
- Fibrinolysis Overview
- Slide Number 27
- Fibrinolysis Releases D-dimers
- Basic Pathophysiology of DIC
- Disseminated Intravascular Coagulation (DIC)
- Purpura Fulminans with DIC Due to Meningococcal Sepsis
- Clinical Conditions Associated With DIC
- Frequency of DIC in Selected Disease States
- Underlying Diseases in DIC Patients
- Slide Number 36
- Slide Number 37
- Slide Number 38
- Slide Number 39
- Pathophysiology of DIC
- Pathogenesis of DIC in Sepsis
- Host Response in Severe Sepsis
- Organ Failure in Severe Sepsis
- Mechanism of DIC in Organ Failure
- Interaction of Inflammation and Coagulation in Sepsis
- Slide Number 47
- Diverse and Opposing Effects of Thrombin
- Coagulation and Fibrinolysis in DIC
- Mechanism of DIC
- Pathophysiology of DIC
- Pathophysiology of DIC - Mechanism
- Pathophysiology of DIC ndash 2 Types of Clinical pictures
- Sub-Acute and Non-Overt DIC Clinical Findings
- Pathophysiology of Overt DIC
- Physiopathology of DIC ndash Overt DIC Findings
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- BREAK
- Diagnostic and Management Approach for DIC
- Diagnosis of DIC
- Lab Diagnosis of DIC ndash Markers of Factor Consumption
- Lab Diagnosis of DIC ndash Screening Tests
- Slide Number 67
- Slide Number 68
- British Journal of Haematology Overt DIC Score
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- DIC Management Goals
- DIC Management and Treatment
- DIC Management Strategies
- Anticoagulant Factor Concentrate Treatment
- Anticoagulant Factor Concentrate Treatment Trials
- Markers of Thrombin amp Plasmin Generation in DIC
- D-dimer FDPs and DIC
- D-Dimer and FDPs in DIC
- Follow Up of DIC State of Disease
- FMD-Dimer in DIC Major Differences
- of Abnormal Results in Patients with Confirmed and Suspected DIC
- Slide Number 85
- Slide Number 86
- Comparing an Automated FM vs Manual FSP Test
- Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Slide Number 94
- Slide Number 95
- Slide Number 96
- Slide Number 97
- Slide Number 98
- Slide Number 99
- DIC Case Studies
- Case Study 1 - Presentation
- Case Study 1 ndash Lab Results
- Case Study 1 ndash Microscopy
- Case Study 1 ndash Diagnosis and Therapy
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Slide Number 110
- Slide Number 111
- Slide Number 112
- Slide Number 113
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
- Slide Number 124
- Slide Number 125
- DIC Take Home Messages
- Slide Number 127
- Slide Number 128
-
Fibrin Formation
Soluble FibrinPolymer
ThrombinFibrinogen
FM+ fibrinopeptides A amp B
Stabilized Fibrin clot(not soluble)
ThrombinXIII XIIIa
(Digestion of Fibrin)
Fibrinolysis
Fibrinolysis Overview
Destroys fibrin fibers
Destroys the scab (dried wound)
Maintains vessel integrity
Fibrinolysis Overview
Fibrin =cement fibers
Plasmin
Plasmin digests fibrin
t-PA
Pro Urokinase
Urokinase
PAI-1PAI-1
Plasminogen Plasmin
1st Step
2nd Step
Fibrinolysis Cascade
t-PA tissue-type plasminogen activator PAI-1 Plasminogen activator inhibitor 1 PK Prekallikrein FDP Fibrinogen degradation products AP Antiplasmin = a2AP alpha 2 Antiplasmin a2MG alpha 2 Macroglobulin
Extrinsic pathway(endothelia l cells)
Intrinsic pathway(plasma)
Fibrin clot
D-dimerFibrin degradation products
Fibrin
TAFIa
APAntiplasmin(amp a2-MG)
PK Kallikrein
XII
Fibrinolysis Releases D-dimers
D-dimer presence fibrin has been formed and digested in patients body
Normal D-dimer level no thrombosis occurred in the patient
Basic Pathophysiology of DIC
Disseminated Intravascular Coagulation (DIC)
Massive activation of coagulation leading to clots forming in multiple locations around the bodyRapid consumption of clotting factors leading to bleedingParadoxical condition leading to both clotting and bleedingA confusing disorder from both diagnostic and therapeutic standpoints Many unrelated diseases can trigger DIC Lack of uniformity in clinical manifestation Lack of uniformity in the laboratory diagnosis Lack of uniformity or consensus on management
Clinical Manifestations of DICOrgan Ischemic Hemorrhagic
Skin Pupura Fulminans Petechiae
Gangrene Echymoses
Acral cyanosis Oozing
CNS Deliriumcoma Intracranial
Infarcts Bleeding
Renal OliguriaAzotemia Hematuria
Cortical Necrosis
Cardiovascular Myocardial dysfunction
Pulmonary DyspneaHypoxia Hemorrhagic lung
Infarct
Gastrointestinal Ulcers infarcts Massive hemorrhage
Endocrine Adrenal infarcts
Purpura Fulminans with DIC Due to Meningococcal Sepsis
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Clinical Conditions Associated With DIC
Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33
Frequency of DIC in Selected Disease States
Disease Frequency
Gram-negative sepsis 30-50
Severe trauma and systemic inflammation 50-70
Metastasized tumors 15
Abruptio placentaamniotic fluid embolism 50
Severe preeclampsia 7
Giant hemangioma 25
Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92
Masao Nakagawa Modified from a research report on the incidence of disseminated intravascular coagulation (DIC) and underlying diseases in Japan Ministry of Health Labour and Welfare Research report published in Fiscal Year 1998 57-64 199 httpwwwrecomodulincomendicindexhtml Accessed Apr 21 2017
Underlying Diseases in DIC Patients
In a Japanese survey from 1997 on incidence of DIC and underlying diseases in 652 divisions and departments of university hospitals DIC occurred in 2193 patients with the number of patient with infections (including sepsis) and hematologic tumors (including leukemia) accounted for 28 and 23 respectively
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Epidemiology of DIC
Impact of DIC Status on Mortality - 1
Okamoto K Wada H Hatada T Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Frequency and hemostatic abnormalities in pre-DIC patients Thromb Res 2010 126 74-8
Patients with positivity of DIC tend to have worse mortality outcomes compared to negative patients or those with pre-DIC
Impact of DIC Status on Mortality - 2
Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4
Patients with positivity of either Overt or Non-Overt DIC tend to have worse mortality outcomes compared to negative patients
Impact of Age on Mortality in DIC Patients
Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4
Older patients with DIC (black bars) generally tend to have worse outcomes compared to non-DIC patients (grey bars)
Pathophysiology of DIC
Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33
Pathogenesis of DIC in Sepsis
Allen KS Sawheny E Kinasewitzet GT Anticoagulant modulation of inflammation in severe sepsis World J Crit Care Med 2015 4 105-15
Bacteria in sepsis infections cause release of TF from immune cells leading to coagulation activation and proinflammatory cytokines cause endothelial cell activation impairing the anticoagulation and fibrinolysis process resulting in DIC
Host Response in Severe Sepsis
Exaggerated inflammation as a result of the host response to sepsis is collateral tissue damage and cell death further resulting in release of danger molecules continuing the inflammatory process in a downward spiral
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Organ Failure in Severe Sepsis
Sepsis associated with microvascular thrombosis as a result of TF mediated coagulation activation results in release of neutrophil extracellular traps (NETs) tissue hypoperfusion and mitochondrial damage resulting in a downward spiral leading to organ failure
Angus DC van der Poll T Severe Sepsis and Septic Shock N Engl J Med 2013 369 840-51
Mechanism of DIC in Organ Failure
Underlying condition(sepsis trauma)
Cytokines
TF-mediatedactivation of coagulation
Depression of inhibitory systems
Reducesfibrinolysis
Fibrin deposition
Organ failure
Inadequate fibrin removal
Fibrinformation
Note impaired fibrinolysis in relation to the clinical need not in absolute value (FDPs are )
Levi M de Jonge E van der Poll T ten Cate H Disseminated intravascular coagulation ThrombHaemost 1999 82 695-705
Interaction of Inflammation and Coagulation in Sepsis
Binding of TF thrombin and other activation coagulation factors to PARs and fibrin to TLRs on inflammatory cells results in inflammation through release of proinflammatory cytokines and chemokines
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Mechanism of Multiple Organ Failure in DIC
Wheeler AP Bernard GR Treating Patients with Severe Sepsis N Engl J Med 1999 340207-14
Inflammatory activation and microvascular thrombosis contributes to multiple organ failure in DIC
lipopolysaccharides
cytokines
coagulation activation
mononuclear cell
tissue factor
Diverse and Opposing Effects of Thrombin
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Coagulation and Fibrinolysis in DIC
Soluble fibrin Polymer
XIIIa
D-Dimer
E
Fibrin clot
Fibrin Degradation Products
Fibrinogen Thrombin
Fibrinogen Degradation
Products
D E
Plasmin
DFM + fibrinopeptides
Soluble FM ComplexesPre-throm
boticPost-throm
botic
Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis Semin Thromb Hemost 2008 34 33-8
Mechanism of DIC
THROMBOSIS
Fibrin
Blood activationEndothelial lysisTF expression
BLEEDING
FDPs
D-Dimer
Plasmin
Pathophysiology of DIC
1st step abnormal activation of coagulation Injury of vessel wall cells venous stasis release of large quantities of
thromboplastin influx of activated cells (monocytes macrophages)
Results in an intravascular deposition of fibrin
Morbidity from disseminated microthrombosis in small and midsize vessels leading to multiple organ failure
Second step Consumption and depletion of coagulation factors inhibitors (Protein C
Protein S AT) and platelets Local fibrinolytic response
bull Local plasmin generation dissolves the thrombusbull Disseminated overwhelming fibrinolytic response leading to production of
FDP and D-Dimer
Bleeding
Pathophysiology of DIC - Mechanism
Systemic activation of coagulation
Intravasculardepositionof fibrin
Thrombosis of small and midsize vessels
and organ failure
Depletion of platelets and
coagulation factors
Bleeding
Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92
Pathophysiology of DIC ndash 2 Types of Clinical pictures
Chronic = non - overt DICMay be unrecognized clinically
Acute = overt DIClife threatening bleedingor multiple organ failure
Sub-Acute and Non-Overt DIC Clinical Findings
Compensated non-overt DIC Steady low level or intermittent activation
bull Compensated by increased production of coagulation components and platelets
Few or no clinical signs or multiple microvascular thrombosis sometimes not clinically obvious
Risk of decompensation leading to overt DIC
Pathophysiology of Overt DIC
Massive activation of coagulation and fibrinolysis
Does not allow for compensatory efforts
Rapid depletion of coagulation factors inhibitors and platelets
Thrombosis multiple organ failures
Bleeding complications and shock
Physiopathology of DIC ndash Overt DIC Findings
Thrombin generation
Thrombosis
Renal liver respiratory failures coma skin necrosis gangrene venous thromboembolism hypotension edema
Cytokine and kinin generation (shock)bull Tachycardia hypotension edema
Plasmin generationHemorrhage
bull Spontaneous bruising petechiae intracranial gastrointestinal and respiratory tract bleeding persistent bleeding at venipuncture sites at surgical wounds
bull Tachycardia hypotension edema
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Pathogenesis Pathways in DIC
Cytokines
TF-mediated dysfunctional impairedthrombin anticoagulant fibrinolysisgeneration mechanism due to PAI-1 deficiency
fibrin inadequateformation fibrin removal
Fibrin deposition
Inflammation
Coagulation
Stago Celebrates Lab Week 2017
NA
Stago 247 Educational Webinar Sites
wwwstago-edvantagecomUS based KOLsPACE accredited ndash all 1 hourAccessible from mobile devicesVirtual exhibit hall
wwwstagowebinarscomMostly European KOLs30 ndash 45 min including 15 min discussion
Stago Educational Apps
HaemoscoreClinical scoring algorithmsApple and AndroidTablet or phone
iHemostasisCoagulation diagramsCase studiesApple amp AndroidTablet only
BREAK
Diagnostic and Management Approach for DIC
Diagnosis of DIC
Clinical diagnosis is obvious in cases of overt DIC
Laboratory tests are necessary To makeconfirm the diagnosis To assess stage of the patient To assess the treatment efficacy
Lab Diagnosis of DIC ndash Markers of Factor Consumption
Routinescreening assays PT APTT Platelets Fibrinogen Thrombin time
Other coagulation assays Factor assays AntithrombinGeneration of Thrombin FMFSPsGeneration of Plasmin D-dimer FDPs
Important to recognize simultaneous formation of thrombin and plasmin
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122
Lab Diagnosis of DIC ndash Screening Tests
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122
Platelet count usually decreasedPT abnormal in 70 of cases (short half-life of FVII)APTT abnormal in 50 of casesThrombin time usually prolonged in overt DIC normal in non-overt DIC and no relation with syndrome severityFibrinogen low in lt 50 of cases sensitivity 22 specificity 87 overall predictive value 64 Normal fibrinogen level should not exclude DIC diagnosis (acute phase reactant initial high
fibrinogen level) repeat testing assesses progression
Screening tests not clinically specific or sensitive for DIC
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Laboratory Changes in Overt DIC
DIC Diagnostic Practices Over Time
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
British Journal of Haematology Overt DIC Score
Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
ISTH Step by Step DIC Algorithm
Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6
US Based Validation of ISTH DIC Score
When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Differential Diagnosis in DIC
aHUS atypical hemolytic uremic syndrome
HUS hemolytic uremic syndrome
HIT heparin-induced thrombocytopenia
ITP immune thrombocytopenic purpura
TTP thrombotic thrombocytopenic purpura
DIC and MAHA
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)
When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation
DIC Management Goals
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction
DIC Management and Treatment
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)
requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)
Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia
DIC Management Strategies
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant Factor Concentrate Treatment
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis
Anticoagulant Factor Concentrate Treatment Trials
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise
Markers of Thrombin amp Plasmin Generation in DIC
D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC
Cut-off value
Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen
degradation products Sensitive assay typically with cutoff adapted for DIC
D-dimer FDPs and DIC
D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC
Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80
Follow Up of DIC State of Disease
Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8
Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility
FMD-Dimer in DIC Major Differences
onset of thrombosis
days
Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8
FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)
D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)
of Abnormal Results in Patients with Confirmed and Suspected DIC
0
20
40
60
80
100
94 85 90N = 62
Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32
Positivity of Test Results ISTH Score and Disease State
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
Red bar positive for 2 points of DIC score
Pink bar positive for 1-2 points of DIC score
HT hematopoietic tumor
IF infection
SC solid cancer
Markers in Patients with or without DIC
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
HT hematopoietic tumorIF infectionSC solid cancer
Comparing an Automated FM vs Manual FSP Test
Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71
Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)
Automated (Mitsubishi) vs Automated (Stago)
In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago
Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC
Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
Non Overt DIC Overt DIC
AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC
Trends in Markers of DIC for Different Patients
Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00
Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients
Trends in Markers of DIC for Different Patients
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes
28 day outcome survival
28 day outcome death
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines
DIC Case Studies
Case Study 1 - Presentation
18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE
WBC count 77 KμL 423 ndash 907 x KμL
RBC count 17 MμL 137 ndash 175 x MμL
Hemoglobin 67 gdL 137 ndash 175 gdL
Hematocrit 195 401 ndash 510
MCV 95 fL 790 ndash 922 fL
MPV 12 fL 94 ndash 124 fL
Platelet count 9 KμL 161 ndash 347 KμL
Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0
Lymphocytes monocytes eosinophils basophils all below normal range
PT 47 sec (corrected on mixing study) 116 ndash 152 sec
APTT 75 sec (corrected on mixing study) 253 ndash 373 sec
Fibrinogen lt 76 mgdL 177 ndash 466 mgdL
D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Microscopy
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Arrow shows giant platelets in this peripheral smear Promyelocytes apparent
Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)
DIC due to TF release by APL blasts
Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases
Transfusions to replace factors along with platelets and RBCs during APL treatment
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started
Case Study 2 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L
PT 30 sec 113 ndash 146 sec
APTT 75 sec 25 ndash 34 sec
D-dimer 078 microgml FEU lt050 microgml FEU
Fibrinogen 92 mgdl 150-400 mgdl
pH 728 738 to 742
PaO2 570 mmHg 80-100 mmHg
WBC 33 times 103mm3 40-11 times 103mm3
ALT 111 IUL 0ndash34 IUL
AST 61 IUL 0ndash34 IUL
BUN 303 mgdL 08-13 mgdL
Case Study 2 ndash Lab Results
Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures
Case Study 2 ndash Diagnosis
60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior
Case Study 3 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L
PT 228 sec 113 ndash 146 sec
APTT 45 sec 25 ndash 34 sec
D-dimer 080 microgml FEU lt050 microgmL FEU
Fibrinogen 82 mgdL 150-400 mgdL
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 134 gdL 14-16 gdL
WBC 81 times 103mm3 40-11 times 103mm3
ALT 32 IUL 0ndash34 IUL
AST 28 IUL 0ndash34 IUL
BUN 09 mgdL 08-13 mgdL
Case Study 3 ndash Lab Results
Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment
Case Study 3 ndash Diagnosis and Therapy
Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91
Case Study 4 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L
PT 28 sec 113 ndash 146 sec
APTT 71 sec 25 ndash 34 sec
D-dimer 31 microgmL FEU lt050 microgml FEU
Fibrinogen 92 mgdL 150-400 mgdl
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 158 gdL 14-16 gdL
WBC 71 times 103mm3 40-11 times 103mm3
ALT 60 IUL 0ndash34 IUL
AST 47 IUL 0ndash34 IUL
BUN 38 mgdL 08-13 mgdL
Case Study 4 ndash Lab Results
Lyme disease with DICProvide antibiotics with supportive measures
Case Study 4 ndash Diagnosis
55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis
Case Study 5 ndash Presentation
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
Case Study 5 ndash Lab Results and Time Course
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
TEST RESULT REFERENCE RANGE
Platelet count 33 x 109L 150-450 x 109L
PT 215 sec 103 ndash 128 sec
APTT 44 sec 26 ndash 36 sec
D-dimer 20 microgmL FEU lt025 microgml FEU
Fibrinogen 34 mgdL 200-375 mgdl
FII FV FVIII Low Not reported (NR)
FVII FIX FX vWF Normal NR
Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)
DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic
dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR
(C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen
(D) Illustration demonstrating repair
Case Study 5 ndash Diagnosis and Treatment
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography
Case Study 6 ndash Presentation
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
Case Study 6 ndash Lab Results
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L
PT 63 sec gt control 113 ndash 146 sec
INR 658 1 ndash 125
APTT 80 sec gt control 25 ndash 34 sec
D-dimer gt200 microgmL DDU 02 microgmL DDU
Urine exam Proteinuria and hematuria 150-400 mgdl
Albumin 28 gdL NR
Hb 58 gdL NR
LDH 1196 UL NR
SGPT 144 IU NR
SGOT 88 IU NR
Bilirubin 32 mgdL NR
DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th
day postop
Case Study 6 ndash Diagnosis and Treatment
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure
Case Study 6 ndash Discussion
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Case Study 7 ndash Lab Results vs Time
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
DIC Take Home Messages
Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation
Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers
DIC
Thank you Questions
- Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
- Learning Objectives
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Wound Sealing
- The Three Steps of Hemostasis
- Vessel Wall
- Slide Number 12
- Slide Number 13
- Platelet Structure UnactivatedActivated
- Primary Hemostasis
- Primary Hemostasis Assays
- Slide Number 17
- Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
- Slide Number 19
- Coagulation factors
- Coagulation Assay Mechanisms
- Slide Number 22
- Fibrin Formation
- Slide Number 24
- Fibrinolysis Overview
- Fibrinolysis Overview
- Slide Number 27
- Fibrinolysis Releases D-dimers
- Basic Pathophysiology of DIC
- Disseminated Intravascular Coagulation (DIC)
- Purpura Fulminans with DIC Due to Meningococcal Sepsis
- Clinical Conditions Associated With DIC
- Frequency of DIC in Selected Disease States
- Underlying Diseases in DIC Patients
- Slide Number 36
- Slide Number 37
- Slide Number 38
- Slide Number 39
- Pathophysiology of DIC
- Pathogenesis of DIC in Sepsis
- Host Response in Severe Sepsis
- Organ Failure in Severe Sepsis
- Mechanism of DIC in Organ Failure
- Interaction of Inflammation and Coagulation in Sepsis
- Slide Number 47
- Diverse and Opposing Effects of Thrombin
- Coagulation and Fibrinolysis in DIC
- Mechanism of DIC
- Pathophysiology of DIC
- Pathophysiology of DIC - Mechanism
- Pathophysiology of DIC ndash 2 Types of Clinical pictures
- Sub-Acute and Non-Overt DIC Clinical Findings
- Pathophysiology of Overt DIC
- Physiopathology of DIC ndash Overt DIC Findings
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- BREAK
- Diagnostic and Management Approach for DIC
- Diagnosis of DIC
- Lab Diagnosis of DIC ndash Markers of Factor Consumption
- Lab Diagnosis of DIC ndash Screening Tests
- Slide Number 67
- Slide Number 68
- British Journal of Haematology Overt DIC Score
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- DIC Management Goals
- DIC Management and Treatment
- DIC Management Strategies
- Anticoagulant Factor Concentrate Treatment
- Anticoagulant Factor Concentrate Treatment Trials
- Markers of Thrombin amp Plasmin Generation in DIC
- D-dimer FDPs and DIC
- D-Dimer and FDPs in DIC
- Follow Up of DIC State of Disease
- FMD-Dimer in DIC Major Differences
- of Abnormal Results in Patients with Confirmed and Suspected DIC
- Slide Number 85
- Slide Number 86
- Comparing an Automated FM vs Manual FSP Test
- Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Slide Number 94
- Slide Number 95
- Slide Number 96
- Slide Number 97
- Slide Number 98
- Slide Number 99
- DIC Case Studies
- Case Study 1 - Presentation
- Case Study 1 ndash Lab Results
- Case Study 1 ndash Microscopy
- Case Study 1 ndash Diagnosis and Therapy
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Slide Number 110
- Slide Number 111
- Slide Number 112
- Slide Number 113
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
- Slide Number 124
- Slide Number 125
- DIC Take Home Messages
- Slide Number 127
- Slide Number 128
-
(Digestion of Fibrin)
Fibrinolysis
Fibrinolysis Overview
Destroys fibrin fibers
Destroys the scab (dried wound)
Maintains vessel integrity
Fibrinolysis Overview
Fibrin =cement fibers
Plasmin
Plasmin digests fibrin
t-PA
Pro Urokinase
Urokinase
PAI-1PAI-1
Plasminogen Plasmin
1st Step
2nd Step
Fibrinolysis Cascade
t-PA tissue-type plasminogen activator PAI-1 Plasminogen activator inhibitor 1 PK Prekallikrein FDP Fibrinogen degradation products AP Antiplasmin = a2AP alpha 2 Antiplasmin a2MG alpha 2 Macroglobulin
Extrinsic pathway(endothelia l cells)
Intrinsic pathway(plasma)
Fibrin clot
D-dimerFibrin degradation products
Fibrin
TAFIa
APAntiplasmin(amp a2-MG)
PK Kallikrein
XII
Fibrinolysis Releases D-dimers
D-dimer presence fibrin has been formed and digested in patients body
Normal D-dimer level no thrombosis occurred in the patient
Basic Pathophysiology of DIC
Disseminated Intravascular Coagulation (DIC)
Massive activation of coagulation leading to clots forming in multiple locations around the bodyRapid consumption of clotting factors leading to bleedingParadoxical condition leading to both clotting and bleedingA confusing disorder from both diagnostic and therapeutic standpoints Many unrelated diseases can trigger DIC Lack of uniformity in clinical manifestation Lack of uniformity in the laboratory diagnosis Lack of uniformity or consensus on management
Clinical Manifestations of DICOrgan Ischemic Hemorrhagic
Skin Pupura Fulminans Petechiae
Gangrene Echymoses
Acral cyanosis Oozing
CNS Deliriumcoma Intracranial
Infarcts Bleeding
Renal OliguriaAzotemia Hematuria
Cortical Necrosis
Cardiovascular Myocardial dysfunction
Pulmonary DyspneaHypoxia Hemorrhagic lung
Infarct
Gastrointestinal Ulcers infarcts Massive hemorrhage
Endocrine Adrenal infarcts
Purpura Fulminans with DIC Due to Meningococcal Sepsis
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Clinical Conditions Associated With DIC
Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33
Frequency of DIC in Selected Disease States
Disease Frequency
Gram-negative sepsis 30-50
Severe trauma and systemic inflammation 50-70
Metastasized tumors 15
Abruptio placentaamniotic fluid embolism 50
Severe preeclampsia 7
Giant hemangioma 25
Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92
Masao Nakagawa Modified from a research report on the incidence of disseminated intravascular coagulation (DIC) and underlying diseases in Japan Ministry of Health Labour and Welfare Research report published in Fiscal Year 1998 57-64 199 httpwwwrecomodulincomendicindexhtml Accessed Apr 21 2017
Underlying Diseases in DIC Patients
In a Japanese survey from 1997 on incidence of DIC and underlying diseases in 652 divisions and departments of university hospitals DIC occurred in 2193 patients with the number of patient with infections (including sepsis) and hematologic tumors (including leukemia) accounted for 28 and 23 respectively
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Epidemiology of DIC
Impact of DIC Status on Mortality - 1
Okamoto K Wada H Hatada T Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Frequency and hemostatic abnormalities in pre-DIC patients Thromb Res 2010 126 74-8
Patients with positivity of DIC tend to have worse mortality outcomes compared to negative patients or those with pre-DIC
Impact of DIC Status on Mortality - 2
Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4
Patients with positivity of either Overt or Non-Overt DIC tend to have worse mortality outcomes compared to negative patients
Impact of Age on Mortality in DIC Patients
Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4
Older patients with DIC (black bars) generally tend to have worse outcomes compared to non-DIC patients (grey bars)
Pathophysiology of DIC
Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33
Pathogenesis of DIC in Sepsis
Allen KS Sawheny E Kinasewitzet GT Anticoagulant modulation of inflammation in severe sepsis World J Crit Care Med 2015 4 105-15
Bacteria in sepsis infections cause release of TF from immune cells leading to coagulation activation and proinflammatory cytokines cause endothelial cell activation impairing the anticoagulation and fibrinolysis process resulting in DIC
Host Response in Severe Sepsis
Exaggerated inflammation as a result of the host response to sepsis is collateral tissue damage and cell death further resulting in release of danger molecules continuing the inflammatory process in a downward spiral
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Organ Failure in Severe Sepsis
Sepsis associated with microvascular thrombosis as a result of TF mediated coagulation activation results in release of neutrophil extracellular traps (NETs) tissue hypoperfusion and mitochondrial damage resulting in a downward spiral leading to organ failure
Angus DC van der Poll T Severe Sepsis and Septic Shock N Engl J Med 2013 369 840-51
Mechanism of DIC in Organ Failure
Underlying condition(sepsis trauma)
Cytokines
TF-mediatedactivation of coagulation
Depression of inhibitory systems
Reducesfibrinolysis
Fibrin deposition
Organ failure
Inadequate fibrin removal
Fibrinformation
Note impaired fibrinolysis in relation to the clinical need not in absolute value (FDPs are )
Levi M de Jonge E van der Poll T ten Cate H Disseminated intravascular coagulation ThrombHaemost 1999 82 695-705
Interaction of Inflammation and Coagulation in Sepsis
Binding of TF thrombin and other activation coagulation factors to PARs and fibrin to TLRs on inflammatory cells results in inflammation through release of proinflammatory cytokines and chemokines
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Mechanism of Multiple Organ Failure in DIC
Wheeler AP Bernard GR Treating Patients with Severe Sepsis N Engl J Med 1999 340207-14
Inflammatory activation and microvascular thrombosis contributes to multiple organ failure in DIC
lipopolysaccharides
cytokines
coagulation activation
mononuclear cell
tissue factor
Diverse and Opposing Effects of Thrombin
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Coagulation and Fibrinolysis in DIC
Soluble fibrin Polymer
XIIIa
D-Dimer
E
Fibrin clot
Fibrin Degradation Products
Fibrinogen Thrombin
Fibrinogen Degradation
Products
D E
Plasmin
DFM + fibrinopeptides
Soluble FM ComplexesPre-throm
boticPost-throm
botic
Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis Semin Thromb Hemost 2008 34 33-8
Mechanism of DIC
THROMBOSIS
Fibrin
Blood activationEndothelial lysisTF expression
BLEEDING
FDPs
D-Dimer
Plasmin
Pathophysiology of DIC
1st step abnormal activation of coagulation Injury of vessel wall cells venous stasis release of large quantities of
thromboplastin influx of activated cells (monocytes macrophages)
Results in an intravascular deposition of fibrin
Morbidity from disseminated microthrombosis in small and midsize vessels leading to multiple organ failure
Second step Consumption and depletion of coagulation factors inhibitors (Protein C
Protein S AT) and platelets Local fibrinolytic response
bull Local plasmin generation dissolves the thrombusbull Disseminated overwhelming fibrinolytic response leading to production of
FDP and D-Dimer
Bleeding
Pathophysiology of DIC - Mechanism
Systemic activation of coagulation
Intravasculardepositionof fibrin
Thrombosis of small and midsize vessels
and organ failure
Depletion of platelets and
coagulation factors
Bleeding
Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92
Pathophysiology of DIC ndash 2 Types of Clinical pictures
Chronic = non - overt DICMay be unrecognized clinically
Acute = overt DIClife threatening bleedingor multiple organ failure
Sub-Acute and Non-Overt DIC Clinical Findings
Compensated non-overt DIC Steady low level or intermittent activation
bull Compensated by increased production of coagulation components and platelets
Few or no clinical signs or multiple microvascular thrombosis sometimes not clinically obvious
Risk of decompensation leading to overt DIC
Pathophysiology of Overt DIC
Massive activation of coagulation and fibrinolysis
Does not allow for compensatory efforts
Rapid depletion of coagulation factors inhibitors and platelets
Thrombosis multiple organ failures
Bleeding complications and shock
Physiopathology of DIC ndash Overt DIC Findings
Thrombin generation
Thrombosis
Renal liver respiratory failures coma skin necrosis gangrene venous thromboembolism hypotension edema
Cytokine and kinin generation (shock)bull Tachycardia hypotension edema
Plasmin generationHemorrhage
bull Spontaneous bruising petechiae intracranial gastrointestinal and respiratory tract bleeding persistent bleeding at venipuncture sites at surgical wounds
bull Tachycardia hypotension edema
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Pathogenesis Pathways in DIC
Cytokines
TF-mediated dysfunctional impairedthrombin anticoagulant fibrinolysisgeneration mechanism due to PAI-1 deficiency
fibrin inadequateformation fibrin removal
Fibrin deposition
Inflammation
Coagulation
Stago Celebrates Lab Week 2017
NA
Stago 247 Educational Webinar Sites
wwwstago-edvantagecomUS based KOLsPACE accredited ndash all 1 hourAccessible from mobile devicesVirtual exhibit hall
wwwstagowebinarscomMostly European KOLs30 ndash 45 min including 15 min discussion
Stago Educational Apps
HaemoscoreClinical scoring algorithmsApple and AndroidTablet or phone
iHemostasisCoagulation diagramsCase studiesApple amp AndroidTablet only
BREAK
Diagnostic and Management Approach for DIC
Diagnosis of DIC
Clinical diagnosis is obvious in cases of overt DIC
Laboratory tests are necessary To makeconfirm the diagnosis To assess stage of the patient To assess the treatment efficacy
Lab Diagnosis of DIC ndash Markers of Factor Consumption
Routinescreening assays PT APTT Platelets Fibrinogen Thrombin time
Other coagulation assays Factor assays AntithrombinGeneration of Thrombin FMFSPsGeneration of Plasmin D-dimer FDPs
Important to recognize simultaneous formation of thrombin and plasmin
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122
Lab Diagnosis of DIC ndash Screening Tests
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122
Platelet count usually decreasedPT abnormal in 70 of cases (short half-life of FVII)APTT abnormal in 50 of casesThrombin time usually prolonged in overt DIC normal in non-overt DIC and no relation with syndrome severityFibrinogen low in lt 50 of cases sensitivity 22 specificity 87 overall predictive value 64 Normal fibrinogen level should not exclude DIC diagnosis (acute phase reactant initial high
fibrinogen level) repeat testing assesses progression
Screening tests not clinically specific or sensitive for DIC
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Laboratory Changes in Overt DIC
DIC Diagnostic Practices Over Time
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
British Journal of Haematology Overt DIC Score
Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
ISTH Step by Step DIC Algorithm
Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6
US Based Validation of ISTH DIC Score
When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Differential Diagnosis in DIC
aHUS atypical hemolytic uremic syndrome
HUS hemolytic uremic syndrome
HIT heparin-induced thrombocytopenia
ITP immune thrombocytopenic purpura
TTP thrombotic thrombocytopenic purpura
DIC and MAHA
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)
When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation
DIC Management Goals
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction
DIC Management and Treatment
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)
requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)
Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia
DIC Management Strategies
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant Factor Concentrate Treatment
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis
Anticoagulant Factor Concentrate Treatment Trials
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise
Markers of Thrombin amp Plasmin Generation in DIC
D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC
Cut-off value
Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen
degradation products Sensitive assay typically with cutoff adapted for DIC
D-dimer FDPs and DIC
D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC
Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80
Follow Up of DIC State of Disease
Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8
Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility
FMD-Dimer in DIC Major Differences
onset of thrombosis
days
Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8
FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)
D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)
of Abnormal Results in Patients with Confirmed and Suspected DIC
0
20
40
60
80
100
94 85 90N = 62
Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32
Positivity of Test Results ISTH Score and Disease State
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
Red bar positive for 2 points of DIC score
Pink bar positive for 1-2 points of DIC score
HT hematopoietic tumor
IF infection
SC solid cancer
Markers in Patients with or without DIC
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
HT hematopoietic tumorIF infectionSC solid cancer
Comparing an Automated FM vs Manual FSP Test
Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71
Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)
Automated (Mitsubishi) vs Automated (Stago)
In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago
Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC
Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
Non Overt DIC Overt DIC
AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC
Trends in Markers of DIC for Different Patients
Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00
Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients
Trends in Markers of DIC for Different Patients
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes
28 day outcome survival
28 day outcome death
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines
DIC Case Studies
Case Study 1 - Presentation
18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE
WBC count 77 KμL 423 ndash 907 x KμL
RBC count 17 MμL 137 ndash 175 x MμL
Hemoglobin 67 gdL 137 ndash 175 gdL
Hematocrit 195 401 ndash 510
MCV 95 fL 790 ndash 922 fL
MPV 12 fL 94 ndash 124 fL
Platelet count 9 KμL 161 ndash 347 KμL
Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0
Lymphocytes monocytes eosinophils basophils all below normal range
PT 47 sec (corrected on mixing study) 116 ndash 152 sec
APTT 75 sec (corrected on mixing study) 253 ndash 373 sec
Fibrinogen lt 76 mgdL 177 ndash 466 mgdL
D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Microscopy
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Arrow shows giant platelets in this peripheral smear Promyelocytes apparent
Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)
DIC due to TF release by APL blasts
Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases
Transfusions to replace factors along with platelets and RBCs during APL treatment
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started
Case Study 2 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L
PT 30 sec 113 ndash 146 sec
APTT 75 sec 25 ndash 34 sec
D-dimer 078 microgml FEU lt050 microgml FEU
Fibrinogen 92 mgdl 150-400 mgdl
pH 728 738 to 742
PaO2 570 mmHg 80-100 mmHg
WBC 33 times 103mm3 40-11 times 103mm3
ALT 111 IUL 0ndash34 IUL
AST 61 IUL 0ndash34 IUL
BUN 303 mgdL 08-13 mgdL
Case Study 2 ndash Lab Results
Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures
Case Study 2 ndash Diagnosis
60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior
Case Study 3 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L
PT 228 sec 113 ndash 146 sec
APTT 45 sec 25 ndash 34 sec
D-dimer 080 microgml FEU lt050 microgmL FEU
Fibrinogen 82 mgdL 150-400 mgdL
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 134 gdL 14-16 gdL
WBC 81 times 103mm3 40-11 times 103mm3
ALT 32 IUL 0ndash34 IUL
AST 28 IUL 0ndash34 IUL
BUN 09 mgdL 08-13 mgdL
Case Study 3 ndash Lab Results
Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment
Case Study 3 ndash Diagnosis and Therapy
Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91
Case Study 4 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L
PT 28 sec 113 ndash 146 sec
APTT 71 sec 25 ndash 34 sec
D-dimer 31 microgmL FEU lt050 microgml FEU
Fibrinogen 92 mgdL 150-400 mgdl
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 158 gdL 14-16 gdL
WBC 71 times 103mm3 40-11 times 103mm3
ALT 60 IUL 0ndash34 IUL
AST 47 IUL 0ndash34 IUL
BUN 38 mgdL 08-13 mgdL
Case Study 4 ndash Lab Results
Lyme disease with DICProvide antibiotics with supportive measures
Case Study 4 ndash Diagnosis
55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis
Case Study 5 ndash Presentation
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
Case Study 5 ndash Lab Results and Time Course
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
TEST RESULT REFERENCE RANGE
Platelet count 33 x 109L 150-450 x 109L
PT 215 sec 103 ndash 128 sec
APTT 44 sec 26 ndash 36 sec
D-dimer 20 microgmL FEU lt025 microgml FEU
Fibrinogen 34 mgdL 200-375 mgdl
FII FV FVIII Low Not reported (NR)
FVII FIX FX vWF Normal NR
Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)
DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic
dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR
(C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen
(D) Illustration demonstrating repair
Case Study 5 ndash Diagnosis and Treatment
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography
Case Study 6 ndash Presentation
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
Case Study 6 ndash Lab Results
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L
PT 63 sec gt control 113 ndash 146 sec
INR 658 1 ndash 125
APTT 80 sec gt control 25 ndash 34 sec
D-dimer gt200 microgmL DDU 02 microgmL DDU
Urine exam Proteinuria and hematuria 150-400 mgdl
Albumin 28 gdL NR
Hb 58 gdL NR
LDH 1196 UL NR
SGPT 144 IU NR
SGOT 88 IU NR
Bilirubin 32 mgdL NR
DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th
day postop
Case Study 6 ndash Diagnosis and Treatment
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure
Case Study 6 ndash Discussion
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Case Study 7 ndash Lab Results vs Time
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
DIC Take Home Messages
Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation
Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers
DIC
Thank you Questions
- Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
- Learning Objectives
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Wound Sealing
- The Three Steps of Hemostasis
- Vessel Wall
- Slide Number 12
- Slide Number 13
- Platelet Structure UnactivatedActivated
- Primary Hemostasis
- Primary Hemostasis Assays
- Slide Number 17
- Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
- Slide Number 19
- Coagulation factors
- Coagulation Assay Mechanisms
- Slide Number 22
- Fibrin Formation
- Slide Number 24
- Fibrinolysis Overview
- Fibrinolysis Overview
- Slide Number 27
- Fibrinolysis Releases D-dimers
- Basic Pathophysiology of DIC
- Disseminated Intravascular Coagulation (DIC)
- Purpura Fulminans with DIC Due to Meningococcal Sepsis
- Clinical Conditions Associated With DIC
- Frequency of DIC in Selected Disease States
- Underlying Diseases in DIC Patients
- Slide Number 36
- Slide Number 37
- Slide Number 38
- Slide Number 39
- Pathophysiology of DIC
- Pathogenesis of DIC in Sepsis
- Host Response in Severe Sepsis
- Organ Failure in Severe Sepsis
- Mechanism of DIC in Organ Failure
- Interaction of Inflammation and Coagulation in Sepsis
- Slide Number 47
- Diverse and Opposing Effects of Thrombin
- Coagulation and Fibrinolysis in DIC
- Mechanism of DIC
- Pathophysiology of DIC
- Pathophysiology of DIC - Mechanism
- Pathophysiology of DIC ndash 2 Types of Clinical pictures
- Sub-Acute and Non-Overt DIC Clinical Findings
- Pathophysiology of Overt DIC
- Physiopathology of DIC ndash Overt DIC Findings
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- BREAK
- Diagnostic and Management Approach for DIC
- Diagnosis of DIC
- Lab Diagnosis of DIC ndash Markers of Factor Consumption
- Lab Diagnosis of DIC ndash Screening Tests
- Slide Number 67
- Slide Number 68
- British Journal of Haematology Overt DIC Score
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- DIC Management Goals
- DIC Management and Treatment
- DIC Management Strategies
- Anticoagulant Factor Concentrate Treatment
- Anticoagulant Factor Concentrate Treatment Trials
- Markers of Thrombin amp Plasmin Generation in DIC
- D-dimer FDPs and DIC
- D-Dimer and FDPs in DIC
- Follow Up of DIC State of Disease
- FMD-Dimer in DIC Major Differences
- of Abnormal Results in Patients with Confirmed and Suspected DIC
- Slide Number 85
- Slide Number 86
- Comparing an Automated FM vs Manual FSP Test
- Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Slide Number 94
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- Slide Number 99
- DIC Case Studies
- Case Study 1 - Presentation
- Case Study 1 ndash Lab Results
- Case Study 1 ndash Microscopy
- Case Study 1 ndash Diagnosis and Therapy
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Slide Number 110
- Slide Number 111
- Slide Number 112
- Slide Number 113
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- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
- Slide Number 124
- Slide Number 125
- DIC Take Home Messages
- Slide Number 127
- Slide Number 128
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Fibrinolysis Overview
Destroys fibrin fibers
Destroys the scab (dried wound)
Maintains vessel integrity
Fibrinolysis Overview
Fibrin =cement fibers
Plasmin
Plasmin digests fibrin
t-PA
Pro Urokinase
Urokinase
PAI-1PAI-1
Plasminogen Plasmin
1st Step
2nd Step
Fibrinolysis Cascade
t-PA tissue-type plasminogen activator PAI-1 Plasminogen activator inhibitor 1 PK Prekallikrein FDP Fibrinogen degradation products AP Antiplasmin = a2AP alpha 2 Antiplasmin a2MG alpha 2 Macroglobulin
Extrinsic pathway(endothelia l cells)
Intrinsic pathway(plasma)
Fibrin clot
D-dimerFibrin degradation products
Fibrin
TAFIa
APAntiplasmin(amp a2-MG)
PK Kallikrein
XII
Fibrinolysis Releases D-dimers
D-dimer presence fibrin has been formed and digested in patients body
Normal D-dimer level no thrombosis occurred in the patient
Basic Pathophysiology of DIC
Disseminated Intravascular Coagulation (DIC)
Massive activation of coagulation leading to clots forming in multiple locations around the bodyRapid consumption of clotting factors leading to bleedingParadoxical condition leading to both clotting and bleedingA confusing disorder from both diagnostic and therapeutic standpoints Many unrelated diseases can trigger DIC Lack of uniformity in clinical manifestation Lack of uniformity in the laboratory diagnosis Lack of uniformity or consensus on management
Clinical Manifestations of DICOrgan Ischemic Hemorrhagic
Skin Pupura Fulminans Petechiae
Gangrene Echymoses
Acral cyanosis Oozing
CNS Deliriumcoma Intracranial
Infarcts Bleeding
Renal OliguriaAzotemia Hematuria
Cortical Necrosis
Cardiovascular Myocardial dysfunction
Pulmonary DyspneaHypoxia Hemorrhagic lung
Infarct
Gastrointestinal Ulcers infarcts Massive hemorrhage
Endocrine Adrenal infarcts
Purpura Fulminans with DIC Due to Meningococcal Sepsis
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Clinical Conditions Associated With DIC
Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33
Frequency of DIC in Selected Disease States
Disease Frequency
Gram-negative sepsis 30-50
Severe trauma and systemic inflammation 50-70
Metastasized tumors 15
Abruptio placentaamniotic fluid embolism 50
Severe preeclampsia 7
Giant hemangioma 25
Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92
Masao Nakagawa Modified from a research report on the incidence of disseminated intravascular coagulation (DIC) and underlying diseases in Japan Ministry of Health Labour and Welfare Research report published in Fiscal Year 1998 57-64 199 httpwwwrecomodulincomendicindexhtml Accessed Apr 21 2017
Underlying Diseases in DIC Patients
In a Japanese survey from 1997 on incidence of DIC and underlying diseases in 652 divisions and departments of university hospitals DIC occurred in 2193 patients with the number of patient with infections (including sepsis) and hematologic tumors (including leukemia) accounted for 28 and 23 respectively
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Epidemiology of DIC
Impact of DIC Status on Mortality - 1
Okamoto K Wada H Hatada T Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Frequency and hemostatic abnormalities in pre-DIC patients Thromb Res 2010 126 74-8
Patients with positivity of DIC tend to have worse mortality outcomes compared to negative patients or those with pre-DIC
Impact of DIC Status on Mortality - 2
Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4
Patients with positivity of either Overt or Non-Overt DIC tend to have worse mortality outcomes compared to negative patients
Impact of Age on Mortality in DIC Patients
Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4
Older patients with DIC (black bars) generally tend to have worse outcomes compared to non-DIC patients (grey bars)
Pathophysiology of DIC
Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33
Pathogenesis of DIC in Sepsis
Allen KS Sawheny E Kinasewitzet GT Anticoagulant modulation of inflammation in severe sepsis World J Crit Care Med 2015 4 105-15
Bacteria in sepsis infections cause release of TF from immune cells leading to coagulation activation and proinflammatory cytokines cause endothelial cell activation impairing the anticoagulation and fibrinolysis process resulting in DIC
Host Response in Severe Sepsis
Exaggerated inflammation as a result of the host response to sepsis is collateral tissue damage and cell death further resulting in release of danger molecules continuing the inflammatory process in a downward spiral
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Organ Failure in Severe Sepsis
Sepsis associated with microvascular thrombosis as a result of TF mediated coagulation activation results in release of neutrophil extracellular traps (NETs) tissue hypoperfusion and mitochondrial damage resulting in a downward spiral leading to organ failure
Angus DC van der Poll T Severe Sepsis and Septic Shock N Engl J Med 2013 369 840-51
Mechanism of DIC in Organ Failure
Underlying condition(sepsis trauma)
Cytokines
TF-mediatedactivation of coagulation
Depression of inhibitory systems
Reducesfibrinolysis
Fibrin deposition
Organ failure
Inadequate fibrin removal
Fibrinformation
Note impaired fibrinolysis in relation to the clinical need not in absolute value (FDPs are )
Levi M de Jonge E van der Poll T ten Cate H Disseminated intravascular coagulation ThrombHaemost 1999 82 695-705
Interaction of Inflammation and Coagulation in Sepsis
Binding of TF thrombin and other activation coagulation factors to PARs and fibrin to TLRs on inflammatory cells results in inflammation through release of proinflammatory cytokines and chemokines
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Mechanism of Multiple Organ Failure in DIC
Wheeler AP Bernard GR Treating Patients with Severe Sepsis N Engl J Med 1999 340207-14
Inflammatory activation and microvascular thrombosis contributes to multiple organ failure in DIC
lipopolysaccharides
cytokines
coagulation activation
mononuclear cell
tissue factor
Diverse and Opposing Effects of Thrombin
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Coagulation and Fibrinolysis in DIC
Soluble fibrin Polymer
XIIIa
D-Dimer
E
Fibrin clot
Fibrin Degradation Products
Fibrinogen Thrombin
Fibrinogen Degradation
Products
D E
Plasmin
DFM + fibrinopeptides
Soluble FM ComplexesPre-throm
boticPost-throm
botic
Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis Semin Thromb Hemost 2008 34 33-8
Mechanism of DIC
THROMBOSIS
Fibrin
Blood activationEndothelial lysisTF expression
BLEEDING
FDPs
D-Dimer
Plasmin
Pathophysiology of DIC
1st step abnormal activation of coagulation Injury of vessel wall cells venous stasis release of large quantities of
thromboplastin influx of activated cells (monocytes macrophages)
Results in an intravascular deposition of fibrin
Morbidity from disseminated microthrombosis in small and midsize vessels leading to multiple organ failure
Second step Consumption and depletion of coagulation factors inhibitors (Protein C
Protein S AT) and platelets Local fibrinolytic response
bull Local plasmin generation dissolves the thrombusbull Disseminated overwhelming fibrinolytic response leading to production of
FDP and D-Dimer
Bleeding
Pathophysiology of DIC - Mechanism
Systemic activation of coagulation
Intravasculardepositionof fibrin
Thrombosis of small and midsize vessels
and organ failure
Depletion of platelets and
coagulation factors
Bleeding
Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92
Pathophysiology of DIC ndash 2 Types of Clinical pictures
Chronic = non - overt DICMay be unrecognized clinically
Acute = overt DIClife threatening bleedingor multiple organ failure
Sub-Acute and Non-Overt DIC Clinical Findings
Compensated non-overt DIC Steady low level or intermittent activation
bull Compensated by increased production of coagulation components and platelets
Few or no clinical signs or multiple microvascular thrombosis sometimes not clinically obvious
Risk of decompensation leading to overt DIC
Pathophysiology of Overt DIC
Massive activation of coagulation and fibrinolysis
Does not allow for compensatory efforts
Rapid depletion of coagulation factors inhibitors and platelets
Thrombosis multiple organ failures
Bleeding complications and shock
Physiopathology of DIC ndash Overt DIC Findings
Thrombin generation
Thrombosis
Renal liver respiratory failures coma skin necrosis gangrene venous thromboembolism hypotension edema
Cytokine and kinin generation (shock)bull Tachycardia hypotension edema
Plasmin generationHemorrhage
bull Spontaneous bruising petechiae intracranial gastrointestinal and respiratory tract bleeding persistent bleeding at venipuncture sites at surgical wounds
bull Tachycardia hypotension edema
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Pathogenesis Pathways in DIC
Cytokines
TF-mediated dysfunctional impairedthrombin anticoagulant fibrinolysisgeneration mechanism due to PAI-1 deficiency
fibrin inadequateformation fibrin removal
Fibrin deposition
Inflammation
Coagulation
Stago Celebrates Lab Week 2017
NA
Stago 247 Educational Webinar Sites
wwwstago-edvantagecomUS based KOLsPACE accredited ndash all 1 hourAccessible from mobile devicesVirtual exhibit hall
wwwstagowebinarscomMostly European KOLs30 ndash 45 min including 15 min discussion
Stago Educational Apps
HaemoscoreClinical scoring algorithmsApple and AndroidTablet or phone
iHemostasisCoagulation diagramsCase studiesApple amp AndroidTablet only
BREAK
Diagnostic and Management Approach for DIC
Diagnosis of DIC
Clinical diagnosis is obvious in cases of overt DIC
Laboratory tests are necessary To makeconfirm the diagnosis To assess stage of the patient To assess the treatment efficacy
Lab Diagnosis of DIC ndash Markers of Factor Consumption
Routinescreening assays PT APTT Platelets Fibrinogen Thrombin time
Other coagulation assays Factor assays AntithrombinGeneration of Thrombin FMFSPsGeneration of Plasmin D-dimer FDPs
Important to recognize simultaneous formation of thrombin and plasmin
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122
Lab Diagnosis of DIC ndash Screening Tests
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122
Platelet count usually decreasedPT abnormal in 70 of cases (short half-life of FVII)APTT abnormal in 50 of casesThrombin time usually prolonged in overt DIC normal in non-overt DIC and no relation with syndrome severityFibrinogen low in lt 50 of cases sensitivity 22 specificity 87 overall predictive value 64 Normal fibrinogen level should not exclude DIC diagnosis (acute phase reactant initial high
fibrinogen level) repeat testing assesses progression
Screening tests not clinically specific or sensitive for DIC
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Laboratory Changes in Overt DIC
DIC Diagnostic Practices Over Time
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
British Journal of Haematology Overt DIC Score
Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
ISTH Step by Step DIC Algorithm
Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6
US Based Validation of ISTH DIC Score
When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Differential Diagnosis in DIC
aHUS atypical hemolytic uremic syndrome
HUS hemolytic uremic syndrome
HIT heparin-induced thrombocytopenia
ITP immune thrombocytopenic purpura
TTP thrombotic thrombocytopenic purpura
DIC and MAHA
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)
When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation
DIC Management Goals
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction
DIC Management and Treatment
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)
requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)
Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia
DIC Management Strategies
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant Factor Concentrate Treatment
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis
Anticoagulant Factor Concentrate Treatment Trials
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise
Markers of Thrombin amp Plasmin Generation in DIC
D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC
Cut-off value
Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen
degradation products Sensitive assay typically with cutoff adapted for DIC
D-dimer FDPs and DIC
D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC
Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80
Follow Up of DIC State of Disease
Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8
Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility
FMD-Dimer in DIC Major Differences
onset of thrombosis
days
Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8
FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)
D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)
of Abnormal Results in Patients with Confirmed and Suspected DIC
0
20
40
60
80
100
94 85 90N = 62
Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32
Positivity of Test Results ISTH Score and Disease State
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
Red bar positive for 2 points of DIC score
Pink bar positive for 1-2 points of DIC score
HT hematopoietic tumor
IF infection
SC solid cancer
Markers in Patients with or without DIC
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
HT hematopoietic tumorIF infectionSC solid cancer
Comparing an Automated FM vs Manual FSP Test
Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71
Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)
Automated (Mitsubishi) vs Automated (Stago)
In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago
Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC
Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
Non Overt DIC Overt DIC
AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC
Trends in Markers of DIC for Different Patients
Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00
Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients
Trends in Markers of DIC for Different Patients
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes
28 day outcome survival
28 day outcome death
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines
DIC Case Studies
Case Study 1 - Presentation
18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE
WBC count 77 KμL 423 ndash 907 x KμL
RBC count 17 MμL 137 ndash 175 x MμL
Hemoglobin 67 gdL 137 ndash 175 gdL
Hematocrit 195 401 ndash 510
MCV 95 fL 790 ndash 922 fL
MPV 12 fL 94 ndash 124 fL
Platelet count 9 KμL 161 ndash 347 KμL
Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0
Lymphocytes monocytes eosinophils basophils all below normal range
PT 47 sec (corrected on mixing study) 116 ndash 152 sec
APTT 75 sec (corrected on mixing study) 253 ndash 373 sec
Fibrinogen lt 76 mgdL 177 ndash 466 mgdL
D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Microscopy
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Arrow shows giant platelets in this peripheral smear Promyelocytes apparent
Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)
DIC due to TF release by APL blasts
Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases
Transfusions to replace factors along with platelets and RBCs during APL treatment
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started
Case Study 2 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L
PT 30 sec 113 ndash 146 sec
APTT 75 sec 25 ndash 34 sec
D-dimer 078 microgml FEU lt050 microgml FEU
Fibrinogen 92 mgdl 150-400 mgdl
pH 728 738 to 742
PaO2 570 mmHg 80-100 mmHg
WBC 33 times 103mm3 40-11 times 103mm3
ALT 111 IUL 0ndash34 IUL
AST 61 IUL 0ndash34 IUL
BUN 303 mgdL 08-13 mgdL
Case Study 2 ndash Lab Results
Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures
Case Study 2 ndash Diagnosis
60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior
Case Study 3 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L
PT 228 sec 113 ndash 146 sec
APTT 45 sec 25 ndash 34 sec
D-dimer 080 microgml FEU lt050 microgmL FEU
Fibrinogen 82 mgdL 150-400 mgdL
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 134 gdL 14-16 gdL
WBC 81 times 103mm3 40-11 times 103mm3
ALT 32 IUL 0ndash34 IUL
AST 28 IUL 0ndash34 IUL
BUN 09 mgdL 08-13 mgdL
Case Study 3 ndash Lab Results
Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment
Case Study 3 ndash Diagnosis and Therapy
Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91
Case Study 4 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L
PT 28 sec 113 ndash 146 sec
APTT 71 sec 25 ndash 34 sec
D-dimer 31 microgmL FEU lt050 microgml FEU
Fibrinogen 92 mgdL 150-400 mgdl
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 158 gdL 14-16 gdL
WBC 71 times 103mm3 40-11 times 103mm3
ALT 60 IUL 0ndash34 IUL
AST 47 IUL 0ndash34 IUL
BUN 38 mgdL 08-13 mgdL
Case Study 4 ndash Lab Results
Lyme disease with DICProvide antibiotics with supportive measures
Case Study 4 ndash Diagnosis
55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis
Case Study 5 ndash Presentation
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
Case Study 5 ndash Lab Results and Time Course
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
TEST RESULT REFERENCE RANGE
Platelet count 33 x 109L 150-450 x 109L
PT 215 sec 103 ndash 128 sec
APTT 44 sec 26 ndash 36 sec
D-dimer 20 microgmL FEU lt025 microgml FEU
Fibrinogen 34 mgdL 200-375 mgdl
FII FV FVIII Low Not reported (NR)
FVII FIX FX vWF Normal NR
Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)
DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic
dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR
(C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen
(D) Illustration demonstrating repair
Case Study 5 ndash Diagnosis and Treatment
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography
Case Study 6 ndash Presentation
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
Case Study 6 ndash Lab Results
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L
PT 63 sec gt control 113 ndash 146 sec
INR 658 1 ndash 125
APTT 80 sec gt control 25 ndash 34 sec
D-dimer gt200 microgmL DDU 02 microgmL DDU
Urine exam Proteinuria and hematuria 150-400 mgdl
Albumin 28 gdL NR
Hb 58 gdL NR
LDH 1196 UL NR
SGPT 144 IU NR
SGOT 88 IU NR
Bilirubin 32 mgdL NR
DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th
day postop
Case Study 6 ndash Diagnosis and Treatment
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure
Case Study 6 ndash Discussion
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Case Study 7 ndash Lab Results vs Time
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
DIC Take Home Messages
Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation
Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers
DIC
Thank you Questions
- Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
- Learning Objectives
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Wound Sealing
- The Three Steps of Hemostasis
- Vessel Wall
- Slide Number 12
- Slide Number 13
- Platelet Structure UnactivatedActivated
- Primary Hemostasis
- Primary Hemostasis Assays
- Slide Number 17
- Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
- Slide Number 19
- Coagulation factors
- Coagulation Assay Mechanisms
- Slide Number 22
- Fibrin Formation
- Slide Number 24
- Fibrinolysis Overview
- Fibrinolysis Overview
- Slide Number 27
- Fibrinolysis Releases D-dimers
- Basic Pathophysiology of DIC
- Disseminated Intravascular Coagulation (DIC)
- Purpura Fulminans with DIC Due to Meningococcal Sepsis
- Clinical Conditions Associated With DIC
- Frequency of DIC in Selected Disease States
- Underlying Diseases in DIC Patients
- Slide Number 36
- Slide Number 37
- Slide Number 38
- Slide Number 39
- Pathophysiology of DIC
- Pathogenesis of DIC in Sepsis
- Host Response in Severe Sepsis
- Organ Failure in Severe Sepsis
- Mechanism of DIC in Organ Failure
- Interaction of Inflammation and Coagulation in Sepsis
- Slide Number 47
- Diverse and Opposing Effects of Thrombin
- Coagulation and Fibrinolysis in DIC
- Mechanism of DIC
- Pathophysiology of DIC
- Pathophysiology of DIC - Mechanism
- Pathophysiology of DIC ndash 2 Types of Clinical pictures
- Sub-Acute and Non-Overt DIC Clinical Findings
- Pathophysiology of Overt DIC
- Physiopathology of DIC ndash Overt DIC Findings
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- BREAK
- Diagnostic and Management Approach for DIC
- Diagnosis of DIC
- Lab Diagnosis of DIC ndash Markers of Factor Consumption
- Lab Diagnosis of DIC ndash Screening Tests
- Slide Number 67
- Slide Number 68
- British Journal of Haematology Overt DIC Score
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- DIC Management Goals
- DIC Management and Treatment
- DIC Management Strategies
- Anticoagulant Factor Concentrate Treatment
- Anticoagulant Factor Concentrate Treatment Trials
- Markers of Thrombin amp Plasmin Generation in DIC
- D-dimer FDPs and DIC
- D-Dimer and FDPs in DIC
- Follow Up of DIC State of Disease
- FMD-Dimer in DIC Major Differences
- of Abnormal Results in Patients with Confirmed and Suspected DIC
- Slide Number 85
- Slide Number 86
- Comparing an Automated FM vs Manual FSP Test
- Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Slide Number 94
- Slide Number 95
- Slide Number 96
- Slide Number 97
- Slide Number 98
- Slide Number 99
- DIC Case Studies
- Case Study 1 - Presentation
- Case Study 1 ndash Lab Results
- Case Study 1 ndash Microscopy
- Case Study 1 ndash Diagnosis and Therapy
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Slide Number 110
- Slide Number 111
- Slide Number 112
- Slide Number 113
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
- Slide Number 124
- Slide Number 125
- DIC Take Home Messages
- Slide Number 127
- Slide Number 128
-
Fibrinolysis Overview
Fibrin =cement fibers
Plasmin
Plasmin digests fibrin
t-PA
Pro Urokinase
Urokinase
PAI-1PAI-1
Plasminogen Plasmin
1st Step
2nd Step
Fibrinolysis Cascade
t-PA tissue-type plasminogen activator PAI-1 Plasminogen activator inhibitor 1 PK Prekallikrein FDP Fibrinogen degradation products AP Antiplasmin = a2AP alpha 2 Antiplasmin a2MG alpha 2 Macroglobulin
Extrinsic pathway(endothelia l cells)
Intrinsic pathway(plasma)
Fibrin clot
D-dimerFibrin degradation products
Fibrin
TAFIa
APAntiplasmin(amp a2-MG)
PK Kallikrein
XII
Fibrinolysis Releases D-dimers
D-dimer presence fibrin has been formed and digested in patients body
Normal D-dimer level no thrombosis occurred in the patient
Basic Pathophysiology of DIC
Disseminated Intravascular Coagulation (DIC)
Massive activation of coagulation leading to clots forming in multiple locations around the bodyRapid consumption of clotting factors leading to bleedingParadoxical condition leading to both clotting and bleedingA confusing disorder from both diagnostic and therapeutic standpoints Many unrelated diseases can trigger DIC Lack of uniformity in clinical manifestation Lack of uniformity in the laboratory diagnosis Lack of uniformity or consensus on management
Clinical Manifestations of DICOrgan Ischemic Hemorrhagic
Skin Pupura Fulminans Petechiae
Gangrene Echymoses
Acral cyanosis Oozing
CNS Deliriumcoma Intracranial
Infarcts Bleeding
Renal OliguriaAzotemia Hematuria
Cortical Necrosis
Cardiovascular Myocardial dysfunction
Pulmonary DyspneaHypoxia Hemorrhagic lung
Infarct
Gastrointestinal Ulcers infarcts Massive hemorrhage
Endocrine Adrenal infarcts
Purpura Fulminans with DIC Due to Meningococcal Sepsis
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Clinical Conditions Associated With DIC
Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33
Frequency of DIC in Selected Disease States
Disease Frequency
Gram-negative sepsis 30-50
Severe trauma and systemic inflammation 50-70
Metastasized tumors 15
Abruptio placentaamniotic fluid embolism 50
Severe preeclampsia 7
Giant hemangioma 25
Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92
Masao Nakagawa Modified from a research report on the incidence of disseminated intravascular coagulation (DIC) and underlying diseases in Japan Ministry of Health Labour and Welfare Research report published in Fiscal Year 1998 57-64 199 httpwwwrecomodulincomendicindexhtml Accessed Apr 21 2017
Underlying Diseases in DIC Patients
In a Japanese survey from 1997 on incidence of DIC and underlying diseases in 652 divisions and departments of university hospitals DIC occurred in 2193 patients with the number of patient with infections (including sepsis) and hematologic tumors (including leukemia) accounted for 28 and 23 respectively
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Epidemiology of DIC
Impact of DIC Status on Mortality - 1
Okamoto K Wada H Hatada T Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Frequency and hemostatic abnormalities in pre-DIC patients Thromb Res 2010 126 74-8
Patients with positivity of DIC tend to have worse mortality outcomes compared to negative patients or those with pre-DIC
Impact of DIC Status on Mortality - 2
Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4
Patients with positivity of either Overt or Non-Overt DIC tend to have worse mortality outcomes compared to negative patients
Impact of Age on Mortality in DIC Patients
Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4
Older patients with DIC (black bars) generally tend to have worse outcomes compared to non-DIC patients (grey bars)
Pathophysiology of DIC
Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33
Pathogenesis of DIC in Sepsis
Allen KS Sawheny E Kinasewitzet GT Anticoagulant modulation of inflammation in severe sepsis World J Crit Care Med 2015 4 105-15
Bacteria in sepsis infections cause release of TF from immune cells leading to coagulation activation and proinflammatory cytokines cause endothelial cell activation impairing the anticoagulation and fibrinolysis process resulting in DIC
Host Response in Severe Sepsis
Exaggerated inflammation as a result of the host response to sepsis is collateral tissue damage and cell death further resulting in release of danger molecules continuing the inflammatory process in a downward spiral
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Organ Failure in Severe Sepsis
Sepsis associated with microvascular thrombosis as a result of TF mediated coagulation activation results in release of neutrophil extracellular traps (NETs) tissue hypoperfusion and mitochondrial damage resulting in a downward spiral leading to organ failure
Angus DC van der Poll T Severe Sepsis and Septic Shock N Engl J Med 2013 369 840-51
Mechanism of DIC in Organ Failure
Underlying condition(sepsis trauma)
Cytokines
TF-mediatedactivation of coagulation
Depression of inhibitory systems
Reducesfibrinolysis
Fibrin deposition
Organ failure
Inadequate fibrin removal
Fibrinformation
Note impaired fibrinolysis in relation to the clinical need not in absolute value (FDPs are )
Levi M de Jonge E van der Poll T ten Cate H Disseminated intravascular coagulation ThrombHaemost 1999 82 695-705
Interaction of Inflammation and Coagulation in Sepsis
Binding of TF thrombin and other activation coagulation factors to PARs and fibrin to TLRs on inflammatory cells results in inflammation through release of proinflammatory cytokines and chemokines
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Mechanism of Multiple Organ Failure in DIC
Wheeler AP Bernard GR Treating Patients with Severe Sepsis N Engl J Med 1999 340207-14
Inflammatory activation and microvascular thrombosis contributes to multiple organ failure in DIC
lipopolysaccharides
cytokines
coagulation activation
mononuclear cell
tissue factor
Diverse and Opposing Effects of Thrombin
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Coagulation and Fibrinolysis in DIC
Soluble fibrin Polymer
XIIIa
D-Dimer
E
Fibrin clot
Fibrin Degradation Products
Fibrinogen Thrombin
Fibrinogen Degradation
Products
D E
Plasmin
DFM + fibrinopeptides
Soluble FM ComplexesPre-throm
boticPost-throm
botic
Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis Semin Thromb Hemost 2008 34 33-8
Mechanism of DIC
THROMBOSIS
Fibrin
Blood activationEndothelial lysisTF expression
BLEEDING
FDPs
D-Dimer
Plasmin
Pathophysiology of DIC
1st step abnormal activation of coagulation Injury of vessel wall cells venous stasis release of large quantities of
thromboplastin influx of activated cells (monocytes macrophages)
Results in an intravascular deposition of fibrin
Morbidity from disseminated microthrombosis in small and midsize vessels leading to multiple organ failure
Second step Consumption and depletion of coagulation factors inhibitors (Protein C
Protein S AT) and platelets Local fibrinolytic response
bull Local plasmin generation dissolves the thrombusbull Disseminated overwhelming fibrinolytic response leading to production of
FDP and D-Dimer
Bleeding
Pathophysiology of DIC - Mechanism
Systemic activation of coagulation
Intravasculardepositionof fibrin
Thrombosis of small and midsize vessels
and organ failure
Depletion of platelets and
coagulation factors
Bleeding
Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92
Pathophysiology of DIC ndash 2 Types of Clinical pictures
Chronic = non - overt DICMay be unrecognized clinically
Acute = overt DIClife threatening bleedingor multiple organ failure
Sub-Acute and Non-Overt DIC Clinical Findings
Compensated non-overt DIC Steady low level or intermittent activation
bull Compensated by increased production of coagulation components and platelets
Few or no clinical signs or multiple microvascular thrombosis sometimes not clinically obvious
Risk of decompensation leading to overt DIC
Pathophysiology of Overt DIC
Massive activation of coagulation and fibrinolysis
Does not allow for compensatory efforts
Rapid depletion of coagulation factors inhibitors and platelets
Thrombosis multiple organ failures
Bleeding complications and shock
Physiopathology of DIC ndash Overt DIC Findings
Thrombin generation
Thrombosis
Renal liver respiratory failures coma skin necrosis gangrene venous thromboembolism hypotension edema
Cytokine and kinin generation (shock)bull Tachycardia hypotension edema
Plasmin generationHemorrhage
bull Spontaneous bruising petechiae intracranial gastrointestinal and respiratory tract bleeding persistent bleeding at venipuncture sites at surgical wounds
bull Tachycardia hypotension edema
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Pathogenesis Pathways in DIC
Cytokines
TF-mediated dysfunctional impairedthrombin anticoagulant fibrinolysisgeneration mechanism due to PAI-1 deficiency
fibrin inadequateformation fibrin removal
Fibrin deposition
Inflammation
Coagulation
Stago Celebrates Lab Week 2017
NA
Stago 247 Educational Webinar Sites
wwwstago-edvantagecomUS based KOLsPACE accredited ndash all 1 hourAccessible from mobile devicesVirtual exhibit hall
wwwstagowebinarscomMostly European KOLs30 ndash 45 min including 15 min discussion
Stago Educational Apps
HaemoscoreClinical scoring algorithmsApple and AndroidTablet or phone
iHemostasisCoagulation diagramsCase studiesApple amp AndroidTablet only
BREAK
Diagnostic and Management Approach for DIC
Diagnosis of DIC
Clinical diagnosis is obvious in cases of overt DIC
Laboratory tests are necessary To makeconfirm the diagnosis To assess stage of the patient To assess the treatment efficacy
Lab Diagnosis of DIC ndash Markers of Factor Consumption
Routinescreening assays PT APTT Platelets Fibrinogen Thrombin time
Other coagulation assays Factor assays AntithrombinGeneration of Thrombin FMFSPsGeneration of Plasmin D-dimer FDPs
Important to recognize simultaneous formation of thrombin and plasmin
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122
Lab Diagnosis of DIC ndash Screening Tests
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122
Platelet count usually decreasedPT abnormal in 70 of cases (short half-life of FVII)APTT abnormal in 50 of casesThrombin time usually prolonged in overt DIC normal in non-overt DIC and no relation with syndrome severityFibrinogen low in lt 50 of cases sensitivity 22 specificity 87 overall predictive value 64 Normal fibrinogen level should not exclude DIC diagnosis (acute phase reactant initial high
fibrinogen level) repeat testing assesses progression
Screening tests not clinically specific or sensitive for DIC
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Laboratory Changes in Overt DIC
DIC Diagnostic Practices Over Time
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
British Journal of Haematology Overt DIC Score
Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
ISTH Step by Step DIC Algorithm
Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6
US Based Validation of ISTH DIC Score
When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Differential Diagnosis in DIC
aHUS atypical hemolytic uremic syndrome
HUS hemolytic uremic syndrome
HIT heparin-induced thrombocytopenia
ITP immune thrombocytopenic purpura
TTP thrombotic thrombocytopenic purpura
DIC and MAHA
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)
When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation
DIC Management Goals
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction
DIC Management and Treatment
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)
requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)
Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia
DIC Management Strategies
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant Factor Concentrate Treatment
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis
Anticoagulant Factor Concentrate Treatment Trials
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise
Markers of Thrombin amp Plasmin Generation in DIC
D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC
Cut-off value
Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen
degradation products Sensitive assay typically with cutoff adapted for DIC
D-dimer FDPs and DIC
D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC
Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80
Follow Up of DIC State of Disease
Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8
Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility
FMD-Dimer in DIC Major Differences
onset of thrombosis
days
Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8
FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)
D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)
of Abnormal Results in Patients with Confirmed and Suspected DIC
0
20
40
60
80
100
94 85 90N = 62
Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32
Positivity of Test Results ISTH Score and Disease State
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
Red bar positive for 2 points of DIC score
Pink bar positive for 1-2 points of DIC score
HT hematopoietic tumor
IF infection
SC solid cancer
Markers in Patients with or without DIC
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
HT hematopoietic tumorIF infectionSC solid cancer
Comparing an Automated FM vs Manual FSP Test
Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71
Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)
Automated (Mitsubishi) vs Automated (Stago)
In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago
Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC
Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
Non Overt DIC Overt DIC
AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC
Trends in Markers of DIC for Different Patients
Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00
Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients
Trends in Markers of DIC for Different Patients
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes
28 day outcome survival
28 day outcome death
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines
DIC Case Studies
Case Study 1 - Presentation
18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE
WBC count 77 KμL 423 ndash 907 x KμL
RBC count 17 MμL 137 ndash 175 x MμL
Hemoglobin 67 gdL 137 ndash 175 gdL
Hematocrit 195 401 ndash 510
MCV 95 fL 790 ndash 922 fL
MPV 12 fL 94 ndash 124 fL
Platelet count 9 KμL 161 ndash 347 KμL
Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0
Lymphocytes monocytes eosinophils basophils all below normal range
PT 47 sec (corrected on mixing study) 116 ndash 152 sec
APTT 75 sec (corrected on mixing study) 253 ndash 373 sec
Fibrinogen lt 76 mgdL 177 ndash 466 mgdL
D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Microscopy
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Arrow shows giant platelets in this peripheral smear Promyelocytes apparent
Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)
DIC due to TF release by APL blasts
Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases
Transfusions to replace factors along with platelets and RBCs during APL treatment
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started
Case Study 2 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L
PT 30 sec 113 ndash 146 sec
APTT 75 sec 25 ndash 34 sec
D-dimer 078 microgml FEU lt050 microgml FEU
Fibrinogen 92 mgdl 150-400 mgdl
pH 728 738 to 742
PaO2 570 mmHg 80-100 mmHg
WBC 33 times 103mm3 40-11 times 103mm3
ALT 111 IUL 0ndash34 IUL
AST 61 IUL 0ndash34 IUL
BUN 303 mgdL 08-13 mgdL
Case Study 2 ndash Lab Results
Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures
Case Study 2 ndash Diagnosis
60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior
Case Study 3 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L
PT 228 sec 113 ndash 146 sec
APTT 45 sec 25 ndash 34 sec
D-dimer 080 microgml FEU lt050 microgmL FEU
Fibrinogen 82 mgdL 150-400 mgdL
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 134 gdL 14-16 gdL
WBC 81 times 103mm3 40-11 times 103mm3
ALT 32 IUL 0ndash34 IUL
AST 28 IUL 0ndash34 IUL
BUN 09 mgdL 08-13 mgdL
Case Study 3 ndash Lab Results
Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment
Case Study 3 ndash Diagnosis and Therapy
Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91
Case Study 4 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L
PT 28 sec 113 ndash 146 sec
APTT 71 sec 25 ndash 34 sec
D-dimer 31 microgmL FEU lt050 microgml FEU
Fibrinogen 92 mgdL 150-400 mgdl
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 158 gdL 14-16 gdL
WBC 71 times 103mm3 40-11 times 103mm3
ALT 60 IUL 0ndash34 IUL
AST 47 IUL 0ndash34 IUL
BUN 38 mgdL 08-13 mgdL
Case Study 4 ndash Lab Results
Lyme disease with DICProvide antibiotics with supportive measures
Case Study 4 ndash Diagnosis
55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis
Case Study 5 ndash Presentation
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
Case Study 5 ndash Lab Results and Time Course
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
TEST RESULT REFERENCE RANGE
Platelet count 33 x 109L 150-450 x 109L
PT 215 sec 103 ndash 128 sec
APTT 44 sec 26 ndash 36 sec
D-dimer 20 microgmL FEU lt025 microgml FEU
Fibrinogen 34 mgdL 200-375 mgdl
FII FV FVIII Low Not reported (NR)
FVII FIX FX vWF Normal NR
Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)
DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic
dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR
(C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen
(D) Illustration demonstrating repair
Case Study 5 ndash Diagnosis and Treatment
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography
Case Study 6 ndash Presentation
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
Case Study 6 ndash Lab Results
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L
PT 63 sec gt control 113 ndash 146 sec
INR 658 1 ndash 125
APTT 80 sec gt control 25 ndash 34 sec
D-dimer gt200 microgmL DDU 02 microgmL DDU
Urine exam Proteinuria and hematuria 150-400 mgdl
Albumin 28 gdL NR
Hb 58 gdL NR
LDH 1196 UL NR
SGPT 144 IU NR
SGOT 88 IU NR
Bilirubin 32 mgdL NR
DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th
day postop
Case Study 6 ndash Diagnosis and Treatment
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure
Case Study 6 ndash Discussion
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Case Study 7 ndash Lab Results vs Time
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
DIC Take Home Messages
Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation
Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers
DIC
Thank you Questions
- Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
- Learning Objectives
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Wound Sealing
- The Three Steps of Hemostasis
- Vessel Wall
- Slide Number 12
- Slide Number 13
- Platelet Structure UnactivatedActivated
- Primary Hemostasis
- Primary Hemostasis Assays
- Slide Number 17
- Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
- Slide Number 19
- Coagulation factors
- Coagulation Assay Mechanisms
- Slide Number 22
- Fibrin Formation
- Slide Number 24
- Fibrinolysis Overview
- Fibrinolysis Overview
- Slide Number 27
- Fibrinolysis Releases D-dimers
- Basic Pathophysiology of DIC
- Disseminated Intravascular Coagulation (DIC)
- Purpura Fulminans with DIC Due to Meningococcal Sepsis
- Clinical Conditions Associated With DIC
- Frequency of DIC in Selected Disease States
- Underlying Diseases in DIC Patients
- Slide Number 36
- Slide Number 37
- Slide Number 38
- Slide Number 39
- Pathophysiology of DIC
- Pathogenesis of DIC in Sepsis
- Host Response in Severe Sepsis
- Organ Failure in Severe Sepsis
- Mechanism of DIC in Organ Failure
- Interaction of Inflammation and Coagulation in Sepsis
- Slide Number 47
- Diverse and Opposing Effects of Thrombin
- Coagulation and Fibrinolysis in DIC
- Mechanism of DIC
- Pathophysiology of DIC
- Pathophysiology of DIC - Mechanism
- Pathophysiology of DIC ndash 2 Types of Clinical pictures
- Sub-Acute and Non-Overt DIC Clinical Findings
- Pathophysiology of Overt DIC
- Physiopathology of DIC ndash Overt DIC Findings
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- BREAK
- Diagnostic and Management Approach for DIC
- Diagnosis of DIC
- Lab Diagnosis of DIC ndash Markers of Factor Consumption
- Lab Diagnosis of DIC ndash Screening Tests
- Slide Number 67
- Slide Number 68
- British Journal of Haematology Overt DIC Score
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- DIC Management Goals
- DIC Management and Treatment
- DIC Management Strategies
- Anticoagulant Factor Concentrate Treatment
- Anticoagulant Factor Concentrate Treatment Trials
- Markers of Thrombin amp Plasmin Generation in DIC
- D-dimer FDPs and DIC
- D-Dimer and FDPs in DIC
- Follow Up of DIC State of Disease
- FMD-Dimer in DIC Major Differences
- of Abnormal Results in Patients with Confirmed and Suspected DIC
- Slide Number 85
- Slide Number 86
- Comparing an Automated FM vs Manual FSP Test
- Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Slide Number 94
- Slide Number 95
- Slide Number 96
- Slide Number 97
- Slide Number 98
- Slide Number 99
- DIC Case Studies
- Case Study 1 - Presentation
- Case Study 1 ndash Lab Results
- Case Study 1 ndash Microscopy
- Case Study 1 ndash Diagnosis and Therapy
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Slide Number 110
- Slide Number 111
- Slide Number 112
- Slide Number 113
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
- Slide Number 124
- Slide Number 125
- DIC Take Home Messages
- Slide Number 127
- Slide Number 128
-
t-PA
Pro Urokinase
Urokinase
PAI-1PAI-1
Plasminogen Plasmin
1st Step
2nd Step
Fibrinolysis Cascade
t-PA tissue-type plasminogen activator PAI-1 Plasminogen activator inhibitor 1 PK Prekallikrein FDP Fibrinogen degradation products AP Antiplasmin = a2AP alpha 2 Antiplasmin a2MG alpha 2 Macroglobulin
Extrinsic pathway(endothelia l cells)
Intrinsic pathway(plasma)
Fibrin clot
D-dimerFibrin degradation products
Fibrin
TAFIa
APAntiplasmin(amp a2-MG)
PK Kallikrein
XII
Fibrinolysis Releases D-dimers
D-dimer presence fibrin has been formed and digested in patients body
Normal D-dimer level no thrombosis occurred in the patient
Basic Pathophysiology of DIC
Disseminated Intravascular Coagulation (DIC)
Massive activation of coagulation leading to clots forming in multiple locations around the bodyRapid consumption of clotting factors leading to bleedingParadoxical condition leading to both clotting and bleedingA confusing disorder from both diagnostic and therapeutic standpoints Many unrelated diseases can trigger DIC Lack of uniformity in clinical manifestation Lack of uniformity in the laboratory diagnosis Lack of uniformity or consensus on management
Clinical Manifestations of DICOrgan Ischemic Hemorrhagic
Skin Pupura Fulminans Petechiae
Gangrene Echymoses
Acral cyanosis Oozing
CNS Deliriumcoma Intracranial
Infarcts Bleeding
Renal OliguriaAzotemia Hematuria
Cortical Necrosis
Cardiovascular Myocardial dysfunction
Pulmonary DyspneaHypoxia Hemorrhagic lung
Infarct
Gastrointestinal Ulcers infarcts Massive hemorrhage
Endocrine Adrenal infarcts
Purpura Fulminans with DIC Due to Meningococcal Sepsis
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Clinical Conditions Associated With DIC
Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33
Frequency of DIC in Selected Disease States
Disease Frequency
Gram-negative sepsis 30-50
Severe trauma and systemic inflammation 50-70
Metastasized tumors 15
Abruptio placentaamniotic fluid embolism 50
Severe preeclampsia 7
Giant hemangioma 25
Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92
Masao Nakagawa Modified from a research report on the incidence of disseminated intravascular coagulation (DIC) and underlying diseases in Japan Ministry of Health Labour and Welfare Research report published in Fiscal Year 1998 57-64 199 httpwwwrecomodulincomendicindexhtml Accessed Apr 21 2017
Underlying Diseases in DIC Patients
In a Japanese survey from 1997 on incidence of DIC and underlying diseases in 652 divisions and departments of university hospitals DIC occurred in 2193 patients with the number of patient with infections (including sepsis) and hematologic tumors (including leukemia) accounted for 28 and 23 respectively
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Epidemiology of DIC
Impact of DIC Status on Mortality - 1
Okamoto K Wada H Hatada T Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Frequency and hemostatic abnormalities in pre-DIC patients Thromb Res 2010 126 74-8
Patients with positivity of DIC tend to have worse mortality outcomes compared to negative patients or those with pre-DIC
Impact of DIC Status on Mortality - 2
Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4
Patients with positivity of either Overt or Non-Overt DIC tend to have worse mortality outcomes compared to negative patients
Impact of Age on Mortality in DIC Patients
Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4
Older patients with DIC (black bars) generally tend to have worse outcomes compared to non-DIC patients (grey bars)
Pathophysiology of DIC
Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33
Pathogenesis of DIC in Sepsis
Allen KS Sawheny E Kinasewitzet GT Anticoagulant modulation of inflammation in severe sepsis World J Crit Care Med 2015 4 105-15
Bacteria in sepsis infections cause release of TF from immune cells leading to coagulation activation and proinflammatory cytokines cause endothelial cell activation impairing the anticoagulation and fibrinolysis process resulting in DIC
Host Response in Severe Sepsis
Exaggerated inflammation as a result of the host response to sepsis is collateral tissue damage and cell death further resulting in release of danger molecules continuing the inflammatory process in a downward spiral
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Organ Failure in Severe Sepsis
Sepsis associated with microvascular thrombosis as a result of TF mediated coagulation activation results in release of neutrophil extracellular traps (NETs) tissue hypoperfusion and mitochondrial damage resulting in a downward spiral leading to organ failure
Angus DC van der Poll T Severe Sepsis and Septic Shock N Engl J Med 2013 369 840-51
Mechanism of DIC in Organ Failure
Underlying condition(sepsis trauma)
Cytokines
TF-mediatedactivation of coagulation
Depression of inhibitory systems
Reducesfibrinolysis
Fibrin deposition
Organ failure
Inadequate fibrin removal
Fibrinformation
Note impaired fibrinolysis in relation to the clinical need not in absolute value (FDPs are )
Levi M de Jonge E van der Poll T ten Cate H Disseminated intravascular coagulation ThrombHaemost 1999 82 695-705
Interaction of Inflammation and Coagulation in Sepsis
Binding of TF thrombin and other activation coagulation factors to PARs and fibrin to TLRs on inflammatory cells results in inflammation through release of proinflammatory cytokines and chemokines
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Mechanism of Multiple Organ Failure in DIC
Wheeler AP Bernard GR Treating Patients with Severe Sepsis N Engl J Med 1999 340207-14
Inflammatory activation and microvascular thrombosis contributes to multiple organ failure in DIC
lipopolysaccharides
cytokines
coagulation activation
mononuclear cell
tissue factor
Diverse and Opposing Effects of Thrombin
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Coagulation and Fibrinolysis in DIC
Soluble fibrin Polymer
XIIIa
D-Dimer
E
Fibrin clot
Fibrin Degradation Products
Fibrinogen Thrombin
Fibrinogen Degradation
Products
D E
Plasmin
DFM + fibrinopeptides
Soluble FM ComplexesPre-throm
boticPost-throm
botic
Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis Semin Thromb Hemost 2008 34 33-8
Mechanism of DIC
THROMBOSIS
Fibrin
Blood activationEndothelial lysisTF expression
BLEEDING
FDPs
D-Dimer
Plasmin
Pathophysiology of DIC
1st step abnormal activation of coagulation Injury of vessel wall cells venous stasis release of large quantities of
thromboplastin influx of activated cells (monocytes macrophages)
Results in an intravascular deposition of fibrin
Morbidity from disseminated microthrombosis in small and midsize vessels leading to multiple organ failure
Second step Consumption and depletion of coagulation factors inhibitors (Protein C
Protein S AT) and platelets Local fibrinolytic response
bull Local plasmin generation dissolves the thrombusbull Disseminated overwhelming fibrinolytic response leading to production of
FDP and D-Dimer
Bleeding
Pathophysiology of DIC - Mechanism
Systemic activation of coagulation
Intravasculardepositionof fibrin
Thrombosis of small and midsize vessels
and organ failure
Depletion of platelets and
coagulation factors
Bleeding
Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92
Pathophysiology of DIC ndash 2 Types of Clinical pictures
Chronic = non - overt DICMay be unrecognized clinically
Acute = overt DIClife threatening bleedingor multiple organ failure
Sub-Acute and Non-Overt DIC Clinical Findings
Compensated non-overt DIC Steady low level or intermittent activation
bull Compensated by increased production of coagulation components and platelets
Few or no clinical signs or multiple microvascular thrombosis sometimes not clinically obvious
Risk of decompensation leading to overt DIC
Pathophysiology of Overt DIC
Massive activation of coagulation and fibrinolysis
Does not allow for compensatory efforts
Rapid depletion of coagulation factors inhibitors and platelets
Thrombosis multiple organ failures
Bleeding complications and shock
Physiopathology of DIC ndash Overt DIC Findings
Thrombin generation
Thrombosis
Renal liver respiratory failures coma skin necrosis gangrene venous thromboembolism hypotension edema
Cytokine and kinin generation (shock)bull Tachycardia hypotension edema
Plasmin generationHemorrhage
bull Spontaneous bruising petechiae intracranial gastrointestinal and respiratory tract bleeding persistent bleeding at venipuncture sites at surgical wounds
bull Tachycardia hypotension edema
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Pathogenesis Pathways in DIC
Cytokines
TF-mediated dysfunctional impairedthrombin anticoagulant fibrinolysisgeneration mechanism due to PAI-1 deficiency
fibrin inadequateformation fibrin removal
Fibrin deposition
Inflammation
Coagulation
Stago Celebrates Lab Week 2017
NA
Stago 247 Educational Webinar Sites
wwwstago-edvantagecomUS based KOLsPACE accredited ndash all 1 hourAccessible from mobile devicesVirtual exhibit hall
wwwstagowebinarscomMostly European KOLs30 ndash 45 min including 15 min discussion
Stago Educational Apps
HaemoscoreClinical scoring algorithmsApple and AndroidTablet or phone
iHemostasisCoagulation diagramsCase studiesApple amp AndroidTablet only
BREAK
Diagnostic and Management Approach for DIC
Diagnosis of DIC
Clinical diagnosis is obvious in cases of overt DIC
Laboratory tests are necessary To makeconfirm the diagnosis To assess stage of the patient To assess the treatment efficacy
Lab Diagnosis of DIC ndash Markers of Factor Consumption
Routinescreening assays PT APTT Platelets Fibrinogen Thrombin time
Other coagulation assays Factor assays AntithrombinGeneration of Thrombin FMFSPsGeneration of Plasmin D-dimer FDPs
Important to recognize simultaneous formation of thrombin and plasmin
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122
Lab Diagnosis of DIC ndash Screening Tests
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122
Platelet count usually decreasedPT abnormal in 70 of cases (short half-life of FVII)APTT abnormal in 50 of casesThrombin time usually prolonged in overt DIC normal in non-overt DIC and no relation with syndrome severityFibrinogen low in lt 50 of cases sensitivity 22 specificity 87 overall predictive value 64 Normal fibrinogen level should not exclude DIC diagnosis (acute phase reactant initial high
fibrinogen level) repeat testing assesses progression
Screening tests not clinically specific or sensitive for DIC
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Laboratory Changes in Overt DIC
DIC Diagnostic Practices Over Time
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
British Journal of Haematology Overt DIC Score
Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
ISTH Step by Step DIC Algorithm
Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6
US Based Validation of ISTH DIC Score
When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Differential Diagnosis in DIC
aHUS atypical hemolytic uremic syndrome
HUS hemolytic uremic syndrome
HIT heparin-induced thrombocytopenia
ITP immune thrombocytopenic purpura
TTP thrombotic thrombocytopenic purpura
DIC and MAHA
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)
When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation
DIC Management Goals
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction
DIC Management and Treatment
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)
requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)
Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia
DIC Management Strategies
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant Factor Concentrate Treatment
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis
Anticoagulant Factor Concentrate Treatment Trials
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise
Markers of Thrombin amp Plasmin Generation in DIC
D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC
Cut-off value
Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen
degradation products Sensitive assay typically with cutoff adapted for DIC
D-dimer FDPs and DIC
D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC
Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80
Follow Up of DIC State of Disease
Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8
Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility
FMD-Dimer in DIC Major Differences
onset of thrombosis
days
Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8
FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)
D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)
of Abnormal Results in Patients with Confirmed and Suspected DIC
0
20
40
60
80
100
94 85 90N = 62
Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32
Positivity of Test Results ISTH Score and Disease State
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
Red bar positive for 2 points of DIC score
Pink bar positive for 1-2 points of DIC score
HT hematopoietic tumor
IF infection
SC solid cancer
Markers in Patients with or without DIC
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
HT hematopoietic tumorIF infectionSC solid cancer
Comparing an Automated FM vs Manual FSP Test
Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71
Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)
Automated (Mitsubishi) vs Automated (Stago)
In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago
Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC
Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
Non Overt DIC Overt DIC
AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC
Trends in Markers of DIC for Different Patients
Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00
Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients
Trends in Markers of DIC for Different Patients
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes
28 day outcome survival
28 day outcome death
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines
DIC Case Studies
Case Study 1 - Presentation
18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE
WBC count 77 KμL 423 ndash 907 x KμL
RBC count 17 MμL 137 ndash 175 x MμL
Hemoglobin 67 gdL 137 ndash 175 gdL
Hematocrit 195 401 ndash 510
MCV 95 fL 790 ndash 922 fL
MPV 12 fL 94 ndash 124 fL
Platelet count 9 KμL 161 ndash 347 KμL
Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0
Lymphocytes monocytes eosinophils basophils all below normal range
PT 47 sec (corrected on mixing study) 116 ndash 152 sec
APTT 75 sec (corrected on mixing study) 253 ndash 373 sec
Fibrinogen lt 76 mgdL 177 ndash 466 mgdL
D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Microscopy
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Arrow shows giant platelets in this peripheral smear Promyelocytes apparent
Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)
DIC due to TF release by APL blasts
Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases
Transfusions to replace factors along with platelets and RBCs during APL treatment
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started
Case Study 2 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L
PT 30 sec 113 ndash 146 sec
APTT 75 sec 25 ndash 34 sec
D-dimer 078 microgml FEU lt050 microgml FEU
Fibrinogen 92 mgdl 150-400 mgdl
pH 728 738 to 742
PaO2 570 mmHg 80-100 mmHg
WBC 33 times 103mm3 40-11 times 103mm3
ALT 111 IUL 0ndash34 IUL
AST 61 IUL 0ndash34 IUL
BUN 303 mgdL 08-13 mgdL
Case Study 2 ndash Lab Results
Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures
Case Study 2 ndash Diagnosis
60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior
Case Study 3 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L
PT 228 sec 113 ndash 146 sec
APTT 45 sec 25 ndash 34 sec
D-dimer 080 microgml FEU lt050 microgmL FEU
Fibrinogen 82 mgdL 150-400 mgdL
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 134 gdL 14-16 gdL
WBC 81 times 103mm3 40-11 times 103mm3
ALT 32 IUL 0ndash34 IUL
AST 28 IUL 0ndash34 IUL
BUN 09 mgdL 08-13 mgdL
Case Study 3 ndash Lab Results
Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment
Case Study 3 ndash Diagnosis and Therapy
Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91
Case Study 4 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L
PT 28 sec 113 ndash 146 sec
APTT 71 sec 25 ndash 34 sec
D-dimer 31 microgmL FEU lt050 microgml FEU
Fibrinogen 92 mgdL 150-400 mgdl
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 158 gdL 14-16 gdL
WBC 71 times 103mm3 40-11 times 103mm3
ALT 60 IUL 0ndash34 IUL
AST 47 IUL 0ndash34 IUL
BUN 38 mgdL 08-13 mgdL
Case Study 4 ndash Lab Results
Lyme disease with DICProvide antibiotics with supportive measures
Case Study 4 ndash Diagnosis
55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis
Case Study 5 ndash Presentation
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
Case Study 5 ndash Lab Results and Time Course
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
TEST RESULT REFERENCE RANGE
Platelet count 33 x 109L 150-450 x 109L
PT 215 sec 103 ndash 128 sec
APTT 44 sec 26 ndash 36 sec
D-dimer 20 microgmL FEU lt025 microgml FEU
Fibrinogen 34 mgdL 200-375 mgdl
FII FV FVIII Low Not reported (NR)
FVII FIX FX vWF Normal NR
Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)
DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic
dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR
(C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen
(D) Illustration demonstrating repair
Case Study 5 ndash Diagnosis and Treatment
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography
Case Study 6 ndash Presentation
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
Case Study 6 ndash Lab Results
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L
PT 63 sec gt control 113 ndash 146 sec
INR 658 1 ndash 125
APTT 80 sec gt control 25 ndash 34 sec
D-dimer gt200 microgmL DDU 02 microgmL DDU
Urine exam Proteinuria and hematuria 150-400 mgdl
Albumin 28 gdL NR
Hb 58 gdL NR
LDH 1196 UL NR
SGPT 144 IU NR
SGOT 88 IU NR
Bilirubin 32 mgdL NR
DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th
day postop
Case Study 6 ndash Diagnosis and Treatment
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure
Case Study 6 ndash Discussion
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Case Study 7 ndash Lab Results vs Time
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
DIC Take Home Messages
Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation
Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers
DIC
Thank you Questions
- Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
- Learning Objectives
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Wound Sealing
- The Three Steps of Hemostasis
- Vessel Wall
- Slide Number 12
- Slide Number 13
- Platelet Structure UnactivatedActivated
- Primary Hemostasis
- Primary Hemostasis Assays
- Slide Number 17
- Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
- Slide Number 19
- Coagulation factors
- Coagulation Assay Mechanisms
- Slide Number 22
- Fibrin Formation
- Slide Number 24
- Fibrinolysis Overview
- Fibrinolysis Overview
- Slide Number 27
- Fibrinolysis Releases D-dimers
- Basic Pathophysiology of DIC
- Disseminated Intravascular Coagulation (DIC)
- Purpura Fulminans with DIC Due to Meningococcal Sepsis
- Clinical Conditions Associated With DIC
- Frequency of DIC in Selected Disease States
- Underlying Diseases in DIC Patients
- Slide Number 36
- Slide Number 37
- Slide Number 38
- Slide Number 39
- Pathophysiology of DIC
- Pathogenesis of DIC in Sepsis
- Host Response in Severe Sepsis
- Organ Failure in Severe Sepsis
- Mechanism of DIC in Organ Failure
- Interaction of Inflammation and Coagulation in Sepsis
- Slide Number 47
- Diverse and Opposing Effects of Thrombin
- Coagulation and Fibrinolysis in DIC
- Mechanism of DIC
- Pathophysiology of DIC
- Pathophysiology of DIC - Mechanism
- Pathophysiology of DIC ndash 2 Types of Clinical pictures
- Sub-Acute and Non-Overt DIC Clinical Findings
- Pathophysiology of Overt DIC
- Physiopathology of DIC ndash Overt DIC Findings
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- BREAK
- Diagnostic and Management Approach for DIC
- Diagnosis of DIC
- Lab Diagnosis of DIC ndash Markers of Factor Consumption
- Lab Diagnosis of DIC ndash Screening Tests
- Slide Number 67
- Slide Number 68
- British Journal of Haematology Overt DIC Score
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- DIC Management Goals
- DIC Management and Treatment
- DIC Management Strategies
- Anticoagulant Factor Concentrate Treatment
- Anticoagulant Factor Concentrate Treatment Trials
- Markers of Thrombin amp Plasmin Generation in DIC
- D-dimer FDPs and DIC
- D-Dimer and FDPs in DIC
- Follow Up of DIC State of Disease
- FMD-Dimer in DIC Major Differences
- of Abnormal Results in Patients with Confirmed and Suspected DIC
- Slide Number 85
- Slide Number 86
- Comparing an Automated FM vs Manual FSP Test
- Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Slide Number 94
- Slide Number 95
- Slide Number 96
- Slide Number 97
- Slide Number 98
- Slide Number 99
- DIC Case Studies
- Case Study 1 - Presentation
- Case Study 1 ndash Lab Results
- Case Study 1 ndash Microscopy
- Case Study 1 ndash Diagnosis and Therapy
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Slide Number 110
- Slide Number 111
- Slide Number 112
- Slide Number 113
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
- Slide Number 124
- Slide Number 125
- DIC Take Home Messages
- Slide Number 127
- Slide Number 128
-
Fibrinolysis Releases D-dimers
D-dimer presence fibrin has been formed and digested in patients body
Normal D-dimer level no thrombosis occurred in the patient
Basic Pathophysiology of DIC
Disseminated Intravascular Coagulation (DIC)
Massive activation of coagulation leading to clots forming in multiple locations around the bodyRapid consumption of clotting factors leading to bleedingParadoxical condition leading to both clotting and bleedingA confusing disorder from both diagnostic and therapeutic standpoints Many unrelated diseases can trigger DIC Lack of uniformity in clinical manifestation Lack of uniformity in the laboratory diagnosis Lack of uniformity or consensus on management
Clinical Manifestations of DICOrgan Ischemic Hemorrhagic
Skin Pupura Fulminans Petechiae
Gangrene Echymoses
Acral cyanosis Oozing
CNS Deliriumcoma Intracranial
Infarcts Bleeding
Renal OliguriaAzotemia Hematuria
Cortical Necrosis
Cardiovascular Myocardial dysfunction
Pulmonary DyspneaHypoxia Hemorrhagic lung
Infarct
Gastrointestinal Ulcers infarcts Massive hemorrhage
Endocrine Adrenal infarcts
Purpura Fulminans with DIC Due to Meningococcal Sepsis
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Clinical Conditions Associated With DIC
Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33
Frequency of DIC in Selected Disease States
Disease Frequency
Gram-negative sepsis 30-50
Severe trauma and systemic inflammation 50-70
Metastasized tumors 15
Abruptio placentaamniotic fluid embolism 50
Severe preeclampsia 7
Giant hemangioma 25
Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92
Masao Nakagawa Modified from a research report on the incidence of disseminated intravascular coagulation (DIC) and underlying diseases in Japan Ministry of Health Labour and Welfare Research report published in Fiscal Year 1998 57-64 199 httpwwwrecomodulincomendicindexhtml Accessed Apr 21 2017
Underlying Diseases in DIC Patients
In a Japanese survey from 1997 on incidence of DIC and underlying diseases in 652 divisions and departments of university hospitals DIC occurred in 2193 patients with the number of patient with infections (including sepsis) and hematologic tumors (including leukemia) accounted for 28 and 23 respectively
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Epidemiology of DIC
Impact of DIC Status on Mortality - 1
Okamoto K Wada H Hatada T Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Frequency and hemostatic abnormalities in pre-DIC patients Thromb Res 2010 126 74-8
Patients with positivity of DIC tend to have worse mortality outcomes compared to negative patients or those with pre-DIC
Impact of DIC Status on Mortality - 2
Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4
Patients with positivity of either Overt or Non-Overt DIC tend to have worse mortality outcomes compared to negative patients
Impact of Age on Mortality in DIC Patients
Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4
Older patients with DIC (black bars) generally tend to have worse outcomes compared to non-DIC patients (grey bars)
Pathophysiology of DIC
Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33
Pathogenesis of DIC in Sepsis
Allen KS Sawheny E Kinasewitzet GT Anticoagulant modulation of inflammation in severe sepsis World J Crit Care Med 2015 4 105-15
Bacteria in sepsis infections cause release of TF from immune cells leading to coagulation activation and proinflammatory cytokines cause endothelial cell activation impairing the anticoagulation and fibrinolysis process resulting in DIC
Host Response in Severe Sepsis
Exaggerated inflammation as a result of the host response to sepsis is collateral tissue damage and cell death further resulting in release of danger molecules continuing the inflammatory process in a downward spiral
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Organ Failure in Severe Sepsis
Sepsis associated with microvascular thrombosis as a result of TF mediated coagulation activation results in release of neutrophil extracellular traps (NETs) tissue hypoperfusion and mitochondrial damage resulting in a downward spiral leading to organ failure
Angus DC van der Poll T Severe Sepsis and Septic Shock N Engl J Med 2013 369 840-51
Mechanism of DIC in Organ Failure
Underlying condition(sepsis trauma)
Cytokines
TF-mediatedactivation of coagulation
Depression of inhibitory systems
Reducesfibrinolysis
Fibrin deposition
Organ failure
Inadequate fibrin removal
Fibrinformation
Note impaired fibrinolysis in relation to the clinical need not in absolute value (FDPs are )
Levi M de Jonge E van der Poll T ten Cate H Disseminated intravascular coagulation ThrombHaemost 1999 82 695-705
Interaction of Inflammation and Coagulation in Sepsis
Binding of TF thrombin and other activation coagulation factors to PARs and fibrin to TLRs on inflammatory cells results in inflammation through release of proinflammatory cytokines and chemokines
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Mechanism of Multiple Organ Failure in DIC
Wheeler AP Bernard GR Treating Patients with Severe Sepsis N Engl J Med 1999 340207-14
Inflammatory activation and microvascular thrombosis contributes to multiple organ failure in DIC
lipopolysaccharides
cytokines
coagulation activation
mononuclear cell
tissue factor
Diverse and Opposing Effects of Thrombin
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Coagulation and Fibrinolysis in DIC
Soluble fibrin Polymer
XIIIa
D-Dimer
E
Fibrin clot
Fibrin Degradation Products
Fibrinogen Thrombin
Fibrinogen Degradation
Products
D E
Plasmin
DFM + fibrinopeptides
Soluble FM ComplexesPre-throm
boticPost-throm
botic
Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis Semin Thromb Hemost 2008 34 33-8
Mechanism of DIC
THROMBOSIS
Fibrin
Blood activationEndothelial lysisTF expression
BLEEDING
FDPs
D-Dimer
Plasmin
Pathophysiology of DIC
1st step abnormal activation of coagulation Injury of vessel wall cells venous stasis release of large quantities of
thromboplastin influx of activated cells (monocytes macrophages)
Results in an intravascular deposition of fibrin
Morbidity from disseminated microthrombosis in small and midsize vessels leading to multiple organ failure
Second step Consumption and depletion of coagulation factors inhibitors (Protein C
Protein S AT) and platelets Local fibrinolytic response
bull Local plasmin generation dissolves the thrombusbull Disseminated overwhelming fibrinolytic response leading to production of
FDP and D-Dimer
Bleeding
Pathophysiology of DIC - Mechanism
Systemic activation of coagulation
Intravasculardepositionof fibrin
Thrombosis of small and midsize vessels
and organ failure
Depletion of platelets and
coagulation factors
Bleeding
Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92
Pathophysiology of DIC ndash 2 Types of Clinical pictures
Chronic = non - overt DICMay be unrecognized clinically
Acute = overt DIClife threatening bleedingor multiple organ failure
Sub-Acute and Non-Overt DIC Clinical Findings
Compensated non-overt DIC Steady low level or intermittent activation
bull Compensated by increased production of coagulation components and platelets
Few or no clinical signs or multiple microvascular thrombosis sometimes not clinically obvious
Risk of decompensation leading to overt DIC
Pathophysiology of Overt DIC
Massive activation of coagulation and fibrinolysis
Does not allow for compensatory efforts
Rapid depletion of coagulation factors inhibitors and platelets
Thrombosis multiple organ failures
Bleeding complications and shock
Physiopathology of DIC ndash Overt DIC Findings
Thrombin generation
Thrombosis
Renal liver respiratory failures coma skin necrosis gangrene venous thromboembolism hypotension edema
Cytokine and kinin generation (shock)bull Tachycardia hypotension edema
Plasmin generationHemorrhage
bull Spontaneous bruising petechiae intracranial gastrointestinal and respiratory tract bleeding persistent bleeding at venipuncture sites at surgical wounds
bull Tachycardia hypotension edema
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Pathogenesis Pathways in DIC
Cytokines
TF-mediated dysfunctional impairedthrombin anticoagulant fibrinolysisgeneration mechanism due to PAI-1 deficiency
fibrin inadequateformation fibrin removal
Fibrin deposition
Inflammation
Coagulation
Stago Celebrates Lab Week 2017
NA
Stago 247 Educational Webinar Sites
wwwstago-edvantagecomUS based KOLsPACE accredited ndash all 1 hourAccessible from mobile devicesVirtual exhibit hall
wwwstagowebinarscomMostly European KOLs30 ndash 45 min including 15 min discussion
Stago Educational Apps
HaemoscoreClinical scoring algorithmsApple and AndroidTablet or phone
iHemostasisCoagulation diagramsCase studiesApple amp AndroidTablet only
BREAK
Diagnostic and Management Approach for DIC
Diagnosis of DIC
Clinical diagnosis is obvious in cases of overt DIC
Laboratory tests are necessary To makeconfirm the diagnosis To assess stage of the patient To assess the treatment efficacy
Lab Diagnosis of DIC ndash Markers of Factor Consumption
Routinescreening assays PT APTT Platelets Fibrinogen Thrombin time
Other coagulation assays Factor assays AntithrombinGeneration of Thrombin FMFSPsGeneration of Plasmin D-dimer FDPs
Important to recognize simultaneous formation of thrombin and plasmin
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122
Lab Diagnosis of DIC ndash Screening Tests
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122
Platelet count usually decreasedPT abnormal in 70 of cases (short half-life of FVII)APTT abnormal in 50 of casesThrombin time usually prolonged in overt DIC normal in non-overt DIC and no relation with syndrome severityFibrinogen low in lt 50 of cases sensitivity 22 specificity 87 overall predictive value 64 Normal fibrinogen level should not exclude DIC diagnosis (acute phase reactant initial high
fibrinogen level) repeat testing assesses progression
Screening tests not clinically specific or sensitive for DIC
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Laboratory Changes in Overt DIC
DIC Diagnostic Practices Over Time
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
British Journal of Haematology Overt DIC Score
Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
ISTH Step by Step DIC Algorithm
Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6
US Based Validation of ISTH DIC Score
When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Differential Diagnosis in DIC
aHUS atypical hemolytic uremic syndrome
HUS hemolytic uremic syndrome
HIT heparin-induced thrombocytopenia
ITP immune thrombocytopenic purpura
TTP thrombotic thrombocytopenic purpura
DIC and MAHA
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)
When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation
DIC Management Goals
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction
DIC Management and Treatment
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)
requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)
Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia
DIC Management Strategies
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant Factor Concentrate Treatment
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis
Anticoagulant Factor Concentrate Treatment Trials
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise
Markers of Thrombin amp Plasmin Generation in DIC
D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC
Cut-off value
Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen
degradation products Sensitive assay typically with cutoff adapted for DIC
D-dimer FDPs and DIC
D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC
Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80
Follow Up of DIC State of Disease
Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8
Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility
FMD-Dimer in DIC Major Differences
onset of thrombosis
days
Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8
FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)
D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)
of Abnormal Results in Patients with Confirmed and Suspected DIC
0
20
40
60
80
100
94 85 90N = 62
Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32
Positivity of Test Results ISTH Score and Disease State
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
Red bar positive for 2 points of DIC score
Pink bar positive for 1-2 points of DIC score
HT hematopoietic tumor
IF infection
SC solid cancer
Markers in Patients with or without DIC
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
HT hematopoietic tumorIF infectionSC solid cancer
Comparing an Automated FM vs Manual FSP Test
Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71
Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)
Automated (Mitsubishi) vs Automated (Stago)
In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago
Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC
Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
Non Overt DIC Overt DIC
AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC
Trends in Markers of DIC for Different Patients
Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00
Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients
Trends in Markers of DIC for Different Patients
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes
28 day outcome survival
28 day outcome death
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines
DIC Case Studies
Case Study 1 - Presentation
18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE
WBC count 77 KμL 423 ndash 907 x KμL
RBC count 17 MμL 137 ndash 175 x MμL
Hemoglobin 67 gdL 137 ndash 175 gdL
Hematocrit 195 401 ndash 510
MCV 95 fL 790 ndash 922 fL
MPV 12 fL 94 ndash 124 fL
Platelet count 9 KμL 161 ndash 347 KμL
Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0
Lymphocytes monocytes eosinophils basophils all below normal range
PT 47 sec (corrected on mixing study) 116 ndash 152 sec
APTT 75 sec (corrected on mixing study) 253 ndash 373 sec
Fibrinogen lt 76 mgdL 177 ndash 466 mgdL
D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Microscopy
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Arrow shows giant platelets in this peripheral smear Promyelocytes apparent
Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)
DIC due to TF release by APL blasts
Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases
Transfusions to replace factors along with platelets and RBCs during APL treatment
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started
Case Study 2 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L
PT 30 sec 113 ndash 146 sec
APTT 75 sec 25 ndash 34 sec
D-dimer 078 microgml FEU lt050 microgml FEU
Fibrinogen 92 mgdl 150-400 mgdl
pH 728 738 to 742
PaO2 570 mmHg 80-100 mmHg
WBC 33 times 103mm3 40-11 times 103mm3
ALT 111 IUL 0ndash34 IUL
AST 61 IUL 0ndash34 IUL
BUN 303 mgdL 08-13 mgdL
Case Study 2 ndash Lab Results
Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures
Case Study 2 ndash Diagnosis
60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior
Case Study 3 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L
PT 228 sec 113 ndash 146 sec
APTT 45 sec 25 ndash 34 sec
D-dimer 080 microgml FEU lt050 microgmL FEU
Fibrinogen 82 mgdL 150-400 mgdL
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 134 gdL 14-16 gdL
WBC 81 times 103mm3 40-11 times 103mm3
ALT 32 IUL 0ndash34 IUL
AST 28 IUL 0ndash34 IUL
BUN 09 mgdL 08-13 mgdL
Case Study 3 ndash Lab Results
Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment
Case Study 3 ndash Diagnosis and Therapy
Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91
Case Study 4 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L
PT 28 sec 113 ndash 146 sec
APTT 71 sec 25 ndash 34 sec
D-dimer 31 microgmL FEU lt050 microgml FEU
Fibrinogen 92 mgdL 150-400 mgdl
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 158 gdL 14-16 gdL
WBC 71 times 103mm3 40-11 times 103mm3
ALT 60 IUL 0ndash34 IUL
AST 47 IUL 0ndash34 IUL
BUN 38 mgdL 08-13 mgdL
Case Study 4 ndash Lab Results
Lyme disease with DICProvide antibiotics with supportive measures
Case Study 4 ndash Diagnosis
55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis
Case Study 5 ndash Presentation
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
Case Study 5 ndash Lab Results and Time Course
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
TEST RESULT REFERENCE RANGE
Platelet count 33 x 109L 150-450 x 109L
PT 215 sec 103 ndash 128 sec
APTT 44 sec 26 ndash 36 sec
D-dimer 20 microgmL FEU lt025 microgml FEU
Fibrinogen 34 mgdL 200-375 mgdl
FII FV FVIII Low Not reported (NR)
FVII FIX FX vWF Normal NR
Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)
DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic
dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR
(C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen
(D) Illustration demonstrating repair
Case Study 5 ndash Diagnosis and Treatment
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography
Case Study 6 ndash Presentation
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
Case Study 6 ndash Lab Results
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L
PT 63 sec gt control 113 ndash 146 sec
INR 658 1 ndash 125
APTT 80 sec gt control 25 ndash 34 sec
D-dimer gt200 microgmL DDU 02 microgmL DDU
Urine exam Proteinuria and hematuria 150-400 mgdl
Albumin 28 gdL NR
Hb 58 gdL NR
LDH 1196 UL NR
SGPT 144 IU NR
SGOT 88 IU NR
Bilirubin 32 mgdL NR
DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th
day postop
Case Study 6 ndash Diagnosis and Treatment
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure
Case Study 6 ndash Discussion
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Case Study 7 ndash Lab Results vs Time
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
DIC Take Home Messages
Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation
Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers
DIC
Thank you Questions
- Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
- Learning Objectives
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Wound Sealing
- The Three Steps of Hemostasis
- Vessel Wall
- Slide Number 12
- Slide Number 13
- Platelet Structure UnactivatedActivated
- Primary Hemostasis
- Primary Hemostasis Assays
- Slide Number 17
- Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
- Slide Number 19
- Coagulation factors
- Coagulation Assay Mechanisms
- Slide Number 22
- Fibrin Formation
- Slide Number 24
- Fibrinolysis Overview
- Fibrinolysis Overview
- Slide Number 27
- Fibrinolysis Releases D-dimers
- Basic Pathophysiology of DIC
- Disseminated Intravascular Coagulation (DIC)
- Purpura Fulminans with DIC Due to Meningococcal Sepsis
- Clinical Conditions Associated With DIC
- Frequency of DIC in Selected Disease States
- Underlying Diseases in DIC Patients
- Slide Number 36
- Slide Number 37
- Slide Number 38
- Slide Number 39
- Pathophysiology of DIC
- Pathogenesis of DIC in Sepsis
- Host Response in Severe Sepsis
- Organ Failure in Severe Sepsis
- Mechanism of DIC in Organ Failure
- Interaction of Inflammation and Coagulation in Sepsis
- Slide Number 47
- Diverse and Opposing Effects of Thrombin
- Coagulation and Fibrinolysis in DIC
- Mechanism of DIC
- Pathophysiology of DIC
- Pathophysiology of DIC - Mechanism
- Pathophysiology of DIC ndash 2 Types of Clinical pictures
- Sub-Acute and Non-Overt DIC Clinical Findings
- Pathophysiology of Overt DIC
- Physiopathology of DIC ndash Overt DIC Findings
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- BREAK
- Diagnostic and Management Approach for DIC
- Diagnosis of DIC
- Lab Diagnosis of DIC ndash Markers of Factor Consumption
- Lab Diagnosis of DIC ndash Screening Tests
- Slide Number 67
- Slide Number 68
- British Journal of Haematology Overt DIC Score
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- DIC Management Goals
- DIC Management and Treatment
- DIC Management Strategies
- Anticoagulant Factor Concentrate Treatment
- Anticoagulant Factor Concentrate Treatment Trials
- Markers of Thrombin amp Plasmin Generation in DIC
- D-dimer FDPs and DIC
- D-Dimer and FDPs in DIC
- Follow Up of DIC State of Disease
- FMD-Dimer in DIC Major Differences
- of Abnormal Results in Patients with Confirmed and Suspected DIC
- Slide Number 85
- Slide Number 86
- Comparing an Automated FM vs Manual FSP Test
- Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Slide Number 94
- Slide Number 95
- Slide Number 96
- Slide Number 97
- Slide Number 98
- Slide Number 99
- DIC Case Studies
- Case Study 1 - Presentation
- Case Study 1 ndash Lab Results
- Case Study 1 ndash Microscopy
- Case Study 1 ndash Diagnosis and Therapy
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Slide Number 110
- Slide Number 111
- Slide Number 112
- Slide Number 113
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
- Slide Number 124
- Slide Number 125
- DIC Take Home Messages
- Slide Number 127
- Slide Number 128
-
Basic Pathophysiology of DIC
Disseminated Intravascular Coagulation (DIC)
Massive activation of coagulation leading to clots forming in multiple locations around the bodyRapid consumption of clotting factors leading to bleedingParadoxical condition leading to both clotting and bleedingA confusing disorder from both diagnostic and therapeutic standpoints Many unrelated diseases can trigger DIC Lack of uniformity in clinical manifestation Lack of uniformity in the laboratory diagnosis Lack of uniformity or consensus on management
Clinical Manifestations of DICOrgan Ischemic Hemorrhagic
Skin Pupura Fulminans Petechiae
Gangrene Echymoses
Acral cyanosis Oozing
CNS Deliriumcoma Intracranial
Infarcts Bleeding
Renal OliguriaAzotemia Hematuria
Cortical Necrosis
Cardiovascular Myocardial dysfunction
Pulmonary DyspneaHypoxia Hemorrhagic lung
Infarct
Gastrointestinal Ulcers infarcts Massive hemorrhage
Endocrine Adrenal infarcts
Purpura Fulminans with DIC Due to Meningococcal Sepsis
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Clinical Conditions Associated With DIC
Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33
Frequency of DIC in Selected Disease States
Disease Frequency
Gram-negative sepsis 30-50
Severe trauma and systemic inflammation 50-70
Metastasized tumors 15
Abruptio placentaamniotic fluid embolism 50
Severe preeclampsia 7
Giant hemangioma 25
Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92
Masao Nakagawa Modified from a research report on the incidence of disseminated intravascular coagulation (DIC) and underlying diseases in Japan Ministry of Health Labour and Welfare Research report published in Fiscal Year 1998 57-64 199 httpwwwrecomodulincomendicindexhtml Accessed Apr 21 2017
Underlying Diseases in DIC Patients
In a Japanese survey from 1997 on incidence of DIC and underlying diseases in 652 divisions and departments of university hospitals DIC occurred in 2193 patients with the number of patient with infections (including sepsis) and hematologic tumors (including leukemia) accounted for 28 and 23 respectively
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Epidemiology of DIC
Impact of DIC Status on Mortality - 1
Okamoto K Wada H Hatada T Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Frequency and hemostatic abnormalities in pre-DIC patients Thromb Res 2010 126 74-8
Patients with positivity of DIC tend to have worse mortality outcomes compared to negative patients or those with pre-DIC
Impact of DIC Status on Mortality - 2
Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4
Patients with positivity of either Overt or Non-Overt DIC tend to have worse mortality outcomes compared to negative patients
Impact of Age on Mortality in DIC Patients
Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4
Older patients with DIC (black bars) generally tend to have worse outcomes compared to non-DIC patients (grey bars)
Pathophysiology of DIC
Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33
Pathogenesis of DIC in Sepsis
Allen KS Sawheny E Kinasewitzet GT Anticoagulant modulation of inflammation in severe sepsis World J Crit Care Med 2015 4 105-15
Bacteria in sepsis infections cause release of TF from immune cells leading to coagulation activation and proinflammatory cytokines cause endothelial cell activation impairing the anticoagulation and fibrinolysis process resulting in DIC
Host Response in Severe Sepsis
Exaggerated inflammation as a result of the host response to sepsis is collateral tissue damage and cell death further resulting in release of danger molecules continuing the inflammatory process in a downward spiral
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Organ Failure in Severe Sepsis
Sepsis associated with microvascular thrombosis as a result of TF mediated coagulation activation results in release of neutrophil extracellular traps (NETs) tissue hypoperfusion and mitochondrial damage resulting in a downward spiral leading to organ failure
Angus DC van der Poll T Severe Sepsis and Septic Shock N Engl J Med 2013 369 840-51
Mechanism of DIC in Organ Failure
Underlying condition(sepsis trauma)
Cytokines
TF-mediatedactivation of coagulation
Depression of inhibitory systems
Reducesfibrinolysis
Fibrin deposition
Organ failure
Inadequate fibrin removal
Fibrinformation
Note impaired fibrinolysis in relation to the clinical need not in absolute value (FDPs are )
Levi M de Jonge E van der Poll T ten Cate H Disseminated intravascular coagulation ThrombHaemost 1999 82 695-705
Interaction of Inflammation and Coagulation in Sepsis
Binding of TF thrombin and other activation coagulation factors to PARs and fibrin to TLRs on inflammatory cells results in inflammation through release of proinflammatory cytokines and chemokines
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Mechanism of Multiple Organ Failure in DIC
Wheeler AP Bernard GR Treating Patients with Severe Sepsis N Engl J Med 1999 340207-14
Inflammatory activation and microvascular thrombosis contributes to multiple organ failure in DIC
lipopolysaccharides
cytokines
coagulation activation
mononuclear cell
tissue factor
Diverse and Opposing Effects of Thrombin
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Coagulation and Fibrinolysis in DIC
Soluble fibrin Polymer
XIIIa
D-Dimer
E
Fibrin clot
Fibrin Degradation Products
Fibrinogen Thrombin
Fibrinogen Degradation
Products
D E
Plasmin
DFM + fibrinopeptides
Soluble FM ComplexesPre-throm
boticPost-throm
botic
Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis Semin Thromb Hemost 2008 34 33-8
Mechanism of DIC
THROMBOSIS
Fibrin
Blood activationEndothelial lysisTF expression
BLEEDING
FDPs
D-Dimer
Plasmin
Pathophysiology of DIC
1st step abnormal activation of coagulation Injury of vessel wall cells venous stasis release of large quantities of
thromboplastin influx of activated cells (monocytes macrophages)
Results in an intravascular deposition of fibrin
Morbidity from disseminated microthrombosis in small and midsize vessels leading to multiple organ failure
Second step Consumption and depletion of coagulation factors inhibitors (Protein C
Protein S AT) and platelets Local fibrinolytic response
bull Local plasmin generation dissolves the thrombusbull Disseminated overwhelming fibrinolytic response leading to production of
FDP and D-Dimer
Bleeding
Pathophysiology of DIC - Mechanism
Systemic activation of coagulation
Intravasculardepositionof fibrin
Thrombosis of small and midsize vessels
and organ failure
Depletion of platelets and
coagulation factors
Bleeding
Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92
Pathophysiology of DIC ndash 2 Types of Clinical pictures
Chronic = non - overt DICMay be unrecognized clinically
Acute = overt DIClife threatening bleedingor multiple organ failure
Sub-Acute and Non-Overt DIC Clinical Findings
Compensated non-overt DIC Steady low level or intermittent activation
bull Compensated by increased production of coagulation components and platelets
Few or no clinical signs or multiple microvascular thrombosis sometimes not clinically obvious
Risk of decompensation leading to overt DIC
Pathophysiology of Overt DIC
Massive activation of coagulation and fibrinolysis
Does not allow for compensatory efforts
Rapid depletion of coagulation factors inhibitors and platelets
Thrombosis multiple organ failures
Bleeding complications and shock
Physiopathology of DIC ndash Overt DIC Findings
Thrombin generation
Thrombosis
Renal liver respiratory failures coma skin necrosis gangrene venous thromboembolism hypotension edema
Cytokine and kinin generation (shock)bull Tachycardia hypotension edema
Plasmin generationHemorrhage
bull Spontaneous bruising petechiae intracranial gastrointestinal and respiratory tract bleeding persistent bleeding at venipuncture sites at surgical wounds
bull Tachycardia hypotension edema
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Pathogenesis Pathways in DIC
Cytokines
TF-mediated dysfunctional impairedthrombin anticoagulant fibrinolysisgeneration mechanism due to PAI-1 deficiency
fibrin inadequateformation fibrin removal
Fibrin deposition
Inflammation
Coagulation
Stago Celebrates Lab Week 2017
NA
Stago 247 Educational Webinar Sites
wwwstago-edvantagecomUS based KOLsPACE accredited ndash all 1 hourAccessible from mobile devicesVirtual exhibit hall
wwwstagowebinarscomMostly European KOLs30 ndash 45 min including 15 min discussion
Stago Educational Apps
HaemoscoreClinical scoring algorithmsApple and AndroidTablet or phone
iHemostasisCoagulation diagramsCase studiesApple amp AndroidTablet only
BREAK
Diagnostic and Management Approach for DIC
Diagnosis of DIC
Clinical diagnosis is obvious in cases of overt DIC
Laboratory tests are necessary To makeconfirm the diagnosis To assess stage of the patient To assess the treatment efficacy
Lab Diagnosis of DIC ndash Markers of Factor Consumption
Routinescreening assays PT APTT Platelets Fibrinogen Thrombin time
Other coagulation assays Factor assays AntithrombinGeneration of Thrombin FMFSPsGeneration of Plasmin D-dimer FDPs
Important to recognize simultaneous formation of thrombin and plasmin
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122
Lab Diagnosis of DIC ndash Screening Tests
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122
Platelet count usually decreasedPT abnormal in 70 of cases (short half-life of FVII)APTT abnormal in 50 of casesThrombin time usually prolonged in overt DIC normal in non-overt DIC and no relation with syndrome severityFibrinogen low in lt 50 of cases sensitivity 22 specificity 87 overall predictive value 64 Normal fibrinogen level should not exclude DIC diagnosis (acute phase reactant initial high
fibrinogen level) repeat testing assesses progression
Screening tests not clinically specific or sensitive for DIC
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Laboratory Changes in Overt DIC
DIC Diagnostic Practices Over Time
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
British Journal of Haematology Overt DIC Score
Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
ISTH Step by Step DIC Algorithm
Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6
US Based Validation of ISTH DIC Score
When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Differential Diagnosis in DIC
aHUS atypical hemolytic uremic syndrome
HUS hemolytic uremic syndrome
HIT heparin-induced thrombocytopenia
ITP immune thrombocytopenic purpura
TTP thrombotic thrombocytopenic purpura
DIC and MAHA
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)
When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation
DIC Management Goals
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction
DIC Management and Treatment
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)
requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)
Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia
DIC Management Strategies
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant Factor Concentrate Treatment
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis
Anticoagulant Factor Concentrate Treatment Trials
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise
Markers of Thrombin amp Plasmin Generation in DIC
D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC
Cut-off value
Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen
degradation products Sensitive assay typically with cutoff adapted for DIC
D-dimer FDPs and DIC
D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC
Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80
Follow Up of DIC State of Disease
Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8
Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility
FMD-Dimer in DIC Major Differences
onset of thrombosis
days
Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8
FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)
D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)
of Abnormal Results in Patients with Confirmed and Suspected DIC
0
20
40
60
80
100
94 85 90N = 62
Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32
Positivity of Test Results ISTH Score and Disease State
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
Red bar positive for 2 points of DIC score
Pink bar positive for 1-2 points of DIC score
HT hematopoietic tumor
IF infection
SC solid cancer
Markers in Patients with or without DIC
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
HT hematopoietic tumorIF infectionSC solid cancer
Comparing an Automated FM vs Manual FSP Test
Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71
Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)
Automated (Mitsubishi) vs Automated (Stago)
In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago
Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC
Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
Non Overt DIC Overt DIC
AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC
Trends in Markers of DIC for Different Patients
Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00
Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients
Trends in Markers of DIC for Different Patients
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes
28 day outcome survival
28 day outcome death
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines
DIC Case Studies
Case Study 1 - Presentation
18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE
WBC count 77 KμL 423 ndash 907 x KμL
RBC count 17 MμL 137 ndash 175 x MμL
Hemoglobin 67 gdL 137 ndash 175 gdL
Hematocrit 195 401 ndash 510
MCV 95 fL 790 ndash 922 fL
MPV 12 fL 94 ndash 124 fL
Platelet count 9 KμL 161 ndash 347 KμL
Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0
Lymphocytes monocytes eosinophils basophils all below normal range
PT 47 sec (corrected on mixing study) 116 ndash 152 sec
APTT 75 sec (corrected on mixing study) 253 ndash 373 sec
Fibrinogen lt 76 mgdL 177 ndash 466 mgdL
D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Microscopy
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Arrow shows giant platelets in this peripheral smear Promyelocytes apparent
Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)
DIC due to TF release by APL blasts
Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases
Transfusions to replace factors along with platelets and RBCs during APL treatment
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started
Case Study 2 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L
PT 30 sec 113 ndash 146 sec
APTT 75 sec 25 ndash 34 sec
D-dimer 078 microgml FEU lt050 microgml FEU
Fibrinogen 92 mgdl 150-400 mgdl
pH 728 738 to 742
PaO2 570 mmHg 80-100 mmHg
WBC 33 times 103mm3 40-11 times 103mm3
ALT 111 IUL 0ndash34 IUL
AST 61 IUL 0ndash34 IUL
BUN 303 mgdL 08-13 mgdL
Case Study 2 ndash Lab Results
Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures
Case Study 2 ndash Diagnosis
60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior
Case Study 3 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L
PT 228 sec 113 ndash 146 sec
APTT 45 sec 25 ndash 34 sec
D-dimer 080 microgml FEU lt050 microgmL FEU
Fibrinogen 82 mgdL 150-400 mgdL
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 134 gdL 14-16 gdL
WBC 81 times 103mm3 40-11 times 103mm3
ALT 32 IUL 0ndash34 IUL
AST 28 IUL 0ndash34 IUL
BUN 09 mgdL 08-13 mgdL
Case Study 3 ndash Lab Results
Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment
Case Study 3 ndash Diagnosis and Therapy
Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91
Case Study 4 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L
PT 28 sec 113 ndash 146 sec
APTT 71 sec 25 ndash 34 sec
D-dimer 31 microgmL FEU lt050 microgml FEU
Fibrinogen 92 mgdL 150-400 mgdl
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 158 gdL 14-16 gdL
WBC 71 times 103mm3 40-11 times 103mm3
ALT 60 IUL 0ndash34 IUL
AST 47 IUL 0ndash34 IUL
BUN 38 mgdL 08-13 mgdL
Case Study 4 ndash Lab Results
Lyme disease with DICProvide antibiotics with supportive measures
Case Study 4 ndash Diagnosis
55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis
Case Study 5 ndash Presentation
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
Case Study 5 ndash Lab Results and Time Course
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
TEST RESULT REFERENCE RANGE
Platelet count 33 x 109L 150-450 x 109L
PT 215 sec 103 ndash 128 sec
APTT 44 sec 26 ndash 36 sec
D-dimer 20 microgmL FEU lt025 microgml FEU
Fibrinogen 34 mgdL 200-375 mgdl
FII FV FVIII Low Not reported (NR)
FVII FIX FX vWF Normal NR
Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)
DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic
dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR
(C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen
(D) Illustration demonstrating repair
Case Study 5 ndash Diagnosis and Treatment
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography
Case Study 6 ndash Presentation
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
Case Study 6 ndash Lab Results
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L
PT 63 sec gt control 113 ndash 146 sec
INR 658 1 ndash 125
APTT 80 sec gt control 25 ndash 34 sec
D-dimer gt200 microgmL DDU 02 microgmL DDU
Urine exam Proteinuria and hematuria 150-400 mgdl
Albumin 28 gdL NR
Hb 58 gdL NR
LDH 1196 UL NR
SGPT 144 IU NR
SGOT 88 IU NR
Bilirubin 32 mgdL NR
DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th
day postop
Case Study 6 ndash Diagnosis and Treatment
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure
Case Study 6 ndash Discussion
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Case Study 7 ndash Lab Results vs Time
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
DIC Take Home Messages
Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation
Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers
DIC
Thank you Questions
- Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
- Learning Objectives
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Wound Sealing
- The Three Steps of Hemostasis
- Vessel Wall
- Slide Number 12
- Slide Number 13
- Platelet Structure UnactivatedActivated
- Primary Hemostasis
- Primary Hemostasis Assays
- Slide Number 17
- Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
- Slide Number 19
- Coagulation factors
- Coagulation Assay Mechanisms
- Slide Number 22
- Fibrin Formation
- Slide Number 24
- Fibrinolysis Overview
- Fibrinolysis Overview
- Slide Number 27
- Fibrinolysis Releases D-dimers
- Basic Pathophysiology of DIC
- Disseminated Intravascular Coagulation (DIC)
- Purpura Fulminans with DIC Due to Meningococcal Sepsis
- Clinical Conditions Associated With DIC
- Frequency of DIC in Selected Disease States
- Underlying Diseases in DIC Patients
- Slide Number 36
- Slide Number 37
- Slide Number 38
- Slide Number 39
- Pathophysiology of DIC
- Pathogenesis of DIC in Sepsis
- Host Response in Severe Sepsis
- Organ Failure in Severe Sepsis
- Mechanism of DIC in Organ Failure
- Interaction of Inflammation and Coagulation in Sepsis
- Slide Number 47
- Diverse and Opposing Effects of Thrombin
- Coagulation and Fibrinolysis in DIC
- Mechanism of DIC
- Pathophysiology of DIC
- Pathophysiology of DIC - Mechanism
- Pathophysiology of DIC ndash 2 Types of Clinical pictures
- Sub-Acute and Non-Overt DIC Clinical Findings
- Pathophysiology of Overt DIC
- Physiopathology of DIC ndash Overt DIC Findings
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- BREAK
- Diagnostic and Management Approach for DIC
- Diagnosis of DIC
- Lab Diagnosis of DIC ndash Markers of Factor Consumption
- Lab Diagnosis of DIC ndash Screening Tests
- Slide Number 67
- Slide Number 68
- British Journal of Haematology Overt DIC Score
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- DIC Management Goals
- DIC Management and Treatment
- DIC Management Strategies
- Anticoagulant Factor Concentrate Treatment
- Anticoagulant Factor Concentrate Treatment Trials
- Markers of Thrombin amp Plasmin Generation in DIC
- D-dimer FDPs and DIC
- D-Dimer and FDPs in DIC
- Follow Up of DIC State of Disease
- FMD-Dimer in DIC Major Differences
- of Abnormal Results in Patients with Confirmed and Suspected DIC
- Slide Number 85
- Slide Number 86
- Comparing an Automated FM vs Manual FSP Test
- Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Slide Number 94
- Slide Number 95
- Slide Number 96
- Slide Number 97
- Slide Number 98
- Slide Number 99
- DIC Case Studies
- Case Study 1 - Presentation
- Case Study 1 ndash Lab Results
- Case Study 1 ndash Microscopy
- Case Study 1 ndash Diagnosis and Therapy
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Slide Number 110
- Slide Number 111
- Slide Number 112
- Slide Number 113
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
- Slide Number 124
- Slide Number 125
- DIC Take Home Messages
- Slide Number 127
- Slide Number 128
-
Disseminated Intravascular Coagulation (DIC)
Massive activation of coagulation leading to clots forming in multiple locations around the bodyRapid consumption of clotting factors leading to bleedingParadoxical condition leading to both clotting and bleedingA confusing disorder from both diagnostic and therapeutic standpoints Many unrelated diseases can trigger DIC Lack of uniformity in clinical manifestation Lack of uniformity in the laboratory diagnosis Lack of uniformity or consensus on management
Clinical Manifestations of DICOrgan Ischemic Hemorrhagic
Skin Pupura Fulminans Petechiae
Gangrene Echymoses
Acral cyanosis Oozing
CNS Deliriumcoma Intracranial
Infarcts Bleeding
Renal OliguriaAzotemia Hematuria
Cortical Necrosis
Cardiovascular Myocardial dysfunction
Pulmonary DyspneaHypoxia Hemorrhagic lung
Infarct
Gastrointestinal Ulcers infarcts Massive hemorrhage
Endocrine Adrenal infarcts
Purpura Fulminans with DIC Due to Meningococcal Sepsis
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Clinical Conditions Associated With DIC
Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33
Frequency of DIC in Selected Disease States
Disease Frequency
Gram-negative sepsis 30-50
Severe trauma and systemic inflammation 50-70
Metastasized tumors 15
Abruptio placentaamniotic fluid embolism 50
Severe preeclampsia 7
Giant hemangioma 25
Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92
Masao Nakagawa Modified from a research report on the incidence of disseminated intravascular coagulation (DIC) and underlying diseases in Japan Ministry of Health Labour and Welfare Research report published in Fiscal Year 1998 57-64 199 httpwwwrecomodulincomendicindexhtml Accessed Apr 21 2017
Underlying Diseases in DIC Patients
In a Japanese survey from 1997 on incidence of DIC and underlying diseases in 652 divisions and departments of university hospitals DIC occurred in 2193 patients with the number of patient with infections (including sepsis) and hematologic tumors (including leukemia) accounted for 28 and 23 respectively
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Epidemiology of DIC
Impact of DIC Status on Mortality - 1
Okamoto K Wada H Hatada T Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Frequency and hemostatic abnormalities in pre-DIC patients Thromb Res 2010 126 74-8
Patients with positivity of DIC tend to have worse mortality outcomes compared to negative patients or those with pre-DIC
Impact of DIC Status on Mortality - 2
Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4
Patients with positivity of either Overt or Non-Overt DIC tend to have worse mortality outcomes compared to negative patients
Impact of Age on Mortality in DIC Patients
Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4
Older patients with DIC (black bars) generally tend to have worse outcomes compared to non-DIC patients (grey bars)
Pathophysiology of DIC
Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33
Pathogenesis of DIC in Sepsis
Allen KS Sawheny E Kinasewitzet GT Anticoagulant modulation of inflammation in severe sepsis World J Crit Care Med 2015 4 105-15
Bacteria in sepsis infections cause release of TF from immune cells leading to coagulation activation and proinflammatory cytokines cause endothelial cell activation impairing the anticoagulation and fibrinolysis process resulting in DIC
Host Response in Severe Sepsis
Exaggerated inflammation as a result of the host response to sepsis is collateral tissue damage and cell death further resulting in release of danger molecules continuing the inflammatory process in a downward spiral
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Organ Failure in Severe Sepsis
Sepsis associated with microvascular thrombosis as a result of TF mediated coagulation activation results in release of neutrophil extracellular traps (NETs) tissue hypoperfusion and mitochondrial damage resulting in a downward spiral leading to organ failure
Angus DC van der Poll T Severe Sepsis and Septic Shock N Engl J Med 2013 369 840-51
Mechanism of DIC in Organ Failure
Underlying condition(sepsis trauma)
Cytokines
TF-mediatedactivation of coagulation
Depression of inhibitory systems
Reducesfibrinolysis
Fibrin deposition
Organ failure
Inadequate fibrin removal
Fibrinformation
Note impaired fibrinolysis in relation to the clinical need not in absolute value (FDPs are )
Levi M de Jonge E van der Poll T ten Cate H Disseminated intravascular coagulation ThrombHaemost 1999 82 695-705
Interaction of Inflammation and Coagulation in Sepsis
Binding of TF thrombin and other activation coagulation factors to PARs and fibrin to TLRs on inflammatory cells results in inflammation through release of proinflammatory cytokines and chemokines
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Mechanism of Multiple Organ Failure in DIC
Wheeler AP Bernard GR Treating Patients with Severe Sepsis N Engl J Med 1999 340207-14
Inflammatory activation and microvascular thrombosis contributes to multiple organ failure in DIC
lipopolysaccharides
cytokines
coagulation activation
mononuclear cell
tissue factor
Diverse and Opposing Effects of Thrombin
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Coagulation and Fibrinolysis in DIC
Soluble fibrin Polymer
XIIIa
D-Dimer
E
Fibrin clot
Fibrin Degradation Products
Fibrinogen Thrombin
Fibrinogen Degradation
Products
D E
Plasmin
DFM + fibrinopeptides
Soluble FM ComplexesPre-throm
boticPost-throm
botic
Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis Semin Thromb Hemost 2008 34 33-8
Mechanism of DIC
THROMBOSIS
Fibrin
Blood activationEndothelial lysisTF expression
BLEEDING
FDPs
D-Dimer
Plasmin
Pathophysiology of DIC
1st step abnormal activation of coagulation Injury of vessel wall cells venous stasis release of large quantities of
thromboplastin influx of activated cells (monocytes macrophages)
Results in an intravascular deposition of fibrin
Morbidity from disseminated microthrombosis in small and midsize vessels leading to multiple organ failure
Second step Consumption and depletion of coagulation factors inhibitors (Protein C
Protein S AT) and platelets Local fibrinolytic response
bull Local plasmin generation dissolves the thrombusbull Disseminated overwhelming fibrinolytic response leading to production of
FDP and D-Dimer
Bleeding
Pathophysiology of DIC - Mechanism
Systemic activation of coagulation
Intravasculardepositionof fibrin
Thrombosis of small and midsize vessels
and organ failure
Depletion of platelets and
coagulation factors
Bleeding
Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92
Pathophysiology of DIC ndash 2 Types of Clinical pictures
Chronic = non - overt DICMay be unrecognized clinically
Acute = overt DIClife threatening bleedingor multiple organ failure
Sub-Acute and Non-Overt DIC Clinical Findings
Compensated non-overt DIC Steady low level or intermittent activation
bull Compensated by increased production of coagulation components and platelets
Few or no clinical signs or multiple microvascular thrombosis sometimes not clinically obvious
Risk of decompensation leading to overt DIC
Pathophysiology of Overt DIC
Massive activation of coagulation and fibrinolysis
Does not allow for compensatory efforts
Rapid depletion of coagulation factors inhibitors and platelets
Thrombosis multiple organ failures
Bleeding complications and shock
Physiopathology of DIC ndash Overt DIC Findings
Thrombin generation
Thrombosis
Renal liver respiratory failures coma skin necrosis gangrene venous thromboembolism hypotension edema
Cytokine and kinin generation (shock)bull Tachycardia hypotension edema
Plasmin generationHemorrhage
bull Spontaneous bruising petechiae intracranial gastrointestinal and respiratory tract bleeding persistent bleeding at venipuncture sites at surgical wounds
bull Tachycardia hypotension edema
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Pathogenesis Pathways in DIC
Cytokines
TF-mediated dysfunctional impairedthrombin anticoagulant fibrinolysisgeneration mechanism due to PAI-1 deficiency
fibrin inadequateformation fibrin removal
Fibrin deposition
Inflammation
Coagulation
Stago Celebrates Lab Week 2017
NA
Stago 247 Educational Webinar Sites
wwwstago-edvantagecomUS based KOLsPACE accredited ndash all 1 hourAccessible from mobile devicesVirtual exhibit hall
wwwstagowebinarscomMostly European KOLs30 ndash 45 min including 15 min discussion
Stago Educational Apps
HaemoscoreClinical scoring algorithmsApple and AndroidTablet or phone
iHemostasisCoagulation diagramsCase studiesApple amp AndroidTablet only
BREAK
Diagnostic and Management Approach for DIC
Diagnosis of DIC
Clinical diagnosis is obvious in cases of overt DIC
Laboratory tests are necessary To makeconfirm the diagnosis To assess stage of the patient To assess the treatment efficacy
Lab Diagnosis of DIC ndash Markers of Factor Consumption
Routinescreening assays PT APTT Platelets Fibrinogen Thrombin time
Other coagulation assays Factor assays AntithrombinGeneration of Thrombin FMFSPsGeneration of Plasmin D-dimer FDPs
Important to recognize simultaneous formation of thrombin and plasmin
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122
Lab Diagnosis of DIC ndash Screening Tests
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122
Platelet count usually decreasedPT abnormal in 70 of cases (short half-life of FVII)APTT abnormal in 50 of casesThrombin time usually prolonged in overt DIC normal in non-overt DIC and no relation with syndrome severityFibrinogen low in lt 50 of cases sensitivity 22 specificity 87 overall predictive value 64 Normal fibrinogen level should not exclude DIC diagnosis (acute phase reactant initial high
fibrinogen level) repeat testing assesses progression
Screening tests not clinically specific or sensitive for DIC
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Laboratory Changes in Overt DIC
DIC Diagnostic Practices Over Time
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
British Journal of Haematology Overt DIC Score
Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
ISTH Step by Step DIC Algorithm
Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6
US Based Validation of ISTH DIC Score
When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Differential Diagnosis in DIC
aHUS atypical hemolytic uremic syndrome
HUS hemolytic uremic syndrome
HIT heparin-induced thrombocytopenia
ITP immune thrombocytopenic purpura
TTP thrombotic thrombocytopenic purpura
DIC and MAHA
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)
When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation
DIC Management Goals
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction
DIC Management and Treatment
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)
requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)
Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia
DIC Management Strategies
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant Factor Concentrate Treatment
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis
Anticoagulant Factor Concentrate Treatment Trials
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise
Markers of Thrombin amp Plasmin Generation in DIC
D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC
Cut-off value
Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen
degradation products Sensitive assay typically with cutoff adapted for DIC
D-dimer FDPs and DIC
D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC
Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80
Follow Up of DIC State of Disease
Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8
Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility
FMD-Dimer in DIC Major Differences
onset of thrombosis
days
Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8
FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)
D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)
of Abnormal Results in Patients with Confirmed and Suspected DIC
0
20
40
60
80
100
94 85 90N = 62
Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32
Positivity of Test Results ISTH Score and Disease State
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
Red bar positive for 2 points of DIC score
Pink bar positive for 1-2 points of DIC score
HT hematopoietic tumor
IF infection
SC solid cancer
Markers in Patients with or without DIC
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
HT hematopoietic tumorIF infectionSC solid cancer
Comparing an Automated FM vs Manual FSP Test
Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71
Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)
Automated (Mitsubishi) vs Automated (Stago)
In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago
Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC
Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
Non Overt DIC Overt DIC
AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC
Trends in Markers of DIC for Different Patients
Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00
Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients
Trends in Markers of DIC for Different Patients
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes
28 day outcome survival
28 day outcome death
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines
DIC Case Studies
Case Study 1 - Presentation
18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE
WBC count 77 KμL 423 ndash 907 x KμL
RBC count 17 MμL 137 ndash 175 x MμL
Hemoglobin 67 gdL 137 ndash 175 gdL
Hematocrit 195 401 ndash 510
MCV 95 fL 790 ndash 922 fL
MPV 12 fL 94 ndash 124 fL
Platelet count 9 KμL 161 ndash 347 KμL
Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0
Lymphocytes monocytes eosinophils basophils all below normal range
PT 47 sec (corrected on mixing study) 116 ndash 152 sec
APTT 75 sec (corrected on mixing study) 253 ndash 373 sec
Fibrinogen lt 76 mgdL 177 ndash 466 mgdL
D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Microscopy
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Arrow shows giant platelets in this peripheral smear Promyelocytes apparent
Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)
DIC due to TF release by APL blasts
Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases
Transfusions to replace factors along with platelets and RBCs during APL treatment
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started
Case Study 2 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L
PT 30 sec 113 ndash 146 sec
APTT 75 sec 25 ndash 34 sec
D-dimer 078 microgml FEU lt050 microgml FEU
Fibrinogen 92 mgdl 150-400 mgdl
pH 728 738 to 742
PaO2 570 mmHg 80-100 mmHg
WBC 33 times 103mm3 40-11 times 103mm3
ALT 111 IUL 0ndash34 IUL
AST 61 IUL 0ndash34 IUL
BUN 303 mgdL 08-13 mgdL
Case Study 2 ndash Lab Results
Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures
Case Study 2 ndash Diagnosis
60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior
Case Study 3 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L
PT 228 sec 113 ndash 146 sec
APTT 45 sec 25 ndash 34 sec
D-dimer 080 microgml FEU lt050 microgmL FEU
Fibrinogen 82 mgdL 150-400 mgdL
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 134 gdL 14-16 gdL
WBC 81 times 103mm3 40-11 times 103mm3
ALT 32 IUL 0ndash34 IUL
AST 28 IUL 0ndash34 IUL
BUN 09 mgdL 08-13 mgdL
Case Study 3 ndash Lab Results
Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment
Case Study 3 ndash Diagnosis and Therapy
Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91
Case Study 4 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L
PT 28 sec 113 ndash 146 sec
APTT 71 sec 25 ndash 34 sec
D-dimer 31 microgmL FEU lt050 microgml FEU
Fibrinogen 92 mgdL 150-400 mgdl
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 158 gdL 14-16 gdL
WBC 71 times 103mm3 40-11 times 103mm3
ALT 60 IUL 0ndash34 IUL
AST 47 IUL 0ndash34 IUL
BUN 38 mgdL 08-13 mgdL
Case Study 4 ndash Lab Results
Lyme disease with DICProvide antibiotics with supportive measures
Case Study 4 ndash Diagnosis
55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis
Case Study 5 ndash Presentation
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
Case Study 5 ndash Lab Results and Time Course
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
TEST RESULT REFERENCE RANGE
Platelet count 33 x 109L 150-450 x 109L
PT 215 sec 103 ndash 128 sec
APTT 44 sec 26 ndash 36 sec
D-dimer 20 microgmL FEU lt025 microgml FEU
Fibrinogen 34 mgdL 200-375 mgdl
FII FV FVIII Low Not reported (NR)
FVII FIX FX vWF Normal NR
Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)
DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic
dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR
(C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen
(D) Illustration demonstrating repair
Case Study 5 ndash Diagnosis and Treatment
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography
Case Study 6 ndash Presentation
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
Case Study 6 ndash Lab Results
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L
PT 63 sec gt control 113 ndash 146 sec
INR 658 1 ndash 125
APTT 80 sec gt control 25 ndash 34 sec
D-dimer gt200 microgmL DDU 02 microgmL DDU
Urine exam Proteinuria and hematuria 150-400 mgdl
Albumin 28 gdL NR
Hb 58 gdL NR
LDH 1196 UL NR
SGPT 144 IU NR
SGOT 88 IU NR
Bilirubin 32 mgdL NR
DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th
day postop
Case Study 6 ndash Diagnosis and Treatment
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure
Case Study 6 ndash Discussion
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Case Study 7 ndash Lab Results vs Time
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
DIC Take Home Messages
Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation
Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers
DIC
Thank you Questions
- Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
- Learning Objectives
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Wound Sealing
- The Three Steps of Hemostasis
- Vessel Wall
- Slide Number 12
- Slide Number 13
- Platelet Structure UnactivatedActivated
- Primary Hemostasis
- Primary Hemostasis Assays
- Slide Number 17
- Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
- Slide Number 19
- Coagulation factors
- Coagulation Assay Mechanisms
- Slide Number 22
- Fibrin Formation
- Slide Number 24
- Fibrinolysis Overview
- Fibrinolysis Overview
- Slide Number 27
- Fibrinolysis Releases D-dimers
- Basic Pathophysiology of DIC
- Disseminated Intravascular Coagulation (DIC)
- Purpura Fulminans with DIC Due to Meningococcal Sepsis
- Clinical Conditions Associated With DIC
- Frequency of DIC in Selected Disease States
- Underlying Diseases in DIC Patients
- Slide Number 36
- Slide Number 37
- Slide Number 38
- Slide Number 39
- Pathophysiology of DIC
- Pathogenesis of DIC in Sepsis
- Host Response in Severe Sepsis
- Organ Failure in Severe Sepsis
- Mechanism of DIC in Organ Failure
- Interaction of Inflammation and Coagulation in Sepsis
- Slide Number 47
- Diverse and Opposing Effects of Thrombin
- Coagulation and Fibrinolysis in DIC
- Mechanism of DIC
- Pathophysiology of DIC
- Pathophysiology of DIC - Mechanism
- Pathophysiology of DIC ndash 2 Types of Clinical pictures
- Sub-Acute and Non-Overt DIC Clinical Findings
- Pathophysiology of Overt DIC
- Physiopathology of DIC ndash Overt DIC Findings
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- BREAK
- Diagnostic and Management Approach for DIC
- Diagnosis of DIC
- Lab Diagnosis of DIC ndash Markers of Factor Consumption
- Lab Diagnosis of DIC ndash Screening Tests
- Slide Number 67
- Slide Number 68
- British Journal of Haematology Overt DIC Score
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- DIC Management Goals
- DIC Management and Treatment
- DIC Management Strategies
- Anticoagulant Factor Concentrate Treatment
- Anticoagulant Factor Concentrate Treatment Trials
- Markers of Thrombin amp Plasmin Generation in DIC
- D-dimer FDPs and DIC
- D-Dimer and FDPs in DIC
- Follow Up of DIC State of Disease
- FMD-Dimer in DIC Major Differences
- of Abnormal Results in Patients with Confirmed and Suspected DIC
- Slide Number 85
- Slide Number 86
- Comparing an Automated FM vs Manual FSP Test
- Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Slide Number 94
- Slide Number 95
- Slide Number 96
- Slide Number 97
- Slide Number 98
- Slide Number 99
- DIC Case Studies
- Case Study 1 - Presentation
- Case Study 1 ndash Lab Results
- Case Study 1 ndash Microscopy
- Case Study 1 ndash Diagnosis and Therapy
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Slide Number 110
- Slide Number 111
- Slide Number 112
- Slide Number 113
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
- Slide Number 124
- Slide Number 125
- DIC Take Home Messages
- Slide Number 127
- Slide Number 128
-
Clinical Manifestations of DICOrgan Ischemic Hemorrhagic
Skin Pupura Fulminans Petechiae
Gangrene Echymoses
Acral cyanosis Oozing
CNS Deliriumcoma Intracranial
Infarcts Bleeding
Renal OliguriaAzotemia Hematuria
Cortical Necrosis
Cardiovascular Myocardial dysfunction
Pulmonary DyspneaHypoxia Hemorrhagic lung
Infarct
Gastrointestinal Ulcers infarcts Massive hemorrhage
Endocrine Adrenal infarcts
Purpura Fulminans with DIC Due to Meningococcal Sepsis
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Clinical Conditions Associated With DIC
Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33
Frequency of DIC in Selected Disease States
Disease Frequency
Gram-negative sepsis 30-50
Severe trauma and systemic inflammation 50-70
Metastasized tumors 15
Abruptio placentaamniotic fluid embolism 50
Severe preeclampsia 7
Giant hemangioma 25
Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92
Masao Nakagawa Modified from a research report on the incidence of disseminated intravascular coagulation (DIC) and underlying diseases in Japan Ministry of Health Labour and Welfare Research report published in Fiscal Year 1998 57-64 199 httpwwwrecomodulincomendicindexhtml Accessed Apr 21 2017
Underlying Diseases in DIC Patients
In a Japanese survey from 1997 on incidence of DIC and underlying diseases in 652 divisions and departments of university hospitals DIC occurred in 2193 patients with the number of patient with infections (including sepsis) and hematologic tumors (including leukemia) accounted for 28 and 23 respectively
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Epidemiology of DIC
Impact of DIC Status on Mortality - 1
Okamoto K Wada H Hatada T Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Frequency and hemostatic abnormalities in pre-DIC patients Thromb Res 2010 126 74-8
Patients with positivity of DIC tend to have worse mortality outcomes compared to negative patients or those with pre-DIC
Impact of DIC Status on Mortality - 2
Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4
Patients with positivity of either Overt or Non-Overt DIC tend to have worse mortality outcomes compared to negative patients
Impact of Age on Mortality in DIC Patients
Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4
Older patients with DIC (black bars) generally tend to have worse outcomes compared to non-DIC patients (grey bars)
Pathophysiology of DIC
Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33
Pathogenesis of DIC in Sepsis
Allen KS Sawheny E Kinasewitzet GT Anticoagulant modulation of inflammation in severe sepsis World J Crit Care Med 2015 4 105-15
Bacteria in sepsis infections cause release of TF from immune cells leading to coagulation activation and proinflammatory cytokines cause endothelial cell activation impairing the anticoagulation and fibrinolysis process resulting in DIC
Host Response in Severe Sepsis
Exaggerated inflammation as a result of the host response to sepsis is collateral tissue damage and cell death further resulting in release of danger molecules continuing the inflammatory process in a downward spiral
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Organ Failure in Severe Sepsis
Sepsis associated with microvascular thrombosis as a result of TF mediated coagulation activation results in release of neutrophil extracellular traps (NETs) tissue hypoperfusion and mitochondrial damage resulting in a downward spiral leading to organ failure
Angus DC van der Poll T Severe Sepsis and Septic Shock N Engl J Med 2013 369 840-51
Mechanism of DIC in Organ Failure
Underlying condition(sepsis trauma)
Cytokines
TF-mediatedactivation of coagulation
Depression of inhibitory systems
Reducesfibrinolysis
Fibrin deposition
Organ failure
Inadequate fibrin removal
Fibrinformation
Note impaired fibrinolysis in relation to the clinical need not in absolute value (FDPs are )
Levi M de Jonge E van der Poll T ten Cate H Disseminated intravascular coagulation ThrombHaemost 1999 82 695-705
Interaction of Inflammation and Coagulation in Sepsis
Binding of TF thrombin and other activation coagulation factors to PARs and fibrin to TLRs on inflammatory cells results in inflammation through release of proinflammatory cytokines and chemokines
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Mechanism of Multiple Organ Failure in DIC
Wheeler AP Bernard GR Treating Patients with Severe Sepsis N Engl J Med 1999 340207-14
Inflammatory activation and microvascular thrombosis contributes to multiple organ failure in DIC
lipopolysaccharides
cytokines
coagulation activation
mononuclear cell
tissue factor
Diverse and Opposing Effects of Thrombin
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Coagulation and Fibrinolysis in DIC
Soluble fibrin Polymer
XIIIa
D-Dimer
E
Fibrin clot
Fibrin Degradation Products
Fibrinogen Thrombin
Fibrinogen Degradation
Products
D E
Plasmin
DFM + fibrinopeptides
Soluble FM ComplexesPre-throm
boticPost-throm
botic
Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis Semin Thromb Hemost 2008 34 33-8
Mechanism of DIC
THROMBOSIS
Fibrin
Blood activationEndothelial lysisTF expression
BLEEDING
FDPs
D-Dimer
Plasmin
Pathophysiology of DIC
1st step abnormal activation of coagulation Injury of vessel wall cells venous stasis release of large quantities of
thromboplastin influx of activated cells (monocytes macrophages)
Results in an intravascular deposition of fibrin
Morbidity from disseminated microthrombosis in small and midsize vessels leading to multiple organ failure
Second step Consumption and depletion of coagulation factors inhibitors (Protein C
Protein S AT) and platelets Local fibrinolytic response
bull Local plasmin generation dissolves the thrombusbull Disseminated overwhelming fibrinolytic response leading to production of
FDP and D-Dimer
Bleeding
Pathophysiology of DIC - Mechanism
Systemic activation of coagulation
Intravasculardepositionof fibrin
Thrombosis of small and midsize vessels
and organ failure
Depletion of platelets and
coagulation factors
Bleeding
Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92
Pathophysiology of DIC ndash 2 Types of Clinical pictures
Chronic = non - overt DICMay be unrecognized clinically
Acute = overt DIClife threatening bleedingor multiple organ failure
Sub-Acute and Non-Overt DIC Clinical Findings
Compensated non-overt DIC Steady low level or intermittent activation
bull Compensated by increased production of coagulation components and platelets
Few or no clinical signs or multiple microvascular thrombosis sometimes not clinically obvious
Risk of decompensation leading to overt DIC
Pathophysiology of Overt DIC
Massive activation of coagulation and fibrinolysis
Does not allow for compensatory efforts
Rapid depletion of coagulation factors inhibitors and platelets
Thrombosis multiple organ failures
Bleeding complications and shock
Physiopathology of DIC ndash Overt DIC Findings
Thrombin generation
Thrombosis
Renal liver respiratory failures coma skin necrosis gangrene venous thromboembolism hypotension edema
Cytokine and kinin generation (shock)bull Tachycardia hypotension edema
Plasmin generationHemorrhage
bull Spontaneous bruising petechiae intracranial gastrointestinal and respiratory tract bleeding persistent bleeding at venipuncture sites at surgical wounds
bull Tachycardia hypotension edema
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Pathogenesis Pathways in DIC
Cytokines
TF-mediated dysfunctional impairedthrombin anticoagulant fibrinolysisgeneration mechanism due to PAI-1 deficiency
fibrin inadequateformation fibrin removal
Fibrin deposition
Inflammation
Coagulation
Stago Celebrates Lab Week 2017
NA
Stago 247 Educational Webinar Sites
wwwstago-edvantagecomUS based KOLsPACE accredited ndash all 1 hourAccessible from mobile devicesVirtual exhibit hall
wwwstagowebinarscomMostly European KOLs30 ndash 45 min including 15 min discussion
Stago Educational Apps
HaemoscoreClinical scoring algorithmsApple and AndroidTablet or phone
iHemostasisCoagulation diagramsCase studiesApple amp AndroidTablet only
BREAK
Diagnostic and Management Approach for DIC
Diagnosis of DIC
Clinical diagnosis is obvious in cases of overt DIC
Laboratory tests are necessary To makeconfirm the diagnosis To assess stage of the patient To assess the treatment efficacy
Lab Diagnosis of DIC ndash Markers of Factor Consumption
Routinescreening assays PT APTT Platelets Fibrinogen Thrombin time
Other coagulation assays Factor assays AntithrombinGeneration of Thrombin FMFSPsGeneration of Plasmin D-dimer FDPs
Important to recognize simultaneous formation of thrombin and plasmin
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122
Lab Diagnosis of DIC ndash Screening Tests
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122
Platelet count usually decreasedPT abnormal in 70 of cases (short half-life of FVII)APTT abnormal in 50 of casesThrombin time usually prolonged in overt DIC normal in non-overt DIC and no relation with syndrome severityFibrinogen low in lt 50 of cases sensitivity 22 specificity 87 overall predictive value 64 Normal fibrinogen level should not exclude DIC diagnosis (acute phase reactant initial high
fibrinogen level) repeat testing assesses progression
Screening tests not clinically specific or sensitive for DIC
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Laboratory Changes in Overt DIC
DIC Diagnostic Practices Over Time
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
British Journal of Haematology Overt DIC Score
Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
ISTH Step by Step DIC Algorithm
Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6
US Based Validation of ISTH DIC Score
When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Differential Diagnosis in DIC
aHUS atypical hemolytic uremic syndrome
HUS hemolytic uremic syndrome
HIT heparin-induced thrombocytopenia
ITP immune thrombocytopenic purpura
TTP thrombotic thrombocytopenic purpura
DIC and MAHA
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)
When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation
DIC Management Goals
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction
DIC Management and Treatment
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)
requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)
Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia
DIC Management Strategies
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant Factor Concentrate Treatment
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis
Anticoagulant Factor Concentrate Treatment Trials
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise
Markers of Thrombin amp Plasmin Generation in DIC
D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC
Cut-off value
Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen
degradation products Sensitive assay typically with cutoff adapted for DIC
D-dimer FDPs and DIC
D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC
Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80
Follow Up of DIC State of Disease
Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8
Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility
FMD-Dimer in DIC Major Differences
onset of thrombosis
days
Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8
FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)
D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)
of Abnormal Results in Patients with Confirmed and Suspected DIC
0
20
40
60
80
100
94 85 90N = 62
Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32
Positivity of Test Results ISTH Score and Disease State
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
Red bar positive for 2 points of DIC score
Pink bar positive for 1-2 points of DIC score
HT hematopoietic tumor
IF infection
SC solid cancer
Markers in Patients with or without DIC
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
HT hematopoietic tumorIF infectionSC solid cancer
Comparing an Automated FM vs Manual FSP Test
Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71
Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)
Automated (Mitsubishi) vs Automated (Stago)
In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago
Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC
Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
Non Overt DIC Overt DIC
AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC
Trends in Markers of DIC for Different Patients
Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00
Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients
Trends in Markers of DIC for Different Patients
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes
28 day outcome survival
28 day outcome death
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines
DIC Case Studies
Case Study 1 - Presentation
18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE
WBC count 77 KμL 423 ndash 907 x KμL
RBC count 17 MμL 137 ndash 175 x MμL
Hemoglobin 67 gdL 137 ndash 175 gdL
Hematocrit 195 401 ndash 510
MCV 95 fL 790 ndash 922 fL
MPV 12 fL 94 ndash 124 fL
Platelet count 9 KμL 161 ndash 347 KμL
Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0
Lymphocytes monocytes eosinophils basophils all below normal range
PT 47 sec (corrected on mixing study) 116 ndash 152 sec
APTT 75 sec (corrected on mixing study) 253 ndash 373 sec
Fibrinogen lt 76 mgdL 177 ndash 466 mgdL
D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Microscopy
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Arrow shows giant platelets in this peripheral smear Promyelocytes apparent
Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)
DIC due to TF release by APL blasts
Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases
Transfusions to replace factors along with platelets and RBCs during APL treatment
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started
Case Study 2 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L
PT 30 sec 113 ndash 146 sec
APTT 75 sec 25 ndash 34 sec
D-dimer 078 microgml FEU lt050 microgml FEU
Fibrinogen 92 mgdl 150-400 mgdl
pH 728 738 to 742
PaO2 570 mmHg 80-100 mmHg
WBC 33 times 103mm3 40-11 times 103mm3
ALT 111 IUL 0ndash34 IUL
AST 61 IUL 0ndash34 IUL
BUN 303 mgdL 08-13 mgdL
Case Study 2 ndash Lab Results
Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures
Case Study 2 ndash Diagnosis
60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior
Case Study 3 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L
PT 228 sec 113 ndash 146 sec
APTT 45 sec 25 ndash 34 sec
D-dimer 080 microgml FEU lt050 microgmL FEU
Fibrinogen 82 mgdL 150-400 mgdL
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 134 gdL 14-16 gdL
WBC 81 times 103mm3 40-11 times 103mm3
ALT 32 IUL 0ndash34 IUL
AST 28 IUL 0ndash34 IUL
BUN 09 mgdL 08-13 mgdL
Case Study 3 ndash Lab Results
Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment
Case Study 3 ndash Diagnosis and Therapy
Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91
Case Study 4 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L
PT 28 sec 113 ndash 146 sec
APTT 71 sec 25 ndash 34 sec
D-dimer 31 microgmL FEU lt050 microgml FEU
Fibrinogen 92 mgdL 150-400 mgdl
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 158 gdL 14-16 gdL
WBC 71 times 103mm3 40-11 times 103mm3
ALT 60 IUL 0ndash34 IUL
AST 47 IUL 0ndash34 IUL
BUN 38 mgdL 08-13 mgdL
Case Study 4 ndash Lab Results
Lyme disease with DICProvide antibiotics with supportive measures
Case Study 4 ndash Diagnosis
55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis
Case Study 5 ndash Presentation
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
Case Study 5 ndash Lab Results and Time Course
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
TEST RESULT REFERENCE RANGE
Platelet count 33 x 109L 150-450 x 109L
PT 215 sec 103 ndash 128 sec
APTT 44 sec 26 ndash 36 sec
D-dimer 20 microgmL FEU lt025 microgml FEU
Fibrinogen 34 mgdL 200-375 mgdl
FII FV FVIII Low Not reported (NR)
FVII FIX FX vWF Normal NR
Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)
DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic
dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR
(C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen
(D) Illustration demonstrating repair
Case Study 5 ndash Diagnosis and Treatment
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography
Case Study 6 ndash Presentation
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
Case Study 6 ndash Lab Results
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L
PT 63 sec gt control 113 ndash 146 sec
INR 658 1 ndash 125
APTT 80 sec gt control 25 ndash 34 sec
D-dimer gt200 microgmL DDU 02 microgmL DDU
Urine exam Proteinuria and hematuria 150-400 mgdl
Albumin 28 gdL NR
Hb 58 gdL NR
LDH 1196 UL NR
SGPT 144 IU NR
SGOT 88 IU NR
Bilirubin 32 mgdL NR
DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th
day postop
Case Study 6 ndash Diagnosis and Treatment
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure
Case Study 6 ndash Discussion
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Case Study 7 ndash Lab Results vs Time
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
DIC Take Home Messages
Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation
Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers
DIC
Thank you Questions
- Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
- Learning Objectives
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Wound Sealing
- The Three Steps of Hemostasis
- Vessel Wall
- Slide Number 12
- Slide Number 13
- Platelet Structure UnactivatedActivated
- Primary Hemostasis
- Primary Hemostasis Assays
- Slide Number 17
- Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
- Slide Number 19
- Coagulation factors
- Coagulation Assay Mechanisms
- Slide Number 22
- Fibrin Formation
- Slide Number 24
- Fibrinolysis Overview
- Fibrinolysis Overview
- Slide Number 27
- Fibrinolysis Releases D-dimers
- Basic Pathophysiology of DIC
- Disseminated Intravascular Coagulation (DIC)
- Purpura Fulminans with DIC Due to Meningococcal Sepsis
- Clinical Conditions Associated With DIC
- Frequency of DIC in Selected Disease States
- Underlying Diseases in DIC Patients
- Slide Number 36
- Slide Number 37
- Slide Number 38
- Slide Number 39
- Pathophysiology of DIC
- Pathogenesis of DIC in Sepsis
- Host Response in Severe Sepsis
- Organ Failure in Severe Sepsis
- Mechanism of DIC in Organ Failure
- Interaction of Inflammation and Coagulation in Sepsis
- Slide Number 47
- Diverse and Opposing Effects of Thrombin
- Coagulation and Fibrinolysis in DIC
- Mechanism of DIC
- Pathophysiology of DIC
- Pathophysiology of DIC - Mechanism
- Pathophysiology of DIC ndash 2 Types of Clinical pictures
- Sub-Acute and Non-Overt DIC Clinical Findings
- Pathophysiology of Overt DIC
- Physiopathology of DIC ndash Overt DIC Findings
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- BREAK
- Diagnostic and Management Approach for DIC
- Diagnosis of DIC
- Lab Diagnosis of DIC ndash Markers of Factor Consumption
- Lab Diagnosis of DIC ndash Screening Tests
- Slide Number 67
- Slide Number 68
- British Journal of Haematology Overt DIC Score
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- DIC Management Goals
- DIC Management and Treatment
- DIC Management Strategies
- Anticoagulant Factor Concentrate Treatment
- Anticoagulant Factor Concentrate Treatment Trials
- Markers of Thrombin amp Plasmin Generation in DIC
- D-dimer FDPs and DIC
- D-Dimer and FDPs in DIC
- Follow Up of DIC State of Disease
- FMD-Dimer in DIC Major Differences
- of Abnormal Results in Patients with Confirmed and Suspected DIC
- Slide Number 85
- Slide Number 86
- Comparing an Automated FM vs Manual FSP Test
- Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Slide Number 94
- Slide Number 95
- Slide Number 96
- Slide Number 97
- Slide Number 98
- Slide Number 99
- DIC Case Studies
- Case Study 1 - Presentation
- Case Study 1 ndash Lab Results
- Case Study 1 ndash Microscopy
- Case Study 1 ndash Diagnosis and Therapy
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Slide Number 110
- Slide Number 111
- Slide Number 112
- Slide Number 113
- Slide Number 114
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- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
- Slide Number 124
- Slide Number 125
- DIC Take Home Messages
- Slide Number 127
- Slide Number 128
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Purpura Fulminans with DIC Due to Meningococcal Sepsis
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Clinical Conditions Associated With DIC
Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33
Frequency of DIC in Selected Disease States
Disease Frequency
Gram-negative sepsis 30-50
Severe trauma and systemic inflammation 50-70
Metastasized tumors 15
Abruptio placentaamniotic fluid embolism 50
Severe preeclampsia 7
Giant hemangioma 25
Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92
Masao Nakagawa Modified from a research report on the incidence of disseminated intravascular coagulation (DIC) and underlying diseases in Japan Ministry of Health Labour and Welfare Research report published in Fiscal Year 1998 57-64 199 httpwwwrecomodulincomendicindexhtml Accessed Apr 21 2017
Underlying Diseases in DIC Patients
In a Japanese survey from 1997 on incidence of DIC and underlying diseases in 652 divisions and departments of university hospitals DIC occurred in 2193 patients with the number of patient with infections (including sepsis) and hematologic tumors (including leukemia) accounted for 28 and 23 respectively
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Epidemiology of DIC
Impact of DIC Status on Mortality - 1
Okamoto K Wada H Hatada T Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Frequency and hemostatic abnormalities in pre-DIC patients Thromb Res 2010 126 74-8
Patients with positivity of DIC tend to have worse mortality outcomes compared to negative patients or those with pre-DIC
Impact of DIC Status on Mortality - 2
Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4
Patients with positivity of either Overt or Non-Overt DIC tend to have worse mortality outcomes compared to negative patients
Impact of Age on Mortality in DIC Patients
Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4
Older patients with DIC (black bars) generally tend to have worse outcomes compared to non-DIC patients (grey bars)
Pathophysiology of DIC
Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33
Pathogenesis of DIC in Sepsis
Allen KS Sawheny E Kinasewitzet GT Anticoagulant modulation of inflammation in severe sepsis World J Crit Care Med 2015 4 105-15
Bacteria in sepsis infections cause release of TF from immune cells leading to coagulation activation and proinflammatory cytokines cause endothelial cell activation impairing the anticoagulation and fibrinolysis process resulting in DIC
Host Response in Severe Sepsis
Exaggerated inflammation as a result of the host response to sepsis is collateral tissue damage and cell death further resulting in release of danger molecules continuing the inflammatory process in a downward spiral
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Organ Failure in Severe Sepsis
Sepsis associated with microvascular thrombosis as a result of TF mediated coagulation activation results in release of neutrophil extracellular traps (NETs) tissue hypoperfusion and mitochondrial damage resulting in a downward spiral leading to organ failure
Angus DC van der Poll T Severe Sepsis and Septic Shock N Engl J Med 2013 369 840-51
Mechanism of DIC in Organ Failure
Underlying condition(sepsis trauma)
Cytokines
TF-mediatedactivation of coagulation
Depression of inhibitory systems
Reducesfibrinolysis
Fibrin deposition
Organ failure
Inadequate fibrin removal
Fibrinformation
Note impaired fibrinolysis in relation to the clinical need not in absolute value (FDPs are )
Levi M de Jonge E van der Poll T ten Cate H Disseminated intravascular coagulation ThrombHaemost 1999 82 695-705
Interaction of Inflammation and Coagulation in Sepsis
Binding of TF thrombin and other activation coagulation factors to PARs and fibrin to TLRs on inflammatory cells results in inflammation through release of proinflammatory cytokines and chemokines
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Mechanism of Multiple Organ Failure in DIC
Wheeler AP Bernard GR Treating Patients with Severe Sepsis N Engl J Med 1999 340207-14
Inflammatory activation and microvascular thrombosis contributes to multiple organ failure in DIC
lipopolysaccharides
cytokines
coagulation activation
mononuclear cell
tissue factor
Diverse and Opposing Effects of Thrombin
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Coagulation and Fibrinolysis in DIC
Soluble fibrin Polymer
XIIIa
D-Dimer
E
Fibrin clot
Fibrin Degradation Products
Fibrinogen Thrombin
Fibrinogen Degradation
Products
D E
Plasmin
DFM + fibrinopeptides
Soluble FM ComplexesPre-throm
boticPost-throm
botic
Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis Semin Thromb Hemost 2008 34 33-8
Mechanism of DIC
THROMBOSIS
Fibrin
Blood activationEndothelial lysisTF expression
BLEEDING
FDPs
D-Dimer
Plasmin
Pathophysiology of DIC
1st step abnormal activation of coagulation Injury of vessel wall cells venous stasis release of large quantities of
thromboplastin influx of activated cells (monocytes macrophages)
Results in an intravascular deposition of fibrin
Morbidity from disseminated microthrombosis in small and midsize vessels leading to multiple organ failure
Second step Consumption and depletion of coagulation factors inhibitors (Protein C
Protein S AT) and platelets Local fibrinolytic response
bull Local plasmin generation dissolves the thrombusbull Disseminated overwhelming fibrinolytic response leading to production of
FDP and D-Dimer
Bleeding
Pathophysiology of DIC - Mechanism
Systemic activation of coagulation
Intravasculardepositionof fibrin
Thrombosis of small and midsize vessels
and organ failure
Depletion of platelets and
coagulation factors
Bleeding
Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92
Pathophysiology of DIC ndash 2 Types of Clinical pictures
Chronic = non - overt DICMay be unrecognized clinically
Acute = overt DIClife threatening bleedingor multiple organ failure
Sub-Acute and Non-Overt DIC Clinical Findings
Compensated non-overt DIC Steady low level or intermittent activation
bull Compensated by increased production of coagulation components and platelets
Few or no clinical signs or multiple microvascular thrombosis sometimes not clinically obvious
Risk of decompensation leading to overt DIC
Pathophysiology of Overt DIC
Massive activation of coagulation and fibrinolysis
Does not allow for compensatory efforts
Rapid depletion of coagulation factors inhibitors and platelets
Thrombosis multiple organ failures
Bleeding complications and shock
Physiopathology of DIC ndash Overt DIC Findings
Thrombin generation
Thrombosis
Renal liver respiratory failures coma skin necrosis gangrene venous thromboembolism hypotension edema
Cytokine and kinin generation (shock)bull Tachycardia hypotension edema
Plasmin generationHemorrhage
bull Spontaneous bruising petechiae intracranial gastrointestinal and respiratory tract bleeding persistent bleeding at venipuncture sites at surgical wounds
bull Tachycardia hypotension edema
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Pathogenesis Pathways in DIC
Cytokines
TF-mediated dysfunctional impairedthrombin anticoagulant fibrinolysisgeneration mechanism due to PAI-1 deficiency
fibrin inadequateformation fibrin removal
Fibrin deposition
Inflammation
Coagulation
Stago Celebrates Lab Week 2017
NA
Stago 247 Educational Webinar Sites
wwwstago-edvantagecomUS based KOLsPACE accredited ndash all 1 hourAccessible from mobile devicesVirtual exhibit hall
wwwstagowebinarscomMostly European KOLs30 ndash 45 min including 15 min discussion
Stago Educational Apps
HaemoscoreClinical scoring algorithmsApple and AndroidTablet or phone
iHemostasisCoagulation diagramsCase studiesApple amp AndroidTablet only
BREAK
Diagnostic and Management Approach for DIC
Diagnosis of DIC
Clinical diagnosis is obvious in cases of overt DIC
Laboratory tests are necessary To makeconfirm the diagnosis To assess stage of the patient To assess the treatment efficacy
Lab Diagnosis of DIC ndash Markers of Factor Consumption
Routinescreening assays PT APTT Platelets Fibrinogen Thrombin time
Other coagulation assays Factor assays AntithrombinGeneration of Thrombin FMFSPsGeneration of Plasmin D-dimer FDPs
Important to recognize simultaneous formation of thrombin and plasmin
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122
Lab Diagnosis of DIC ndash Screening Tests
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122
Platelet count usually decreasedPT abnormal in 70 of cases (short half-life of FVII)APTT abnormal in 50 of casesThrombin time usually prolonged in overt DIC normal in non-overt DIC and no relation with syndrome severityFibrinogen low in lt 50 of cases sensitivity 22 specificity 87 overall predictive value 64 Normal fibrinogen level should not exclude DIC diagnosis (acute phase reactant initial high
fibrinogen level) repeat testing assesses progression
Screening tests not clinically specific or sensitive for DIC
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Laboratory Changes in Overt DIC
DIC Diagnostic Practices Over Time
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
British Journal of Haematology Overt DIC Score
Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
ISTH Step by Step DIC Algorithm
Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6
US Based Validation of ISTH DIC Score
When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Differential Diagnosis in DIC
aHUS atypical hemolytic uremic syndrome
HUS hemolytic uremic syndrome
HIT heparin-induced thrombocytopenia
ITP immune thrombocytopenic purpura
TTP thrombotic thrombocytopenic purpura
DIC and MAHA
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)
When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation
DIC Management Goals
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction
DIC Management and Treatment
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)
requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)
Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia
DIC Management Strategies
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant Factor Concentrate Treatment
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis
Anticoagulant Factor Concentrate Treatment Trials
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise
Markers of Thrombin amp Plasmin Generation in DIC
D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC
Cut-off value
Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen
degradation products Sensitive assay typically with cutoff adapted for DIC
D-dimer FDPs and DIC
D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC
Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80
Follow Up of DIC State of Disease
Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8
Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility
FMD-Dimer in DIC Major Differences
onset of thrombosis
days
Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8
FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)
D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)
of Abnormal Results in Patients with Confirmed and Suspected DIC
0
20
40
60
80
100
94 85 90N = 62
Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32
Positivity of Test Results ISTH Score and Disease State
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
Red bar positive for 2 points of DIC score
Pink bar positive for 1-2 points of DIC score
HT hematopoietic tumor
IF infection
SC solid cancer
Markers in Patients with or without DIC
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
HT hematopoietic tumorIF infectionSC solid cancer
Comparing an Automated FM vs Manual FSP Test
Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71
Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)
Automated (Mitsubishi) vs Automated (Stago)
In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago
Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC
Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
Non Overt DIC Overt DIC
AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC
Trends in Markers of DIC for Different Patients
Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00
Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients
Trends in Markers of DIC for Different Patients
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes
28 day outcome survival
28 day outcome death
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines
DIC Case Studies
Case Study 1 - Presentation
18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE
WBC count 77 KμL 423 ndash 907 x KμL
RBC count 17 MμL 137 ndash 175 x MμL
Hemoglobin 67 gdL 137 ndash 175 gdL
Hematocrit 195 401 ndash 510
MCV 95 fL 790 ndash 922 fL
MPV 12 fL 94 ndash 124 fL
Platelet count 9 KμL 161 ndash 347 KμL
Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0
Lymphocytes monocytes eosinophils basophils all below normal range
PT 47 sec (corrected on mixing study) 116 ndash 152 sec
APTT 75 sec (corrected on mixing study) 253 ndash 373 sec
Fibrinogen lt 76 mgdL 177 ndash 466 mgdL
D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Microscopy
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Arrow shows giant platelets in this peripheral smear Promyelocytes apparent
Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)
DIC due to TF release by APL blasts
Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases
Transfusions to replace factors along with platelets and RBCs during APL treatment
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started
Case Study 2 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L
PT 30 sec 113 ndash 146 sec
APTT 75 sec 25 ndash 34 sec
D-dimer 078 microgml FEU lt050 microgml FEU
Fibrinogen 92 mgdl 150-400 mgdl
pH 728 738 to 742
PaO2 570 mmHg 80-100 mmHg
WBC 33 times 103mm3 40-11 times 103mm3
ALT 111 IUL 0ndash34 IUL
AST 61 IUL 0ndash34 IUL
BUN 303 mgdL 08-13 mgdL
Case Study 2 ndash Lab Results
Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures
Case Study 2 ndash Diagnosis
60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior
Case Study 3 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L
PT 228 sec 113 ndash 146 sec
APTT 45 sec 25 ndash 34 sec
D-dimer 080 microgml FEU lt050 microgmL FEU
Fibrinogen 82 mgdL 150-400 mgdL
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 134 gdL 14-16 gdL
WBC 81 times 103mm3 40-11 times 103mm3
ALT 32 IUL 0ndash34 IUL
AST 28 IUL 0ndash34 IUL
BUN 09 mgdL 08-13 mgdL
Case Study 3 ndash Lab Results
Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment
Case Study 3 ndash Diagnosis and Therapy
Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91
Case Study 4 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L
PT 28 sec 113 ndash 146 sec
APTT 71 sec 25 ndash 34 sec
D-dimer 31 microgmL FEU lt050 microgml FEU
Fibrinogen 92 mgdL 150-400 mgdl
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 158 gdL 14-16 gdL
WBC 71 times 103mm3 40-11 times 103mm3
ALT 60 IUL 0ndash34 IUL
AST 47 IUL 0ndash34 IUL
BUN 38 mgdL 08-13 mgdL
Case Study 4 ndash Lab Results
Lyme disease with DICProvide antibiotics with supportive measures
Case Study 4 ndash Diagnosis
55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis
Case Study 5 ndash Presentation
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
Case Study 5 ndash Lab Results and Time Course
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
TEST RESULT REFERENCE RANGE
Platelet count 33 x 109L 150-450 x 109L
PT 215 sec 103 ndash 128 sec
APTT 44 sec 26 ndash 36 sec
D-dimer 20 microgmL FEU lt025 microgml FEU
Fibrinogen 34 mgdL 200-375 mgdl
FII FV FVIII Low Not reported (NR)
FVII FIX FX vWF Normal NR
Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)
DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic
dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR
(C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen
(D) Illustration demonstrating repair
Case Study 5 ndash Diagnosis and Treatment
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography
Case Study 6 ndash Presentation
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
Case Study 6 ndash Lab Results
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L
PT 63 sec gt control 113 ndash 146 sec
INR 658 1 ndash 125
APTT 80 sec gt control 25 ndash 34 sec
D-dimer gt200 microgmL DDU 02 microgmL DDU
Urine exam Proteinuria and hematuria 150-400 mgdl
Albumin 28 gdL NR
Hb 58 gdL NR
LDH 1196 UL NR
SGPT 144 IU NR
SGOT 88 IU NR
Bilirubin 32 mgdL NR
DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th
day postop
Case Study 6 ndash Diagnosis and Treatment
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure
Case Study 6 ndash Discussion
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Case Study 7 ndash Lab Results vs Time
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
DIC Take Home Messages
Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation
Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers
DIC
Thank you Questions
- Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
- Learning Objectives
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Wound Sealing
- The Three Steps of Hemostasis
- Vessel Wall
- Slide Number 12
- Slide Number 13
- Platelet Structure UnactivatedActivated
- Primary Hemostasis
- Primary Hemostasis Assays
- Slide Number 17
- Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
- Slide Number 19
- Coagulation factors
- Coagulation Assay Mechanisms
- Slide Number 22
- Fibrin Formation
- Slide Number 24
- Fibrinolysis Overview
- Fibrinolysis Overview
- Slide Number 27
- Fibrinolysis Releases D-dimers
- Basic Pathophysiology of DIC
- Disseminated Intravascular Coagulation (DIC)
- Purpura Fulminans with DIC Due to Meningococcal Sepsis
- Clinical Conditions Associated With DIC
- Frequency of DIC in Selected Disease States
- Underlying Diseases in DIC Patients
- Slide Number 36
- Slide Number 37
- Slide Number 38
- Slide Number 39
- Pathophysiology of DIC
- Pathogenesis of DIC in Sepsis
- Host Response in Severe Sepsis
- Organ Failure in Severe Sepsis
- Mechanism of DIC in Organ Failure
- Interaction of Inflammation and Coagulation in Sepsis
- Slide Number 47
- Diverse and Opposing Effects of Thrombin
- Coagulation and Fibrinolysis in DIC
- Mechanism of DIC
- Pathophysiology of DIC
- Pathophysiology of DIC - Mechanism
- Pathophysiology of DIC ndash 2 Types of Clinical pictures
- Sub-Acute and Non-Overt DIC Clinical Findings
- Pathophysiology of Overt DIC
- Physiopathology of DIC ndash Overt DIC Findings
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- BREAK
- Diagnostic and Management Approach for DIC
- Diagnosis of DIC
- Lab Diagnosis of DIC ndash Markers of Factor Consumption
- Lab Diagnosis of DIC ndash Screening Tests
- Slide Number 67
- Slide Number 68
- British Journal of Haematology Overt DIC Score
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- DIC Management Goals
- DIC Management and Treatment
- DIC Management Strategies
- Anticoagulant Factor Concentrate Treatment
- Anticoagulant Factor Concentrate Treatment Trials
- Markers of Thrombin amp Plasmin Generation in DIC
- D-dimer FDPs and DIC
- D-Dimer and FDPs in DIC
- Follow Up of DIC State of Disease
- FMD-Dimer in DIC Major Differences
- of Abnormal Results in Patients with Confirmed and Suspected DIC
- Slide Number 85
- Slide Number 86
- Comparing an Automated FM vs Manual FSP Test
- Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Slide Number 94
- Slide Number 95
- Slide Number 96
- Slide Number 97
- Slide Number 98
- Slide Number 99
- DIC Case Studies
- Case Study 1 - Presentation
- Case Study 1 ndash Lab Results
- Case Study 1 ndash Microscopy
- Case Study 1 ndash Diagnosis and Therapy
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Slide Number 110
- Slide Number 111
- Slide Number 112
- Slide Number 113
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
- Slide Number 124
- Slide Number 125
- DIC Take Home Messages
- Slide Number 127
- Slide Number 128
-
Clinical Conditions Associated With DIC
Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33
Frequency of DIC in Selected Disease States
Disease Frequency
Gram-negative sepsis 30-50
Severe trauma and systemic inflammation 50-70
Metastasized tumors 15
Abruptio placentaamniotic fluid embolism 50
Severe preeclampsia 7
Giant hemangioma 25
Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92
Masao Nakagawa Modified from a research report on the incidence of disseminated intravascular coagulation (DIC) and underlying diseases in Japan Ministry of Health Labour and Welfare Research report published in Fiscal Year 1998 57-64 199 httpwwwrecomodulincomendicindexhtml Accessed Apr 21 2017
Underlying Diseases in DIC Patients
In a Japanese survey from 1997 on incidence of DIC and underlying diseases in 652 divisions and departments of university hospitals DIC occurred in 2193 patients with the number of patient with infections (including sepsis) and hematologic tumors (including leukemia) accounted for 28 and 23 respectively
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Epidemiology of DIC
Impact of DIC Status on Mortality - 1
Okamoto K Wada H Hatada T Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Frequency and hemostatic abnormalities in pre-DIC patients Thromb Res 2010 126 74-8
Patients with positivity of DIC tend to have worse mortality outcomes compared to negative patients or those with pre-DIC
Impact of DIC Status on Mortality - 2
Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4
Patients with positivity of either Overt or Non-Overt DIC tend to have worse mortality outcomes compared to negative patients
Impact of Age on Mortality in DIC Patients
Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4
Older patients with DIC (black bars) generally tend to have worse outcomes compared to non-DIC patients (grey bars)
Pathophysiology of DIC
Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33
Pathogenesis of DIC in Sepsis
Allen KS Sawheny E Kinasewitzet GT Anticoagulant modulation of inflammation in severe sepsis World J Crit Care Med 2015 4 105-15
Bacteria in sepsis infections cause release of TF from immune cells leading to coagulation activation and proinflammatory cytokines cause endothelial cell activation impairing the anticoagulation and fibrinolysis process resulting in DIC
Host Response in Severe Sepsis
Exaggerated inflammation as a result of the host response to sepsis is collateral tissue damage and cell death further resulting in release of danger molecules continuing the inflammatory process in a downward spiral
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Organ Failure in Severe Sepsis
Sepsis associated with microvascular thrombosis as a result of TF mediated coagulation activation results in release of neutrophil extracellular traps (NETs) tissue hypoperfusion and mitochondrial damage resulting in a downward spiral leading to organ failure
Angus DC van der Poll T Severe Sepsis and Septic Shock N Engl J Med 2013 369 840-51
Mechanism of DIC in Organ Failure
Underlying condition(sepsis trauma)
Cytokines
TF-mediatedactivation of coagulation
Depression of inhibitory systems
Reducesfibrinolysis
Fibrin deposition
Organ failure
Inadequate fibrin removal
Fibrinformation
Note impaired fibrinolysis in relation to the clinical need not in absolute value (FDPs are )
Levi M de Jonge E van der Poll T ten Cate H Disseminated intravascular coagulation ThrombHaemost 1999 82 695-705
Interaction of Inflammation and Coagulation in Sepsis
Binding of TF thrombin and other activation coagulation factors to PARs and fibrin to TLRs on inflammatory cells results in inflammation through release of proinflammatory cytokines and chemokines
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Mechanism of Multiple Organ Failure in DIC
Wheeler AP Bernard GR Treating Patients with Severe Sepsis N Engl J Med 1999 340207-14
Inflammatory activation and microvascular thrombosis contributes to multiple organ failure in DIC
lipopolysaccharides
cytokines
coagulation activation
mononuclear cell
tissue factor
Diverse and Opposing Effects of Thrombin
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Coagulation and Fibrinolysis in DIC
Soluble fibrin Polymer
XIIIa
D-Dimer
E
Fibrin clot
Fibrin Degradation Products
Fibrinogen Thrombin
Fibrinogen Degradation
Products
D E
Plasmin
DFM + fibrinopeptides
Soluble FM ComplexesPre-throm
boticPost-throm
botic
Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis Semin Thromb Hemost 2008 34 33-8
Mechanism of DIC
THROMBOSIS
Fibrin
Blood activationEndothelial lysisTF expression
BLEEDING
FDPs
D-Dimer
Plasmin
Pathophysiology of DIC
1st step abnormal activation of coagulation Injury of vessel wall cells venous stasis release of large quantities of
thromboplastin influx of activated cells (monocytes macrophages)
Results in an intravascular deposition of fibrin
Morbidity from disseminated microthrombosis in small and midsize vessels leading to multiple organ failure
Second step Consumption and depletion of coagulation factors inhibitors (Protein C
Protein S AT) and platelets Local fibrinolytic response
bull Local plasmin generation dissolves the thrombusbull Disseminated overwhelming fibrinolytic response leading to production of
FDP and D-Dimer
Bleeding
Pathophysiology of DIC - Mechanism
Systemic activation of coagulation
Intravasculardepositionof fibrin
Thrombosis of small and midsize vessels
and organ failure
Depletion of platelets and
coagulation factors
Bleeding
Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92
Pathophysiology of DIC ndash 2 Types of Clinical pictures
Chronic = non - overt DICMay be unrecognized clinically
Acute = overt DIClife threatening bleedingor multiple organ failure
Sub-Acute and Non-Overt DIC Clinical Findings
Compensated non-overt DIC Steady low level or intermittent activation
bull Compensated by increased production of coagulation components and platelets
Few or no clinical signs or multiple microvascular thrombosis sometimes not clinically obvious
Risk of decompensation leading to overt DIC
Pathophysiology of Overt DIC
Massive activation of coagulation and fibrinolysis
Does not allow for compensatory efforts
Rapid depletion of coagulation factors inhibitors and platelets
Thrombosis multiple organ failures
Bleeding complications and shock
Physiopathology of DIC ndash Overt DIC Findings
Thrombin generation
Thrombosis
Renal liver respiratory failures coma skin necrosis gangrene venous thromboembolism hypotension edema
Cytokine and kinin generation (shock)bull Tachycardia hypotension edema
Plasmin generationHemorrhage
bull Spontaneous bruising petechiae intracranial gastrointestinal and respiratory tract bleeding persistent bleeding at venipuncture sites at surgical wounds
bull Tachycardia hypotension edema
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Pathogenesis Pathways in DIC
Cytokines
TF-mediated dysfunctional impairedthrombin anticoagulant fibrinolysisgeneration mechanism due to PAI-1 deficiency
fibrin inadequateformation fibrin removal
Fibrin deposition
Inflammation
Coagulation
Stago Celebrates Lab Week 2017
NA
Stago 247 Educational Webinar Sites
wwwstago-edvantagecomUS based KOLsPACE accredited ndash all 1 hourAccessible from mobile devicesVirtual exhibit hall
wwwstagowebinarscomMostly European KOLs30 ndash 45 min including 15 min discussion
Stago Educational Apps
HaemoscoreClinical scoring algorithmsApple and AndroidTablet or phone
iHemostasisCoagulation diagramsCase studiesApple amp AndroidTablet only
BREAK
Diagnostic and Management Approach for DIC
Diagnosis of DIC
Clinical diagnosis is obvious in cases of overt DIC
Laboratory tests are necessary To makeconfirm the diagnosis To assess stage of the patient To assess the treatment efficacy
Lab Diagnosis of DIC ndash Markers of Factor Consumption
Routinescreening assays PT APTT Platelets Fibrinogen Thrombin time
Other coagulation assays Factor assays AntithrombinGeneration of Thrombin FMFSPsGeneration of Plasmin D-dimer FDPs
Important to recognize simultaneous formation of thrombin and plasmin
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122
Lab Diagnosis of DIC ndash Screening Tests
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122
Platelet count usually decreasedPT abnormal in 70 of cases (short half-life of FVII)APTT abnormal in 50 of casesThrombin time usually prolonged in overt DIC normal in non-overt DIC and no relation with syndrome severityFibrinogen low in lt 50 of cases sensitivity 22 specificity 87 overall predictive value 64 Normal fibrinogen level should not exclude DIC diagnosis (acute phase reactant initial high
fibrinogen level) repeat testing assesses progression
Screening tests not clinically specific or sensitive for DIC
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Laboratory Changes in Overt DIC
DIC Diagnostic Practices Over Time
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
British Journal of Haematology Overt DIC Score
Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
ISTH Step by Step DIC Algorithm
Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6
US Based Validation of ISTH DIC Score
When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Differential Diagnosis in DIC
aHUS atypical hemolytic uremic syndrome
HUS hemolytic uremic syndrome
HIT heparin-induced thrombocytopenia
ITP immune thrombocytopenic purpura
TTP thrombotic thrombocytopenic purpura
DIC and MAHA
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)
When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation
DIC Management Goals
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction
DIC Management and Treatment
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)
requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)
Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia
DIC Management Strategies
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant Factor Concentrate Treatment
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis
Anticoagulant Factor Concentrate Treatment Trials
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise
Markers of Thrombin amp Plasmin Generation in DIC
D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC
Cut-off value
Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen
degradation products Sensitive assay typically with cutoff adapted for DIC
D-dimer FDPs and DIC
D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC
Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80
Follow Up of DIC State of Disease
Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8
Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility
FMD-Dimer in DIC Major Differences
onset of thrombosis
days
Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8
FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)
D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)
of Abnormal Results in Patients with Confirmed and Suspected DIC
0
20
40
60
80
100
94 85 90N = 62
Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32
Positivity of Test Results ISTH Score and Disease State
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
Red bar positive for 2 points of DIC score
Pink bar positive for 1-2 points of DIC score
HT hematopoietic tumor
IF infection
SC solid cancer
Markers in Patients with or without DIC
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
HT hematopoietic tumorIF infectionSC solid cancer
Comparing an Automated FM vs Manual FSP Test
Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71
Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)
Automated (Mitsubishi) vs Automated (Stago)
In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago
Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC
Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
Non Overt DIC Overt DIC
AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC
Trends in Markers of DIC for Different Patients
Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00
Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients
Trends in Markers of DIC for Different Patients
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes
28 day outcome survival
28 day outcome death
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines
DIC Case Studies
Case Study 1 - Presentation
18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE
WBC count 77 KμL 423 ndash 907 x KμL
RBC count 17 MμL 137 ndash 175 x MμL
Hemoglobin 67 gdL 137 ndash 175 gdL
Hematocrit 195 401 ndash 510
MCV 95 fL 790 ndash 922 fL
MPV 12 fL 94 ndash 124 fL
Platelet count 9 KμL 161 ndash 347 KμL
Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0
Lymphocytes monocytes eosinophils basophils all below normal range
PT 47 sec (corrected on mixing study) 116 ndash 152 sec
APTT 75 sec (corrected on mixing study) 253 ndash 373 sec
Fibrinogen lt 76 mgdL 177 ndash 466 mgdL
D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Microscopy
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Arrow shows giant platelets in this peripheral smear Promyelocytes apparent
Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)
DIC due to TF release by APL blasts
Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases
Transfusions to replace factors along with platelets and RBCs during APL treatment
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started
Case Study 2 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L
PT 30 sec 113 ndash 146 sec
APTT 75 sec 25 ndash 34 sec
D-dimer 078 microgml FEU lt050 microgml FEU
Fibrinogen 92 mgdl 150-400 mgdl
pH 728 738 to 742
PaO2 570 mmHg 80-100 mmHg
WBC 33 times 103mm3 40-11 times 103mm3
ALT 111 IUL 0ndash34 IUL
AST 61 IUL 0ndash34 IUL
BUN 303 mgdL 08-13 mgdL
Case Study 2 ndash Lab Results
Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures
Case Study 2 ndash Diagnosis
60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior
Case Study 3 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L
PT 228 sec 113 ndash 146 sec
APTT 45 sec 25 ndash 34 sec
D-dimer 080 microgml FEU lt050 microgmL FEU
Fibrinogen 82 mgdL 150-400 mgdL
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 134 gdL 14-16 gdL
WBC 81 times 103mm3 40-11 times 103mm3
ALT 32 IUL 0ndash34 IUL
AST 28 IUL 0ndash34 IUL
BUN 09 mgdL 08-13 mgdL
Case Study 3 ndash Lab Results
Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment
Case Study 3 ndash Diagnosis and Therapy
Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91
Case Study 4 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L
PT 28 sec 113 ndash 146 sec
APTT 71 sec 25 ndash 34 sec
D-dimer 31 microgmL FEU lt050 microgml FEU
Fibrinogen 92 mgdL 150-400 mgdl
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 158 gdL 14-16 gdL
WBC 71 times 103mm3 40-11 times 103mm3
ALT 60 IUL 0ndash34 IUL
AST 47 IUL 0ndash34 IUL
BUN 38 mgdL 08-13 mgdL
Case Study 4 ndash Lab Results
Lyme disease with DICProvide antibiotics with supportive measures
Case Study 4 ndash Diagnosis
55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis
Case Study 5 ndash Presentation
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
Case Study 5 ndash Lab Results and Time Course
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
TEST RESULT REFERENCE RANGE
Platelet count 33 x 109L 150-450 x 109L
PT 215 sec 103 ndash 128 sec
APTT 44 sec 26 ndash 36 sec
D-dimer 20 microgmL FEU lt025 microgml FEU
Fibrinogen 34 mgdL 200-375 mgdl
FII FV FVIII Low Not reported (NR)
FVII FIX FX vWF Normal NR
Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)
DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic
dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR
(C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen
(D) Illustration demonstrating repair
Case Study 5 ndash Diagnosis and Treatment
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography
Case Study 6 ndash Presentation
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
Case Study 6 ndash Lab Results
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L
PT 63 sec gt control 113 ndash 146 sec
INR 658 1 ndash 125
APTT 80 sec gt control 25 ndash 34 sec
D-dimer gt200 microgmL DDU 02 microgmL DDU
Urine exam Proteinuria and hematuria 150-400 mgdl
Albumin 28 gdL NR
Hb 58 gdL NR
LDH 1196 UL NR
SGPT 144 IU NR
SGOT 88 IU NR
Bilirubin 32 mgdL NR
DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th
day postop
Case Study 6 ndash Diagnosis and Treatment
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure
Case Study 6 ndash Discussion
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Case Study 7 ndash Lab Results vs Time
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
DIC Take Home Messages
Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation
Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers
DIC
Thank you Questions
- Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
- Learning Objectives
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Wound Sealing
- The Three Steps of Hemostasis
- Vessel Wall
- Slide Number 12
- Slide Number 13
- Platelet Structure UnactivatedActivated
- Primary Hemostasis
- Primary Hemostasis Assays
- Slide Number 17
- Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
- Slide Number 19
- Coagulation factors
- Coagulation Assay Mechanisms
- Slide Number 22
- Fibrin Formation
- Slide Number 24
- Fibrinolysis Overview
- Fibrinolysis Overview
- Slide Number 27
- Fibrinolysis Releases D-dimers
- Basic Pathophysiology of DIC
- Disseminated Intravascular Coagulation (DIC)
- Purpura Fulminans with DIC Due to Meningococcal Sepsis
- Clinical Conditions Associated With DIC
- Frequency of DIC in Selected Disease States
- Underlying Diseases in DIC Patients
- Slide Number 36
- Slide Number 37
- Slide Number 38
- Slide Number 39
- Pathophysiology of DIC
- Pathogenesis of DIC in Sepsis
- Host Response in Severe Sepsis
- Organ Failure in Severe Sepsis
- Mechanism of DIC in Organ Failure
- Interaction of Inflammation and Coagulation in Sepsis
- Slide Number 47
- Diverse and Opposing Effects of Thrombin
- Coagulation and Fibrinolysis in DIC
- Mechanism of DIC
- Pathophysiology of DIC
- Pathophysiology of DIC - Mechanism
- Pathophysiology of DIC ndash 2 Types of Clinical pictures
- Sub-Acute and Non-Overt DIC Clinical Findings
- Pathophysiology of Overt DIC
- Physiopathology of DIC ndash Overt DIC Findings
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- BREAK
- Diagnostic and Management Approach for DIC
- Diagnosis of DIC
- Lab Diagnosis of DIC ndash Markers of Factor Consumption
- Lab Diagnosis of DIC ndash Screening Tests
- Slide Number 67
- Slide Number 68
- British Journal of Haematology Overt DIC Score
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- DIC Management Goals
- DIC Management and Treatment
- DIC Management Strategies
- Anticoagulant Factor Concentrate Treatment
- Anticoagulant Factor Concentrate Treatment Trials
- Markers of Thrombin amp Plasmin Generation in DIC
- D-dimer FDPs and DIC
- D-Dimer and FDPs in DIC
- Follow Up of DIC State of Disease
- FMD-Dimer in DIC Major Differences
- of Abnormal Results in Patients with Confirmed and Suspected DIC
- Slide Number 85
- Slide Number 86
- Comparing an Automated FM vs Manual FSP Test
- Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Slide Number 94
- Slide Number 95
- Slide Number 96
- Slide Number 97
- Slide Number 98
- Slide Number 99
- DIC Case Studies
- Case Study 1 - Presentation
- Case Study 1 ndash Lab Results
- Case Study 1 ndash Microscopy
- Case Study 1 ndash Diagnosis and Therapy
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Slide Number 110
- Slide Number 111
- Slide Number 112
- Slide Number 113
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
- Slide Number 124
- Slide Number 125
- DIC Take Home Messages
- Slide Number 127
- Slide Number 128
-
Frequency of DIC in Selected Disease States
Disease Frequency
Gram-negative sepsis 30-50
Severe trauma and systemic inflammation 50-70
Metastasized tumors 15
Abruptio placentaamniotic fluid embolism 50
Severe preeclampsia 7
Giant hemangioma 25
Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92
Masao Nakagawa Modified from a research report on the incidence of disseminated intravascular coagulation (DIC) and underlying diseases in Japan Ministry of Health Labour and Welfare Research report published in Fiscal Year 1998 57-64 199 httpwwwrecomodulincomendicindexhtml Accessed Apr 21 2017
Underlying Diseases in DIC Patients
In a Japanese survey from 1997 on incidence of DIC and underlying diseases in 652 divisions and departments of university hospitals DIC occurred in 2193 patients with the number of patient with infections (including sepsis) and hematologic tumors (including leukemia) accounted for 28 and 23 respectively
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Epidemiology of DIC
Impact of DIC Status on Mortality - 1
Okamoto K Wada H Hatada T Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Frequency and hemostatic abnormalities in pre-DIC patients Thromb Res 2010 126 74-8
Patients with positivity of DIC tend to have worse mortality outcomes compared to negative patients or those with pre-DIC
Impact of DIC Status on Mortality - 2
Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4
Patients with positivity of either Overt or Non-Overt DIC tend to have worse mortality outcomes compared to negative patients
Impact of Age on Mortality in DIC Patients
Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4
Older patients with DIC (black bars) generally tend to have worse outcomes compared to non-DIC patients (grey bars)
Pathophysiology of DIC
Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33
Pathogenesis of DIC in Sepsis
Allen KS Sawheny E Kinasewitzet GT Anticoagulant modulation of inflammation in severe sepsis World J Crit Care Med 2015 4 105-15
Bacteria in sepsis infections cause release of TF from immune cells leading to coagulation activation and proinflammatory cytokines cause endothelial cell activation impairing the anticoagulation and fibrinolysis process resulting in DIC
Host Response in Severe Sepsis
Exaggerated inflammation as a result of the host response to sepsis is collateral tissue damage and cell death further resulting in release of danger molecules continuing the inflammatory process in a downward spiral
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Organ Failure in Severe Sepsis
Sepsis associated with microvascular thrombosis as a result of TF mediated coagulation activation results in release of neutrophil extracellular traps (NETs) tissue hypoperfusion and mitochondrial damage resulting in a downward spiral leading to organ failure
Angus DC van der Poll T Severe Sepsis and Septic Shock N Engl J Med 2013 369 840-51
Mechanism of DIC in Organ Failure
Underlying condition(sepsis trauma)
Cytokines
TF-mediatedactivation of coagulation
Depression of inhibitory systems
Reducesfibrinolysis
Fibrin deposition
Organ failure
Inadequate fibrin removal
Fibrinformation
Note impaired fibrinolysis in relation to the clinical need not in absolute value (FDPs are )
Levi M de Jonge E van der Poll T ten Cate H Disseminated intravascular coagulation ThrombHaemost 1999 82 695-705
Interaction of Inflammation and Coagulation in Sepsis
Binding of TF thrombin and other activation coagulation factors to PARs and fibrin to TLRs on inflammatory cells results in inflammation through release of proinflammatory cytokines and chemokines
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Mechanism of Multiple Organ Failure in DIC
Wheeler AP Bernard GR Treating Patients with Severe Sepsis N Engl J Med 1999 340207-14
Inflammatory activation and microvascular thrombosis contributes to multiple organ failure in DIC
lipopolysaccharides
cytokines
coagulation activation
mononuclear cell
tissue factor
Diverse and Opposing Effects of Thrombin
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Coagulation and Fibrinolysis in DIC
Soluble fibrin Polymer
XIIIa
D-Dimer
E
Fibrin clot
Fibrin Degradation Products
Fibrinogen Thrombin
Fibrinogen Degradation
Products
D E
Plasmin
DFM + fibrinopeptides
Soluble FM ComplexesPre-throm
boticPost-throm
botic
Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis Semin Thromb Hemost 2008 34 33-8
Mechanism of DIC
THROMBOSIS
Fibrin
Blood activationEndothelial lysisTF expression
BLEEDING
FDPs
D-Dimer
Plasmin
Pathophysiology of DIC
1st step abnormal activation of coagulation Injury of vessel wall cells venous stasis release of large quantities of
thromboplastin influx of activated cells (monocytes macrophages)
Results in an intravascular deposition of fibrin
Morbidity from disseminated microthrombosis in small and midsize vessels leading to multiple organ failure
Second step Consumption and depletion of coagulation factors inhibitors (Protein C
Protein S AT) and platelets Local fibrinolytic response
bull Local plasmin generation dissolves the thrombusbull Disseminated overwhelming fibrinolytic response leading to production of
FDP and D-Dimer
Bleeding
Pathophysiology of DIC - Mechanism
Systemic activation of coagulation
Intravasculardepositionof fibrin
Thrombosis of small and midsize vessels
and organ failure
Depletion of platelets and
coagulation factors
Bleeding
Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92
Pathophysiology of DIC ndash 2 Types of Clinical pictures
Chronic = non - overt DICMay be unrecognized clinically
Acute = overt DIClife threatening bleedingor multiple organ failure
Sub-Acute and Non-Overt DIC Clinical Findings
Compensated non-overt DIC Steady low level or intermittent activation
bull Compensated by increased production of coagulation components and platelets
Few or no clinical signs or multiple microvascular thrombosis sometimes not clinically obvious
Risk of decompensation leading to overt DIC
Pathophysiology of Overt DIC
Massive activation of coagulation and fibrinolysis
Does not allow for compensatory efforts
Rapid depletion of coagulation factors inhibitors and platelets
Thrombosis multiple organ failures
Bleeding complications and shock
Physiopathology of DIC ndash Overt DIC Findings
Thrombin generation
Thrombosis
Renal liver respiratory failures coma skin necrosis gangrene venous thromboembolism hypotension edema
Cytokine and kinin generation (shock)bull Tachycardia hypotension edema
Plasmin generationHemorrhage
bull Spontaneous bruising petechiae intracranial gastrointestinal and respiratory tract bleeding persistent bleeding at venipuncture sites at surgical wounds
bull Tachycardia hypotension edema
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Pathogenesis Pathways in DIC
Cytokines
TF-mediated dysfunctional impairedthrombin anticoagulant fibrinolysisgeneration mechanism due to PAI-1 deficiency
fibrin inadequateformation fibrin removal
Fibrin deposition
Inflammation
Coagulation
Stago Celebrates Lab Week 2017
NA
Stago 247 Educational Webinar Sites
wwwstago-edvantagecomUS based KOLsPACE accredited ndash all 1 hourAccessible from mobile devicesVirtual exhibit hall
wwwstagowebinarscomMostly European KOLs30 ndash 45 min including 15 min discussion
Stago Educational Apps
HaemoscoreClinical scoring algorithmsApple and AndroidTablet or phone
iHemostasisCoagulation diagramsCase studiesApple amp AndroidTablet only
BREAK
Diagnostic and Management Approach for DIC
Diagnosis of DIC
Clinical diagnosis is obvious in cases of overt DIC
Laboratory tests are necessary To makeconfirm the diagnosis To assess stage of the patient To assess the treatment efficacy
Lab Diagnosis of DIC ndash Markers of Factor Consumption
Routinescreening assays PT APTT Platelets Fibrinogen Thrombin time
Other coagulation assays Factor assays AntithrombinGeneration of Thrombin FMFSPsGeneration of Plasmin D-dimer FDPs
Important to recognize simultaneous formation of thrombin and plasmin
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122
Lab Diagnosis of DIC ndash Screening Tests
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122
Platelet count usually decreasedPT abnormal in 70 of cases (short half-life of FVII)APTT abnormal in 50 of casesThrombin time usually prolonged in overt DIC normal in non-overt DIC and no relation with syndrome severityFibrinogen low in lt 50 of cases sensitivity 22 specificity 87 overall predictive value 64 Normal fibrinogen level should not exclude DIC diagnosis (acute phase reactant initial high
fibrinogen level) repeat testing assesses progression
Screening tests not clinically specific or sensitive for DIC
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Laboratory Changes in Overt DIC
DIC Diagnostic Practices Over Time
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
British Journal of Haematology Overt DIC Score
Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
ISTH Step by Step DIC Algorithm
Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6
US Based Validation of ISTH DIC Score
When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Differential Diagnosis in DIC
aHUS atypical hemolytic uremic syndrome
HUS hemolytic uremic syndrome
HIT heparin-induced thrombocytopenia
ITP immune thrombocytopenic purpura
TTP thrombotic thrombocytopenic purpura
DIC and MAHA
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)
When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation
DIC Management Goals
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction
DIC Management and Treatment
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)
requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)
Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia
DIC Management Strategies
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant Factor Concentrate Treatment
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis
Anticoagulant Factor Concentrate Treatment Trials
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise
Markers of Thrombin amp Plasmin Generation in DIC
D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC
Cut-off value
Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen
degradation products Sensitive assay typically with cutoff adapted for DIC
D-dimer FDPs and DIC
D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC
Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80
Follow Up of DIC State of Disease
Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8
Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility
FMD-Dimer in DIC Major Differences
onset of thrombosis
days
Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8
FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)
D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)
of Abnormal Results in Patients with Confirmed and Suspected DIC
0
20
40
60
80
100
94 85 90N = 62
Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32
Positivity of Test Results ISTH Score and Disease State
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
Red bar positive for 2 points of DIC score
Pink bar positive for 1-2 points of DIC score
HT hematopoietic tumor
IF infection
SC solid cancer
Markers in Patients with or without DIC
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
HT hematopoietic tumorIF infectionSC solid cancer
Comparing an Automated FM vs Manual FSP Test
Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71
Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)
Automated (Mitsubishi) vs Automated (Stago)
In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago
Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC
Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
Non Overt DIC Overt DIC
AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC
Trends in Markers of DIC for Different Patients
Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00
Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients
Trends in Markers of DIC for Different Patients
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes
28 day outcome survival
28 day outcome death
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines
DIC Case Studies
Case Study 1 - Presentation
18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE
WBC count 77 KμL 423 ndash 907 x KμL
RBC count 17 MμL 137 ndash 175 x MμL
Hemoglobin 67 gdL 137 ndash 175 gdL
Hematocrit 195 401 ndash 510
MCV 95 fL 790 ndash 922 fL
MPV 12 fL 94 ndash 124 fL
Platelet count 9 KμL 161 ndash 347 KμL
Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0
Lymphocytes monocytes eosinophils basophils all below normal range
PT 47 sec (corrected on mixing study) 116 ndash 152 sec
APTT 75 sec (corrected on mixing study) 253 ndash 373 sec
Fibrinogen lt 76 mgdL 177 ndash 466 mgdL
D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Microscopy
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Arrow shows giant platelets in this peripheral smear Promyelocytes apparent
Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)
DIC due to TF release by APL blasts
Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases
Transfusions to replace factors along with platelets and RBCs during APL treatment
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started
Case Study 2 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L
PT 30 sec 113 ndash 146 sec
APTT 75 sec 25 ndash 34 sec
D-dimer 078 microgml FEU lt050 microgml FEU
Fibrinogen 92 mgdl 150-400 mgdl
pH 728 738 to 742
PaO2 570 mmHg 80-100 mmHg
WBC 33 times 103mm3 40-11 times 103mm3
ALT 111 IUL 0ndash34 IUL
AST 61 IUL 0ndash34 IUL
BUN 303 mgdL 08-13 mgdL
Case Study 2 ndash Lab Results
Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures
Case Study 2 ndash Diagnosis
60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior
Case Study 3 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L
PT 228 sec 113 ndash 146 sec
APTT 45 sec 25 ndash 34 sec
D-dimer 080 microgml FEU lt050 microgmL FEU
Fibrinogen 82 mgdL 150-400 mgdL
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 134 gdL 14-16 gdL
WBC 81 times 103mm3 40-11 times 103mm3
ALT 32 IUL 0ndash34 IUL
AST 28 IUL 0ndash34 IUL
BUN 09 mgdL 08-13 mgdL
Case Study 3 ndash Lab Results
Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment
Case Study 3 ndash Diagnosis and Therapy
Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91
Case Study 4 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L
PT 28 sec 113 ndash 146 sec
APTT 71 sec 25 ndash 34 sec
D-dimer 31 microgmL FEU lt050 microgml FEU
Fibrinogen 92 mgdL 150-400 mgdl
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 158 gdL 14-16 gdL
WBC 71 times 103mm3 40-11 times 103mm3
ALT 60 IUL 0ndash34 IUL
AST 47 IUL 0ndash34 IUL
BUN 38 mgdL 08-13 mgdL
Case Study 4 ndash Lab Results
Lyme disease with DICProvide antibiotics with supportive measures
Case Study 4 ndash Diagnosis
55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis
Case Study 5 ndash Presentation
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
Case Study 5 ndash Lab Results and Time Course
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
TEST RESULT REFERENCE RANGE
Platelet count 33 x 109L 150-450 x 109L
PT 215 sec 103 ndash 128 sec
APTT 44 sec 26 ndash 36 sec
D-dimer 20 microgmL FEU lt025 microgml FEU
Fibrinogen 34 mgdL 200-375 mgdl
FII FV FVIII Low Not reported (NR)
FVII FIX FX vWF Normal NR
Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)
DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic
dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR
(C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen
(D) Illustration demonstrating repair
Case Study 5 ndash Diagnosis and Treatment
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography
Case Study 6 ndash Presentation
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
Case Study 6 ndash Lab Results
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L
PT 63 sec gt control 113 ndash 146 sec
INR 658 1 ndash 125
APTT 80 sec gt control 25 ndash 34 sec
D-dimer gt200 microgmL DDU 02 microgmL DDU
Urine exam Proteinuria and hematuria 150-400 mgdl
Albumin 28 gdL NR
Hb 58 gdL NR
LDH 1196 UL NR
SGPT 144 IU NR
SGOT 88 IU NR
Bilirubin 32 mgdL NR
DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th
day postop
Case Study 6 ndash Diagnosis and Treatment
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure
Case Study 6 ndash Discussion
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Case Study 7 ndash Lab Results vs Time
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
DIC Take Home Messages
Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation
Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers
DIC
Thank you Questions
- Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
- Learning Objectives
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Wound Sealing
- The Three Steps of Hemostasis
- Vessel Wall
- Slide Number 12
- Slide Number 13
- Platelet Structure UnactivatedActivated
- Primary Hemostasis
- Primary Hemostasis Assays
- Slide Number 17
- Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
- Slide Number 19
- Coagulation factors
- Coagulation Assay Mechanisms
- Slide Number 22
- Fibrin Formation
- Slide Number 24
- Fibrinolysis Overview
- Fibrinolysis Overview
- Slide Number 27
- Fibrinolysis Releases D-dimers
- Basic Pathophysiology of DIC
- Disseminated Intravascular Coagulation (DIC)
- Purpura Fulminans with DIC Due to Meningococcal Sepsis
- Clinical Conditions Associated With DIC
- Frequency of DIC in Selected Disease States
- Underlying Diseases in DIC Patients
- Slide Number 36
- Slide Number 37
- Slide Number 38
- Slide Number 39
- Pathophysiology of DIC
- Pathogenesis of DIC in Sepsis
- Host Response in Severe Sepsis
- Organ Failure in Severe Sepsis
- Mechanism of DIC in Organ Failure
- Interaction of Inflammation and Coagulation in Sepsis
- Slide Number 47
- Diverse and Opposing Effects of Thrombin
- Coagulation and Fibrinolysis in DIC
- Mechanism of DIC
- Pathophysiology of DIC
- Pathophysiology of DIC - Mechanism
- Pathophysiology of DIC ndash 2 Types of Clinical pictures
- Sub-Acute and Non-Overt DIC Clinical Findings
- Pathophysiology of Overt DIC
- Physiopathology of DIC ndash Overt DIC Findings
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- BREAK
- Diagnostic and Management Approach for DIC
- Diagnosis of DIC
- Lab Diagnosis of DIC ndash Markers of Factor Consumption
- Lab Diagnosis of DIC ndash Screening Tests
- Slide Number 67
- Slide Number 68
- British Journal of Haematology Overt DIC Score
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- DIC Management Goals
- DIC Management and Treatment
- DIC Management Strategies
- Anticoagulant Factor Concentrate Treatment
- Anticoagulant Factor Concentrate Treatment Trials
- Markers of Thrombin amp Plasmin Generation in DIC
- D-dimer FDPs and DIC
- D-Dimer and FDPs in DIC
- Follow Up of DIC State of Disease
- FMD-Dimer in DIC Major Differences
- of Abnormal Results in Patients with Confirmed and Suspected DIC
- Slide Number 85
- Slide Number 86
- Comparing an Automated FM vs Manual FSP Test
- Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Slide Number 94
- Slide Number 95
- Slide Number 96
- Slide Number 97
- Slide Number 98
- Slide Number 99
- DIC Case Studies
- Case Study 1 - Presentation
- Case Study 1 ndash Lab Results
- Case Study 1 ndash Microscopy
- Case Study 1 ndash Diagnosis and Therapy
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Slide Number 110
- Slide Number 111
- Slide Number 112
- Slide Number 113
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
- Slide Number 124
- Slide Number 125
- DIC Take Home Messages
- Slide Number 127
- Slide Number 128
-
Masao Nakagawa Modified from a research report on the incidence of disseminated intravascular coagulation (DIC) and underlying diseases in Japan Ministry of Health Labour and Welfare Research report published in Fiscal Year 1998 57-64 199 httpwwwrecomodulincomendicindexhtml Accessed Apr 21 2017
Underlying Diseases in DIC Patients
In a Japanese survey from 1997 on incidence of DIC and underlying diseases in 652 divisions and departments of university hospitals DIC occurred in 2193 patients with the number of patient with infections (including sepsis) and hematologic tumors (including leukemia) accounted for 28 and 23 respectively
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Epidemiology of DIC
Impact of DIC Status on Mortality - 1
Okamoto K Wada H Hatada T Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Frequency and hemostatic abnormalities in pre-DIC patients Thromb Res 2010 126 74-8
Patients with positivity of DIC tend to have worse mortality outcomes compared to negative patients or those with pre-DIC
Impact of DIC Status on Mortality - 2
Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4
Patients with positivity of either Overt or Non-Overt DIC tend to have worse mortality outcomes compared to negative patients
Impact of Age on Mortality in DIC Patients
Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4
Older patients with DIC (black bars) generally tend to have worse outcomes compared to non-DIC patients (grey bars)
Pathophysiology of DIC
Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33
Pathogenesis of DIC in Sepsis
Allen KS Sawheny E Kinasewitzet GT Anticoagulant modulation of inflammation in severe sepsis World J Crit Care Med 2015 4 105-15
Bacteria in sepsis infections cause release of TF from immune cells leading to coagulation activation and proinflammatory cytokines cause endothelial cell activation impairing the anticoagulation and fibrinolysis process resulting in DIC
Host Response in Severe Sepsis
Exaggerated inflammation as a result of the host response to sepsis is collateral tissue damage and cell death further resulting in release of danger molecules continuing the inflammatory process in a downward spiral
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Organ Failure in Severe Sepsis
Sepsis associated with microvascular thrombosis as a result of TF mediated coagulation activation results in release of neutrophil extracellular traps (NETs) tissue hypoperfusion and mitochondrial damage resulting in a downward spiral leading to organ failure
Angus DC van der Poll T Severe Sepsis and Septic Shock N Engl J Med 2013 369 840-51
Mechanism of DIC in Organ Failure
Underlying condition(sepsis trauma)
Cytokines
TF-mediatedactivation of coagulation
Depression of inhibitory systems
Reducesfibrinolysis
Fibrin deposition
Organ failure
Inadequate fibrin removal
Fibrinformation
Note impaired fibrinolysis in relation to the clinical need not in absolute value (FDPs are )
Levi M de Jonge E van der Poll T ten Cate H Disseminated intravascular coagulation ThrombHaemost 1999 82 695-705
Interaction of Inflammation and Coagulation in Sepsis
Binding of TF thrombin and other activation coagulation factors to PARs and fibrin to TLRs on inflammatory cells results in inflammation through release of proinflammatory cytokines and chemokines
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Mechanism of Multiple Organ Failure in DIC
Wheeler AP Bernard GR Treating Patients with Severe Sepsis N Engl J Med 1999 340207-14
Inflammatory activation and microvascular thrombosis contributes to multiple organ failure in DIC
lipopolysaccharides
cytokines
coagulation activation
mononuclear cell
tissue factor
Diverse and Opposing Effects of Thrombin
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Coagulation and Fibrinolysis in DIC
Soluble fibrin Polymer
XIIIa
D-Dimer
E
Fibrin clot
Fibrin Degradation Products
Fibrinogen Thrombin
Fibrinogen Degradation
Products
D E
Plasmin
DFM + fibrinopeptides
Soluble FM ComplexesPre-throm
boticPost-throm
botic
Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis Semin Thromb Hemost 2008 34 33-8
Mechanism of DIC
THROMBOSIS
Fibrin
Blood activationEndothelial lysisTF expression
BLEEDING
FDPs
D-Dimer
Plasmin
Pathophysiology of DIC
1st step abnormal activation of coagulation Injury of vessel wall cells venous stasis release of large quantities of
thromboplastin influx of activated cells (monocytes macrophages)
Results in an intravascular deposition of fibrin
Morbidity from disseminated microthrombosis in small and midsize vessels leading to multiple organ failure
Second step Consumption and depletion of coagulation factors inhibitors (Protein C
Protein S AT) and platelets Local fibrinolytic response
bull Local plasmin generation dissolves the thrombusbull Disseminated overwhelming fibrinolytic response leading to production of
FDP and D-Dimer
Bleeding
Pathophysiology of DIC - Mechanism
Systemic activation of coagulation
Intravasculardepositionof fibrin
Thrombosis of small and midsize vessels
and organ failure
Depletion of platelets and
coagulation factors
Bleeding
Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92
Pathophysiology of DIC ndash 2 Types of Clinical pictures
Chronic = non - overt DICMay be unrecognized clinically
Acute = overt DIClife threatening bleedingor multiple organ failure
Sub-Acute and Non-Overt DIC Clinical Findings
Compensated non-overt DIC Steady low level or intermittent activation
bull Compensated by increased production of coagulation components and platelets
Few or no clinical signs or multiple microvascular thrombosis sometimes not clinically obvious
Risk of decompensation leading to overt DIC
Pathophysiology of Overt DIC
Massive activation of coagulation and fibrinolysis
Does not allow for compensatory efforts
Rapid depletion of coagulation factors inhibitors and platelets
Thrombosis multiple organ failures
Bleeding complications and shock
Physiopathology of DIC ndash Overt DIC Findings
Thrombin generation
Thrombosis
Renal liver respiratory failures coma skin necrosis gangrene venous thromboembolism hypotension edema
Cytokine and kinin generation (shock)bull Tachycardia hypotension edema
Plasmin generationHemorrhage
bull Spontaneous bruising petechiae intracranial gastrointestinal and respiratory tract bleeding persistent bleeding at venipuncture sites at surgical wounds
bull Tachycardia hypotension edema
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Pathogenesis Pathways in DIC
Cytokines
TF-mediated dysfunctional impairedthrombin anticoagulant fibrinolysisgeneration mechanism due to PAI-1 deficiency
fibrin inadequateformation fibrin removal
Fibrin deposition
Inflammation
Coagulation
Stago Celebrates Lab Week 2017
NA
Stago 247 Educational Webinar Sites
wwwstago-edvantagecomUS based KOLsPACE accredited ndash all 1 hourAccessible from mobile devicesVirtual exhibit hall
wwwstagowebinarscomMostly European KOLs30 ndash 45 min including 15 min discussion
Stago Educational Apps
HaemoscoreClinical scoring algorithmsApple and AndroidTablet or phone
iHemostasisCoagulation diagramsCase studiesApple amp AndroidTablet only
BREAK
Diagnostic and Management Approach for DIC
Diagnosis of DIC
Clinical diagnosis is obvious in cases of overt DIC
Laboratory tests are necessary To makeconfirm the diagnosis To assess stage of the patient To assess the treatment efficacy
Lab Diagnosis of DIC ndash Markers of Factor Consumption
Routinescreening assays PT APTT Platelets Fibrinogen Thrombin time
Other coagulation assays Factor assays AntithrombinGeneration of Thrombin FMFSPsGeneration of Plasmin D-dimer FDPs
Important to recognize simultaneous formation of thrombin and plasmin
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122
Lab Diagnosis of DIC ndash Screening Tests
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122
Platelet count usually decreasedPT abnormal in 70 of cases (short half-life of FVII)APTT abnormal in 50 of casesThrombin time usually prolonged in overt DIC normal in non-overt DIC and no relation with syndrome severityFibrinogen low in lt 50 of cases sensitivity 22 specificity 87 overall predictive value 64 Normal fibrinogen level should not exclude DIC diagnosis (acute phase reactant initial high
fibrinogen level) repeat testing assesses progression
Screening tests not clinically specific or sensitive for DIC
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Laboratory Changes in Overt DIC
DIC Diagnostic Practices Over Time
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
British Journal of Haematology Overt DIC Score
Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
ISTH Step by Step DIC Algorithm
Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6
US Based Validation of ISTH DIC Score
When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Differential Diagnosis in DIC
aHUS atypical hemolytic uremic syndrome
HUS hemolytic uremic syndrome
HIT heparin-induced thrombocytopenia
ITP immune thrombocytopenic purpura
TTP thrombotic thrombocytopenic purpura
DIC and MAHA
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)
When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation
DIC Management Goals
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction
DIC Management and Treatment
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)
requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)
Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia
DIC Management Strategies
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant Factor Concentrate Treatment
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis
Anticoagulant Factor Concentrate Treatment Trials
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise
Markers of Thrombin amp Plasmin Generation in DIC
D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC
Cut-off value
Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen
degradation products Sensitive assay typically with cutoff adapted for DIC
D-dimer FDPs and DIC
D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC
Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80
Follow Up of DIC State of Disease
Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8
Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility
FMD-Dimer in DIC Major Differences
onset of thrombosis
days
Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8
FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)
D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)
of Abnormal Results in Patients with Confirmed and Suspected DIC
0
20
40
60
80
100
94 85 90N = 62
Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32
Positivity of Test Results ISTH Score and Disease State
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
Red bar positive for 2 points of DIC score
Pink bar positive for 1-2 points of DIC score
HT hematopoietic tumor
IF infection
SC solid cancer
Markers in Patients with or without DIC
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
HT hematopoietic tumorIF infectionSC solid cancer
Comparing an Automated FM vs Manual FSP Test
Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71
Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)
Automated (Mitsubishi) vs Automated (Stago)
In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago
Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC
Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
Non Overt DIC Overt DIC
AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC
Trends in Markers of DIC for Different Patients
Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00
Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients
Trends in Markers of DIC for Different Patients
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes
28 day outcome survival
28 day outcome death
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines
DIC Case Studies
Case Study 1 - Presentation
18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE
WBC count 77 KμL 423 ndash 907 x KμL
RBC count 17 MμL 137 ndash 175 x MμL
Hemoglobin 67 gdL 137 ndash 175 gdL
Hematocrit 195 401 ndash 510
MCV 95 fL 790 ndash 922 fL
MPV 12 fL 94 ndash 124 fL
Platelet count 9 KμL 161 ndash 347 KμL
Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0
Lymphocytes monocytes eosinophils basophils all below normal range
PT 47 sec (corrected on mixing study) 116 ndash 152 sec
APTT 75 sec (corrected on mixing study) 253 ndash 373 sec
Fibrinogen lt 76 mgdL 177 ndash 466 mgdL
D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Microscopy
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Arrow shows giant platelets in this peripheral smear Promyelocytes apparent
Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)
DIC due to TF release by APL blasts
Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases
Transfusions to replace factors along with platelets and RBCs during APL treatment
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started
Case Study 2 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L
PT 30 sec 113 ndash 146 sec
APTT 75 sec 25 ndash 34 sec
D-dimer 078 microgml FEU lt050 microgml FEU
Fibrinogen 92 mgdl 150-400 mgdl
pH 728 738 to 742
PaO2 570 mmHg 80-100 mmHg
WBC 33 times 103mm3 40-11 times 103mm3
ALT 111 IUL 0ndash34 IUL
AST 61 IUL 0ndash34 IUL
BUN 303 mgdL 08-13 mgdL
Case Study 2 ndash Lab Results
Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures
Case Study 2 ndash Diagnosis
60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior
Case Study 3 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L
PT 228 sec 113 ndash 146 sec
APTT 45 sec 25 ndash 34 sec
D-dimer 080 microgml FEU lt050 microgmL FEU
Fibrinogen 82 mgdL 150-400 mgdL
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 134 gdL 14-16 gdL
WBC 81 times 103mm3 40-11 times 103mm3
ALT 32 IUL 0ndash34 IUL
AST 28 IUL 0ndash34 IUL
BUN 09 mgdL 08-13 mgdL
Case Study 3 ndash Lab Results
Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment
Case Study 3 ndash Diagnosis and Therapy
Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91
Case Study 4 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L
PT 28 sec 113 ndash 146 sec
APTT 71 sec 25 ndash 34 sec
D-dimer 31 microgmL FEU lt050 microgml FEU
Fibrinogen 92 mgdL 150-400 mgdl
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 158 gdL 14-16 gdL
WBC 71 times 103mm3 40-11 times 103mm3
ALT 60 IUL 0ndash34 IUL
AST 47 IUL 0ndash34 IUL
BUN 38 mgdL 08-13 mgdL
Case Study 4 ndash Lab Results
Lyme disease with DICProvide antibiotics with supportive measures
Case Study 4 ndash Diagnosis
55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis
Case Study 5 ndash Presentation
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
Case Study 5 ndash Lab Results and Time Course
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
TEST RESULT REFERENCE RANGE
Platelet count 33 x 109L 150-450 x 109L
PT 215 sec 103 ndash 128 sec
APTT 44 sec 26 ndash 36 sec
D-dimer 20 microgmL FEU lt025 microgml FEU
Fibrinogen 34 mgdL 200-375 mgdl
FII FV FVIII Low Not reported (NR)
FVII FIX FX vWF Normal NR
Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)
DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic
dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR
(C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen
(D) Illustration demonstrating repair
Case Study 5 ndash Diagnosis and Treatment
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography
Case Study 6 ndash Presentation
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
Case Study 6 ndash Lab Results
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L
PT 63 sec gt control 113 ndash 146 sec
INR 658 1 ndash 125
APTT 80 sec gt control 25 ndash 34 sec
D-dimer gt200 microgmL DDU 02 microgmL DDU
Urine exam Proteinuria and hematuria 150-400 mgdl
Albumin 28 gdL NR
Hb 58 gdL NR
LDH 1196 UL NR
SGPT 144 IU NR
SGOT 88 IU NR
Bilirubin 32 mgdL NR
DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th
day postop
Case Study 6 ndash Diagnosis and Treatment
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure
Case Study 6 ndash Discussion
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Case Study 7 ndash Lab Results vs Time
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
DIC Take Home Messages
Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation
Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers
DIC
Thank you Questions
- Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
- Learning Objectives
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Wound Sealing
- The Three Steps of Hemostasis
- Vessel Wall
- Slide Number 12
- Slide Number 13
- Platelet Structure UnactivatedActivated
- Primary Hemostasis
- Primary Hemostasis Assays
- Slide Number 17
- Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
- Slide Number 19
- Coagulation factors
- Coagulation Assay Mechanisms
- Slide Number 22
- Fibrin Formation
- Slide Number 24
- Fibrinolysis Overview
- Fibrinolysis Overview
- Slide Number 27
- Fibrinolysis Releases D-dimers
- Basic Pathophysiology of DIC
- Disseminated Intravascular Coagulation (DIC)
- Purpura Fulminans with DIC Due to Meningococcal Sepsis
- Clinical Conditions Associated With DIC
- Frequency of DIC in Selected Disease States
- Underlying Diseases in DIC Patients
- Slide Number 36
- Slide Number 37
- Slide Number 38
- Slide Number 39
- Pathophysiology of DIC
- Pathogenesis of DIC in Sepsis
- Host Response in Severe Sepsis
- Organ Failure in Severe Sepsis
- Mechanism of DIC in Organ Failure
- Interaction of Inflammation and Coagulation in Sepsis
- Slide Number 47
- Diverse and Opposing Effects of Thrombin
- Coagulation and Fibrinolysis in DIC
- Mechanism of DIC
- Pathophysiology of DIC
- Pathophysiology of DIC - Mechanism
- Pathophysiology of DIC ndash 2 Types of Clinical pictures
- Sub-Acute and Non-Overt DIC Clinical Findings
- Pathophysiology of Overt DIC
- Physiopathology of DIC ndash Overt DIC Findings
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- BREAK
- Diagnostic and Management Approach for DIC
- Diagnosis of DIC
- Lab Diagnosis of DIC ndash Markers of Factor Consumption
- Lab Diagnosis of DIC ndash Screening Tests
- Slide Number 67
- Slide Number 68
- British Journal of Haematology Overt DIC Score
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- DIC Management Goals
- DIC Management and Treatment
- DIC Management Strategies
- Anticoagulant Factor Concentrate Treatment
- Anticoagulant Factor Concentrate Treatment Trials
- Markers of Thrombin amp Plasmin Generation in DIC
- D-dimer FDPs and DIC
- D-Dimer and FDPs in DIC
- Follow Up of DIC State of Disease
- FMD-Dimer in DIC Major Differences
- of Abnormal Results in Patients with Confirmed and Suspected DIC
- Slide Number 85
- Slide Number 86
- Comparing an Automated FM vs Manual FSP Test
- Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Slide Number 94
- Slide Number 95
- Slide Number 96
- Slide Number 97
- Slide Number 98
- Slide Number 99
- DIC Case Studies
- Case Study 1 - Presentation
- Case Study 1 ndash Lab Results
- Case Study 1 ndash Microscopy
- Case Study 1 ndash Diagnosis and Therapy
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Slide Number 110
- Slide Number 111
- Slide Number 112
- Slide Number 113
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
- Slide Number 124
- Slide Number 125
- DIC Take Home Messages
- Slide Number 127
- Slide Number 128
-
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Epidemiology of DIC
Impact of DIC Status on Mortality - 1
Okamoto K Wada H Hatada T Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Frequency and hemostatic abnormalities in pre-DIC patients Thromb Res 2010 126 74-8
Patients with positivity of DIC tend to have worse mortality outcomes compared to negative patients or those with pre-DIC
Impact of DIC Status on Mortality - 2
Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4
Patients with positivity of either Overt or Non-Overt DIC tend to have worse mortality outcomes compared to negative patients
Impact of Age on Mortality in DIC Patients
Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4
Older patients with DIC (black bars) generally tend to have worse outcomes compared to non-DIC patients (grey bars)
Pathophysiology of DIC
Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33
Pathogenesis of DIC in Sepsis
Allen KS Sawheny E Kinasewitzet GT Anticoagulant modulation of inflammation in severe sepsis World J Crit Care Med 2015 4 105-15
Bacteria in sepsis infections cause release of TF from immune cells leading to coagulation activation and proinflammatory cytokines cause endothelial cell activation impairing the anticoagulation and fibrinolysis process resulting in DIC
Host Response in Severe Sepsis
Exaggerated inflammation as a result of the host response to sepsis is collateral tissue damage and cell death further resulting in release of danger molecules continuing the inflammatory process in a downward spiral
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Organ Failure in Severe Sepsis
Sepsis associated with microvascular thrombosis as a result of TF mediated coagulation activation results in release of neutrophil extracellular traps (NETs) tissue hypoperfusion and mitochondrial damage resulting in a downward spiral leading to organ failure
Angus DC van der Poll T Severe Sepsis and Septic Shock N Engl J Med 2013 369 840-51
Mechanism of DIC in Organ Failure
Underlying condition(sepsis trauma)
Cytokines
TF-mediatedactivation of coagulation
Depression of inhibitory systems
Reducesfibrinolysis
Fibrin deposition
Organ failure
Inadequate fibrin removal
Fibrinformation
Note impaired fibrinolysis in relation to the clinical need not in absolute value (FDPs are )
Levi M de Jonge E van der Poll T ten Cate H Disseminated intravascular coagulation ThrombHaemost 1999 82 695-705
Interaction of Inflammation and Coagulation in Sepsis
Binding of TF thrombin and other activation coagulation factors to PARs and fibrin to TLRs on inflammatory cells results in inflammation through release of proinflammatory cytokines and chemokines
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Mechanism of Multiple Organ Failure in DIC
Wheeler AP Bernard GR Treating Patients with Severe Sepsis N Engl J Med 1999 340207-14
Inflammatory activation and microvascular thrombosis contributes to multiple organ failure in DIC
lipopolysaccharides
cytokines
coagulation activation
mononuclear cell
tissue factor
Diverse and Opposing Effects of Thrombin
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Coagulation and Fibrinolysis in DIC
Soluble fibrin Polymer
XIIIa
D-Dimer
E
Fibrin clot
Fibrin Degradation Products
Fibrinogen Thrombin
Fibrinogen Degradation
Products
D E
Plasmin
DFM + fibrinopeptides
Soluble FM ComplexesPre-throm
boticPost-throm
botic
Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis Semin Thromb Hemost 2008 34 33-8
Mechanism of DIC
THROMBOSIS
Fibrin
Blood activationEndothelial lysisTF expression
BLEEDING
FDPs
D-Dimer
Plasmin
Pathophysiology of DIC
1st step abnormal activation of coagulation Injury of vessel wall cells venous stasis release of large quantities of
thromboplastin influx of activated cells (monocytes macrophages)
Results in an intravascular deposition of fibrin
Morbidity from disseminated microthrombosis in small and midsize vessels leading to multiple organ failure
Second step Consumption and depletion of coagulation factors inhibitors (Protein C
Protein S AT) and platelets Local fibrinolytic response
bull Local plasmin generation dissolves the thrombusbull Disseminated overwhelming fibrinolytic response leading to production of
FDP and D-Dimer
Bleeding
Pathophysiology of DIC - Mechanism
Systemic activation of coagulation
Intravasculardepositionof fibrin
Thrombosis of small and midsize vessels
and organ failure
Depletion of platelets and
coagulation factors
Bleeding
Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92
Pathophysiology of DIC ndash 2 Types of Clinical pictures
Chronic = non - overt DICMay be unrecognized clinically
Acute = overt DIClife threatening bleedingor multiple organ failure
Sub-Acute and Non-Overt DIC Clinical Findings
Compensated non-overt DIC Steady low level or intermittent activation
bull Compensated by increased production of coagulation components and platelets
Few or no clinical signs or multiple microvascular thrombosis sometimes not clinically obvious
Risk of decompensation leading to overt DIC
Pathophysiology of Overt DIC
Massive activation of coagulation and fibrinolysis
Does not allow for compensatory efforts
Rapid depletion of coagulation factors inhibitors and platelets
Thrombosis multiple organ failures
Bleeding complications and shock
Physiopathology of DIC ndash Overt DIC Findings
Thrombin generation
Thrombosis
Renal liver respiratory failures coma skin necrosis gangrene venous thromboembolism hypotension edema
Cytokine and kinin generation (shock)bull Tachycardia hypotension edema
Plasmin generationHemorrhage
bull Spontaneous bruising petechiae intracranial gastrointestinal and respiratory tract bleeding persistent bleeding at venipuncture sites at surgical wounds
bull Tachycardia hypotension edema
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Pathogenesis Pathways in DIC
Cytokines
TF-mediated dysfunctional impairedthrombin anticoagulant fibrinolysisgeneration mechanism due to PAI-1 deficiency
fibrin inadequateformation fibrin removal
Fibrin deposition
Inflammation
Coagulation
Stago Celebrates Lab Week 2017
NA
Stago 247 Educational Webinar Sites
wwwstago-edvantagecomUS based KOLsPACE accredited ndash all 1 hourAccessible from mobile devicesVirtual exhibit hall
wwwstagowebinarscomMostly European KOLs30 ndash 45 min including 15 min discussion
Stago Educational Apps
HaemoscoreClinical scoring algorithmsApple and AndroidTablet or phone
iHemostasisCoagulation diagramsCase studiesApple amp AndroidTablet only
BREAK
Diagnostic and Management Approach for DIC
Diagnosis of DIC
Clinical diagnosis is obvious in cases of overt DIC
Laboratory tests are necessary To makeconfirm the diagnosis To assess stage of the patient To assess the treatment efficacy
Lab Diagnosis of DIC ndash Markers of Factor Consumption
Routinescreening assays PT APTT Platelets Fibrinogen Thrombin time
Other coagulation assays Factor assays AntithrombinGeneration of Thrombin FMFSPsGeneration of Plasmin D-dimer FDPs
Important to recognize simultaneous formation of thrombin and plasmin
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122
Lab Diagnosis of DIC ndash Screening Tests
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122
Platelet count usually decreasedPT abnormal in 70 of cases (short half-life of FVII)APTT abnormal in 50 of casesThrombin time usually prolonged in overt DIC normal in non-overt DIC and no relation with syndrome severityFibrinogen low in lt 50 of cases sensitivity 22 specificity 87 overall predictive value 64 Normal fibrinogen level should not exclude DIC diagnosis (acute phase reactant initial high
fibrinogen level) repeat testing assesses progression
Screening tests not clinically specific or sensitive for DIC
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Laboratory Changes in Overt DIC
DIC Diagnostic Practices Over Time
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
British Journal of Haematology Overt DIC Score
Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
ISTH Step by Step DIC Algorithm
Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6
US Based Validation of ISTH DIC Score
When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Differential Diagnosis in DIC
aHUS atypical hemolytic uremic syndrome
HUS hemolytic uremic syndrome
HIT heparin-induced thrombocytopenia
ITP immune thrombocytopenic purpura
TTP thrombotic thrombocytopenic purpura
DIC and MAHA
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)
When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation
DIC Management Goals
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction
DIC Management and Treatment
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)
requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)
Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia
DIC Management Strategies
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant Factor Concentrate Treatment
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis
Anticoagulant Factor Concentrate Treatment Trials
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise
Markers of Thrombin amp Plasmin Generation in DIC
D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC
Cut-off value
Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen
degradation products Sensitive assay typically with cutoff adapted for DIC
D-dimer FDPs and DIC
D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC
Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80
Follow Up of DIC State of Disease
Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8
Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility
FMD-Dimer in DIC Major Differences
onset of thrombosis
days
Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8
FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)
D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)
of Abnormal Results in Patients with Confirmed and Suspected DIC
0
20
40
60
80
100
94 85 90N = 62
Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32
Positivity of Test Results ISTH Score and Disease State
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
Red bar positive for 2 points of DIC score
Pink bar positive for 1-2 points of DIC score
HT hematopoietic tumor
IF infection
SC solid cancer
Markers in Patients with or without DIC
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
HT hematopoietic tumorIF infectionSC solid cancer
Comparing an Automated FM vs Manual FSP Test
Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71
Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)
Automated (Mitsubishi) vs Automated (Stago)
In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago
Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC
Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
Non Overt DIC Overt DIC
AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC
Trends in Markers of DIC for Different Patients
Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00
Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients
Trends in Markers of DIC for Different Patients
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes
28 day outcome survival
28 day outcome death
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines
DIC Case Studies
Case Study 1 - Presentation
18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE
WBC count 77 KμL 423 ndash 907 x KμL
RBC count 17 MμL 137 ndash 175 x MμL
Hemoglobin 67 gdL 137 ndash 175 gdL
Hematocrit 195 401 ndash 510
MCV 95 fL 790 ndash 922 fL
MPV 12 fL 94 ndash 124 fL
Platelet count 9 KμL 161 ndash 347 KμL
Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0
Lymphocytes monocytes eosinophils basophils all below normal range
PT 47 sec (corrected on mixing study) 116 ndash 152 sec
APTT 75 sec (corrected on mixing study) 253 ndash 373 sec
Fibrinogen lt 76 mgdL 177 ndash 466 mgdL
D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Microscopy
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Arrow shows giant platelets in this peripheral smear Promyelocytes apparent
Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)
DIC due to TF release by APL blasts
Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases
Transfusions to replace factors along with platelets and RBCs during APL treatment
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started
Case Study 2 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L
PT 30 sec 113 ndash 146 sec
APTT 75 sec 25 ndash 34 sec
D-dimer 078 microgml FEU lt050 microgml FEU
Fibrinogen 92 mgdl 150-400 mgdl
pH 728 738 to 742
PaO2 570 mmHg 80-100 mmHg
WBC 33 times 103mm3 40-11 times 103mm3
ALT 111 IUL 0ndash34 IUL
AST 61 IUL 0ndash34 IUL
BUN 303 mgdL 08-13 mgdL
Case Study 2 ndash Lab Results
Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures
Case Study 2 ndash Diagnosis
60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior
Case Study 3 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L
PT 228 sec 113 ndash 146 sec
APTT 45 sec 25 ndash 34 sec
D-dimer 080 microgml FEU lt050 microgmL FEU
Fibrinogen 82 mgdL 150-400 mgdL
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 134 gdL 14-16 gdL
WBC 81 times 103mm3 40-11 times 103mm3
ALT 32 IUL 0ndash34 IUL
AST 28 IUL 0ndash34 IUL
BUN 09 mgdL 08-13 mgdL
Case Study 3 ndash Lab Results
Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment
Case Study 3 ndash Diagnosis and Therapy
Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91
Case Study 4 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L
PT 28 sec 113 ndash 146 sec
APTT 71 sec 25 ndash 34 sec
D-dimer 31 microgmL FEU lt050 microgml FEU
Fibrinogen 92 mgdL 150-400 mgdl
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 158 gdL 14-16 gdL
WBC 71 times 103mm3 40-11 times 103mm3
ALT 60 IUL 0ndash34 IUL
AST 47 IUL 0ndash34 IUL
BUN 38 mgdL 08-13 mgdL
Case Study 4 ndash Lab Results
Lyme disease with DICProvide antibiotics with supportive measures
Case Study 4 ndash Diagnosis
55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis
Case Study 5 ndash Presentation
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
Case Study 5 ndash Lab Results and Time Course
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
TEST RESULT REFERENCE RANGE
Platelet count 33 x 109L 150-450 x 109L
PT 215 sec 103 ndash 128 sec
APTT 44 sec 26 ndash 36 sec
D-dimer 20 microgmL FEU lt025 microgml FEU
Fibrinogen 34 mgdL 200-375 mgdl
FII FV FVIII Low Not reported (NR)
FVII FIX FX vWF Normal NR
Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)
DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic
dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR
(C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen
(D) Illustration demonstrating repair
Case Study 5 ndash Diagnosis and Treatment
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography
Case Study 6 ndash Presentation
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
Case Study 6 ndash Lab Results
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L
PT 63 sec gt control 113 ndash 146 sec
INR 658 1 ndash 125
APTT 80 sec gt control 25 ndash 34 sec
D-dimer gt200 microgmL DDU 02 microgmL DDU
Urine exam Proteinuria and hematuria 150-400 mgdl
Albumin 28 gdL NR
Hb 58 gdL NR
LDH 1196 UL NR
SGPT 144 IU NR
SGOT 88 IU NR
Bilirubin 32 mgdL NR
DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th
day postop
Case Study 6 ndash Diagnosis and Treatment
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure
Case Study 6 ndash Discussion
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Case Study 7 ndash Lab Results vs Time
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
DIC Take Home Messages
Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation
Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers
DIC
Thank you Questions
- Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
- Learning Objectives
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Wound Sealing
- The Three Steps of Hemostasis
- Vessel Wall
- Slide Number 12
- Slide Number 13
- Platelet Structure UnactivatedActivated
- Primary Hemostasis
- Primary Hemostasis Assays
- Slide Number 17
- Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
- Slide Number 19
- Coagulation factors
- Coagulation Assay Mechanisms
- Slide Number 22
- Fibrin Formation
- Slide Number 24
- Fibrinolysis Overview
- Fibrinolysis Overview
- Slide Number 27
- Fibrinolysis Releases D-dimers
- Basic Pathophysiology of DIC
- Disseminated Intravascular Coagulation (DIC)
- Purpura Fulminans with DIC Due to Meningococcal Sepsis
- Clinical Conditions Associated With DIC
- Frequency of DIC in Selected Disease States
- Underlying Diseases in DIC Patients
- Slide Number 36
- Slide Number 37
- Slide Number 38
- Slide Number 39
- Pathophysiology of DIC
- Pathogenesis of DIC in Sepsis
- Host Response in Severe Sepsis
- Organ Failure in Severe Sepsis
- Mechanism of DIC in Organ Failure
- Interaction of Inflammation and Coagulation in Sepsis
- Slide Number 47
- Diverse and Opposing Effects of Thrombin
- Coagulation and Fibrinolysis in DIC
- Mechanism of DIC
- Pathophysiology of DIC
- Pathophysiology of DIC - Mechanism
- Pathophysiology of DIC ndash 2 Types of Clinical pictures
- Sub-Acute and Non-Overt DIC Clinical Findings
- Pathophysiology of Overt DIC
- Physiopathology of DIC ndash Overt DIC Findings
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- BREAK
- Diagnostic and Management Approach for DIC
- Diagnosis of DIC
- Lab Diagnosis of DIC ndash Markers of Factor Consumption
- Lab Diagnosis of DIC ndash Screening Tests
- Slide Number 67
- Slide Number 68
- British Journal of Haematology Overt DIC Score
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- DIC Management Goals
- DIC Management and Treatment
- DIC Management Strategies
- Anticoagulant Factor Concentrate Treatment
- Anticoagulant Factor Concentrate Treatment Trials
- Markers of Thrombin amp Plasmin Generation in DIC
- D-dimer FDPs and DIC
- D-Dimer and FDPs in DIC
- Follow Up of DIC State of Disease
- FMD-Dimer in DIC Major Differences
- of Abnormal Results in Patients with Confirmed and Suspected DIC
- Slide Number 85
- Slide Number 86
- Comparing an Automated FM vs Manual FSP Test
- Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Slide Number 94
- Slide Number 95
- Slide Number 96
- Slide Number 97
- Slide Number 98
- Slide Number 99
- DIC Case Studies
- Case Study 1 - Presentation
- Case Study 1 ndash Lab Results
- Case Study 1 ndash Microscopy
- Case Study 1 ndash Diagnosis and Therapy
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Slide Number 110
- Slide Number 111
- Slide Number 112
- Slide Number 113
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
- Slide Number 124
- Slide Number 125
- DIC Take Home Messages
- Slide Number 127
- Slide Number 128
-
Impact of DIC Status on Mortality - 1
Okamoto K Wada H Hatada T Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Frequency and hemostatic abnormalities in pre-DIC patients Thromb Res 2010 126 74-8
Patients with positivity of DIC tend to have worse mortality outcomes compared to negative patients or those with pre-DIC
Impact of DIC Status on Mortality - 2
Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4
Patients with positivity of either Overt or Non-Overt DIC tend to have worse mortality outcomes compared to negative patients
Impact of Age on Mortality in DIC Patients
Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4
Older patients with DIC (black bars) generally tend to have worse outcomes compared to non-DIC patients (grey bars)
Pathophysiology of DIC
Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33
Pathogenesis of DIC in Sepsis
Allen KS Sawheny E Kinasewitzet GT Anticoagulant modulation of inflammation in severe sepsis World J Crit Care Med 2015 4 105-15
Bacteria in sepsis infections cause release of TF from immune cells leading to coagulation activation and proinflammatory cytokines cause endothelial cell activation impairing the anticoagulation and fibrinolysis process resulting in DIC
Host Response in Severe Sepsis
Exaggerated inflammation as a result of the host response to sepsis is collateral tissue damage and cell death further resulting in release of danger molecules continuing the inflammatory process in a downward spiral
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Organ Failure in Severe Sepsis
Sepsis associated with microvascular thrombosis as a result of TF mediated coagulation activation results in release of neutrophil extracellular traps (NETs) tissue hypoperfusion and mitochondrial damage resulting in a downward spiral leading to organ failure
Angus DC van der Poll T Severe Sepsis and Septic Shock N Engl J Med 2013 369 840-51
Mechanism of DIC in Organ Failure
Underlying condition(sepsis trauma)
Cytokines
TF-mediatedactivation of coagulation
Depression of inhibitory systems
Reducesfibrinolysis
Fibrin deposition
Organ failure
Inadequate fibrin removal
Fibrinformation
Note impaired fibrinolysis in relation to the clinical need not in absolute value (FDPs are )
Levi M de Jonge E van der Poll T ten Cate H Disseminated intravascular coagulation ThrombHaemost 1999 82 695-705
Interaction of Inflammation and Coagulation in Sepsis
Binding of TF thrombin and other activation coagulation factors to PARs and fibrin to TLRs on inflammatory cells results in inflammation through release of proinflammatory cytokines and chemokines
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Mechanism of Multiple Organ Failure in DIC
Wheeler AP Bernard GR Treating Patients with Severe Sepsis N Engl J Med 1999 340207-14
Inflammatory activation and microvascular thrombosis contributes to multiple organ failure in DIC
lipopolysaccharides
cytokines
coagulation activation
mononuclear cell
tissue factor
Diverse and Opposing Effects of Thrombin
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Coagulation and Fibrinolysis in DIC
Soluble fibrin Polymer
XIIIa
D-Dimer
E
Fibrin clot
Fibrin Degradation Products
Fibrinogen Thrombin
Fibrinogen Degradation
Products
D E
Plasmin
DFM + fibrinopeptides
Soluble FM ComplexesPre-throm
boticPost-throm
botic
Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis Semin Thromb Hemost 2008 34 33-8
Mechanism of DIC
THROMBOSIS
Fibrin
Blood activationEndothelial lysisTF expression
BLEEDING
FDPs
D-Dimer
Plasmin
Pathophysiology of DIC
1st step abnormal activation of coagulation Injury of vessel wall cells venous stasis release of large quantities of
thromboplastin influx of activated cells (monocytes macrophages)
Results in an intravascular deposition of fibrin
Morbidity from disseminated microthrombosis in small and midsize vessels leading to multiple organ failure
Second step Consumption and depletion of coagulation factors inhibitors (Protein C
Protein S AT) and platelets Local fibrinolytic response
bull Local plasmin generation dissolves the thrombusbull Disseminated overwhelming fibrinolytic response leading to production of
FDP and D-Dimer
Bleeding
Pathophysiology of DIC - Mechanism
Systemic activation of coagulation
Intravasculardepositionof fibrin
Thrombosis of small and midsize vessels
and organ failure
Depletion of platelets and
coagulation factors
Bleeding
Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92
Pathophysiology of DIC ndash 2 Types of Clinical pictures
Chronic = non - overt DICMay be unrecognized clinically
Acute = overt DIClife threatening bleedingor multiple organ failure
Sub-Acute and Non-Overt DIC Clinical Findings
Compensated non-overt DIC Steady low level or intermittent activation
bull Compensated by increased production of coagulation components and platelets
Few or no clinical signs or multiple microvascular thrombosis sometimes not clinically obvious
Risk of decompensation leading to overt DIC
Pathophysiology of Overt DIC
Massive activation of coagulation and fibrinolysis
Does not allow for compensatory efforts
Rapid depletion of coagulation factors inhibitors and platelets
Thrombosis multiple organ failures
Bleeding complications and shock
Physiopathology of DIC ndash Overt DIC Findings
Thrombin generation
Thrombosis
Renal liver respiratory failures coma skin necrosis gangrene venous thromboembolism hypotension edema
Cytokine and kinin generation (shock)bull Tachycardia hypotension edema
Plasmin generationHemorrhage
bull Spontaneous bruising petechiae intracranial gastrointestinal and respiratory tract bleeding persistent bleeding at venipuncture sites at surgical wounds
bull Tachycardia hypotension edema
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Pathogenesis Pathways in DIC
Cytokines
TF-mediated dysfunctional impairedthrombin anticoagulant fibrinolysisgeneration mechanism due to PAI-1 deficiency
fibrin inadequateformation fibrin removal
Fibrin deposition
Inflammation
Coagulation
Stago Celebrates Lab Week 2017
NA
Stago 247 Educational Webinar Sites
wwwstago-edvantagecomUS based KOLsPACE accredited ndash all 1 hourAccessible from mobile devicesVirtual exhibit hall
wwwstagowebinarscomMostly European KOLs30 ndash 45 min including 15 min discussion
Stago Educational Apps
HaemoscoreClinical scoring algorithmsApple and AndroidTablet or phone
iHemostasisCoagulation diagramsCase studiesApple amp AndroidTablet only
BREAK
Diagnostic and Management Approach for DIC
Diagnosis of DIC
Clinical diagnosis is obvious in cases of overt DIC
Laboratory tests are necessary To makeconfirm the diagnosis To assess stage of the patient To assess the treatment efficacy
Lab Diagnosis of DIC ndash Markers of Factor Consumption
Routinescreening assays PT APTT Platelets Fibrinogen Thrombin time
Other coagulation assays Factor assays AntithrombinGeneration of Thrombin FMFSPsGeneration of Plasmin D-dimer FDPs
Important to recognize simultaneous formation of thrombin and plasmin
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122
Lab Diagnosis of DIC ndash Screening Tests
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122
Platelet count usually decreasedPT abnormal in 70 of cases (short half-life of FVII)APTT abnormal in 50 of casesThrombin time usually prolonged in overt DIC normal in non-overt DIC and no relation with syndrome severityFibrinogen low in lt 50 of cases sensitivity 22 specificity 87 overall predictive value 64 Normal fibrinogen level should not exclude DIC diagnosis (acute phase reactant initial high
fibrinogen level) repeat testing assesses progression
Screening tests not clinically specific or sensitive for DIC
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Laboratory Changes in Overt DIC
DIC Diagnostic Practices Over Time
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
British Journal of Haematology Overt DIC Score
Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
ISTH Step by Step DIC Algorithm
Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6
US Based Validation of ISTH DIC Score
When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Differential Diagnosis in DIC
aHUS atypical hemolytic uremic syndrome
HUS hemolytic uremic syndrome
HIT heparin-induced thrombocytopenia
ITP immune thrombocytopenic purpura
TTP thrombotic thrombocytopenic purpura
DIC and MAHA
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)
When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation
DIC Management Goals
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction
DIC Management and Treatment
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)
requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)
Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia
DIC Management Strategies
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant Factor Concentrate Treatment
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis
Anticoagulant Factor Concentrate Treatment Trials
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise
Markers of Thrombin amp Plasmin Generation in DIC
D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC
Cut-off value
Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen
degradation products Sensitive assay typically with cutoff adapted for DIC
D-dimer FDPs and DIC
D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC
Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80
Follow Up of DIC State of Disease
Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8
Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility
FMD-Dimer in DIC Major Differences
onset of thrombosis
days
Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8
FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)
D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)
of Abnormal Results in Patients with Confirmed and Suspected DIC
0
20
40
60
80
100
94 85 90N = 62
Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32
Positivity of Test Results ISTH Score and Disease State
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
Red bar positive for 2 points of DIC score
Pink bar positive for 1-2 points of DIC score
HT hematopoietic tumor
IF infection
SC solid cancer
Markers in Patients with or without DIC
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
HT hematopoietic tumorIF infectionSC solid cancer
Comparing an Automated FM vs Manual FSP Test
Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71
Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)
Automated (Mitsubishi) vs Automated (Stago)
In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago
Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC
Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
Non Overt DIC Overt DIC
AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC
Trends in Markers of DIC for Different Patients
Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00
Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients
Trends in Markers of DIC for Different Patients
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes
28 day outcome survival
28 day outcome death
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines
DIC Case Studies
Case Study 1 - Presentation
18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE
WBC count 77 KμL 423 ndash 907 x KμL
RBC count 17 MμL 137 ndash 175 x MμL
Hemoglobin 67 gdL 137 ndash 175 gdL
Hematocrit 195 401 ndash 510
MCV 95 fL 790 ndash 922 fL
MPV 12 fL 94 ndash 124 fL
Platelet count 9 KμL 161 ndash 347 KμL
Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0
Lymphocytes monocytes eosinophils basophils all below normal range
PT 47 sec (corrected on mixing study) 116 ndash 152 sec
APTT 75 sec (corrected on mixing study) 253 ndash 373 sec
Fibrinogen lt 76 mgdL 177 ndash 466 mgdL
D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Microscopy
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Arrow shows giant platelets in this peripheral smear Promyelocytes apparent
Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)
DIC due to TF release by APL blasts
Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases
Transfusions to replace factors along with platelets and RBCs during APL treatment
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started
Case Study 2 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L
PT 30 sec 113 ndash 146 sec
APTT 75 sec 25 ndash 34 sec
D-dimer 078 microgml FEU lt050 microgml FEU
Fibrinogen 92 mgdl 150-400 mgdl
pH 728 738 to 742
PaO2 570 mmHg 80-100 mmHg
WBC 33 times 103mm3 40-11 times 103mm3
ALT 111 IUL 0ndash34 IUL
AST 61 IUL 0ndash34 IUL
BUN 303 mgdL 08-13 mgdL
Case Study 2 ndash Lab Results
Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures
Case Study 2 ndash Diagnosis
60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior
Case Study 3 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L
PT 228 sec 113 ndash 146 sec
APTT 45 sec 25 ndash 34 sec
D-dimer 080 microgml FEU lt050 microgmL FEU
Fibrinogen 82 mgdL 150-400 mgdL
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 134 gdL 14-16 gdL
WBC 81 times 103mm3 40-11 times 103mm3
ALT 32 IUL 0ndash34 IUL
AST 28 IUL 0ndash34 IUL
BUN 09 mgdL 08-13 mgdL
Case Study 3 ndash Lab Results
Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment
Case Study 3 ndash Diagnosis and Therapy
Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91
Case Study 4 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L
PT 28 sec 113 ndash 146 sec
APTT 71 sec 25 ndash 34 sec
D-dimer 31 microgmL FEU lt050 microgml FEU
Fibrinogen 92 mgdL 150-400 mgdl
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 158 gdL 14-16 gdL
WBC 71 times 103mm3 40-11 times 103mm3
ALT 60 IUL 0ndash34 IUL
AST 47 IUL 0ndash34 IUL
BUN 38 mgdL 08-13 mgdL
Case Study 4 ndash Lab Results
Lyme disease with DICProvide antibiotics with supportive measures
Case Study 4 ndash Diagnosis
55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis
Case Study 5 ndash Presentation
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
Case Study 5 ndash Lab Results and Time Course
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
TEST RESULT REFERENCE RANGE
Platelet count 33 x 109L 150-450 x 109L
PT 215 sec 103 ndash 128 sec
APTT 44 sec 26 ndash 36 sec
D-dimer 20 microgmL FEU lt025 microgml FEU
Fibrinogen 34 mgdL 200-375 mgdl
FII FV FVIII Low Not reported (NR)
FVII FIX FX vWF Normal NR
Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)
DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic
dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR
(C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen
(D) Illustration demonstrating repair
Case Study 5 ndash Diagnosis and Treatment
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography
Case Study 6 ndash Presentation
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
Case Study 6 ndash Lab Results
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L
PT 63 sec gt control 113 ndash 146 sec
INR 658 1 ndash 125
APTT 80 sec gt control 25 ndash 34 sec
D-dimer gt200 microgmL DDU 02 microgmL DDU
Urine exam Proteinuria and hematuria 150-400 mgdl
Albumin 28 gdL NR
Hb 58 gdL NR
LDH 1196 UL NR
SGPT 144 IU NR
SGOT 88 IU NR
Bilirubin 32 mgdL NR
DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th
day postop
Case Study 6 ndash Diagnosis and Treatment
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure
Case Study 6 ndash Discussion
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Case Study 7 ndash Lab Results vs Time
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
DIC Take Home Messages
Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation
Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers
DIC
Thank you Questions
- Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
- Learning Objectives
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Wound Sealing
- The Three Steps of Hemostasis
- Vessel Wall
- Slide Number 12
- Slide Number 13
- Platelet Structure UnactivatedActivated
- Primary Hemostasis
- Primary Hemostasis Assays
- Slide Number 17
- Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
- Slide Number 19
- Coagulation factors
- Coagulation Assay Mechanisms
- Slide Number 22
- Fibrin Formation
- Slide Number 24
- Fibrinolysis Overview
- Fibrinolysis Overview
- Slide Number 27
- Fibrinolysis Releases D-dimers
- Basic Pathophysiology of DIC
- Disseminated Intravascular Coagulation (DIC)
- Purpura Fulminans with DIC Due to Meningococcal Sepsis
- Clinical Conditions Associated With DIC
- Frequency of DIC in Selected Disease States
- Underlying Diseases in DIC Patients
- Slide Number 36
- Slide Number 37
- Slide Number 38
- Slide Number 39
- Pathophysiology of DIC
- Pathogenesis of DIC in Sepsis
- Host Response in Severe Sepsis
- Organ Failure in Severe Sepsis
- Mechanism of DIC in Organ Failure
- Interaction of Inflammation and Coagulation in Sepsis
- Slide Number 47
- Diverse and Opposing Effects of Thrombin
- Coagulation and Fibrinolysis in DIC
- Mechanism of DIC
- Pathophysiology of DIC
- Pathophysiology of DIC - Mechanism
- Pathophysiology of DIC ndash 2 Types of Clinical pictures
- Sub-Acute and Non-Overt DIC Clinical Findings
- Pathophysiology of Overt DIC
- Physiopathology of DIC ndash Overt DIC Findings
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- BREAK
- Diagnostic and Management Approach for DIC
- Diagnosis of DIC
- Lab Diagnosis of DIC ndash Markers of Factor Consumption
- Lab Diagnosis of DIC ndash Screening Tests
- Slide Number 67
- Slide Number 68
- British Journal of Haematology Overt DIC Score
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- DIC Management Goals
- DIC Management and Treatment
- DIC Management Strategies
- Anticoagulant Factor Concentrate Treatment
- Anticoagulant Factor Concentrate Treatment Trials
- Markers of Thrombin amp Plasmin Generation in DIC
- D-dimer FDPs and DIC
- D-Dimer and FDPs in DIC
- Follow Up of DIC State of Disease
- FMD-Dimer in DIC Major Differences
- of Abnormal Results in Patients with Confirmed and Suspected DIC
- Slide Number 85
- Slide Number 86
- Comparing an Automated FM vs Manual FSP Test
- Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Slide Number 94
- Slide Number 95
- Slide Number 96
- Slide Number 97
- Slide Number 98
- Slide Number 99
- DIC Case Studies
- Case Study 1 - Presentation
- Case Study 1 ndash Lab Results
- Case Study 1 ndash Microscopy
- Case Study 1 ndash Diagnosis and Therapy
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Slide Number 110
- Slide Number 111
- Slide Number 112
- Slide Number 113
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
- Slide Number 124
- Slide Number 125
- DIC Take Home Messages
- Slide Number 127
- Slide Number 128
-
Impact of DIC Status on Mortality - 2
Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4
Patients with positivity of either Overt or Non-Overt DIC tend to have worse mortality outcomes compared to negative patients
Impact of Age on Mortality in DIC Patients
Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4
Older patients with DIC (black bars) generally tend to have worse outcomes compared to non-DIC patients (grey bars)
Pathophysiology of DIC
Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33
Pathogenesis of DIC in Sepsis
Allen KS Sawheny E Kinasewitzet GT Anticoagulant modulation of inflammation in severe sepsis World J Crit Care Med 2015 4 105-15
Bacteria in sepsis infections cause release of TF from immune cells leading to coagulation activation and proinflammatory cytokines cause endothelial cell activation impairing the anticoagulation and fibrinolysis process resulting in DIC
Host Response in Severe Sepsis
Exaggerated inflammation as a result of the host response to sepsis is collateral tissue damage and cell death further resulting in release of danger molecules continuing the inflammatory process in a downward spiral
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Organ Failure in Severe Sepsis
Sepsis associated with microvascular thrombosis as a result of TF mediated coagulation activation results in release of neutrophil extracellular traps (NETs) tissue hypoperfusion and mitochondrial damage resulting in a downward spiral leading to organ failure
Angus DC van der Poll T Severe Sepsis and Septic Shock N Engl J Med 2013 369 840-51
Mechanism of DIC in Organ Failure
Underlying condition(sepsis trauma)
Cytokines
TF-mediatedactivation of coagulation
Depression of inhibitory systems
Reducesfibrinolysis
Fibrin deposition
Organ failure
Inadequate fibrin removal
Fibrinformation
Note impaired fibrinolysis in relation to the clinical need not in absolute value (FDPs are )
Levi M de Jonge E van der Poll T ten Cate H Disseminated intravascular coagulation ThrombHaemost 1999 82 695-705
Interaction of Inflammation and Coagulation in Sepsis
Binding of TF thrombin and other activation coagulation factors to PARs and fibrin to TLRs on inflammatory cells results in inflammation through release of proinflammatory cytokines and chemokines
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Mechanism of Multiple Organ Failure in DIC
Wheeler AP Bernard GR Treating Patients with Severe Sepsis N Engl J Med 1999 340207-14
Inflammatory activation and microvascular thrombosis contributes to multiple organ failure in DIC
lipopolysaccharides
cytokines
coagulation activation
mononuclear cell
tissue factor
Diverse and Opposing Effects of Thrombin
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Coagulation and Fibrinolysis in DIC
Soluble fibrin Polymer
XIIIa
D-Dimer
E
Fibrin clot
Fibrin Degradation Products
Fibrinogen Thrombin
Fibrinogen Degradation
Products
D E
Plasmin
DFM + fibrinopeptides
Soluble FM ComplexesPre-throm
boticPost-throm
botic
Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis Semin Thromb Hemost 2008 34 33-8
Mechanism of DIC
THROMBOSIS
Fibrin
Blood activationEndothelial lysisTF expression
BLEEDING
FDPs
D-Dimer
Plasmin
Pathophysiology of DIC
1st step abnormal activation of coagulation Injury of vessel wall cells venous stasis release of large quantities of
thromboplastin influx of activated cells (monocytes macrophages)
Results in an intravascular deposition of fibrin
Morbidity from disseminated microthrombosis in small and midsize vessels leading to multiple organ failure
Second step Consumption and depletion of coagulation factors inhibitors (Protein C
Protein S AT) and platelets Local fibrinolytic response
bull Local plasmin generation dissolves the thrombusbull Disseminated overwhelming fibrinolytic response leading to production of
FDP and D-Dimer
Bleeding
Pathophysiology of DIC - Mechanism
Systemic activation of coagulation
Intravasculardepositionof fibrin
Thrombosis of small and midsize vessels
and organ failure
Depletion of platelets and
coagulation factors
Bleeding
Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92
Pathophysiology of DIC ndash 2 Types of Clinical pictures
Chronic = non - overt DICMay be unrecognized clinically
Acute = overt DIClife threatening bleedingor multiple organ failure
Sub-Acute and Non-Overt DIC Clinical Findings
Compensated non-overt DIC Steady low level or intermittent activation
bull Compensated by increased production of coagulation components and platelets
Few or no clinical signs or multiple microvascular thrombosis sometimes not clinically obvious
Risk of decompensation leading to overt DIC
Pathophysiology of Overt DIC
Massive activation of coagulation and fibrinolysis
Does not allow for compensatory efforts
Rapid depletion of coagulation factors inhibitors and platelets
Thrombosis multiple organ failures
Bleeding complications and shock
Physiopathology of DIC ndash Overt DIC Findings
Thrombin generation
Thrombosis
Renal liver respiratory failures coma skin necrosis gangrene venous thromboembolism hypotension edema
Cytokine and kinin generation (shock)bull Tachycardia hypotension edema
Plasmin generationHemorrhage
bull Spontaneous bruising petechiae intracranial gastrointestinal and respiratory tract bleeding persistent bleeding at venipuncture sites at surgical wounds
bull Tachycardia hypotension edema
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Pathogenesis Pathways in DIC
Cytokines
TF-mediated dysfunctional impairedthrombin anticoagulant fibrinolysisgeneration mechanism due to PAI-1 deficiency
fibrin inadequateformation fibrin removal
Fibrin deposition
Inflammation
Coagulation
Stago Celebrates Lab Week 2017
NA
Stago 247 Educational Webinar Sites
wwwstago-edvantagecomUS based KOLsPACE accredited ndash all 1 hourAccessible from mobile devicesVirtual exhibit hall
wwwstagowebinarscomMostly European KOLs30 ndash 45 min including 15 min discussion
Stago Educational Apps
HaemoscoreClinical scoring algorithmsApple and AndroidTablet or phone
iHemostasisCoagulation diagramsCase studiesApple amp AndroidTablet only
BREAK
Diagnostic and Management Approach for DIC
Diagnosis of DIC
Clinical diagnosis is obvious in cases of overt DIC
Laboratory tests are necessary To makeconfirm the diagnosis To assess stage of the patient To assess the treatment efficacy
Lab Diagnosis of DIC ndash Markers of Factor Consumption
Routinescreening assays PT APTT Platelets Fibrinogen Thrombin time
Other coagulation assays Factor assays AntithrombinGeneration of Thrombin FMFSPsGeneration of Plasmin D-dimer FDPs
Important to recognize simultaneous formation of thrombin and plasmin
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122
Lab Diagnosis of DIC ndash Screening Tests
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122
Platelet count usually decreasedPT abnormal in 70 of cases (short half-life of FVII)APTT abnormal in 50 of casesThrombin time usually prolonged in overt DIC normal in non-overt DIC and no relation with syndrome severityFibrinogen low in lt 50 of cases sensitivity 22 specificity 87 overall predictive value 64 Normal fibrinogen level should not exclude DIC diagnosis (acute phase reactant initial high
fibrinogen level) repeat testing assesses progression
Screening tests not clinically specific or sensitive for DIC
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Laboratory Changes in Overt DIC
DIC Diagnostic Practices Over Time
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
British Journal of Haematology Overt DIC Score
Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
ISTH Step by Step DIC Algorithm
Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6
US Based Validation of ISTH DIC Score
When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Differential Diagnosis in DIC
aHUS atypical hemolytic uremic syndrome
HUS hemolytic uremic syndrome
HIT heparin-induced thrombocytopenia
ITP immune thrombocytopenic purpura
TTP thrombotic thrombocytopenic purpura
DIC and MAHA
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)
When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation
DIC Management Goals
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction
DIC Management and Treatment
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)
requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)
Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia
DIC Management Strategies
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant Factor Concentrate Treatment
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis
Anticoagulant Factor Concentrate Treatment Trials
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise
Markers of Thrombin amp Plasmin Generation in DIC
D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC
Cut-off value
Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen
degradation products Sensitive assay typically with cutoff adapted for DIC
D-dimer FDPs and DIC
D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC
Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80
Follow Up of DIC State of Disease
Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8
Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility
FMD-Dimer in DIC Major Differences
onset of thrombosis
days
Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8
FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)
D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)
of Abnormal Results in Patients with Confirmed and Suspected DIC
0
20
40
60
80
100
94 85 90N = 62
Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32
Positivity of Test Results ISTH Score and Disease State
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
Red bar positive for 2 points of DIC score
Pink bar positive for 1-2 points of DIC score
HT hematopoietic tumor
IF infection
SC solid cancer
Markers in Patients with or without DIC
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
HT hematopoietic tumorIF infectionSC solid cancer
Comparing an Automated FM vs Manual FSP Test
Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71
Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)
Automated (Mitsubishi) vs Automated (Stago)
In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago
Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC
Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
Non Overt DIC Overt DIC
AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC
Trends in Markers of DIC for Different Patients
Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00
Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients
Trends in Markers of DIC for Different Patients
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes
28 day outcome survival
28 day outcome death
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines
DIC Case Studies
Case Study 1 - Presentation
18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE
WBC count 77 KμL 423 ndash 907 x KμL
RBC count 17 MμL 137 ndash 175 x MμL
Hemoglobin 67 gdL 137 ndash 175 gdL
Hematocrit 195 401 ndash 510
MCV 95 fL 790 ndash 922 fL
MPV 12 fL 94 ndash 124 fL
Platelet count 9 KμL 161 ndash 347 KμL
Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0
Lymphocytes monocytes eosinophils basophils all below normal range
PT 47 sec (corrected on mixing study) 116 ndash 152 sec
APTT 75 sec (corrected on mixing study) 253 ndash 373 sec
Fibrinogen lt 76 mgdL 177 ndash 466 mgdL
D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Microscopy
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Arrow shows giant platelets in this peripheral smear Promyelocytes apparent
Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)
DIC due to TF release by APL blasts
Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases
Transfusions to replace factors along with platelets and RBCs during APL treatment
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started
Case Study 2 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L
PT 30 sec 113 ndash 146 sec
APTT 75 sec 25 ndash 34 sec
D-dimer 078 microgml FEU lt050 microgml FEU
Fibrinogen 92 mgdl 150-400 mgdl
pH 728 738 to 742
PaO2 570 mmHg 80-100 mmHg
WBC 33 times 103mm3 40-11 times 103mm3
ALT 111 IUL 0ndash34 IUL
AST 61 IUL 0ndash34 IUL
BUN 303 mgdL 08-13 mgdL
Case Study 2 ndash Lab Results
Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures
Case Study 2 ndash Diagnosis
60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior
Case Study 3 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L
PT 228 sec 113 ndash 146 sec
APTT 45 sec 25 ndash 34 sec
D-dimer 080 microgml FEU lt050 microgmL FEU
Fibrinogen 82 mgdL 150-400 mgdL
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 134 gdL 14-16 gdL
WBC 81 times 103mm3 40-11 times 103mm3
ALT 32 IUL 0ndash34 IUL
AST 28 IUL 0ndash34 IUL
BUN 09 mgdL 08-13 mgdL
Case Study 3 ndash Lab Results
Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment
Case Study 3 ndash Diagnosis and Therapy
Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91
Case Study 4 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L
PT 28 sec 113 ndash 146 sec
APTT 71 sec 25 ndash 34 sec
D-dimer 31 microgmL FEU lt050 microgml FEU
Fibrinogen 92 mgdL 150-400 mgdl
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 158 gdL 14-16 gdL
WBC 71 times 103mm3 40-11 times 103mm3
ALT 60 IUL 0ndash34 IUL
AST 47 IUL 0ndash34 IUL
BUN 38 mgdL 08-13 mgdL
Case Study 4 ndash Lab Results
Lyme disease with DICProvide antibiotics with supportive measures
Case Study 4 ndash Diagnosis
55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis
Case Study 5 ndash Presentation
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
Case Study 5 ndash Lab Results and Time Course
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
TEST RESULT REFERENCE RANGE
Platelet count 33 x 109L 150-450 x 109L
PT 215 sec 103 ndash 128 sec
APTT 44 sec 26 ndash 36 sec
D-dimer 20 microgmL FEU lt025 microgml FEU
Fibrinogen 34 mgdL 200-375 mgdl
FII FV FVIII Low Not reported (NR)
FVII FIX FX vWF Normal NR
Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)
DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic
dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR
(C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen
(D) Illustration demonstrating repair
Case Study 5 ndash Diagnosis and Treatment
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography
Case Study 6 ndash Presentation
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
Case Study 6 ndash Lab Results
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L
PT 63 sec gt control 113 ndash 146 sec
INR 658 1 ndash 125
APTT 80 sec gt control 25 ndash 34 sec
D-dimer gt200 microgmL DDU 02 microgmL DDU
Urine exam Proteinuria and hematuria 150-400 mgdl
Albumin 28 gdL NR
Hb 58 gdL NR
LDH 1196 UL NR
SGPT 144 IU NR
SGOT 88 IU NR
Bilirubin 32 mgdL NR
DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th
day postop
Case Study 6 ndash Diagnosis and Treatment
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure
Case Study 6 ndash Discussion
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Case Study 7 ndash Lab Results vs Time
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
DIC Take Home Messages
Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation
Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers
DIC
Thank you Questions
- Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
- Learning Objectives
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Wound Sealing
- The Three Steps of Hemostasis
- Vessel Wall
- Slide Number 12
- Slide Number 13
- Platelet Structure UnactivatedActivated
- Primary Hemostasis
- Primary Hemostasis Assays
- Slide Number 17
- Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
- Slide Number 19
- Coagulation factors
- Coagulation Assay Mechanisms
- Slide Number 22
- Fibrin Formation
- Slide Number 24
- Fibrinolysis Overview
- Fibrinolysis Overview
- Slide Number 27
- Fibrinolysis Releases D-dimers
- Basic Pathophysiology of DIC
- Disseminated Intravascular Coagulation (DIC)
- Purpura Fulminans with DIC Due to Meningococcal Sepsis
- Clinical Conditions Associated With DIC
- Frequency of DIC in Selected Disease States
- Underlying Diseases in DIC Patients
- Slide Number 36
- Slide Number 37
- Slide Number 38
- Slide Number 39
- Pathophysiology of DIC
- Pathogenesis of DIC in Sepsis
- Host Response in Severe Sepsis
- Organ Failure in Severe Sepsis
- Mechanism of DIC in Organ Failure
- Interaction of Inflammation and Coagulation in Sepsis
- Slide Number 47
- Diverse and Opposing Effects of Thrombin
- Coagulation and Fibrinolysis in DIC
- Mechanism of DIC
- Pathophysiology of DIC
- Pathophysiology of DIC - Mechanism
- Pathophysiology of DIC ndash 2 Types of Clinical pictures
- Sub-Acute and Non-Overt DIC Clinical Findings
- Pathophysiology of Overt DIC
- Physiopathology of DIC ndash Overt DIC Findings
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- BREAK
- Diagnostic and Management Approach for DIC
- Diagnosis of DIC
- Lab Diagnosis of DIC ndash Markers of Factor Consumption
- Lab Diagnosis of DIC ndash Screening Tests
- Slide Number 67
- Slide Number 68
- British Journal of Haematology Overt DIC Score
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- DIC Management Goals
- DIC Management and Treatment
- DIC Management Strategies
- Anticoagulant Factor Concentrate Treatment
- Anticoagulant Factor Concentrate Treatment Trials
- Markers of Thrombin amp Plasmin Generation in DIC
- D-dimer FDPs and DIC
- D-Dimer and FDPs in DIC
- Follow Up of DIC State of Disease
- FMD-Dimer in DIC Major Differences
- of Abnormal Results in Patients with Confirmed and Suspected DIC
- Slide Number 85
- Slide Number 86
- Comparing an Automated FM vs Manual FSP Test
- Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Slide Number 94
- Slide Number 95
- Slide Number 96
- Slide Number 97
- Slide Number 98
- Slide Number 99
- DIC Case Studies
- Case Study 1 - Presentation
- Case Study 1 ndash Lab Results
- Case Study 1 ndash Microscopy
- Case Study 1 ndash Diagnosis and Therapy
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Slide Number 110
- Slide Number 111
- Slide Number 112
- Slide Number 113
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
- Slide Number 124
- Slide Number 125
- DIC Take Home Messages
- Slide Number 127
- Slide Number 128
-
Impact of Age on Mortality in DIC Patients
Wada H Hatada T Okamoto K Uchiyama T Kawasugi K Mayumi T et al Japanese Society of Thrombosis HemostasisDIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC Am J Hematol 2010 85 691-4
Older patients with DIC (black bars) generally tend to have worse outcomes compared to non-DIC patients (grey bars)
Pathophysiology of DIC
Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33
Pathogenesis of DIC in Sepsis
Allen KS Sawheny E Kinasewitzet GT Anticoagulant modulation of inflammation in severe sepsis World J Crit Care Med 2015 4 105-15
Bacteria in sepsis infections cause release of TF from immune cells leading to coagulation activation and proinflammatory cytokines cause endothelial cell activation impairing the anticoagulation and fibrinolysis process resulting in DIC
Host Response in Severe Sepsis
Exaggerated inflammation as a result of the host response to sepsis is collateral tissue damage and cell death further resulting in release of danger molecules continuing the inflammatory process in a downward spiral
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Organ Failure in Severe Sepsis
Sepsis associated with microvascular thrombosis as a result of TF mediated coagulation activation results in release of neutrophil extracellular traps (NETs) tissue hypoperfusion and mitochondrial damage resulting in a downward spiral leading to organ failure
Angus DC van der Poll T Severe Sepsis and Septic Shock N Engl J Med 2013 369 840-51
Mechanism of DIC in Organ Failure
Underlying condition(sepsis trauma)
Cytokines
TF-mediatedactivation of coagulation
Depression of inhibitory systems
Reducesfibrinolysis
Fibrin deposition
Organ failure
Inadequate fibrin removal
Fibrinformation
Note impaired fibrinolysis in relation to the clinical need not in absolute value (FDPs are )
Levi M de Jonge E van der Poll T ten Cate H Disseminated intravascular coagulation ThrombHaemost 1999 82 695-705
Interaction of Inflammation and Coagulation in Sepsis
Binding of TF thrombin and other activation coagulation factors to PARs and fibrin to TLRs on inflammatory cells results in inflammation through release of proinflammatory cytokines and chemokines
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Mechanism of Multiple Organ Failure in DIC
Wheeler AP Bernard GR Treating Patients with Severe Sepsis N Engl J Med 1999 340207-14
Inflammatory activation and microvascular thrombosis contributes to multiple organ failure in DIC
lipopolysaccharides
cytokines
coagulation activation
mononuclear cell
tissue factor
Diverse and Opposing Effects of Thrombin
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Coagulation and Fibrinolysis in DIC
Soluble fibrin Polymer
XIIIa
D-Dimer
E
Fibrin clot
Fibrin Degradation Products
Fibrinogen Thrombin
Fibrinogen Degradation
Products
D E
Plasmin
DFM + fibrinopeptides
Soluble FM ComplexesPre-throm
boticPost-throm
botic
Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis Semin Thromb Hemost 2008 34 33-8
Mechanism of DIC
THROMBOSIS
Fibrin
Blood activationEndothelial lysisTF expression
BLEEDING
FDPs
D-Dimer
Plasmin
Pathophysiology of DIC
1st step abnormal activation of coagulation Injury of vessel wall cells venous stasis release of large quantities of
thromboplastin influx of activated cells (monocytes macrophages)
Results in an intravascular deposition of fibrin
Morbidity from disseminated microthrombosis in small and midsize vessels leading to multiple organ failure
Second step Consumption and depletion of coagulation factors inhibitors (Protein C
Protein S AT) and platelets Local fibrinolytic response
bull Local plasmin generation dissolves the thrombusbull Disseminated overwhelming fibrinolytic response leading to production of
FDP and D-Dimer
Bleeding
Pathophysiology of DIC - Mechanism
Systemic activation of coagulation
Intravasculardepositionof fibrin
Thrombosis of small and midsize vessels
and organ failure
Depletion of platelets and
coagulation factors
Bleeding
Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92
Pathophysiology of DIC ndash 2 Types of Clinical pictures
Chronic = non - overt DICMay be unrecognized clinically
Acute = overt DIClife threatening bleedingor multiple organ failure
Sub-Acute and Non-Overt DIC Clinical Findings
Compensated non-overt DIC Steady low level or intermittent activation
bull Compensated by increased production of coagulation components and platelets
Few or no clinical signs or multiple microvascular thrombosis sometimes not clinically obvious
Risk of decompensation leading to overt DIC
Pathophysiology of Overt DIC
Massive activation of coagulation and fibrinolysis
Does not allow for compensatory efforts
Rapid depletion of coagulation factors inhibitors and platelets
Thrombosis multiple organ failures
Bleeding complications and shock
Physiopathology of DIC ndash Overt DIC Findings
Thrombin generation
Thrombosis
Renal liver respiratory failures coma skin necrosis gangrene venous thromboembolism hypotension edema
Cytokine and kinin generation (shock)bull Tachycardia hypotension edema
Plasmin generationHemorrhage
bull Spontaneous bruising petechiae intracranial gastrointestinal and respiratory tract bleeding persistent bleeding at venipuncture sites at surgical wounds
bull Tachycardia hypotension edema
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Pathogenesis Pathways in DIC
Cytokines
TF-mediated dysfunctional impairedthrombin anticoagulant fibrinolysisgeneration mechanism due to PAI-1 deficiency
fibrin inadequateformation fibrin removal
Fibrin deposition
Inflammation
Coagulation
Stago Celebrates Lab Week 2017
NA
Stago 247 Educational Webinar Sites
wwwstago-edvantagecomUS based KOLsPACE accredited ndash all 1 hourAccessible from mobile devicesVirtual exhibit hall
wwwstagowebinarscomMostly European KOLs30 ndash 45 min including 15 min discussion
Stago Educational Apps
HaemoscoreClinical scoring algorithmsApple and AndroidTablet or phone
iHemostasisCoagulation diagramsCase studiesApple amp AndroidTablet only
BREAK
Diagnostic and Management Approach for DIC
Diagnosis of DIC
Clinical diagnosis is obvious in cases of overt DIC
Laboratory tests are necessary To makeconfirm the diagnosis To assess stage of the patient To assess the treatment efficacy
Lab Diagnosis of DIC ndash Markers of Factor Consumption
Routinescreening assays PT APTT Platelets Fibrinogen Thrombin time
Other coagulation assays Factor assays AntithrombinGeneration of Thrombin FMFSPsGeneration of Plasmin D-dimer FDPs
Important to recognize simultaneous formation of thrombin and plasmin
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122
Lab Diagnosis of DIC ndash Screening Tests
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122
Platelet count usually decreasedPT abnormal in 70 of cases (short half-life of FVII)APTT abnormal in 50 of casesThrombin time usually prolonged in overt DIC normal in non-overt DIC and no relation with syndrome severityFibrinogen low in lt 50 of cases sensitivity 22 specificity 87 overall predictive value 64 Normal fibrinogen level should not exclude DIC diagnosis (acute phase reactant initial high
fibrinogen level) repeat testing assesses progression
Screening tests not clinically specific or sensitive for DIC
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Laboratory Changes in Overt DIC
DIC Diagnostic Practices Over Time
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
British Journal of Haematology Overt DIC Score
Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
ISTH Step by Step DIC Algorithm
Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6
US Based Validation of ISTH DIC Score
When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Differential Diagnosis in DIC
aHUS atypical hemolytic uremic syndrome
HUS hemolytic uremic syndrome
HIT heparin-induced thrombocytopenia
ITP immune thrombocytopenic purpura
TTP thrombotic thrombocytopenic purpura
DIC and MAHA
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)
When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation
DIC Management Goals
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction
DIC Management and Treatment
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)
requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)
Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia
DIC Management Strategies
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant Factor Concentrate Treatment
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis
Anticoagulant Factor Concentrate Treatment Trials
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise
Markers of Thrombin amp Plasmin Generation in DIC
D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC
Cut-off value
Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen
degradation products Sensitive assay typically with cutoff adapted for DIC
D-dimer FDPs and DIC
D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC
Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80
Follow Up of DIC State of Disease
Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8
Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility
FMD-Dimer in DIC Major Differences
onset of thrombosis
days
Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8
FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)
D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)
of Abnormal Results in Patients with Confirmed and Suspected DIC
0
20
40
60
80
100
94 85 90N = 62
Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32
Positivity of Test Results ISTH Score and Disease State
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
Red bar positive for 2 points of DIC score
Pink bar positive for 1-2 points of DIC score
HT hematopoietic tumor
IF infection
SC solid cancer
Markers in Patients with or without DIC
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
HT hematopoietic tumorIF infectionSC solid cancer
Comparing an Automated FM vs Manual FSP Test
Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71
Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)
Automated (Mitsubishi) vs Automated (Stago)
In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago
Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC
Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
Non Overt DIC Overt DIC
AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC
Trends in Markers of DIC for Different Patients
Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00
Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients
Trends in Markers of DIC for Different Patients
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes
28 day outcome survival
28 day outcome death
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines
DIC Case Studies
Case Study 1 - Presentation
18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE
WBC count 77 KμL 423 ndash 907 x KμL
RBC count 17 MμL 137 ndash 175 x MμL
Hemoglobin 67 gdL 137 ndash 175 gdL
Hematocrit 195 401 ndash 510
MCV 95 fL 790 ndash 922 fL
MPV 12 fL 94 ndash 124 fL
Platelet count 9 KμL 161 ndash 347 KμL
Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0
Lymphocytes monocytes eosinophils basophils all below normal range
PT 47 sec (corrected on mixing study) 116 ndash 152 sec
APTT 75 sec (corrected on mixing study) 253 ndash 373 sec
Fibrinogen lt 76 mgdL 177 ndash 466 mgdL
D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Microscopy
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Arrow shows giant platelets in this peripheral smear Promyelocytes apparent
Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)
DIC due to TF release by APL blasts
Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases
Transfusions to replace factors along with platelets and RBCs during APL treatment
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started
Case Study 2 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L
PT 30 sec 113 ndash 146 sec
APTT 75 sec 25 ndash 34 sec
D-dimer 078 microgml FEU lt050 microgml FEU
Fibrinogen 92 mgdl 150-400 mgdl
pH 728 738 to 742
PaO2 570 mmHg 80-100 mmHg
WBC 33 times 103mm3 40-11 times 103mm3
ALT 111 IUL 0ndash34 IUL
AST 61 IUL 0ndash34 IUL
BUN 303 mgdL 08-13 mgdL
Case Study 2 ndash Lab Results
Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures
Case Study 2 ndash Diagnosis
60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior
Case Study 3 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L
PT 228 sec 113 ndash 146 sec
APTT 45 sec 25 ndash 34 sec
D-dimer 080 microgml FEU lt050 microgmL FEU
Fibrinogen 82 mgdL 150-400 mgdL
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 134 gdL 14-16 gdL
WBC 81 times 103mm3 40-11 times 103mm3
ALT 32 IUL 0ndash34 IUL
AST 28 IUL 0ndash34 IUL
BUN 09 mgdL 08-13 mgdL
Case Study 3 ndash Lab Results
Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment
Case Study 3 ndash Diagnosis and Therapy
Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91
Case Study 4 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L
PT 28 sec 113 ndash 146 sec
APTT 71 sec 25 ndash 34 sec
D-dimer 31 microgmL FEU lt050 microgml FEU
Fibrinogen 92 mgdL 150-400 mgdl
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 158 gdL 14-16 gdL
WBC 71 times 103mm3 40-11 times 103mm3
ALT 60 IUL 0ndash34 IUL
AST 47 IUL 0ndash34 IUL
BUN 38 mgdL 08-13 mgdL
Case Study 4 ndash Lab Results
Lyme disease with DICProvide antibiotics with supportive measures
Case Study 4 ndash Diagnosis
55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis
Case Study 5 ndash Presentation
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
Case Study 5 ndash Lab Results and Time Course
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
TEST RESULT REFERENCE RANGE
Platelet count 33 x 109L 150-450 x 109L
PT 215 sec 103 ndash 128 sec
APTT 44 sec 26 ndash 36 sec
D-dimer 20 microgmL FEU lt025 microgml FEU
Fibrinogen 34 mgdL 200-375 mgdl
FII FV FVIII Low Not reported (NR)
FVII FIX FX vWF Normal NR
Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)
DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic
dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR
(C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen
(D) Illustration demonstrating repair
Case Study 5 ndash Diagnosis and Treatment
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography
Case Study 6 ndash Presentation
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
Case Study 6 ndash Lab Results
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L
PT 63 sec gt control 113 ndash 146 sec
INR 658 1 ndash 125
APTT 80 sec gt control 25 ndash 34 sec
D-dimer gt200 microgmL DDU 02 microgmL DDU
Urine exam Proteinuria and hematuria 150-400 mgdl
Albumin 28 gdL NR
Hb 58 gdL NR
LDH 1196 UL NR
SGPT 144 IU NR
SGOT 88 IU NR
Bilirubin 32 mgdL NR
DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th
day postop
Case Study 6 ndash Diagnosis and Treatment
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure
Case Study 6 ndash Discussion
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Case Study 7 ndash Lab Results vs Time
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
DIC Take Home Messages
Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation
Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers
DIC
Thank you Questions
- Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
- Learning Objectives
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Wound Sealing
- The Three Steps of Hemostasis
- Vessel Wall
- Slide Number 12
- Slide Number 13
- Platelet Structure UnactivatedActivated
- Primary Hemostasis
- Primary Hemostasis Assays
- Slide Number 17
- Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
- Slide Number 19
- Coagulation factors
- Coagulation Assay Mechanisms
- Slide Number 22
- Fibrin Formation
- Slide Number 24
- Fibrinolysis Overview
- Fibrinolysis Overview
- Slide Number 27
- Fibrinolysis Releases D-dimers
- Basic Pathophysiology of DIC
- Disseminated Intravascular Coagulation (DIC)
- Purpura Fulminans with DIC Due to Meningococcal Sepsis
- Clinical Conditions Associated With DIC
- Frequency of DIC in Selected Disease States
- Underlying Diseases in DIC Patients
- Slide Number 36
- Slide Number 37
- Slide Number 38
- Slide Number 39
- Pathophysiology of DIC
- Pathogenesis of DIC in Sepsis
- Host Response in Severe Sepsis
- Organ Failure in Severe Sepsis
- Mechanism of DIC in Organ Failure
- Interaction of Inflammation and Coagulation in Sepsis
- Slide Number 47
- Diverse and Opposing Effects of Thrombin
- Coagulation and Fibrinolysis in DIC
- Mechanism of DIC
- Pathophysiology of DIC
- Pathophysiology of DIC - Mechanism
- Pathophysiology of DIC ndash 2 Types of Clinical pictures
- Sub-Acute and Non-Overt DIC Clinical Findings
- Pathophysiology of Overt DIC
- Physiopathology of DIC ndash Overt DIC Findings
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- BREAK
- Diagnostic and Management Approach for DIC
- Diagnosis of DIC
- Lab Diagnosis of DIC ndash Markers of Factor Consumption
- Lab Diagnosis of DIC ndash Screening Tests
- Slide Number 67
- Slide Number 68
- British Journal of Haematology Overt DIC Score
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- DIC Management Goals
- DIC Management and Treatment
- DIC Management Strategies
- Anticoagulant Factor Concentrate Treatment
- Anticoagulant Factor Concentrate Treatment Trials
- Markers of Thrombin amp Plasmin Generation in DIC
- D-dimer FDPs and DIC
- D-Dimer and FDPs in DIC
- Follow Up of DIC State of Disease
- FMD-Dimer in DIC Major Differences
- of Abnormal Results in Patients with Confirmed and Suspected DIC
- Slide Number 85
- Slide Number 86
- Comparing an Automated FM vs Manual FSP Test
- Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Slide Number 94
- Slide Number 95
- Slide Number 96
- Slide Number 97
- Slide Number 98
- Slide Number 99
- DIC Case Studies
- Case Study 1 - Presentation
- Case Study 1 ndash Lab Results
- Case Study 1 ndash Microscopy
- Case Study 1 ndash Diagnosis and Therapy
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Slide Number 110
- Slide Number 111
- Slide Number 112
- Slide Number 113
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
- Slide Number 124
- Slide Number 125
- DIC Take Home Messages
- Slide Number 127
- Slide Number 128
-
Pathophysiology of DIC
Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33
Pathogenesis of DIC in Sepsis
Allen KS Sawheny E Kinasewitzet GT Anticoagulant modulation of inflammation in severe sepsis World J Crit Care Med 2015 4 105-15
Bacteria in sepsis infections cause release of TF from immune cells leading to coagulation activation and proinflammatory cytokines cause endothelial cell activation impairing the anticoagulation and fibrinolysis process resulting in DIC
Host Response in Severe Sepsis
Exaggerated inflammation as a result of the host response to sepsis is collateral tissue damage and cell death further resulting in release of danger molecules continuing the inflammatory process in a downward spiral
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Organ Failure in Severe Sepsis
Sepsis associated with microvascular thrombosis as a result of TF mediated coagulation activation results in release of neutrophil extracellular traps (NETs) tissue hypoperfusion and mitochondrial damage resulting in a downward spiral leading to organ failure
Angus DC van der Poll T Severe Sepsis and Septic Shock N Engl J Med 2013 369 840-51
Mechanism of DIC in Organ Failure
Underlying condition(sepsis trauma)
Cytokines
TF-mediatedactivation of coagulation
Depression of inhibitory systems
Reducesfibrinolysis
Fibrin deposition
Organ failure
Inadequate fibrin removal
Fibrinformation
Note impaired fibrinolysis in relation to the clinical need not in absolute value (FDPs are )
Levi M de Jonge E van der Poll T ten Cate H Disseminated intravascular coagulation ThrombHaemost 1999 82 695-705
Interaction of Inflammation and Coagulation in Sepsis
Binding of TF thrombin and other activation coagulation factors to PARs and fibrin to TLRs on inflammatory cells results in inflammation through release of proinflammatory cytokines and chemokines
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Mechanism of Multiple Organ Failure in DIC
Wheeler AP Bernard GR Treating Patients with Severe Sepsis N Engl J Med 1999 340207-14
Inflammatory activation and microvascular thrombosis contributes to multiple organ failure in DIC
lipopolysaccharides
cytokines
coagulation activation
mononuclear cell
tissue factor
Diverse and Opposing Effects of Thrombin
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Coagulation and Fibrinolysis in DIC
Soluble fibrin Polymer
XIIIa
D-Dimer
E
Fibrin clot
Fibrin Degradation Products
Fibrinogen Thrombin
Fibrinogen Degradation
Products
D E
Plasmin
DFM + fibrinopeptides
Soluble FM ComplexesPre-throm
boticPost-throm
botic
Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis Semin Thromb Hemost 2008 34 33-8
Mechanism of DIC
THROMBOSIS
Fibrin
Blood activationEndothelial lysisTF expression
BLEEDING
FDPs
D-Dimer
Plasmin
Pathophysiology of DIC
1st step abnormal activation of coagulation Injury of vessel wall cells venous stasis release of large quantities of
thromboplastin influx of activated cells (monocytes macrophages)
Results in an intravascular deposition of fibrin
Morbidity from disseminated microthrombosis in small and midsize vessels leading to multiple organ failure
Second step Consumption and depletion of coagulation factors inhibitors (Protein C
Protein S AT) and platelets Local fibrinolytic response
bull Local plasmin generation dissolves the thrombusbull Disseminated overwhelming fibrinolytic response leading to production of
FDP and D-Dimer
Bleeding
Pathophysiology of DIC - Mechanism
Systemic activation of coagulation
Intravasculardepositionof fibrin
Thrombosis of small and midsize vessels
and organ failure
Depletion of platelets and
coagulation factors
Bleeding
Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92
Pathophysiology of DIC ndash 2 Types of Clinical pictures
Chronic = non - overt DICMay be unrecognized clinically
Acute = overt DIClife threatening bleedingor multiple organ failure
Sub-Acute and Non-Overt DIC Clinical Findings
Compensated non-overt DIC Steady low level or intermittent activation
bull Compensated by increased production of coagulation components and platelets
Few or no clinical signs or multiple microvascular thrombosis sometimes not clinically obvious
Risk of decompensation leading to overt DIC
Pathophysiology of Overt DIC
Massive activation of coagulation and fibrinolysis
Does not allow for compensatory efforts
Rapid depletion of coagulation factors inhibitors and platelets
Thrombosis multiple organ failures
Bleeding complications and shock
Physiopathology of DIC ndash Overt DIC Findings
Thrombin generation
Thrombosis
Renal liver respiratory failures coma skin necrosis gangrene venous thromboembolism hypotension edema
Cytokine and kinin generation (shock)bull Tachycardia hypotension edema
Plasmin generationHemorrhage
bull Spontaneous bruising petechiae intracranial gastrointestinal and respiratory tract bleeding persistent bleeding at venipuncture sites at surgical wounds
bull Tachycardia hypotension edema
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Pathogenesis Pathways in DIC
Cytokines
TF-mediated dysfunctional impairedthrombin anticoagulant fibrinolysisgeneration mechanism due to PAI-1 deficiency
fibrin inadequateformation fibrin removal
Fibrin deposition
Inflammation
Coagulation
Stago Celebrates Lab Week 2017
NA
Stago 247 Educational Webinar Sites
wwwstago-edvantagecomUS based KOLsPACE accredited ndash all 1 hourAccessible from mobile devicesVirtual exhibit hall
wwwstagowebinarscomMostly European KOLs30 ndash 45 min including 15 min discussion
Stago Educational Apps
HaemoscoreClinical scoring algorithmsApple and AndroidTablet or phone
iHemostasisCoagulation diagramsCase studiesApple amp AndroidTablet only
BREAK
Diagnostic and Management Approach for DIC
Diagnosis of DIC
Clinical diagnosis is obvious in cases of overt DIC
Laboratory tests are necessary To makeconfirm the diagnosis To assess stage of the patient To assess the treatment efficacy
Lab Diagnosis of DIC ndash Markers of Factor Consumption
Routinescreening assays PT APTT Platelets Fibrinogen Thrombin time
Other coagulation assays Factor assays AntithrombinGeneration of Thrombin FMFSPsGeneration of Plasmin D-dimer FDPs
Important to recognize simultaneous formation of thrombin and plasmin
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122
Lab Diagnosis of DIC ndash Screening Tests
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122
Platelet count usually decreasedPT abnormal in 70 of cases (short half-life of FVII)APTT abnormal in 50 of casesThrombin time usually prolonged in overt DIC normal in non-overt DIC and no relation with syndrome severityFibrinogen low in lt 50 of cases sensitivity 22 specificity 87 overall predictive value 64 Normal fibrinogen level should not exclude DIC diagnosis (acute phase reactant initial high
fibrinogen level) repeat testing assesses progression
Screening tests not clinically specific or sensitive for DIC
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Laboratory Changes in Overt DIC
DIC Diagnostic Practices Over Time
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
British Journal of Haematology Overt DIC Score
Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
ISTH Step by Step DIC Algorithm
Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6
US Based Validation of ISTH DIC Score
When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Differential Diagnosis in DIC
aHUS atypical hemolytic uremic syndrome
HUS hemolytic uremic syndrome
HIT heparin-induced thrombocytopenia
ITP immune thrombocytopenic purpura
TTP thrombotic thrombocytopenic purpura
DIC and MAHA
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)
When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation
DIC Management Goals
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction
DIC Management and Treatment
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)
requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)
Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia
DIC Management Strategies
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant Factor Concentrate Treatment
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis
Anticoagulant Factor Concentrate Treatment Trials
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise
Markers of Thrombin amp Plasmin Generation in DIC
D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC
Cut-off value
Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen
degradation products Sensitive assay typically with cutoff adapted for DIC
D-dimer FDPs and DIC
D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC
Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80
Follow Up of DIC State of Disease
Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8
Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility
FMD-Dimer in DIC Major Differences
onset of thrombosis
days
Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8
FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)
D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)
of Abnormal Results in Patients with Confirmed and Suspected DIC
0
20
40
60
80
100
94 85 90N = 62
Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32
Positivity of Test Results ISTH Score and Disease State
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
Red bar positive for 2 points of DIC score
Pink bar positive for 1-2 points of DIC score
HT hematopoietic tumor
IF infection
SC solid cancer
Markers in Patients with or without DIC
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
HT hematopoietic tumorIF infectionSC solid cancer
Comparing an Automated FM vs Manual FSP Test
Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71
Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)
Automated (Mitsubishi) vs Automated (Stago)
In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago
Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC
Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
Non Overt DIC Overt DIC
AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC
Trends in Markers of DIC for Different Patients
Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00
Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients
Trends in Markers of DIC for Different Patients
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes
28 day outcome survival
28 day outcome death
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines
DIC Case Studies
Case Study 1 - Presentation
18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE
WBC count 77 KμL 423 ndash 907 x KμL
RBC count 17 MμL 137 ndash 175 x MμL
Hemoglobin 67 gdL 137 ndash 175 gdL
Hematocrit 195 401 ndash 510
MCV 95 fL 790 ndash 922 fL
MPV 12 fL 94 ndash 124 fL
Platelet count 9 KμL 161 ndash 347 KμL
Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0
Lymphocytes monocytes eosinophils basophils all below normal range
PT 47 sec (corrected on mixing study) 116 ndash 152 sec
APTT 75 sec (corrected on mixing study) 253 ndash 373 sec
Fibrinogen lt 76 mgdL 177 ndash 466 mgdL
D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Microscopy
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Arrow shows giant platelets in this peripheral smear Promyelocytes apparent
Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)
DIC due to TF release by APL blasts
Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases
Transfusions to replace factors along with platelets and RBCs during APL treatment
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started
Case Study 2 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L
PT 30 sec 113 ndash 146 sec
APTT 75 sec 25 ndash 34 sec
D-dimer 078 microgml FEU lt050 microgml FEU
Fibrinogen 92 mgdl 150-400 mgdl
pH 728 738 to 742
PaO2 570 mmHg 80-100 mmHg
WBC 33 times 103mm3 40-11 times 103mm3
ALT 111 IUL 0ndash34 IUL
AST 61 IUL 0ndash34 IUL
BUN 303 mgdL 08-13 mgdL
Case Study 2 ndash Lab Results
Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures
Case Study 2 ndash Diagnosis
60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior
Case Study 3 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L
PT 228 sec 113 ndash 146 sec
APTT 45 sec 25 ndash 34 sec
D-dimer 080 microgml FEU lt050 microgmL FEU
Fibrinogen 82 mgdL 150-400 mgdL
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 134 gdL 14-16 gdL
WBC 81 times 103mm3 40-11 times 103mm3
ALT 32 IUL 0ndash34 IUL
AST 28 IUL 0ndash34 IUL
BUN 09 mgdL 08-13 mgdL
Case Study 3 ndash Lab Results
Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment
Case Study 3 ndash Diagnosis and Therapy
Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91
Case Study 4 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L
PT 28 sec 113 ndash 146 sec
APTT 71 sec 25 ndash 34 sec
D-dimer 31 microgmL FEU lt050 microgml FEU
Fibrinogen 92 mgdL 150-400 mgdl
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 158 gdL 14-16 gdL
WBC 71 times 103mm3 40-11 times 103mm3
ALT 60 IUL 0ndash34 IUL
AST 47 IUL 0ndash34 IUL
BUN 38 mgdL 08-13 mgdL
Case Study 4 ndash Lab Results
Lyme disease with DICProvide antibiotics with supportive measures
Case Study 4 ndash Diagnosis
55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis
Case Study 5 ndash Presentation
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
Case Study 5 ndash Lab Results and Time Course
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
TEST RESULT REFERENCE RANGE
Platelet count 33 x 109L 150-450 x 109L
PT 215 sec 103 ndash 128 sec
APTT 44 sec 26 ndash 36 sec
D-dimer 20 microgmL FEU lt025 microgml FEU
Fibrinogen 34 mgdL 200-375 mgdl
FII FV FVIII Low Not reported (NR)
FVII FIX FX vWF Normal NR
Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)
DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic
dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR
(C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen
(D) Illustration demonstrating repair
Case Study 5 ndash Diagnosis and Treatment
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography
Case Study 6 ndash Presentation
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
Case Study 6 ndash Lab Results
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L
PT 63 sec gt control 113 ndash 146 sec
INR 658 1 ndash 125
APTT 80 sec gt control 25 ndash 34 sec
D-dimer gt200 microgmL DDU 02 microgmL DDU
Urine exam Proteinuria and hematuria 150-400 mgdl
Albumin 28 gdL NR
Hb 58 gdL NR
LDH 1196 UL NR
SGPT 144 IU NR
SGOT 88 IU NR
Bilirubin 32 mgdL NR
DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th
day postop
Case Study 6 ndash Diagnosis and Treatment
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure
Case Study 6 ndash Discussion
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Case Study 7 ndash Lab Results vs Time
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
DIC Take Home Messages
Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation
Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers
DIC
Thank you Questions
- Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
- Learning Objectives
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Wound Sealing
- The Three Steps of Hemostasis
- Vessel Wall
- Slide Number 12
- Slide Number 13
- Platelet Structure UnactivatedActivated
- Primary Hemostasis
- Primary Hemostasis Assays
- Slide Number 17
- Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
- Slide Number 19
- Coagulation factors
- Coagulation Assay Mechanisms
- Slide Number 22
- Fibrin Formation
- Slide Number 24
- Fibrinolysis Overview
- Fibrinolysis Overview
- Slide Number 27
- Fibrinolysis Releases D-dimers
- Basic Pathophysiology of DIC
- Disseminated Intravascular Coagulation (DIC)
- Purpura Fulminans with DIC Due to Meningococcal Sepsis
- Clinical Conditions Associated With DIC
- Frequency of DIC in Selected Disease States
- Underlying Diseases in DIC Patients
- Slide Number 36
- Slide Number 37
- Slide Number 38
- Slide Number 39
- Pathophysiology of DIC
- Pathogenesis of DIC in Sepsis
- Host Response in Severe Sepsis
- Organ Failure in Severe Sepsis
- Mechanism of DIC in Organ Failure
- Interaction of Inflammation and Coagulation in Sepsis
- Slide Number 47
- Diverse and Opposing Effects of Thrombin
- Coagulation and Fibrinolysis in DIC
- Mechanism of DIC
- Pathophysiology of DIC
- Pathophysiology of DIC - Mechanism
- Pathophysiology of DIC ndash 2 Types of Clinical pictures
- Sub-Acute and Non-Overt DIC Clinical Findings
- Pathophysiology of Overt DIC
- Physiopathology of DIC ndash Overt DIC Findings
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- BREAK
- Diagnostic and Management Approach for DIC
- Diagnosis of DIC
- Lab Diagnosis of DIC ndash Markers of Factor Consumption
- Lab Diagnosis of DIC ndash Screening Tests
- Slide Number 67
- Slide Number 68
- British Journal of Haematology Overt DIC Score
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- DIC Management Goals
- DIC Management and Treatment
- DIC Management Strategies
- Anticoagulant Factor Concentrate Treatment
- Anticoagulant Factor Concentrate Treatment Trials
- Markers of Thrombin amp Plasmin Generation in DIC
- D-dimer FDPs and DIC
- D-Dimer and FDPs in DIC
- Follow Up of DIC State of Disease
- FMD-Dimer in DIC Major Differences
- of Abnormal Results in Patients with Confirmed and Suspected DIC
- Slide Number 85
- Slide Number 86
- Comparing an Automated FM vs Manual FSP Test
- Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Slide Number 94
- Slide Number 95
- Slide Number 96
- Slide Number 97
- Slide Number 98
- Slide Number 99
- DIC Case Studies
- Case Study 1 - Presentation
- Case Study 1 ndash Lab Results
- Case Study 1 ndash Microscopy
- Case Study 1 ndash Diagnosis and Therapy
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- DIC Take Home Messages
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Pathogenesis of DIC in Sepsis
Allen KS Sawheny E Kinasewitzet GT Anticoagulant modulation of inflammation in severe sepsis World J Crit Care Med 2015 4 105-15
Bacteria in sepsis infections cause release of TF from immune cells leading to coagulation activation and proinflammatory cytokines cause endothelial cell activation impairing the anticoagulation and fibrinolysis process resulting in DIC
Host Response in Severe Sepsis
Exaggerated inflammation as a result of the host response to sepsis is collateral tissue damage and cell death further resulting in release of danger molecules continuing the inflammatory process in a downward spiral
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Organ Failure in Severe Sepsis
Sepsis associated with microvascular thrombosis as a result of TF mediated coagulation activation results in release of neutrophil extracellular traps (NETs) tissue hypoperfusion and mitochondrial damage resulting in a downward spiral leading to organ failure
Angus DC van der Poll T Severe Sepsis and Septic Shock N Engl J Med 2013 369 840-51
Mechanism of DIC in Organ Failure
Underlying condition(sepsis trauma)
Cytokines
TF-mediatedactivation of coagulation
Depression of inhibitory systems
Reducesfibrinolysis
Fibrin deposition
Organ failure
Inadequate fibrin removal
Fibrinformation
Note impaired fibrinolysis in relation to the clinical need not in absolute value (FDPs are )
Levi M de Jonge E van der Poll T ten Cate H Disseminated intravascular coagulation ThrombHaemost 1999 82 695-705
Interaction of Inflammation and Coagulation in Sepsis
Binding of TF thrombin and other activation coagulation factors to PARs and fibrin to TLRs on inflammatory cells results in inflammation through release of proinflammatory cytokines and chemokines
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Mechanism of Multiple Organ Failure in DIC
Wheeler AP Bernard GR Treating Patients with Severe Sepsis N Engl J Med 1999 340207-14
Inflammatory activation and microvascular thrombosis contributes to multiple organ failure in DIC
lipopolysaccharides
cytokines
coagulation activation
mononuclear cell
tissue factor
Diverse and Opposing Effects of Thrombin
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Coagulation and Fibrinolysis in DIC
Soluble fibrin Polymer
XIIIa
D-Dimer
E
Fibrin clot
Fibrin Degradation Products
Fibrinogen Thrombin
Fibrinogen Degradation
Products
D E
Plasmin
DFM + fibrinopeptides
Soluble FM ComplexesPre-throm
boticPost-throm
botic
Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis Semin Thromb Hemost 2008 34 33-8
Mechanism of DIC
THROMBOSIS
Fibrin
Blood activationEndothelial lysisTF expression
BLEEDING
FDPs
D-Dimer
Plasmin
Pathophysiology of DIC
1st step abnormal activation of coagulation Injury of vessel wall cells venous stasis release of large quantities of
thromboplastin influx of activated cells (monocytes macrophages)
Results in an intravascular deposition of fibrin
Morbidity from disseminated microthrombosis in small and midsize vessels leading to multiple organ failure
Second step Consumption and depletion of coagulation factors inhibitors (Protein C
Protein S AT) and platelets Local fibrinolytic response
bull Local plasmin generation dissolves the thrombusbull Disseminated overwhelming fibrinolytic response leading to production of
FDP and D-Dimer
Bleeding
Pathophysiology of DIC - Mechanism
Systemic activation of coagulation
Intravasculardepositionof fibrin
Thrombosis of small and midsize vessels
and organ failure
Depletion of platelets and
coagulation factors
Bleeding
Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92
Pathophysiology of DIC ndash 2 Types of Clinical pictures
Chronic = non - overt DICMay be unrecognized clinically
Acute = overt DIClife threatening bleedingor multiple organ failure
Sub-Acute and Non-Overt DIC Clinical Findings
Compensated non-overt DIC Steady low level or intermittent activation
bull Compensated by increased production of coagulation components and platelets
Few or no clinical signs or multiple microvascular thrombosis sometimes not clinically obvious
Risk of decompensation leading to overt DIC
Pathophysiology of Overt DIC
Massive activation of coagulation and fibrinolysis
Does not allow for compensatory efforts
Rapid depletion of coagulation factors inhibitors and platelets
Thrombosis multiple organ failures
Bleeding complications and shock
Physiopathology of DIC ndash Overt DIC Findings
Thrombin generation
Thrombosis
Renal liver respiratory failures coma skin necrosis gangrene venous thromboembolism hypotension edema
Cytokine and kinin generation (shock)bull Tachycardia hypotension edema
Plasmin generationHemorrhage
bull Spontaneous bruising petechiae intracranial gastrointestinal and respiratory tract bleeding persistent bleeding at venipuncture sites at surgical wounds
bull Tachycardia hypotension edema
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Pathogenesis Pathways in DIC
Cytokines
TF-mediated dysfunctional impairedthrombin anticoagulant fibrinolysisgeneration mechanism due to PAI-1 deficiency
fibrin inadequateformation fibrin removal
Fibrin deposition
Inflammation
Coagulation
Stago Celebrates Lab Week 2017
NA
Stago 247 Educational Webinar Sites
wwwstago-edvantagecomUS based KOLsPACE accredited ndash all 1 hourAccessible from mobile devicesVirtual exhibit hall
wwwstagowebinarscomMostly European KOLs30 ndash 45 min including 15 min discussion
Stago Educational Apps
HaemoscoreClinical scoring algorithmsApple and AndroidTablet or phone
iHemostasisCoagulation diagramsCase studiesApple amp AndroidTablet only
BREAK
Diagnostic and Management Approach for DIC
Diagnosis of DIC
Clinical diagnosis is obvious in cases of overt DIC
Laboratory tests are necessary To makeconfirm the diagnosis To assess stage of the patient To assess the treatment efficacy
Lab Diagnosis of DIC ndash Markers of Factor Consumption
Routinescreening assays PT APTT Platelets Fibrinogen Thrombin time
Other coagulation assays Factor assays AntithrombinGeneration of Thrombin FMFSPsGeneration of Plasmin D-dimer FDPs
Important to recognize simultaneous formation of thrombin and plasmin
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122
Lab Diagnosis of DIC ndash Screening Tests
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122
Platelet count usually decreasedPT abnormal in 70 of cases (short half-life of FVII)APTT abnormal in 50 of casesThrombin time usually prolonged in overt DIC normal in non-overt DIC and no relation with syndrome severityFibrinogen low in lt 50 of cases sensitivity 22 specificity 87 overall predictive value 64 Normal fibrinogen level should not exclude DIC diagnosis (acute phase reactant initial high
fibrinogen level) repeat testing assesses progression
Screening tests not clinically specific or sensitive for DIC
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Laboratory Changes in Overt DIC
DIC Diagnostic Practices Over Time
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
British Journal of Haematology Overt DIC Score
Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
ISTH Step by Step DIC Algorithm
Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6
US Based Validation of ISTH DIC Score
When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Differential Diagnosis in DIC
aHUS atypical hemolytic uremic syndrome
HUS hemolytic uremic syndrome
HIT heparin-induced thrombocytopenia
ITP immune thrombocytopenic purpura
TTP thrombotic thrombocytopenic purpura
DIC and MAHA
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)
When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation
DIC Management Goals
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction
DIC Management and Treatment
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)
requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)
Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia
DIC Management Strategies
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant Factor Concentrate Treatment
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis
Anticoagulant Factor Concentrate Treatment Trials
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise
Markers of Thrombin amp Plasmin Generation in DIC
D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC
Cut-off value
Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen
degradation products Sensitive assay typically with cutoff adapted for DIC
D-dimer FDPs and DIC
D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC
Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80
Follow Up of DIC State of Disease
Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8
Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility
FMD-Dimer in DIC Major Differences
onset of thrombosis
days
Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8
FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)
D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)
of Abnormal Results in Patients with Confirmed and Suspected DIC
0
20
40
60
80
100
94 85 90N = 62
Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32
Positivity of Test Results ISTH Score and Disease State
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
Red bar positive for 2 points of DIC score
Pink bar positive for 1-2 points of DIC score
HT hematopoietic tumor
IF infection
SC solid cancer
Markers in Patients with or without DIC
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
HT hematopoietic tumorIF infectionSC solid cancer
Comparing an Automated FM vs Manual FSP Test
Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71
Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)
Automated (Mitsubishi) vs Automated (Stago)
In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago
Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC
Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
Non Overt DIC Overt DIC
AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC
Trends in Markers of DIC for Different Patients
Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00
Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients
Trends in Markers of DIC for Different Patients
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes
28 day outcome survival
28 day outcome death
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines
DIC Case Studies
Case Study 1 - Presentation
18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE
WBC count 77 KμL 423 ndash 907 x KμL
RBC count 17 MμL 137 ndash 175 x MμL
Hemoglobin 67 gdL 137 ndash 175 gdL
Hematocrit 195 401 ndash 510
MCV 95 fL 790 ndash 922 fL
MPV 12 fL 94 ndash 124 fL
Platelet count 9 KμL 161 ndash 347 KμL
Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0
Lymphocytes monocytes eosinophils basophils all below normal range
PT 47 sec (corrected on mixing study) 116 ndash 152 sec
APTT 75 sec (corrected on mixing study) 253 ndash 373 sec
Fibrinogen lt 76 mgdL 177 ndash 466 mgdL
D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Microscopy
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Arrow shows giant platelets in this peripheral smear Promyelocytes apparent
Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)
DIC due to TF release by APL blasts
Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases
Transfusions to replace factors along with platelets and RBCs during APL treatment
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started
Case Study 2 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L
PT 30 sec 113 ndash 146 sec
APTT 75 sec 25 ndash 34 sec
D-dimer 078 microgml FEU lt050 microgml FEU
Fibrinogen 92 mgdl 150-400 mgdl
pH 728 738 to 742
PaO2 570 mmHg 80-100 mmHg
WBC 33 times 103mm3 40-11 times 103mm3
ALT 111 IUL 0ndash34 IUL
AST 61 IUL 0ndash34 IUL
BUN 303 mgdL 08-13 mgdL
Case Study 2 ndash Lab Results
Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures
Case Study 2 ndash Diagnosis
60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior
Case Study 3 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L
PT 228 sec 113 ndash 146 sec
APTT 45 sec 25 ndash 34 sec
D-dimer 080 microgml FEU lt050 microgmL FEU
Fibrinogen 82 mgdL 150-400 mgdL
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 134 gdL 14-16 gdL
WBC 81 times 103mm3 40-11 times 103mm3
ALT 32 IUL 0ndash34 IUL
AST 28 IUL 0ndash34 IUL
BUN 09 mgdL 08-13 mgdL
Case Study 3 ndash Lab Results
Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment
Case Study 3 ndash Diagnosis and Therapy
Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91
Case Study 4 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L
PT 28 sec 113 ndash 146 sec
APTT 71 sec 25 ndash 34 sec
D-dimer 31 microgmL FEU lt050 microgml FEU
Fibrinogen 92 mgdL 150-400 mgdl
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 158 gdL 14-16 gdL
WBC 71 times 103mm3 40-11 times 103mm3
ALT 60 IUL 0ndash34 IUL
AST 47 IUL 0ndash34 IUL
BUN 38 mgdL 08-13 mgdL
Case Study 4 ndash Lab Results
Lyme disease with DICProvide antibiotics with supportive measures
Case Study 4 ndash Diagnosis
55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis
Case Study 5 ndash Presentation
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
Case Study 5 ndash Lab Results and Time Course
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
TEST RESULT REFERENCE RANGE
Platelet count 33 x 109L 150-450 x 109L
PT 215 sec 103 ndash 128 sec
APTT 44 sec 26 ndash 36 sec
D-dimer 20 microgmL FEU lt025 microgml FEU
Fibrinogen 34 mgdL 200-375 mgdl
FII FV FVIII Low Not reported (NR)
FVII FIX FX vWF Normal NR
Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)
DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic
dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR
(C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen
(D) Illustration demonstrating repair
Case Study 5 ndash Diagnosis and Treatment
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography
Case Study 6 ndash Presentation
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
Case Study 6 ndash Lab Results
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L
PT 63 sec gt control 113 ndash 146 sec
INR 658 1 ndash 125
APTT 80 sec gt control 25 ndash 34 sec
D-dimer gt200 microgmL DDU 02 microgmL DDU
Urine exam Proteinuria and hematuria 150-400 mgdl
Albumin 28 gdL NR
Hb 58 gdL NR
LDH 1196 UL NR
SGPT 144 IU NR
SGOT 88 IU NR
Bilirubin 32 mgdL NR
DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th
day postop
Case Study 6 ndash Diagnosis and Treatment
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure
Case Study 6 ndash Discussion
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Case Study 7 ndash Lab Results vs Time
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
DIC Take Home Messages
Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation
Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers
DIC
Thank you Questions
- Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
- Learning Objectives
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Wound Sealing
- The Three Steps of Hemostasis
- Vessel Wall
- Slide Number 12
- Slide Number 13
- Platelet Structure UnactivatedActivated
- Primary Hemostasis
- Primary Hemostasis Assays
- Slide Number 17
- Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
- Slide Number 19
- Coagulation factors
- Coagulation Assay Mechanisms
- Slide Number 22
- Fibrin Formation
- Slide Number 24
- Fibrinolysis Overview
- Fibrinolysis Overview
- Slide Number 27
- Fibrinolysis Releases D-dimers
- Basic Pathophysiology of DIC
- Disseminated Intravascular Coagulation (DIC)
- Purpura Fulminans with DIC Due to Meningococcal Sepsis
- Clinical Conditions Associated With DIC
- Frequency of DIC in Selected Disease States
- Underlying Diseases in DIC Patients
- Slide Number 36
- Slide Number 37
- Slide Number 38
- Slide Number 39
- Pathophysiology of DIC
- Pathogenesis of DIC in Sepsis
- Host Response in Severe Sepsis
- Organ Failure in Severe Sepsis
- Mechanism of DIC in Organ Failure
- Interaction of Inflammation and Coagulation in Sepsis
- Slide Number 47
- Diverse and Opposing Effects of Thrombin
- Coagulation and Fibrinolysis in DIC
- Mechanism of DIC
- Pathophysiology of DIC
- Pathophysiology of DIC - Mechanism
- Pathophysiology of DIC ndash 2 Types of Clinical pictures
- Sub-Acute and Non-Overt DIC Clinical Findings
- Pathophysiology of Overt DIC
- Physiopathology of DIC ndash Overt DIC Findings
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- BREAK
- Diagnostic and Management Approach for DIC
- Diagnosis of DIC
- Lab Diagnosis of DIC ndash Markers of Factor Consumption
- Lab Diagnosis of DIC ndash Screening Tests
- Slide Number 67
- Slide Number 68
- British Journal of Haematology Overt DIC Score
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- DIC Management Goals
- DIC Management and Treatment
- DIC Management Strategies
- Anticoagulant Factor Concentrate Treatment
- Anticoagulant Factor Concentrate Treatment Trials
- Markers of Thrombin amp Plasmin Generation in DIC
- D-dimer FDPs and DIC
- D-Dimer and FDPs in DIC
- Follow Up of DIC State of Disease
- FMD-Dimer in DIC Major Differences
- of Abnormal Results in Patients with Confirmed and Suspected DIC
- Slide Number 85
- Slide Number 86
- Comparing an Automated FM vs Manual FSP Test
- Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Slide Number 94
- Slide Number 95
- Slide Number 96
- Slide Number 97
- Slide Number 98
- Slide Number 99
- DIC Case Studies
- Case Study 1 - Presentation
- Case Study 1 ndash Lab Results
- Case Study 1 ndash Microscopy
- Case Study 1 ndash Diagnosis and Therapy
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Slide Number 110
- Slide Number 111
- Slide Number 112
- Slide Number 113
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
- Slide Number 124
- Slide Number 125
- DIC Take Home Messages
- Slide Number 127
- Slide Number 128
-
Host Response in Severe Sepsis
Exaggerated inflammation as a result of the host response to sepsis is collateral tissue damage and cell death further resulting in release of danger molecules continuing the inflammatory process in a downward spiral
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Organ Failure in Severe Sepsis
Sepsis associated with microvascular thrombosis as a result of TF mediated coagulation activation results in release of neutrophil extracellular traps (NETs) tissue hypoperfusion and mitochondrial damage resulting in a downward spiral leading to organ failure
Angus DC van der Poll T Severe Sepsis and Septic Shock N Engl J Med 2013 369 840-51
Mechanism of DIC in Organ Failure
Underlying condition(sepsis trauma)
Cytokines
TF-mediatedactivation of coagulation
Depression of inhibitory systems
Reducesfibrinolysis
Fibrin deposition
Organ failure
Inadequate fibrin removal
Fibrinformation
Note impaired fibrinolysis in relation to the clinical need not in absolute value (FDPs are )
Levi M de Jonge E van der Poll T ten Cate H Disseminated intravascular coagulation ThrombHaemost 1999 82 695-705
Interaction of Inflammation and Coagulation in Sepsis
Binding of TF thrombin and other activation coagulation factors to PARs and fibrin to TLRs on inflammatory cells results in inflammation through release of proinflammatory cytokines and chemokines
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Mechanism of Multiple Organ Failure in DIC
Wheeler AP Bernard GR Treating Patients with Severe Sepsis N Engl J Med 1999 340207-14
Inflammatory activation and microvascular thrombosis contributes to multiple organ failure in DIC
lipopolysaccharides
cytokines
coagulation activation
mononuclear cell
tissue factor
Diverse and Opposing Effects of Thrombin
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Coagulation and Fibrinolysis in DIC
Soluble fibrin Polymer
XIIIa
D-Dimer
E
Fibrin clot
Fibrin Degradation Products
Fibrinogen Thrombin
Fibrinogen Degradation
Products
D E
Plasmin
DFM + fibrinopeptides
Soluble FM ComplexesPre-throm
boticPost-throm
botic
Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis Semin Thromb Hemost 2008 34 33-8
Mechanism of DIC
THROMBOSIS
Fibrin
Blood activationEndothelial lysisTF expression
BLEEDING
FDPs
D-Dimer
Plasmin
Pathophysiology of DIC
1st step abnormal activation of coagulation Injury of vessel wall cells venous stasis release of large quantities of
thromboplastin influx of activated cells (monocytes macrophages)
Results in an intravascular deposition of fibrin
Morbidity from disseminated microthrombosis in small and midsize vessels leading to multiple organ failure
Second step Consumption and depletion of coagulation factors inhibitors (Protein C
Protein S AT) and platelets Local fibrinolytic response
bull Local plasmin generation dissolves the thrombusbull Disseminated overwhelming fibrinolytic response leading to production of
FDP and D-Dimer
Bleeding
Pathophysiology of DIC - Mechanism
Systemic activation of coagulation
Intravasculardepositionof fibrin
Thrombosis of small and midsize vessels
and organ failure
Depletion of platelets and
coagulation factors
Bleeding
Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92
Pathophysiology of DIC ndash 2 Types of Clinical pictures
Chronic = non - overt DICMay be unrecognized clinically
Acute = overt DIClife threatening bleedingor multiple organ failure
Sub-Acute and Non-Overt DIC Clinical Findings
Compensated non-overt DIC Steady low level or intermittent activation
bull Compensated by increased production of coagulation components and platelets
Few or no clinical signs or multiple microvascular thrombosis sometimes not clinically obvious
Risk of decompensation leading to overt DIC
Pathophysiology of Overt DIC
Massive activation of coagulation and fibrinolysis
Does not allow for compensatory efforts
Rapid depletion of coagulation factors inhibitors and platelets
Thrombosis multiple organ failures
Bleeding complications and shock
Physiopathology of DIC ndash Overt DIC Findings
Thrombin generation
Thrombosis
Renal liver respiratory failures coma skin necrosis gangrene venous thromboembolism hypotension edema
Cytokine and kinin generation (shock)bull Tachycardia hypotension edema
Plasmin generationHemorrhage
bull Spontaneous bruising petechiae intracranial gastrointestinal and respiratory tract bleeding persistent bleeding at venipuncture sites at surgical wounds
bull Tachycardia hypotension edema
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Pathogenesis Pathways in DIC
Cytokines
TF-mediated dysfunctional impairedthrombin anticoagulant fibrinolysisgeneration mechanism due to PAI-1 deficiency
fibrin inadequateformation fibrin removal
Fibrin deposition
Inflammation
Coagulation
Stago Celebrates Lab Week 2017
NA
Stago 247 Educational Webinar Sites
wwwstago-edvantagecomUS based KOLsPACE accredited ndash all 1 hourAccessible from mobile devicesVirtual exhibit hall
wwwstagowebinarscomMostly European KOLs30 ndash 45 min including 15 min discussion
Stago Educational Apps
HaemoscoreClinical scoring algorithmsApple and AndroidTablet or phone
iHemostasisCoagulation diagramsCase studiesApple amp AndroidTablet only
BREAK
Diagnostic and Management Approach for DIC
Diagnosis of DIC
Clinical diagnosis is obvious in cases of overt DIC
Laboratory tests are necessary To makeconfirm the diagnosis To assess stage of the patient To assess the treatment efficacy
Lab Diagnosis of DIC ndash Markers of Factor Consumption
Routinescreening assays PT APTT Platelets Fibrinogen Thrombin time
Other coagulation assays Factor assays AntithrombinGeneration of Thrombin FMFSPsGeneration of Plasmin D-dimer FDPs
Important to recognize simultaneous formation of thrombin and plasmin
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122
Lab Diagnosis of DIC ndash Screening Tests
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122
Platelet count usually decreasedPT abnormal in 70 of cases (short half-life of FVII)APTT abnormal in 50 of casesThrombin time usually prolonged in overt DIC normal in non-overt DIC and no relation with syndrome severityFibrinogen low in lt 50 of cases sensitivity 22 specificity 87 overall predictive value 64 Normal fibrinogen level should not exclude DIC diagnosis (acute phase reactant initial high
fibrinogen level) repeat testing assesses progression
Screening tests not clinically specific or sensitive for DIC
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Laboratory Changes in Overt DIC
DIC Diagnostic Practices Over Time
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
British Journal of Haematology Overt DIC Score
Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
ISTH Step by Step DIC Algorithm
Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6
US Based Validation of ISTH DIC Score
When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Differential Diagnosis in DIC
aHUS atypical hemolytic uremic syndrome
HUS hemolytic uremic syndrome
HIT heparin-induced thrombocytopenia
ITP immune thrombocytopenic purpura
TTP thrombotic thrombocytopenic purpura
DIC and MAHA
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)
When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation
DIC Management Goals
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction
DIC Management and Treatment
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)
requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)
Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia
DIC Management Strategies
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant Factor Concentrate Treatment
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis
Anticoagulant Factor Concentrate Treatment Trials
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise
Markers of Thrombin amp Plasmin Generation in DIC
D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC
Cut-off value
Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen
degradation products Sensitive assay typically with cutoff adapted for DIC
D-dimer FDPs and DIC
D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC
Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80
Follow Up of DIC State of Disease
Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8
Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility
FMD-Dimer in DIC Major Differences
onset of thrombosis
days
Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8
FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)
D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)
of Abnormal Results in Patients with Confirmed and Suspected DIC
0
20
40
60
80
100
94 85 90N = 62
Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32
Positivity of Test Results ISTH Score and Disease State
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
Red bar positive for 2 points of DIC score
Pink bar positive for 1-2 points of DIC score
HT hematopoietic tumor
IF infection
SC solid cancer
Markers in Patients with or without DIC
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
HT hematopoietic tumorIF infectionSC solid cancer
Comparing an Automated FM vs Manual FSP Test
Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71
Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)
Automated (Mitsubishi) vs Automated (Stago)
In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago
Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC
Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
Non Overt DIC Overt DIC
AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC
Trends in Markers of DIC for Different Patients
Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00
Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients
Trends in Markers of DIC for Different Patients
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes
28 day outcome survival
28 day outcome death
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines
DIC Case Studies
Case Study 1 - Presentation
18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE
WBC count 77 KμL 423 ndash 907 x KμL
RBC count 17 MμL 137 ndash 175 x MμL
Hemoglobin 67 gdL 137 ndash 175 gdL
Hematocrit 195 401 ndash 510
MCV 95 fL 790 ndash 922 fL
MPV 12 fL 94 ndash 124 fL
Platelet count 9 KμL 161 ndash 347 KμL
Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0
Lymphocytes monocytes eosinophils basophils all below normal range
PT 47 sec (corrected on mixing study) 116 ndash 152 sec
APTT 75 sec (corrected on mixing study) 253 ndash 373 sec
Fibrinogen lt 76 mgdL 177 ndash 466 mgdL
D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Microscopy
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Arrow shows giant platelets in this peripheral smear Promyelocytes apparent
Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)
DIC due to TF release by APL blasts
Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases
Transfusions to replace factors along with platelets and RBCs during APL treatment
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started
Case Study 2 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L
PT 30 sec 113 ndash 146 sec
APTT 75 sec 25 ndash 34 sec
D-dimer 078 microgml FEU lt050 microgml FEU
Fibrinogen 92 mgdl 150-400 mgdl
pH 728 738 to 742
PaO2 570 mmHg 80-100 mmHg
WBC 33 times 103mm3 40-11 times 103mm3
ALT 111 IUL 0ndash34 IUL
AST 61 IUL 0ndash34 IUL
BUN 303 mgdL 08-13 mgdL
Case Study 2 ndash Lab Results
Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures
Case Study 2 ndash Diagnosis
60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior
Case Study 3 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L
PT 228 sec 113 ndash 146 sec
APTT 45 sec 25 ndash 34 sec
D-dimer 080 microgml FEU lt050 microgmL FEU
Fibrinogen 82 mgdL 150-400 mgdL
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 134 gdL 14-16 gdL
WBC 81 times 103mm3 40-11 times 103mm3
ALT 32 IUL 0ndash34 IUL
AST 28 IUL 0ndash34 IUL
BUN 09 mgdL 08-13 mgdL
Case Study 3 ndash Lab Results
Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment
Case Study 3 ndash Diagnosis and Therapy
Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91
Case Study 4 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L
PT 28 sec 113 ndash 146 sec
APTT 71 sec 25 ndash 34 sec
D-dimer 31 microgmL FEU lt050 microgml FEU
Fibrinogen 92 mgdL 150-400 mgdl
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 158 gdL 14-16 gdL
WBC 71 times 103mm3 40-11 times 103mm3
ALT 60 IUL 0ndash34 IUL
AST 47 IUL 0ndash34 IUL
BUN 38 mgdL 08-13 mgdL
Case Study 4 ndash Lab Results
Lyme disease with DICProvide antibiotics with supportive measures
Case Study 4 ndash Diagnosis
55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis
Case Study 5 ndash Presentation
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
Case Study 5 ndash Lab Results and Time Course
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
TEST RESULT REFERENCE RANGE
Platelet count 33 x 109L 150-450 x 109L
PT 215 sec 103 ndash 128 sec
APTT 44 sec 26 ndash 36 sec
D-dimer 20 microgmL FEU lt025 microgml FEU
Fibrinogen 34 mgdL 200-375 mgdl
FII FV FVIII Low Not reported (NR)
FVII FIX FX vWF Normal NR
Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)
DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic
dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR
(C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen
(D) Illustration demonstrating repair
Case Study 5 ndash Diagnosis and Treatment
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography
Case Study 6 ndash Presentation
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
Case Study 6 ndash Lab Results
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L
PT 63 sec gt control 113 ndash 146 sec
INR 658 1 ndash 125
APTT 80 sec gt control 25 ndash 34 sec
D-dimer gt200 microgmL DDU 02 microgmL DDU
Urine exam Proteinuria and hematuria 150-400 mgdl
Albumin 28 gdL NR
Hb 58 gdL NR
LDH 1196 UL NR
SGPT 144 IU NR
SGOT 88 IU NR
Bilirubin 32 mgdL NR
DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th
day postop
Case Study 6 ndash Diagnosis and Treatment
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure
Case Study 6 ndash Discussion
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Case Study 7 ndash Lab Results vs Time
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
DIC Take Home Messages
Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation
Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers
DIC
Thank you Questions
- Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
- Learning Objectives
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Wound Sealing
- The Three Steps of Hemostasis
- Vessel Wall
- Slide Number 12
- Slide Number 13
- Platelet Structure UnactivatedActivated
- Primary Hemostasis
- Primary Hemostasis Assays
- Slide Number 17
- Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
- Slide Number 19
- Coagulation factors
- Coagulation Assay Mechanisms
- Slide Number 22
- Fibrin Formation
- Slide Number 24
- Fibrinolysis Overview
- Fibrinolysis Overview
- Slide Number 27
- Fibrinolysis Releases D-dimers
- Basic Pathophysiology of DIC
- Disseminated Intravascular Coagulation (DIC)
- Purpura Fulminans with DIC Due to Meningococcal Sepsis
- Clinical Conditions Associated With DIC
- Frequency of DIC in Selected Disease States
- Underlying Diseases in DIC Patients
- Slide Number 36
- Slide Number 37
- Slide Number 38
- Slide Number 39
- Pathophysiology of DIC
- Pathogenesis of DIC in Sepsis
- Host Response in Severe Sepsis
- Organ Failure in Severe Sepsis
- Mechanism of DIC in Organ Failure
- Interaction of Inflammation and Coagulation in Sepsis
- Slide Number 47
- Diverse and Opposing Effects of Thrombin
- Coagulation and Fibrinolysis in DIC
- Mechanism of DIC
- Pathophysiology of DIC
- Pathophysiology of DIC - Mechanism
- Pathophysiology of DIC ndash 2 Types of Clinical pictures
- Sub-Acute and Non-Overt DIC Clinical Findings
- Pathophysiology of Overt DIC
- Physiopathology of DIC ndash Overt DIC Findings
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- BREAK
- Diagnostic and Management Approach for DIC
- Diagnosis of DIC
- Lab Diagnosis of DIC ndash Markers of Factor Consumption
- Lab Diagnosis of DIC ndash Screening Tests
- Slide Number 67
- Slide Number 68
- British Journal of Haematology Overt DIC Score
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- DIC Management Goals
- DIC Management and Treatment
- DIC Management Strategies
- Anticoagulant Factor Concentrate Treatment
- Anticoagulant Factor Concentrate Treatment Trials
- Markers of Thrombin amp Plasmin Generation in DIC
- D-dimer FDPs and DIC
- D-Dimer and FDPs in DIC
- Follow Up of DIC State of Disease
- FMD-Dimer in DIC Major Differences
- of Abnormal Results in Patients with Confirmed and Suspected DIC
- Slide Number 85
- Slide Number 86
- Comparing an Automated FM vs Manual FSP Test
- Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Slide Number 94
- Slide Number 95
- Slide Number 96
- Slide Number 97
- Slide Number 98
- Slide Number 99
- DIC Case Studies
- Case Study 1 - Presentation
- Case Study 1 ndash Lab Results
- Case Study 1 ndash Microscopy
- Case Study 1 ndash Diagnosis and Therapy
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Slide Number 110
- Slide Number 111
- Slide Number 112
- Slide Number 113
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
- Slide Number 124
- Slide Number 125
- DIC Take Home Messages
- Slide Number 127
- Slide Number 128
-
Organ Failure in Severe Sepsis
Sepsis associated with microvascular thrombosis as a result of TF mediated coagulation activation results in release of neutrophil extracellular traps (NETs) tissue hypoperfusion and mitochondrial damage resulting in a downward spiral leading to organ failure
Angus DC van der Poll T Severe Sepsis and Septic Shock N Engl J Med 2013 369 840-51
Mechanism of DIC in Organ Failure
Underlying condition(sepsis trauma)
Cytokines
TF-mediatedactivation of coagulation
Depression of inhibitory systems
Reducesfibrinolysis
Fibrin deposition
Organ failure
Inadequate fibrin removal
Fibrinformation
Note impaired fibrinolysis in relation to the clinical need not in absolute value (FDPs are )
Levi M de Jonge E van der Poll T ten Cate H Disseminated intravascular coagulation ThrombHaemost 1999 82 695-705
Interaction of Inflammation and Coagulation in Sepsis
Binding of TF thrombin and other activation coagulation factors to PARs and fibrin to TLRs on inflammatory cells results in inflammation through release of proinflammatory cytokines and chemokines
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Mechanism of Multiple Organ Failure in DIC
Wheeler AP Bernard GR Treating Patients with Severe Sepsis N Engl J Med 1999 340207-14
Inflammatory activation and microvascular thrombosis contributes to multiple organ failure in DIC
lipopolysaccharides
cytokines
coagulation activation
mononuclear cell
tissue factor
Diverse and Opposing Effects of Thrombin
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Coagulation and Fibrinolysis in DIC
Soluble fibrin Polymer
XIIIa
D-Dimer
E
Fibrin clot
Fibrin Degradation Products
Fibrinogen Thrombin
Fibrinogen Degradation
Products
D E
Plasmin
DFM + fibrinopeptides
Soluble FM ComplexesPre-throm
boticPost-throm
botic
Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis Semin Thromb Hemost 2008 34 33-8
Mechanism of DIC
THROMBOSIS
Fibrin
Blood activationEndothelial lysisTF expression
BLEEDING
FDPs
D-Dimer
Plasmin
Pathophysiology of DIC
1st step abnormal activation of coagulation Injury of vessel wall cells venous stasis release of large quantities of
thromboplastin influx of activated cells (monocytes macrophages)
Results in an intravascular deposition of fibrin
Morbidity from disseminated microthrombosis in small and midsize vessels leading to multiple organ failure
Second step Consumption and depletion of coagulation factors inhibitors (Protein C
Protein S AT) and platelets Local fibrinolytic response
bull Local plasmin generation dissolves the thrombusbull Disseminated overwhelming fibrinolytic response leading to production of
FDP and D-Dimer
Bleeding
Pathophysiology of DIC - Mechanism
Systemic activation of coagulation
Intravasculardepositionof fibrin
Thrombosis of small and midsize vessels
and organ failure
Depletion of platelets and
coagulation factors
Bleeding
Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92
Pathophysiology of DIC ndash 2 Types of Clinical pictures
Chronic = non - overt DICMay be unrecognized clinically
Acute = overt DIClife threatening bleedingor multiple organ failure
Sub-Acute and Non-Overt DIC Clinical Findings
Compensated non-overt DIC Steady low level or intermittent activation
bull Compensated by increased production of coagulation components and platelets
Few or no clinical signs or multiple microvascular thrombosis sometimes not clinically obvious
Risk of decompensation leading to overt DIC
Pathophysiology of Overt DIC
Massive activation of coagulation and fibrinolysis
Does not allow for compensatory efforts
Rapid depletion of coagulation factors inhibitors and platelets
Thrombosis multiple organ failures
Bleeding complications and shock
Physiopathology of DIC ndash Overt DIC Findings
Thrombin generation
Thrombosis
Renal liver respiratory failures coma skin necrosis gangrene venous thromboembolism hypotension edema
Cytokine and kinin generation (shock)bull Tachycardia hypotension edema
Plasmin generationHemorrhage
bull Spontaneous bruising petechiae intracranial gastrointestinal and respiratory tract bleeding persistent bleeding at venipuncture sites at surgical wounds
bull Tachycardia hypotension edema
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Pathogenesis Pathways in DIC
Cytokines
TF-mediated dysfunctional impairedthrombin anticoagulant fibrinolysisgeneration mechanism due to PAI-1 deficiency
fibrin inadequateformation fibrin removal
Fibrin deposition
Inflammation
Coagulation
Stago Celebrates Lab Week 2017
NA
Stago 247 Educational Webinar Sites
wwwstago-edvantagecomUS based KOLsPACE accredited ndash all 1 hourAccessible from mobile devicesVirtual exhibit hall
wwwstagowebinarscomMostly European KOLs30 ndash 45 min including 15 min discussion
Stago Educational Apps
HaemoscoreClinical scoring algorithmsApple and AndroidTablet or phone
iHemostasisCoagulation diagramsCase studiesApple amp AndroidTablet only
BREAK
Diagnostic and Management Approach for DIC
Diagnosis of DIC
Clinical diagnosis is obvious in cases of overt DIC
Laboratory tests are necessary To makeconfirm the diagnosis To assess stage of the patient To assess the treatment efficacy
Lab Diagnosis of DIC ndash Markers of Factor Consumption
Routinescreening assays PT APTT Platelets Fibrinogen Thrombin time
Other coagulation assays Factor assays AntithrombinGeneration of Thrombin FMFSPsGeneration of Plasmin D-dimer FDPs
Important to recognize simultaneous formation of thrombin and plasmin
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122
Lab Diagnosis of DIC ndash Screening Tests
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122
Platelet count usually decreasedPT abnormal in 70 of cases (short half-life of FVII)APTT abnormal in 50 of casesThrombin time usually prolonged in overt DIC normal in non-overt DIC and no relation with syndrome severityFibrinogen low in lt 50 of cases sensitivity 22 specificity 87 overall predictive value 64 Normal fibrinogen level should not exclude DIC diagnosis (acute phase reactant initial high
fibrinogen level) repeat testing assesses progression
Screening tests not clinically specific or sensitive for DIC
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Laboratory Changes in Overt DIC
DIC Diagnostic Practices Over Time
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
British Journal of Haematology Overt DIC Score
Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
ISTH Step by Step DIC Algorithm
Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6
US Based Validation of ISTH DIC Score
When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Differential Diagnosis in DIC
aHUS atypical hemolytic uremic syndrome
HUS hemolytic uremic syndrome
HIT heparin-induced thrombocytopenia
ITP immune thrombocytopenic purpura
TTP thrombotic thrombocytopenic purpura
DIC and MAHA
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)
When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation
DIC Management Goals
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction
DIC Management and Treatment
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)
requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)
Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia
DIC Management Strategies
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant Factor Concentrate Treatment
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis
Anticoagulant Factor Concentrate Treatment Trials
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise
Markers of Thrombin amp Plasmin Generation in DIC
D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC
Cut-off value
Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen
degradation products Sensitive assay typically with cutoff adapted for DIC
D-dimer FDPs and DIC
D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC
Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80
Follow Up of DIC State of Disease
Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8
Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility
FMD-Dimer in DIC Major Differences
onset of thrombosis
days
Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8
FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)
D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)
of Abnormal Results in Patients with Confirmed and Suspected DIC
0
20
40
60
80
100
94 85 90N = 62
Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32
Positivity of Test Results ISTH Score and Disease State
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
Red bar positive for 2 points of DIC score
Pink bar positive for 1-2 points of DIC score
HT hematopoietic tumor
IF infection
SC solid cancer
Markers in Patients with or without DIC
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
HT hematopoietic tumorIF infectionSC solid cancer
Comparing an Automated FM vs Manual FSP Test
Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71
Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)
Automated (Mitsubishi) vs Automated (Stago)
In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago
Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC
Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
Non Overt DIC Overt DIC
AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC
Trends in Markers of DIC for Different Patients
Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00
Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients
Trends in Markers of DIC for Different Patients
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes
28 day outcome survival
28 day outcome death
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines
DIC Case Studies
Case Study 1 - Presentation
18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE
WBC count 77 KμL 423 ndash 907 x KμL
RBC count 17 MμL 137 ndash 175 x MμL
Hemoglobin 67 gdL 137 ndash 175 gdL
Hematocrit 195 401 ndash 510
MCV 95 fL 790 ndash 922 fL
MPV 12 fL 94 ndash 124 fL
Platelet count 9 KμL 161 ndash 347 KμL
Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0
Lymphocytes monocytes eosinophils basophils all below normal range
PT 47 sec (corrected on mixing study) 116 ndash 152 sec
APTT 75 sec (corrected on mixing study) 253 ndash 373 sec
Fibrinogen lt 76 mgdL 177 ndash 466 mgdL
D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Microscopy
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Arrow shows giant platelets in this peripheral smear Promyelocytes apparent
Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)
DIC due to TF release by APL blasts
Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases
Transfusions to replace factors along with platelets and RBCs during APL treatment
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started
Case Study 2 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L
PT 30 sec 113 ndash 146 sec
APTT 75 sec 25 ndash 34 sec
D-dimer 078 microgml FEU lt050 microgml FEU
Fibrinogen 92 mgdl 150-400 mgdl
pH 728 738 to 742
PaO2 570 mmHg 80-100 mmHg
WBC 33 times 103mm3 40-11 times 103mm3
ALT 111 IUL 0ndash34 IUL
AST 61 IUL 0ndash34 IUL
BUN 303 mgdL 08-13 mgdL
Case Study 2 ndash Lab Results
Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures
Case Study 2 ndash Diagnosis
60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior
Case Study 3 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L
PT 228 sec 113 ndash 146 sec
APTT 45 sec 25 ndash 34 sec
D-dimer 080 microgml FEU lt050 microgmL FEU
Fibrinogen 82 mgdL 150-400 mgdL
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 134 gdL 14-16 gdL
WBC 81 times 103mm3 40-11 times 103mm3
ALT 32 IUL 0ndash34 IUL
AST 28 IUL 0ndash34 IUL
BUN 09 mgdL 08-13 mgdL
Case Study 3 ndash Lab Results
Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment
Case Study 3 ndash Diagnosis and Therapy
Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91
Case Study 4 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L
PT 28 sec 113 ndash 146 sec
APTT 71 sec 25 ndash 34 sec
D-dimer 31 microgmL FEU lt050 microgml FEU
Fibrinogen 92 mgdL 150-400 mgdl
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 158 gdL 14-16 gdL
WBC 71 times 103mm3 40-11 times 103mm3
ALT 60 IUL 0ndash34 IUL
AST 47 IUL 0ndash34 IUL
BUN 38 mgdL 08-13 mgdL
Case Study 4 ndash Lab Results
Lyme disease with DICProvide antibiotics with supportive measures
Case Study 4 ndash Diagnosis
55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis
Case Study 5 ndash Presentation
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
Case Study 5 ndash Lab Results and Time Course
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
TEST RESULT REFERENCE RANGE
Platelet count 33 x 109L 150-450 x 109L
PT 215 sec 103 ndash 128 sec
APTT 44 sec 26 ndash 36 sec
D-dimer 20 microgmL FEU lt025 microgml FEU
Fibrinogen 34 mgdL 200-375 mgdl
FII FV FVIII Low Not reported (NR)
FVII FIX FX vWF Normal NR
Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)
DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic
dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR
(C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen
(D) Illustration demonstrating repair
Case Study 5 ndash Diagnosis and Treatment
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography
Case Study 6 ndash Presentation
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
Case Study 6 ndash Lab Results
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L
PT 63 sec gt control 113 ndash 146 sec
INR 658 1 ndash 125
APTT 80 sec gt control 25 ndash 34 sec
D-dimer gt200 microgmL DDU 02 microgmL DDU
Urine exam Proteinuria and hematuria 150-400 mgdl
Albumin 28 gdL NR
Hb 58 gdL NR
LDH 1196 UL NR
SGPT 144 IU NR
SGOT 88 IU NR
Bilirubin 32 mgdL NR
DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th
day postop
Case Study 6 ndash Diagnosis and Treatment
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure
Case Study 6 ndash Discussion
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Case Study 7 ndash Lab Results vs Time
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
DIC Take Home Messages
Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation
Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers
DIC
Thank you Questions
- Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
- Learning Objectives
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Wound Sealing
- The Three Steps of Hemostasis
- Vessel Wall
- Slide Number 12
- Slide Number 13
- Platelet Structure UnactivatedActivated
- Primary Hemostasis
- Primary Hemostasis Assays
- Slide Number 17
- Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
- Slide Number 19
- Coagulation factors
- Coagulation Assay Mechanisms
- Slide Number 22
- Fibrin Formation
- Slide Number 24
- Fibrinolysis Overview
- Fibrinolysis Overview
- Slide Number 27
- Fibrinolysis Releases D-dimers
- Basic Pathophysiology of DIC
- Disseminated Intravascular Coagulation (DIC)
- Purpura Fulminans with DIC Due to Meningococcal Sepsis
- Clinical Conditions Associated With DIC
- Frequency of DIC in Selected Disease States
- Underlying Diseases in DIC Patients
- Slide Number 36
- Slide Number 37
- Slide Number 38
- Slide Number 39
- Pathophysiology of DIC
- Pathogenesis of DIC in Sepsis
- Host Response in Severe Sepsis
- Organ Failure in Severe Sepsis
- Mechanism of DIC in Organ Failure
- Interaction of Inflammation and Coagulation in Sepsis
- Slide Number 47
- Diverse and Opposing Effects of Thrombin
- Coagulation and Fibrinolysis in DIC
- Mechanism of DIC
- Pathophysiology of DIC
- Pathophysiology of DIC - Mechanism
- Pathophysiology of DIC ndash 2 Types of Clinical pictures
- Sub-Acute and Non-Overt DIC Clinical Findings
- Pathophysiology of Overt DIC
- Physiopathology of DIC ndash Overt DIC Findings
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- BREAK
- Diagnostic and Management Approach for DIC
- Diagnosis of DIC
- Lab Diagnosis of DIC ndash Markers of Factor Consumption
- Lab Diagnosis of DIC ndash Screening Tests
- Slide Number 67
- Slide Number 68
- British Journal of Haematology Overt DIC Score
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- DIC Management Goals
- DIC Management and Treatment
- DIC Management Strategies
- Anticoagulant Factor Concentrate Treatment
- Anticoagulant Factor Concentrate Treatment Trials
- Markers of Thrombin amp Plasmin Generation in DIC
- D-dimer FDPs and DIC
- D-Dimer and FDPs in DIC
- Follow Up of DIC State of Disease
- FMD-Dimer in DIC Major Differences
- of Abnormal Results in Patients with Confirmed and Suspected DIC
- Slide Number 85
- Slide Number 86
- Comparing an Automated FM vs Manual FSP Test
- Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Slide Number 94
- Slide Number 95
- Slide Number 96
- Slide Number 97
- Slide Number 98
- Slide Number 99
- DIC Case Studies
- Case Study 1 - Presentation
- Case Study 1 ndash Lab Results
- Case Study 1 ndash Microscopy
- Case Study 1 ndash Diagnosis and Therapy
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Slide Number 110
- Slide Number 111
- Slide Number 112
- Slide Number 113
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
- Slide Number 124
- Slide Number 125
- DIC Take Home Messages
- Slide Number 127
- Slide Number 128
-
Mechanism of DIC in Organ Failure
Underlying condition(sepsis trauma)
Cytokines
TF-mediatedactivation of coagulation
Depression of inhibitory systems
Reducesfibrinolysis
Fibrin deposition
Organ failure
Inadequate fibrin removal
Fibrinformation
Note impaired fibrinolysis in relation to the clinical need not in absolute value (FDPs are )
Levi M de Jonge E van der Poll T ten Cate H Disseminated intravascular coagulation ThrombHaemost 1999 82 695-705
Interaction of Inflammation and Coagulation in Sepsis
Binding of TF thrombin and other activation coagulation factors to PARs and fibrin to TLRs on inflammatory cells results in inflammation through release of proinflammatory cytokines and chemokines
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Mechanism of Multiple Organ Failure in DIC
Wheeler AP Bernard GR Treating Patients with Severe Sepsis N Engl J Med 1999 340207-14
Inflammatory activation and microvascular thrombosis contributes to multiple organ failure in DIC
lipopolysaccharides
cytokines
coagulation activation
mononuclear cell
tissue factor
Diverse and Opposing Effects of Thrombin
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Coagulation and Fibrinolysis in DIC
Soluble fibrin Polymer
XIIIa
D-Dimer
E
Fibrin clot
Fibrin Degradation Products
Fibrinogen Thrombin
Fibrinogen Degradation
Products
D E
Plasmin
DFM + fibrinopeptides
Soluble FM ComplexesPre-throm
boticPost-throm
botic
Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis Semin Thromb Hemost 2008 34 33-8
Mechanism of DIC
THROMBOSIS
Fibrin
Blood activationEndothelial lysisTF expression
BLEEDING
FDPs
D-Dimer
Plasmin
Pathophysiology of DIC
1st step abnormal activation of coagulation Injury of vessel wall cells venous stasis release of large quantities of
thromboplastin influx of activated cells (monocytes macrophages)
Results in an intravascular deposition of fibrin
Morbidity from disseminated microthrombosis in small and midsize vessels leading to multiple organ failure
Second step Consumption and depletion of coagulation factors inhibitors (Protein C
Protein S AT) and platelets Local fibrinolytic response
bull Local plasmin generation dissolves the thrombusbull Disseminated overwhelming fibrinolytic response leading to production of
FDP and D-Dimer
Bleeding
Pathophysiology of DIC - Mechanism
Systemic activation of coagulation
Intravasculardepositionof fibrin
Thrombosis of small and midsize vessels
and organ failure
Depletion of platelets and
coagulation factors
Bleeding
Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92
Pathophysiology of DIC ndash 2 Types of Clinical pictures
Chronic = non - overt DICMay be unrecognized clinically
Acute = overt DIClife threatening bleedingor multiple organ failure
Sub-Acute and Non-Overt DIC Clinical Findings
Compensated non-overt DIC Steady low level or intermittent activation
bull Compensated by increased production of coagulation components and platelets
Few or no clinical signs or multiple microvascular thrombosis sometimes not clinically obvious
Risk of decompensation leading to overt DIC
Pathophysiology of Overt DIC
Massive activation of coagulation and fibrinolysis
Does not allow for compensatory efforts
Rapid depletion of coagulation factors inhibitors and platelets
Thrombosis multiple organ failures
Bleeding complications and shock
Physiopathology of DIC ndash Overt DIC Findings
Thrombin generation
Thrombosis
Renal liver respiratory failures coma skin necrosis gangrene venous thromboembolism hypotension edema
Cytokine and kinin generation (shock)bull Tachycardia hypotension edema
Plasmin generationHemorrhage
bull Spontaneous bruising petechiae intracranial gastrointestinal and respiratory tract bleeding persistent bleeding at venipuncture sites at surgical wounds
bull Tachycardia hypotension edema
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Pathogenesis Pathways in DIC
Cytokines
TF-mediated dysfunctional impairedthrombin anticoagulant fibrinolysisgeneration mechanism due to PAI-1 deficiency
fibrin inadequateformation fibrin removal
Fibrin deposition
Inflammation
Coagulation
Stago Celebrates Lab Week 2017
NA
Stago 247 Educational Webinar Sites
wwwstago-edvantagecomUS based KOLsPACE accredited ndash all 1 hourAccessible from mobile devicesVirtual exhibit hall
wwwstagowebinarscomMostly European KOLs30 ndash 45 min including 15 min discussion
Stago Educational Apps
HaemoscoreClinical scoring algorithmsApple and AndroidTablet or phone
iHemostasisCoagulation diagramsCase studiesApple amp AndroidTablet only
BREAK
Diagnostic and Management Approach for DIC
Diagnosis of DIC
Clinical diagnosis is obvious in cases of overt DIC
Laboratory tests are necessary To makeconfirm the diagnosis To assess stage of the patient To assess the treatment efficacy
Lab Diagnosis of DIC ndash Markers of Factor Consumption
Routinescreening assays PT APTT Platelets Fibrinogen Thrombin time
Other coagulation assays Factor assays AntithrombinGeneration of Thrombin FMFSPsGeneration of Plasmin D-dimer FDPs
Important to recognize simultaneous formation of thrombin and plasmin
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122
Lab Diagnosis of DIC ndash Screening Tests
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122
Platelet count usually decreasedPT abnormal in 70 of cases (short half-life of FVII)APTT abnormal in 50 of casesThrombin time usually prolonged in overt DIC normal in non-overt DIC and no relation with syndrome severityFibrinogen low in lt 50 of cases sensitivity 22 specificity 87 overall predictive value 64 Normal fibrinogen level should not exclude DIC diagnosis (acute phase reactant initial high
fibrinogen level) repeat testing assesses progression
Screening tests not clinically specific or sensitive for DIC
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Laboratory Changes in Overt DIC
DIC Diagnostic Practices Over Time
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
British Journal of Haematology Overt DIC Score
Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
ISTH Step by Step DIC Algorithm
Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6
US Based Validation of ISTH DIC Score
When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Differential Diagnosis in DIC
aHUS atypical hemolytic uremic syndrome
HUS hemolytic uremic syndrome
HIT heparin-induced thrombocytopenia
ITP immune thrombocytopenic purpura
TTP thrombotic thrombocytopenic purpura
DIC and MAHA
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)
When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation
DIC Management Goals
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction
DIC Management and Treatment
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)
requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)
Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia
DIC Management Strategies
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant Factor Concentrate Treatment
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis
Anticoagulant Factor Concentrate Treatment Trials
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise
Markers of Thrombin amp Plasmin Generation in DIC
D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC
Cut-off value
Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen
degradation products Sensitive assay typically with cutoff adapted for DIC
D-dimer FDPs and DIC
D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC
Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80
Follow Up of DIC State of Disease
Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8
Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility
FMD-Dimer in DIC Major Differences
onset of thrombosis
days
Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8
FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)
D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)
of Abnormal Results in Patients with Confirmed and Suspected DIC
0
20
40
60
80
100
94 85 90N = 62
Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32
Positivity of Test Results ISTH Score and Disease State
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
Red bar positive for 2 points of DIC score
Pink bar positive for 1-2 points of DIC score
HT hematopoietic tumor
IF infection
SC solid cancer
Markers in Patients with or without DIC
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
HT hematopoietic tumorIF infectionSC solid cancer
Comparing an Automated FM vs Manual FSP Test
Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71
Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)
Automated (Mitsubishi) vs Automated (Stago)
In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago
Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC
Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
Non Overt DIC Overt DIC
AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC
Trends in Markers of DIC for Different Patients
Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00
Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients
Trends in Markers of DIC for Different Patients
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes
28 day outcome survival
28 day outcome death
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines
DIC Case Studies
Case Study 1 - Presentation
18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE
WBC count 77 KμL 423 ndash 907 x KμL
RBC count 17 MμL 137 ndash 175 x MμL
Hemoglobin 67 gdL 137 ndash 175 gdL
Hematocrit 195 401 ndash 510
MCV 95 fL 790 ndash 922 fL
MPV 12 fL 94 ndash 124 fL
Platelet count 9 KμL 161 ndash 347 KμL
Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0
Lymphocytes monocytes eosinophils basophils all below normal range
PT 47 sec (corrected on mixing study) 116 ndash 152 sec
APTT 75 sec (corrected on mixing study) 253 ndash 373 sec
Fibrinogen lt 76 mgdL 177 ndash 466 mgdL
D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Microscopy
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Arrow shows giant platelets in this peripheral smear Promyelocytes apparent
Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)
DIC due to TF release by APL blasts
Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases
Transfusions to replace factors along with platelets and RBCs during APL treatment
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started
Case Study 2 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L
PT 30 sec 113 ndash 146 sec
APTT 75 sec 25 ndash 34 sec
D-dimer 078 microgml FEU lt050 microgml FEU
Fibrinogen 92 mgdl 150-400 mgdl
pH 728 738 to 742
PaO2 570 mmHg 80-100 mmHg
WBC 33 times 103mm3 40-11 times 103mm3
ALT 111 IUL 0ndash34 IUL
AST 61 IUL 0ndash34 IUL
BUN 303 mgdL 08-13 mgdL
Case Study 2 ndash Lab Results
Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures
Case Study 2 ndash Diagnosis
60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior
Case Study 3 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L
PT 228 sec 113 ndash 146 sec
APTT 45 sec 25 ndash 34 sec
D-dimer 080 microgml FEU lt050 microgmL FEU
Fibrinogen 82 mgdL 150-400 mgdL
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 134 gdL 14-16 gdL
WBC 81 times 103mm3 40-11 times 103mm3
ALT 32 IUL 0ndash34 IUL
AST 28 IUL 0ndash34 IUL
BUN 09 mgdL 08-13 mgdL
Case Study 3 ndash Lab Results
Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment
Case Study 3 ndash Diagnosis and Therapy
Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91
Case Study 4 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L
PT 28 sec 113 ndash 146 sec
APTT 71 sec 25 ndash 34 sec
D-dimer 31 microgmL FEU lt050 microgml FEU
Fibrinogen 92 mgdL 150-400 mgdl
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 158 gdL 14-16 gdL
WBC 71 times 103mm3 40-11 times 103mm3
ALT 60 IUL 0ndash34 IUL
AST 47 IUL 0ndash34 IUL
BUN 38 mgdL 08-13 mgdL
Case Study 4 ndash Lab Results
Lyme disease with DICProvide antibiotics with supportive measures
Case Study 4 ndash Diagnosis
55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis
Case Study 5 ndash Presentation
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
Case Study 5 ndash Lab Results and Time Course
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
TEST RESULT REFERENCE RANGE
Platelet count 33 x 109L 150-450 x 109L
PT 215 sec 103 ndash 128 sec
APTT 44 sec 26 ndash 36 sec
D-dimer 20 microgmL FEU lt025 microgml FEU
Fibrinogen 34 mgdL 200-375 mgdl
FII FV FVIII Low Not reported (NR)
FVII FIX FX vWF Normal NR
Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)
DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic
dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR
(C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen
(D) Illustration demonstrating repair
Case Study 5 ndash Diagnosis and Treatment
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography
Case Study 6 ndash Presentation
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
Case Study 6 ndash Lab Results
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L
PT 63 sec gt control 113 ndash 146 sec
INR 658 1 ndash 125
APTT 80 sec gt control 25 ndash 34 sec
D-dimer gt200 microgmL DDU 02 microgmL DDU
Urine exam Proteinuria and hematuria 150-400 mgdl
Albumin 28 gdL NR
Hb 58 gdL NR
LDH 1196 UL NR
SGPT 144 IU NR
SGOT 88 IU NR
Bilirubin 32 mgdL NR
DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th
day postop
Case Study 6 ndash Diagnosis and Treatment
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure
Case Study 6 ndash Discussion
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Case Study 7 ndash Lab Results vs Time
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
DIC Take Home Messages
Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation
Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers
DIC
Thank you Questions
- Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
- Learning Objectives
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Wound Sealing
- The Three Steps of Hemostasis
- Vessel Wall
- Slide Number 12
- Slide Number 13
- Platelet Structure UnactivatedActivated
- Primary Hemostasis
- Primary Hemostasis Assays
- Slide Number 17
- Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
- Slide Number 19
- Coagulation factors
- Coagulation Assay Mechanisms
- Slide Number 22
- Fibrin Formation
- Slide Number 24
- Fibrinolysis Overview
- Fibrinolysis Overview
- Slide Number 27
- Fibrinolysis Releases D-dimers
- Basic Pathophysiology of DIC
- Disseminated Intravascular Coagulation (DIC)
- Purpura Fulminans with DIC Due to Meningococcal Sepsis
- Clinical Conditions Associated With DIC
- Frequency of DIC in Selected Disease States
- Underlying Diseases in DIC Patients
- Slide Number 36
- Slide Number 37
- Slide Number 38
- Slide Number 39
- Pathophysiology of DIC
- Pathogenesis of DIC in Sepsis
- Host Response in Severe Sepsis
- Organ Failure in Severe Sepsis
- Mechanism of DIC in Organ Failure
- Interaction of Inflammation and Coagulation in Sepsis
- Slide Number 47
- Diverse and Opposing Effects of Thrombin
- Coagulation and Fibrinolysis in DIC
- Mechanism of DIC
- Pathophysiology of DIC
- Pathophysiology of DIC - Mechanism
- Pathophysiology of DIC ndash 2 Types of Clinical pictures
- Sub-Acute and Non-Overt DIC Clinical Findings
- Pathophysiology of Overt DIC
- Physiopathology of DIC ndash Overt DIC Findings
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- BREAK
- Diagnostic and Management Approach for DIC
- Diagnosis of DIC
- Lab Diagnosis of DIC ndash Markers of Factor Consumption
- Lab Diagnosis of DIC ndash Screening Tests
- Slide Number 67
- Slide Number 68
- British Journal of Haematology Overt DIC Score
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- DIC Management Goals
- DIC Management and Treatment
- DIC Management Strategies
- Anticoagulant Factor Concentrate Treatment
- Anticoagulant Factor Concentrate Treatment Trials
- Markers of Thrombin amp Plasmin Generation in DIC
- D-dimer FDPs and DIC
- D-Dimer and FDPs in DIC
- Follow Up of DIC State of Disease
- FMD-Dimer in DIC Major Differences
- of Abnormal Results in Patients with Confirmed and Suspected DIC
- Slide Number 85
- Slide Number 86
- Comparing an Automated FM vs Manual FSP Test
- Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Slide Number 94
- Slide Number 95
- Slide Number 96
- Slide Number 97
- Slide Number 98
- Slide Number 99
- DIC Case Studies
- Case Study 1 - Presentation
- Case Study 1 ndash Lab Results
- Case Study 1 ndash Microscopy
- Case Study 1 ndash Diagnosis and Therapy
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Slide Number 110
- Slide Number 111
- Slide Number 112
- Slide Number 113
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
- Slide Number 124
- Slide Number 125
- DIC Take Home Messages
- Slide Number 127
- Slide Number 128
-
Interaction of Inflammation and Coagulation in Sepsis
Binding of TF thrombin and other activation coagulation factors to PARs and fibrin to TLRs on inflammatory cells results in inflammation through release of proinflammatory cytokines and chemokines
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Mechanism of Multiple Organ Failure in DIC
Wheeler AP Bernard GR Treating Patients with Severe Sepsis N Engl J Med 1999 340207-14
Inflammatory activation and microvascular thrombosis contributes to multiple organ failure in DIC
lipopolysaccharides
cytokines
coagulation activation
mononuclear cell
tissue factor
Diverse and Opposing Effects of Thrombin
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Coagulation and Fibrinolysis in DIC
Soluble fibrin Polymer
XIIIa
D-Dimer
E
Fibrin clot
Fibrin Degradation Products
Fibrinogen Thrombin
Fibrinogen Degradation
Products
D E
Plasmin
DFM + fibrinopeptides
Soluble FM ComplexesPre-throm
boticPost-throm
botic
Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis Semin Thromb Hemost 2008 34 33-8
Mechanism of DIC
THROMBOSIS
Fibrin
Blood activationEndothelial lysisTF expression
BLEEDING
FDPs
D-Dimer
Plasmin
Pathophysiology of DIC
1st step abnormal activation of coagulation Injury of vessel wall cells venous stasis release of large quantities of
thromboplastin influx of activated cells (monocytes macrophages)
Results in an intravascular deposition of fibrin
Morbidity from disseminated microthrombosis in small and midsize vessels leading to multiple organ failure
Second step Consumption and depletion of coagulation factors inhibitors (Protein C
Protein S AT) and platelets Local fibrinolytic response
bull Local plasmin generation dissolves the thrombusbull Disseminated overwhelming fibrinolytic response leading to production of
FDP and D-Dimer
Bleeding
Pathophysiology of DIC - Mechanism
Systemic activation of coagulation
Intravasculardepositionof fibrin
Thrombosis of small and midsize vessels
and organ failure
Depletion of platelets and
coagulation factors
Bleeding
Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92
Pathophysiology of DIC ndash 2 Types of Clinical pictures
Chronic = non - overt DICMay be unrecognized clinically
Acute = overt DIClife threatening bleedingor multiple organ failure
Sub-Acute and Non-Overt DIC Clinical Findings
Compensated non-overt DIC Steady low level or intermittent activation
bull Compensated by increased production of coagulation components and platelets
Few or no clinical signs or multiple microvascular thrombosis sometimes not clinically obvious
Risk of decompensation leading to overt DIC
Pathophysiology of Overt DIC
Massive activation of coagulation and fibrinolysis
Does not allow for compensatory efforts
Rapid depletion of coagulation factors inhibitors and platelets
Thrombosis multiple organ failures
Bleeding complications and shock
Physiopathology of DIC ndash Overt DIC Findings
Thrombin generation
Thrombosis
Renal liver respiratory failures coma skin necrosis gangrene venous thromboembolism hypotension edema
Cytokine and kinin generation (shock)bull Tachycardia hypotension edema
Plasmin generationHemorrhage
bull Spontaneous bruising petechiae intracranial gastrointestinal and respiratory tract bleeding persistent bleeding at venipuncture sites at surgical wounds
bull Tachycardia hypotension edema
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Pathogenesis Pathways in DIC
Cytokines
TF-mediated dysfunctional impairedthrombin anticoagulant fibrinolysisgeneration mechanism due to PAI-1 deficiency
fibrin inadequateformation fibrin removal
Fibrin deposition
Inflammation
Coagulation
Stago Celebrates Lab Week 2017
NA
Stago 247 Educational Webinar Sites
wwwstago-edvantagecomUS based KOLsPACE accredited ndash all 1 hourAccessible from mobile devicesVirtual exhibit hall
wwwstagowebinarscomMostly European KOLs30 ndash 45 min including 15 min discussion
Stago Educational Apps
HaemoscoreClinical scoring algorithmsApple and AndroidTablet or phone
iHemostasisCoagulation diagramsCase studiesApple amp AndroidTablet only
BREAK
Diagnostic and Management Approach for DIC
Diagnosis of DIC
Clinical diagnosis is obvious in cases of overt DIC
Laboratory tests are necessary To makeconfirm the diagnosis To assess stage of the patient To assess the treatment efficacy
Lab Diagnosis of DIC ndash Markers of Factor Consumption
Routinescreening assays PT APTT Platelets Fibrinogen Thrombin time
Other coagulation assays Factor assays AntithrombinGeneration of Thrombin FMFSPsGeneration of Plasmin D-dimer FDPs
Important to recognize simultaneous formation of thrombin and plasmin
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122
Lab Diagnosis of DIC ndash Screening Tests
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122
Platelet count usually decreasedPT abnormal in 70 of cases (short half-life of FVII)APTT abnormal in 50 of casesThrombin time usually prolonged in overt DIC normal in non-overt DIC and no relation with syndrome severityFibrinogen low in lt 50 of cases sensitivity 22 specificity 87 overall predictive value 64 Normal fibrinogen level should not exclude DIC diagnosis (acute phase reactant initial high
fibrinogen level) repeat testing assesses progression
Screening tests not clinically specific or sensitive for DIC
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Laboratory Changes in Overt DIC
DIC Diagnostic Practices Over Time
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
British Journal of Haematology Overt DIC Score
Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
ISTH Step by Step DIC Algorithm
Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6
US Based Validation of ISTH DIC Score
When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Differential Diagnosis in DIC
aHUS atypical hemolytic uremic syndrome
HUS hemolytic uremic syndrome
HIT heparin-induced thrombocytopenia
ITP immune thrombocytopenic purpura
TTP thrombotic thrombocytopenic purpura
DIC and MAHA
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)
When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation
DIC Management Goals
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction
DIC Management and Treatment
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)
requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)
Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia
DIC Management Strategies
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant Factor Concentrate Treatment
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis
Anticoagulant Factor Concentrate Treatment Trials
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise
Markers of Thrombin amp Plasmin Generation in DIC
D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC
Cut-off value
Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen
degradation products Sensitive assay typically with cutoff adapted for DIC
D-dimer FDPs and DIC
D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC
Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80
Follow Up of DIC State of Disease
Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8
Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility
FMD-Dimer in DIC Major Differences
onset of thrombosis
days
Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8
FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)
D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)
of Abnormal Results in Patients with Confirmed and Suspected DIC
0
20
40
60
80
100
94 85 90N = 62
Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32
Positivity of Test Results ISTH Score and Disease State
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
Red bar positive for 2 points of DIC score
Pink bar positive for 1-2 points of DIC score
HT hematopoietic tumor
IF infection
SC solid cancer
Markers in Patients with or without DIC
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
HT hematopoietic tumorIF infectionSC solid cancer
Comparing an Automated FM vs Manual FSP Test
Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71
Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)
Automated (Mitsubishi) vs Automated (Stago)
In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago
Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC
Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
Non Overt DIC Overt DIC
AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC
Trends in Markers of DIC for Different Patients
Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00
Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients
Trends in Markers of DIC for Different Patients
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes
28 day outcome survival
28 day outcome death
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines
DIC Case Studies
Case Study 1 - Presentation
18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE
WBC count 77 KμL 423 ndash 907 x KμL
RBC count 17 MμL 137 ndash 175 x MμL
Hemoglobin 67 gdL 137 ndash 175 gdL
Hematocrit 195 401 ndash 510
MCV 95 fL 790 ndash 922 fL
MPV 12 fL 94 ndash 124 fL
Platelet count 9 KμL 161 ndash 347 KμL
Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0
Lymphocytes monocytes eosinophils basophils all below normal range
PT 47 sec (corrected on mixing study) 116 ndash 152 sec
APTT 75 sec (corrected on mixing study) 253 ndash 373 sec
Fibrinogen lt 76 mgdL 177 ndash 466 mgdL
D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Microscopy
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Arrow shows giant platelets in this peripheral smear Promyelocytes apparent
Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)
DIC due to TF release by APL blasts
Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases
Transfusions to replace factors along with platelets and RBCs during APL treatment
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started
Case Study 2 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L
PT 30 sec 113 ndash 146 sec
APTT 75 sec 25 ndash 34 sec
D-dimer 078 microgml FEU lt050 microgml FEU
Fibrinogen 92 mgdl 150-400 mgdl
pH 728 738 to 742
PaO2 570 mmHg 80-100 mmHg
WBC 33 times 103mm3 40-11 times 103mm3
ALT 111 IUL 0ndash34 IUL
AST 61 IUL 0ndash34 IUL
BUN 303 mgdL 08-13 mgdL
Case Study 2 ndash Lab Results
Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures
Case Study 2 ndash Diagnosis
60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior
Case Study 3 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L
PT 228 sec 113 ndash 146 sec
APTT 45 sec 25 ndash 34 sec
D-dimer 080 microgml FEU lt050 microgmL FEU
Fibrinogen 82 mgdL 150-400 mgdL
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 134 gdL 14-16 gdL
WBC 81 times 103mm3 40-11 times 103mm3
ALT 32 IUL 0ndash34 IUL
AST 28 IUL 0ndash34 IUL
BUN 09 mgdL 08-13 mgdL
Case Study 3 ndash Lab Results
Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment
Case Study 3 ndash Diagnosis and Therapy
Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91
Case Study 4 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L
PT 28 sec 113 ndash 146 sec
APTT 71 sec 25 ndash 34 sec
D-dimer 31 microgmL FEU lt050 microgml FEU
Fibrinogen 92 mgdL 150-400 mgdl
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 158 gdL 14-16 gdL
WBC 71 times 103mm3 40-11 times 103mm3
ALT 60 IUL 0ndash34 IUL
AST 47 IUL 0ndash34 IUL
BUN 38 mgdL 08-13 mgdL
Case Study 4 ndash Lab Results
Lyme disease with DICProvide antibiotics with supportive measures
Case Study 4 ndash Diagnosis
55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis
Case Study 5 ndash Presentation
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
Case Study 5 ndash Lab Results and Time Course
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
TEST RESULT REFERENCE RANGE
Platelet count 33 x 109L 150-450 x 109L
PT 215 sec 103 ndash 128 sec
APTT 44 sec 26 ndash 36 sec
D-dimer 20 microgmL FEU lt025 microgml FEU
Fibrinogen 34 mgdL 200-375 mgdl
FII FV FVIII Low Not reported (NR)
FVII FIX FX vWF Normal NR
Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)
DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic
dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR
(C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen
(D) Illustration demonstrating repair
Case Study 5 ndash Diagnosis and Treatment
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography
Case Study 6 ndash Presentation
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
Case Study 6 ndash Lab Results
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L
PT 63 sec gt control 113 ndash 146 sec
INR 658 1 ndash 125
APTT 80 sec gt control 25 ndash 34 sec
D-dimer gt200 microgmL DDU 02 microgmL DDU
Urine exam Proteinuria and hematuria 150-400 mgdl
Albumin 28 gdL NR
Hb 58 gdL NR
LDH 1196 UL NR
SGPT 144 IU NR
SGOT 88 IU NR
Bilirubin 32 mgdL NR
DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th
day postop
Case Study 6 ndash Diagnosis and Treatment
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure
Case Study 6 ndash Discussion
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Case Study 7 ndash Lab Results vs Time
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
DIC Take Home Messages
Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation
Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers
DIC
Thank you Questions
- Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
- Learning Objectives
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Wound Sealing
- The Three Steps of Hemostasis
- Vessel Wall
- Slide Number 12
- Slide Number 13
- Platelet Structure UnactivatedActivated
- Primary Hemostasis
- Primary Hemostasis Assays
- Slide Number 17
- Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
- Slide Number 19
- Coagulation factors
- Coagulation Assay Mechanisms
- Slide Number 22
- Fibrin Formation
- Slide Number 24
- Fibrinolysis Overview
- Fibrinolysis Overview
- Slide Number 27
- Fibrinolysis Releases D-dimers
- Basic Pathophysiology of DIC
- Disseminated Intravascular Coagulation (DIC)
- Purpura Fulminans with DIC Due to Meningococcal Sepsis
- Clinical Conditions Associated With DIC
- Frequency of DIC in Selected Disease States
- Underlying Diseases in DIC Patients
- Slide Number 36
- Slide Number 37
- Slide Number 38
- Slide Number 39
- Pathophysiology of DIC
- Pathogenesis of DIC in Sepsis
- Host Response in Severe Sepsis
- Organ Failure in Severe Sepsis
- Mechanism of DIC in Organ Failure
- Interaction of Inflammation and Coagulation in Sepsis
- Slide Number 47
- Diverse and Opposing Effects of Thrombin
- Coagulation and Fibrinolysis in DIC
- Mechanism of DIC
- Pathophysiology of DIC
- Pathophysiology of DIC - Mechanism
- Pathophysiology of DIC ndash 2 Types of Clinical pictures
- Sub-Acute and Non-Overt DIC Clinical Findings
- Pathophysiology of Overt DIC
- Physiopathology of DIC ndash Overt DIC Findings
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- BREAK
- Diagnostic and Management Approach for DIC
- Diagnosis of DIC
- Lab Diagnosis of DIC ndash Markers of Factor Consumption
- Lab Diagnosis of DIC ndash Screening Tests
- Slide Number 67
- Slide Number 68
- British Journal of Haematology Overt DIC Score
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- DIC Management Goals
- DIC Management and Treatment
- DIC Management Strategies
- Anticoagulant Factor Concentrate Treatment
- Anticoagulant Factor Concentrate Treatment Trials
- Markers of Thrombin amp Plasmin Generation in DIC
- D-dimer FDPs and DIC
- D-Dimer and FDPs in DIC
- Follow Up of DIC State of Disease
- FMD-Dimer in DIC Major Differences
- of Abnormal Results in Patients with Confirmed and Suspected DIC
- Slide Number 85
- Slide Number 86
- Comparing an Automated FM vs Manual FSP Test
- Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Slide Number 94
- Slide Number 95
- Slide Number 96
- Slide Number 97
- Slide Number 98
- Slide Number 99
- DIC Case Studies
- Case Study 1 - Presentation
- Case Study 1 ndash Lab Results
- Case Study 1 ndash Microscopy
- Case Study 1 ndash Diagnosis and Therapy
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Slide Number 110
- Slide Number 111
- Slide Number 112
- Slide Number 113
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
- Slide Number 124
- Slide Number 125
- DIC Take Home Messages
- Slide Number 127
- Slide Number 128
-
Mechanism of Multiple Organ Failure in DIC
Wheeler AP Bernard GR Treating Patients with Severe Sepsis N Engl J Med 1999 340207-14
Inflammatory activation and microvascular thrombosis contributes to multiple organ failure in DIC
lipopolysaccharides
cytokines
coagulation activation
mononuclear cell
tissue factor
Diverse and Opposing Effects of Thrombin
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Coagulation and Fibrinolysis in DIC
Soluble fibrin Polymer
XIIIa
D-Dimer
E
Fibrin clot
Fibrin Degradation Products
Fibrinogen Thrombin
Fibrinogen Degradation
Products
D E
Plasmin
DFM + fibrinopeptides
Soluble FM ComplexesPre-throm
boticPost-throm
botic
Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis Semin Thromb Hemost 2008 34 33-8
Mechanism of DIC
THROMBOSIS
Fibrin
Blood activationEndothelial lysisTF expression
BLEEDING
FDPs
D-Dimer
Plasmin
Pathophysiology of DIC
1st step abnormal activation of coagulation Injury of vessel wall cells venous stasis release of large quantities of
thromboplastin influx of activated cells (monocytes macrophages)
Results in an intravascular deposition of fibrin
Morbidity from disseminated microthrombosis in small and midsize vessels leading to multiple organ failure
Second step Consumption and depletion of coagulation factors inhibitors (Protein C
Protein S AT) and platelets Local fibrinolytic response
bull Local plasmin generation dissolves the thrombusbull Disseminated overwhelming fibrinolytic response leading to production of
FDP and D-Dimer
Bleeding
Pathophysiology of DIC - Mechanism
Systemic activation of coagulation
Intravasculardepositionof fibrin
Thrombosis of small and midsize vessels
and organ failure
Depletion of platelets and
coagulation factors
Bleeding
Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92
Pathophysiology of DIC ndash 2 Types of Clinical pictures
Chronic = non - overt DICMay be unrecognized clinically
Acute = overt DIClife threatening bleedingor multiple organ failure
Sub-Acute and Non-Overt DIC Clinical Findings
Compensated non-overt DIC Steady low level or intermittent activation
bull Compensated by increased production of coagulation components and platelets
Few or no clinical signs or multiple microvascular thrombosis sometimes not clinically obvious
Risk of decompensation leading to overt DIC
Pathophysiology of Overt DIC
Massive activation of coagulation and fibrinolysis
Does not allow for compensatory efforts
Rapid depletion of coagulation factors inhibitors and platelets
Thrombosis multiple organ failures
Bleeding complications and shock
Physiopathology of DIC ndash Overt DIC Findings
Thrombin generation
Thrombosis
Renal liver respiratory failures coma skin necrosis gangrene venous thromboembolism hypotension edema
Cytokine and kinin generation (shock)bull Tachycardia hypotension edema
Plasmin generationHemorrhage
bull Spontaneous bruising petechiae intracranial gastrointestinal and respiratory tract bleeding persistent bleeding at venipuncture sites at surgical wounds
bull Tachycardia hypotension edema
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Pathogenesis Pathways in DIC
Cytokines
TF-mediated dysfunctional impairedthrombin anticoagulant fibrinolysisgeneration mechanism due to PAI-1 deficiency
fibrin inadequateformation fibrin removal
Fibrin deposition
Inflammation
Coagulation
Stago Celebrates Lab Week 2017
NA
Stago 247 Educational Webinar Sites
wwwstago-edvantagecomUS based KOLsPACE accredited ndash all 1 hourAccessible from mobile devicesVirtual exhibit hall
wwwstagowebinarscomMostly European KOLs30 ndash 45 min including 15 min discussion
Stago Educational Apps
HaemoscoreClinical scoring algorithmsApple and AndroidTablet or phone
iHemostasisCoagulation diagramsCase studiesApple amp AndroidTablet only
BREAK
Diagnostic and Management Approach for DIC
Diagnosis of DIC
Clinical diagnosis is obvious in cases of overt DIC
Laboratory tests are necessary To makeconfirm the diagnosis To assess stage of the patient To assess the treatment efficacy
Lab Diagnosis of DIC ndash Markers of Factor Consumption
Routinescreening assays PT APTT Platelets Fibrinogen Thrombin time
Other coagulation assays Factor assays AntithrombinGeneration of Thrombin FMFSPsGeneration of Plasmin D-dimer FDPs
Important to recognize simultaneous formation of thrombin and plasmin
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122
Lab Diagnosis of DIC ndash Screening Tests
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122
Platelet count usually decreasedPT abnormal in 70 of cases (short half-life of FVII)APTT abnormal in 50 of casesThrombin time usually prolonged in overt DIC normal in non-overt DIC and no relation with syndrome severityFibrinogen low in lt 50 of cases sensitivity 22 specificity 87 overall predictive value 64 Normal fibrinogen level should not exclude DIC diagnosis (acute phase reactant initial high
fibrinogen level) repeat testing assesses progression
Screening tests not clinically specific or sensitive for DIC
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Laboratory Changes in Overt DIC
DIC Diagnostic Practices Over Time
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
British Journal of Haematology Overt DIC Score
Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
ISTH Step by Step DIC Algorithm
Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6
US Based Validation of ISTH DIC Score
When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Differential Diagnosis in DIC
aHUS atypical hemolytic uremic syndrome
HUS hemolytic uremic syndrome
HIT heparin-induced thrombocytopenia
ITP immune thrombocytopenic purpura
TTP thrombotic thrombocytopenic purpura
DIC and MAHA
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)
When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation
DIC Management Goals
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction
DIC Management and Treatment
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)
requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)
Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia
DIC Management Strategies
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant Factor Concentrate Treatment
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis
Anticoagulant Factor Concentrate Treatment Trials
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise
Markers of Thrombin amp Plasmin Generation in DIC
D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC
Cut-off value
Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen
degradation products Sensitive assay typically with cutoff adapted for DIC
D-dimer FDPs and DIC
D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC
Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80
Follow Up of DIC State of Disease
Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8
Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility
FMD-Dimer in DIC Major Differences
onset of thrombosis
days
Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8
FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)
D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)
of Abnormal Results in Patients with Confirmed and Suspected DIC
0
20
40
60
80
100
94 85 90N = 62
Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32
Positivity of Test Results ISTH Score and Disease State
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
Red bar positive for 2 points of DIC score
Pink bar positive for 1-2 points of DIC score
HT hematopoietic tumor
IF infection
SC solid cancer
Markers in Patients with or without DIC
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
HT hematopoietic tumorIF infectionSC solid cancer
Comparing an Automated FM vs Manual FSP Test
Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71
Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)
Automated (Mitsubishi) vs Automated (Stago)
In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago
Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC
Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
Non Overt DIC Overt DIC
AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC
Trends in Markers of DIC for Different Patients
Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00
Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients
Trends in Markers of DIC for Different Patients
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes
28 day outcome survival
28 day outcome death
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines
DIC Case Studies
Case Study 1 - Presentation
18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE
WBC count 77 KμL 423 ndash 907 x KμL
RBC count 17 MμL 137 ndash 175 x MμL
Hemoglobin 67 gdL 137 ndash 175 gdL
Hematocrit 195 401 ndash 510
MCV 95 fL 790 ndash 922 fL
MPV 12 fL 94 ndash 124 fL
Platelet count 9 KμL 161 ndash 347 KμL
Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0
Lymphocytes monocytes eosinophils basophils all below normal range
PT 47 sec (corrected on mixing study) 116 ndash 152 sec
APTT 75 sec (corrected on mixing study) 253 ndash 373 sec
Fibrinogen lt 76 mgdL 177 ndash 466 mgdL
D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Microscopy
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Arrow shows giant platelets in this peripheral smear Promyelocytes apparent
Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)
DIC due to TF release by APL blasts
Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases
Transfusions to replace factors along with platelets and RBCs during APL treatment
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started
Case Study 2 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L
PT 30 sec 113 ndash 146 sec
APTT 75 sec 25 ndash 34 sec
D-dimer 078 microgml FEU lt050 microgml FEU
Fibrinogen 92 mgdl 150-400 mgdl
pH 728 738 to 742
PaO2 570 mmHg 80-100 mmHg
WBC 33 times 103mm3 40-11 times 103mm3
ALT 111 IUL 0ndash34 IUL
AST 61 IUL 0ndash34 IUL
BUN 303 mgdL 08-13 mgdL
Case Study 2 ndash Lab Results
Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures
Case Study 2 ndash Diagnosis
60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior
Case Study 3 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L
PT 228 sec 113 ndash 146 sec
APTT 45 sec 25 ndash 34 sec
D-dimer 080 microgml FEU lt050 microgmL FEU
Fibrinogen 82 mgdL 150-400 mgdL
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 134 gdL 14-16 gdL
WBC 81 times 103mm3 40-11 times 103mm3
ALT 32 IUL 0ndash34 IUL
AST 28 IUL 0ndash34 IUL
BUN 09 mgdL 08-13 mgdL
Case Study 3 ndash Lab Results
Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment
Case Study 3 ndash Diagnosis and Therapy
Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91
Case Study 4 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L
PT 28 sec 113 ndash 146 sec
APTT 71 sec 25 ndash 34 sec
D-dimer 31 microgmL FEU lt050 microgml FEU
Fibrinogen 92 mgdL 150-400 mgdl
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 158 gdL 14-16 gdL
WBC 71 times 103mm3 40-11 times 103mm3
ALT 60 IUL 0ndash34 IUL
AST 47 IUL 0ndash34 IUL
BUN 38 mgdL 08-13 mgdL
Case Study 4 ndash Lab Results
Lyme disease with DICProvide antibiotics with supportive measures
Case Study 4 ndash Diagnosis
55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis
Case Study 5 ndash Presentation
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
Case Study 5 ndash Lab Results and Time Course
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
TEST RESULT REFERENCE RANGE
Platelet count 33 x 109L 150-450 x 109L
PT 215 sec 103 ndash 128 sec
APTT 44 sec 26 ndash 36 sec
D-dimer 20 microgmL FEU lt025 microgml FEU
Fibrinogen 34 mgdL 200-375 mgdl
FII FV FVIII Low Not reported (NR)
FVII FIX FX vWF Normal NR
Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)
DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic
dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR
(C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen
(D) Illustration demonstrating repair
Case Study 5 ndash Diagnosis and Treatment
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography
Case Study 6 ndash Presentation
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
Case Study 6 ndash Lab Results
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L
PT 63 sec gt control 113 ndash 146 sec
INR 658 1 ndash 125
APTT 80 sec gt control 25 ndash 34 sec
D-dimer gt200 microgmL DDU 02 microgmL DDU
Urine exam Proteinuria and hematuria 150-400 mgdl
Albumin 28 gdL NR
Hb 58 gdL NR
LDH 1196 UL NR
SGPT 144 IU NR
SGOT 88 IU NR
Bilirubin 32 mgdL NR
DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th
day postop
Case Study 6 ndash Diagnosis and Treatment
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure
Case Study 6 ndash Discussion
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Case Study 7 ndash Lab Results vs Time
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
DIC Take Home Messages
Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation
Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers
DIC
Thank you Questions
- Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
- Learning Objectives
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Wound Sealing
- The Three Steps of Hemostasis
- Vessel Wall
- Slide Number 12
- Slide Number 13
- Platelet Structure UnactivatedActivated
- Primary Hemostasis
- Primary Hemostasis Assays
- Slide Number 17
- Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
- Slide Number 19
- Coagulation factors
- Coagulation Assay Mechanisms
- Slide Number 22
- Fibrin Formation
- Slide Number 24
- Fibrinolysis Overview
- Fibrinolysis Overview
- Slide Number 27
- Fibrinolysis Releases D-dimers
- Basic Pathophysiology of DIC
- Disseminated Intravascular Coagulation (DIC)
- Purpura Fulminans with DIC Due to Meningococcal Sepsis
- Clinical Conditions Associated With DIC
- Frequency of DIC in Selected Disease States
- Underlying Diseases in DIC Patients
- Slide Number 36
- Slide Number 37
- Slide Number 38
- Slide Number 39
- Pathophysiology of DIC
- Pathogenesis of DIC in Sepsis
- Host Response in Severe Sepsis
- Organ Failure in Severe Sepsis
- Mechanism of DIC in Organ Failure
- Interaction of Inflammation and Coagulation in Sepsis
- Slide Number 47
- Diverse and Opposing Effects of Thrombin
- Coagulation and Fibrinolysis in DIC
- Mechanism of DIC
- Pathophysiology of DIC
- Pathophysiology of DIC - Mechanism
- Pathophysiology of DIC ndash 2 Types of Clinical pictures
- Sub-Acute and Non-Overt DIC Clinical Findings
- Pathophysiology of Overt DIC
- Physiopathology of DIC ndash Overt DIC Findings
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- BREAK
- Diagnostic and Management Approach for DIC
- Diagnosis of DIC
- Lab Diagnosis of DIC ndash Markers of Factor Consumption
- Lab Diagnosis of DIC ndash Screening Tests
- Slide Number 67
- Slide Number 68
- British Journal of Haematology Overt DIC Score
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- DIC Management Goals
- DIC Management and Treatment
- DIC Management Strategies
- Anticoagulant Factor Concentrate Treatment
- Anticoagulant Factor Concentrate Treatment Trials
- Markers of Thrombin amp Plasmin Generation in DIC
- D-dimer FDPs and DIC
- D-Dimer and FDPs in DIC
- Follow Up of DIC State of Disease
- FMD-Dimer in DIC Major Differences
- of Abnormal Results in Patients with Confirmed and Suspected DIC
- Slide Number 85
- Slide Number 86
- Comparing an Automated FM vs Manual FSP Test
- Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Slide Number 94
- Slide Number 95
- Slide Number 96
- Slide Number 97
- Slide Number 98
- Slide Number 99
- DIC Case Studies
- Case Study 1 - Presentation
- Case Study 1 ndash Lab Results
- Case Study 1 ndash Microscopy
- Case Study 1 ndash Diagnosis and Therapy
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Slide Number 110
- Slide Number 111
- Slide Number 112
- Slide Number 113
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
- Slide Number 124
- Slide Number 125
- DIC Take Home Messages
- Slide Number 127
- Slide Number 128
-
lipopolysaccharides
cytokines
coagulation activation
mononuclear cell
tissue factor
Diverse and Opposing Effects of Thrombin
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Coagulation and Fibrinolysis in DIC
Soluble fibrin Polymer
XIIIa
D-Dimer
E
Fibrin clot
Fibrin Degradation Products
Fibrinogen Thrombin
Fibrinogen Degradation
Products
D E
Plasmin
DFM + fibrinopeptides
Soluble FM ComplexesPre-throm
boticPost-throm
botic
Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis Semin Thromb Hemost 2008 34 33-8
Mechanism of DIC
THROMBOSIS
Fibrin
Blood activationEndothelial lysisTF expression
BLEEDING
FDPs
D-Dimer
Plasmin
Pathophysiology of DIC
1st step abnormal activation of coagulation Injury of vessel wall cells venous stasis release of large quantities of
thromboplastin influx of activated cells (monocytes macrophages)
Results in an intravascular deposition of fibrin
Morbidity from disseminated microthrombosis in small and midsize vessels leading to multiple organ failure
Second step Consumption and depletion of coagulation factors inhibitors (Protein C
Protein S AT) and platelets Local fibrinolytic response
bull Local plasmin generation dissolves the thrombusbull Disseminated overwhelming fibrinolytic response leading to production of
FDP and D-Dimer
Bleeding
Pathophysiology of DIC - Mechanism
Systemic activation of coagulation
Intravasculardepositionof fibrin
Thrombosis of small and midsize vessels
and organ failure
Depletion of platelets and
coagulation factors
Bleeding
Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92
Pathophysiology of DIC ndash 2 Types of Clinical pictures
Chronic = non - overt DICMay be unrecognized clinically
Acute = overt DIClife threatening bleedingor multiple organ failure
Sub-Acute and Non-Overt DIC Clinical Findings
Compensated non-overt DIC Steady low level or intermittent activation
bull Compensated by increased production of coagulation components and platelets
Few or no clinical signs or multiple microvascular thrombosis sometimes not clinically obvious
Risk of decompensation leading to overt DIC
Pathophysiology of Overt DIC
Massive activation of coagulation and fibrinolysis
Does not allow for compensatory efforts
Rapid depletion of coagulation factors inhibitors and platelets
Thrombosis multiple organ failures
Bleeding complications and shock
Physiopathology of DIC ndash Overt DIC Findings
Thrombin generation
Thrombosis
Renal liver respiratory failures coma skin necrosis gangrene venous thromboembolism hypotension edema
Cytokine and kinin generation (shock)bull Tachycardia hypotension edema
Plasmin generationHemorrhage
bull Spontaneous bruising petechiae intracranial gastrointestinal and respiratory tract bleeding persistent bleeding at venipuncture sites at surgical wounds
bull Tachycardia hypotension edema
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Pathogenesis Pathways in DIC
Cytokines
TF-mediated dysfunctional impairedthrombin anticoagulant fibrinolysisgeneration mechanism due to PAI-1 deficiency
fibrin inadequateformation fibrin removal
Fibrin deposition
Inflammation
Coagulation
Stago Celebrates Lab Week 2017
NA
Stago 247 Educational Webinar Sites
wwwstago-edvantagecomUS based KOLsPACE accredited ndash all 1 hourAccessible from mobile devicesVirtual exhibit hall
wwwstagowebinarscomMostly European KOLs30 ndash 45 min including 15 min discussion
Stago Educational Apps
HaemoscoreClinical scoring algorithmsApple and AndroidTablet or phone
iHemostasisCoagulation diagramsCase studiesApple amp AndroidTablet only
BREAK
Diagnostic and Management Approach for DIC
Diagnosis of DIC
Clinical diagnosis is obvious in cases of overt DIC
Laboratory tests are necessary To makeconfirm the diagnosis To assess stage of the patient To assess the treatment efficacy
Lab Diagnosis of DIC ndash Markers of Factor Consumption
Routinescreening assays PT APTT Platelets Fibrinogen Thrombin time
Other coagulation assays Factor assays AntithrombinGeneration of Thrombin FMFSPsGeneration of Plasmin D-dimer FDPs
Important to recognize simultaneous formation of thrombin and plasmin
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122
Lab Diagnosis of DIC ndash Screening Tests
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122
Platelet count usually decreasedPT abnormal in 70 of cases (short half-life of FVII)APTT abnormal in 50 of casesThrombin time usually prolonged in overt DIC normal in non-overt DIC and no relation with syndrome severityFibrinogen low in lt 50 of cases sensitivity 22 specificity 87 overall predictive value 64 Normal fibrinogen level should not exclude DIC diagnosis (acute phase reactant initial high
fibrinogen level) repeat testing assesses progression
Screening tests not clinically specific or sensitive for DIC
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Laboratory Changes in Overt DIC
DIC Diagnostic Practices Over Time
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
British Journal of Haematology Overt DIC Score
Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
ISTH Step by Step DIC Algorithm
Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6
US Based Validation of ISTH DIC Score
When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Differential Diagnosis in DIC
aHUS atypical hemolytic uremic syndrome
HUS hemolytic uremic syndrome
HIT heparin-induced thrombocytopenia
ITP immune thrombocytopenic purpura
TTP thrombotic thrombocytopenic purpura
DIC and MAHA
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)
When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation
DIC Management Goals
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction
DIC Management and Treatment
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)
requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)
Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia
DIC Management Strategies
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant Factor Concentrate Treatment
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis
Anticoagulant Factor Concentrate Treatment Trials
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise
Markers of Thrombin amp Plasmin Generation in DIC
D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC
Cut-off value
Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen
degradation products Sensitive assay typically with cutoff adapted for DIC
D-dimer FDPs and DIC
D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC
Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80
Follow Up of DIC State of Disease
Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8
Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility
FMD-Dimer in DIC Major Differences
onset of thrombosis
days
Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8
FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)
D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)
of Abnormal Results in Patients with Confirmed and Suspected DIC
0
20
40
60
80
100
94 85 90N = 62
Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32
Positivity of Test Results ISTH Score and Disease State
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
Red bar positive for 2 points of DIC score
Pink bar positive for 1-2 points of DIC score
HT hematopoietic tumor
IF infection
SC solid cancer
Markers in Patients with or without DIC
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
HT hematopoietic tumorIF infectionSC solid cancer
Comparing an Automated FM vs Manual FSP Test
Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71
Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)
Automated (Mitsubishi) vs Automated (Stago)
In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago
Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC
Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
Non Overt DIC Overt DIC
AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC
Trends in Markers of DIC for Different Patients
Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00
Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients
Trends in Markers of DIC for Different Patients
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes
28 day outcome survival
28 day outcome death
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines
DIC Case Studies
Case Study 1 - Presentation
18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE
WBC count 77 KμL 423 ndash 907 x KμL
RBC count 17 MμL 137 ndash 175 x MμL
Hemoglobin 67 gdL 137 ndash 175 gdL
Hematocrit 195 401 ndash 510
MCV 95 fL 790 ndash 922 fL
MPV 12 fL 94 ndash 124 fL
Platelet count 9 KμL 161 ndash 347 KμL
Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0
Lymphocytes monocytes eosinophils basophils all below normal range
PT 47 sec (corrected on mixing study) 116 ndash 152 sec
APTT 75 sec (corrected on mixing study) 253 ndash 373 sec
Fibrinogen lt 76 mgdL 177 ndash 466 mgdL
D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Microscopy
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Arrow shows giant platelets in this peripheral smear Promyelocytes apparent
Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)
DIC due to TF release by APL blasts
Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases
Transfusions to replace factors along with platelets and RBCs during APL treatment
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started
Case Study 2 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L
PT 30 sec 113 ndash 146 sec
APTT 75 sec 25 ndash 34 sec
D-dimer 078 microgml FEU lt050 microgml FEU
Fibrinogen 92 mgdl 150-400 mgdl
pH 728 738 to 742
PaO2 570 mmHg 80-100 mmHg
WBC 33 times 103mm3 40-11 times 103mm3
ALT 111 IUL 0ndash34 IUL
AST 61 IUL 0ndash34 IUL
BUN 303 mgdL 08-13 mgdL
Case Study 2 ndash Lab Results
Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures
Case Study 2 ndash Diagnosis
60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior
Case Study 3 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L
PT 228 sec 113 ndash 146 sec
APTT 45 sec 25 ndash 34 sec
D-dimer 080 microgml FEU lt050 microgmL FEU
Fibrinogen 82 mgdL 150-400 mgdL
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 134 gdL 14-16 gdL
WBC 81 times 103mm3 40-11 times 103mm3
ALT 32 IUL 0ndash34 IUL
AST 28 IUL 0ndash34 IUL
BUN 09 mgdL 08-13 mgdL
Case Study 3 ndash Lab Results
Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment
Case Study 3 ndash Diagnosis and Therapy
Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91
Case Study 4 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L
PT 28 sec 113 ndash 146 sec
APTT 71 sec 25 ndash 34 sec
D-dimer 31 microgmL FEU lt050 microgml FEU
Fibrinogen 92 mgdL 150-400 mgdl
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 158 gdL 14-16 gdL
WBC 71 times 103mm3 40-11 times 103mm3
ALT 60 IUL 0ndash34 IUL
AST 47 IUL 0ndash34 IUL
BUN 38 mgdL 08-13 mgdL
Case Study 4 ndash Lab Results
Lyme disease with DICProvide antibiotics with supportive measures
Case Study 4 ndash Diagnosis
55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis
Case Study 5 ndash Presentation
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
Case Study 5 ndash Lab Results and Time Course
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
TEST RESULT REFERENCE RANGE
Platelet count 33 x 109L 150-450 x 109L
PT 215 sec 103 ndash 128 sec
APTT 44 sec 26 ndash 36 sec
D-dimer 20 microgmL FEU lt025 microgml FEU
Fibrinogen 34 mgdL 200-375 mgdl
FII FV FVIII Low Not reported (NR)
FVII FIX FX vWF Normal NR
Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)
DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic
dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR
(C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen
(D) Illustration demonstrating repair
Case Study 5 ndash Diagnosis and Treatment
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography
Case Study 6 ndash Presentation
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
Case Study 6 ndash Lab Results
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L
PT 63 sec gt control 113 ndash 146 sec
INR 658 1 ndash 125
APTT 80 sec gt control 25 ndash 34 sec
D-dimer gt200 microgmL DDU 02 microgmL DDU
Urine exam Proteinuria and hematuria 150-400 mgdl
Albumin 28 gdL NR
Hb 58 gdL NR
LDH 1196 UL NR
SGPT 144 IU NR
SGOT 88 IU NR
Bilirubin 32 mgdL NR
DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th
day postop
Case Study 6 ndash Diagnosis and Treatment
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure
Case Study 6 ndash Discussion
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Case Study 7 ndash Lab Results vs Time
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
DIC Take Home Messages
Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation
Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers
DIC
Thank you Questions
- Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
- Learning Objectives
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Wound Sealing
- The Three Steps of Hemostasis
- Vessel Wall
- Slide Number 12
- Slide Number 13
- Platelet Structure UnactivatedActivated
- Primary Hemostasis
- Primary Hemostasis Assays
- Slide Number 17
- Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
- Slide Number 19
- Coagulation factors
- Coagulation Assay Mechanisms
- Slide Number 22
- Fibrin Formation
- Slide Number 24
- Fibrinolysis Overview
- Fibrinolysis Overview
- Slide Number 27
- Fibrinolysis Releases D-dimers
- Basic Pathophysiology of DIC
- Disseminated Intravascular Coagulation (DIC)
- Purpura Fulminans with DIC Due to Meningococcal Sepsis
- Clinical Conditions Associated With DIC
- Frequency of DIC in Selected Disease States
- Underlying Diseases in DIC Patients
- Slide Number 36
- Slide Number 37
- Slide Number 38
- Slide Number 39
- Pathophysiology of DIC
- Pathogenesis of DIC in Sepsis
- Host Response in Severe Sepsis
- Organ Failure in Severe Sepsis
- Mechanism of DIC in Organ Failure
- Interaction of Inflammation and Coagulation in Sepsis
- Slide Number 47
- Diverse and Opposing Effects of Thrombin
- Coagulation and Fibrinolysis in DIC
- Mechanism of DIC
- Pathophysiology of DIC
- Pathophysiology of DIC - Mechanism
- Pathophysiology of DIC ndash 2 Types of Clinical pictures
- Sub-Acute and Non-Overt DIC Clinical Findings
- Pathophysiology of Overt DIC
- Physiopathology of DIC ndash Overt DIC Findings
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- BREAK
- Diagnostic and Management Approach for DIC
- Diagnosis of DIC
- Lab Diagnosis of DIC ndash Markers of Factor Consumption
- Lab Diagnosis of DIC ndash Screening Tests
- Slide Number 67
- Slide Number 68
- British Journal of Haematology Overt DIC Score
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- DIC Management Goals
- DIC Management and Treatment
- DIC Management Strategies
- Anticoagulant Factor Concentrate Treatment
- Anticoagulant Factor Concentrate Treatment Trials
- Markers of Thrombin amp Plasmin Generation in DIC
- D-dimer FDPs and DIC
- D-Dimer and FDPs in DIC
- Follow Up of DIC State of Disease
- FMD-Dimer in DIC Major Differences
- of Abnormal Results in Patients with Confirmed and Suspected DIC
- Slide Number 85
- Slide Number 86
- Comparing an Automated FM vs Manual FSP Test
- Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Slide Number 94
- Slide Number 95
- Slide Number 96
- Slide Number 97
- Slide Number 98
- Slide Number 99
- DIC Case Studies
- Case Study 1 - Presentation
- Case Study 1 ndash Lab Results
- Case Study 1 ndash Microscopy
- Case Study 1 ndash Diagnosis and Therapy
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Slide Number 110
- Slide Number 111
- Slide Number 112
- Slide Number 113
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
- Slide Number 124
- Slide Number 125
- DIC Take Home Messages
- Slide Number 127
- Slide Number 128
-
Diverse and Opposing Effects of Thrombin
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Coagulation and Fibrinolysis in DIC
Soluble fibrin Polymer
XIIIa
D-Dimer
E
Fibrin clot
Fibrin Degradation Products
Fibrinogen Thrombin
Fibrinogen Degradation
Products
D E
Plasmin
DFM + fibrinopeptides
Soluble FM ComplexesPre-throm
boticPost-throm
botic
Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis Semin Thromb Hemost 2008 34 33-8
Mechanism of DIC
THROMBOSIS
Fibrin
Blood activationEndothelial lysisTF expression
BLEEDING
FDPs
D-Dimer
Plasmin
Pathophysiology of DIC
1st step abnormal activation of coagulation Injury of vessel wall cells venous stasis release of large quantities of
thromboplastin influx of activated cells (monocytes macrophages)
Results in an intravascular deposition of fibrin
Morbidity from disseminated microthrombosis in small and midsize vessels leading to multiple organ failure
Second step Consumption and depletion of coagulation factors inhibitors (Protein C
Protein S AT) and platelets Local fibrinolytic response
bull Local plasmin generation dissolves the thrombusbull Disseminated overwhelming fibrinolytic response leading to production of
FDP and D-Dimer
Bleeding
Pathophysiology of DIC - Mechanism
Systemic activation of coagulation
Intravasculardepositionof fibrin
Thrombosis of small and midsize vessels
and organ failure
Depletion of platelets and
coagulation factors
Bleeding
Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92
Pathophysiology of DIC ndash 2 Types of Clinical pictures
Chronic = non - overt DICMay be unrecognized clinically
Acute = overt DIClife threatening bleedingor multiple organ failure
Sub-Acute and Non-Overt DIC Clinical Findings
Compensated non-overt DIC Steady low level or intermittent activation
bull Compensated by increased production of coagulation components and platelets
Few or no clinical signs or multiple microvascular thrombosis sometimes not clinically obvious
Risk of decompensation leading to overt DIC
Pathophysiology of Overt DIC
Massive activation of coagulation and fibrinolysis
Does not allow for compensatory efforts
Rapid depletion of coagulation factors inhibitors and platelets
Thrombosis multiple organ failures
Bleeding complications and shock
Physiopathology of DIC ndash Overt DIC Findings
Thrombin generation
Thrombosis
Renal liver respiratory failures coma skin necrosis gangrene venous thromboembolism hypotension edema
Cytokine and kinin generation (shock)bull Tachycardia hypotension edema
Plasmin generationHemorrhage
bull Spontaneous bruising petechiae intracranial gastrointestinal and respiratory tract bleeding persistent bleeding at venipuncture sites at surgical wounds
bull Tachycardia hypotension edema
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Pathogenesis Pathways in DIC
Cytokines
TF-mediated dysfunctional impairedthrombin anticoagulant fibrinolysisgeneration mechanism due to PAI-1 deficiency
fibrin inadequateformation fibrin removal
Fibrin deposition
Inflammation
Coagulation
Stago Celebrates Lab Week 2017
NA
Stago 247 Educational Webinar Sites
wwwstago-edvantagecomUS based KOLsPACE accredited ndash all 1 hourAccessible from mobile devicesVirtual exhibit hall
wwwstagowebinarscomMostly European KOLs30 ndash 45 min including 15 min discussion
Stago Educational Apps
HaemoscoreClinical scoring algorithmsApple and AndroidTablet or phone
iHemostasisCoagulation diagramsCase studiesApple amp AndroidTablet only
BREAK
Diagnostic and Management Approach for DIC
Diagnosis of DIC
Clinical diagnosis is obvious in cases of overt DIC
Laboratory tests are necessary To makeconfirm the diagnosis To assess stage of the patient To assess the treatment efficacy
Lab Diagnosis of DIC ndash Markers of Factor Consumption
Routinescreening assays PT APTT Platelets Fibrinogen Thrombin time
Other coagulation assays Factor assays AntithrombinGeneration of Thrombin FMFSPsGeneration of Plasmin D-dimer FDPs
Important to recognize simultaneous formation of thrombin and plasmin
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122
Lab Diagnosis of DIC ndash Screening Tests
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122
Platelet count usually decreasedPT abnormal in 70 of cases (short half-life of FVII)APTT abnormal in 50 of casesThrombin time usually prolonged in overt DIC normal in non-overt DIC and no relation with syndrome severityFibrinogen low in lt 50 of cases sensitivity 22 specificity 87 overall predictive value 64 Normal fibrinogen level should not exclude DIC diagnosis (acute phase reactant initial high
fibrinogen level) repeat testing assesses progression
Screening tests not clinically specific or sensitive for DIC
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Laboratory Changes in Overt DIC
DIC Diagnostic Practices Over Time
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
British Journal of Haematology Overt DIC Score
Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
ISTH Step by Step DIC Algorithm
Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6
US Based Validation of ISTH DIC Score
When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Differential Diagnosis in DIC
aHUS atypical hemolytic uremic syndrome
HUS hemolytic uremic syndrome
HIT heparin-induced thrombocytopenia
ITP immune thrombocytopenic purpura
TTP thrombotic thrombocytopenic purpura
DIC and MAHA
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)
When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation
DIC Management Goals
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction
DIC Management and Treatment
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)
requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)
Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia
DIC Management Strategies
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant Factor Concentrate Treatment
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis
Anticoagulant Factor Concentrate Treatment Trials
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise
Markers of Thrombin amp Plasmin Generation in DIC
D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC
Cut-off value
Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen
degradation products Sensitive assay typically with cutoff adapted for DIC
D-dimer FDPs and DIC
D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC
Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80
Follow Up of DIC State of Disease
Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8
Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility
FMD-Dimer in DIC Major Differences
onset of thrombosis
days
Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8
FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)
D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)
of Abnormal Results in Patients with Confirmed and Suspected DIC
0
20
40
60
80
100
94 85 90N = 62
Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32
Positivity of Test Results ISTH Score and Disease State
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
Red bar positive for 2 points of DIC score
Pink bar positive for 1-2 points of DIC score
HT hematopoietic tumor
IF infection
SC solid cancer
Markers in Patients with or without DIC
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
HT hematopoietic tumorIF infectionSC solid cancer
Comparing an Automated FM vs Manual FSP Test
Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71
Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)
Automated (Mitsubishi) vs Automated (Stago)
In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago
Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC
Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
Non Overt DIC Overt DIC
AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC
Trends in Markers of DIC for Different Patients
Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00
Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients
Trends in Markers of DIC for Different Patients
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes
28 day outcome survival
28 day outcome death
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines
DIC Case Studies
Case Study 1 - Presentation
18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE
WBC count 77 KμL 423 ndash 907 x KμL
RBC count 17 MμL 137 ndash 175 x MμL
Hemoglobin 67 gdL 137 ndash 175 gdL
Hematocrit 195 401 ndash 510
MCV 95 fL 790 ndash 922 fL
MPV 12 fL 94 ndash 124 fL
Platelet count 9 KμL 161 ndash 347 KμL
Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0
Lymphocytes monocytes eosinophils basophils all below normal range
PT 47 sec (corrected on mixing study) 116 ndash 152 sec
APTT 75 sec (corrected on mixing study) 253 ndash 373 sec
Fibrinogen lt 76 mgdL 177 ndash 466 mgdL
D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Microscopy
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Arrow shows giant platelets in this peripheral smear Promyelocytes apparent
Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)
DIC due to TF release by APL blasts
Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases
Transfusions to replace factors along with platelets and RBCs during APL treatment
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started
Case Study 2 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L
PT 30 sec 113 ndash 146 sec
APTT 75 sec 25 ndash 34 sec
D-dimer 078 microgml FEU lt050 microgml FEU
Fibrinogen 92 mgdl 150-400 mgdl
pH 728 738 to 742
PaO2 570 mmHg 80-100 mmHg
WBC 33 times 103mm3 40-11 times 103mm3
ALT 111 IUL 0ndash34 IUL
AST 61 IUL 0ndash34 IUL
BUN 303 mgdL 08-13 mgdL
Case Study 2 ndash Lab Results
Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures
Case Study 2 ndash Diagnosis
60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior
Case Study 3 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L
PT 228 sec 113 ndash 146 sec
APTT 45 sec 25 ndash 34 sec
D-dimer 080 microgml FEU lt050 microgmL FEU
Fibrinogen 82 mgdL 150-400 mgdL
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 134 gdL 14-16 gdL
WBC 81 times 103mm3 40-11 times 103mm3
ALT 32 IUL 0ndash34 IUL
AST 28 IUL 0ndash34 IUL
BUN 09 mgdL 08-13 mgdL
Case Study 3 ndash Lab Results
Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment
Case Study 3 ndash Diagnosis and Therapy
Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91
Case Study 4 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L
PT 28 sec 113 ndash 146 sec
APTT 71 sec 25 ndash 34 sec
D-dimer 31 microgmL FEU lt050 microgml FEU
Fibrinogen 92 mgdL 150-400 mgdl
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 158 gdL 14-16 gdL
WBC 71 times 103mm3 40-11 times 103mm3
ALT 60 IUL 0ndash34 IUL
AST 47 IUL 0ndash34 IUL
BUN 38 mgdL 08-13 mgdL
Case Study 4 ndash Lab Results
Lyme disease with DICProvide antibiotics with supportive measures
Case Study 4 ndash Diagnosis
55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis
Case Study 5 ndash Presentation
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
Case Study 5 ndash Lab Results and Time Course
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
TEST RESULT REFERENCE RANGE
Platelet count 33 x 109L 150-450 x 109L
PT 215 sec 103 ndash 128 sec
APTT 44 sec 26 ndash 36 sec
D-dimer 20 microgmL FEU lt025 microgml FEU
Fibrinogen 34 mgdL 200-375 mgdl
FII FV FVIII Low Not reported (NR)
FVII FIX FX vWF Normal NR
Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)
DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic
dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR
(C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen
(D) Illustration demonstrating repair
Case Study 5 ndash Diagnosis and Treatment
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography
Case Study 6 ndash Presentation
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
Case Study 6 ndash Lab Results
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L
PT 63 sec gt control 113 ndash 146 sec
INR 658 1 ndash 125
APTT 80 sec gt control 25 ndash 34 sec
D-dimer gt200 microgmL DDU 02 microgmL DDU
Urine exam Proteinuria and hematuria 150-400 mgdl
Albumin 28 gdL NR
Hb 58 gdL NR
LDH 1196 UL NR
SGPT 144 IU NR
SGOT 88 IU NR
Bilirubin 32 mgdL NR
DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th
day postop
Case Study 6 ndash Diagnosis and Treatment
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure
Case Study 6 ndash Discussion
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Case Study 7 ndash Lab Results vs Time
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
DIC Take Home Messages
Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation
Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers
DIC
Thank you Questions
- Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
- Learning Objectives
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Wound Sealing
- The Three Steps of Hemostasis
- Vessel Wall
- Slide Number 12
- Slide Number 13
- Platelet Structure UnactivatedActivated
- Primary Hemostasis
- Primary Hemostasis Assays
- Slide Number 17
- Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
- Slide Number 19
- Coagulation factors
- Coagulation Assay Mechanisms
- Slide Number 22
- Fibrin Formation
- Slide Number 24
- Fibrinolysis Overview
- Fibrinolysis Overview
- Slide Number 27
- Fibrinolysis Releases D-dimers
- Basic Pathophysiology of DIC
- Disseminated Intravascular Coagulation (DIC)
- Purpura Fulminans with DIC Due to Meningococcal Sepsis
- Clinical Conditions Associated With DIC
- Frequency of DIC in Selected Disease States
- Underlying Diseases in DIC Patients
- Slide Number 36
- Slide Number 37
- Slide Number 38
- Slide Number 39
- Pathophysiology of DIC
- Pathogenesis of DIC in Sepsis
- Host Response in Severe Sepsis
- Organ Failure in Severe Sepsis
- Mechanism of DIC in Organ Failure
- Interaction of Inflammation and Coagulation in Sepsis
- Slide Number 47
- Diverse and Opposing Effects of Thrombin
- Coagulation and Fibrinolysis in DIC
- Mechanism of DIC
- Pathophysiology of DIC
- Pathophysiology of DIC - Mechanism
- Pathophysiology of DIC ndash 2 Types of Clinical pictures
- Sub-Acute and Non-Overt DIC Clinical Findings
- Pathophysiology of Overt DIC
- Physiopathology of DIC ndash Overt DIC Findings
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- BREAK
- Diagnostic and Management Approach for DIC
- Diagnosis of DIC
- Lab Diagnosis of DIC ndash Markers of Factor Consumption
- Lab Diagnosis of DIC ndash Screening Tests
- Slide Number 67
- Slide Number 68
- British Journal of Haematology Overt DIC Score
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- DIC Management Goals
- DIC Management and Treatment
- DIC Management Strategies
- Anticoagulant Factor Concentrate Treatment
- Anticoagulant Factor Concentrate Treatment Trials
- Markers of Thrombin amp Plasmin Generation in DIC
- D-dimer FDPs and DIC
- D-Dimer and FDPs in DIC
- Follow Up of DIC State of Disease
- FMD-Dimer in DIC Major Differences
- of Abnormal Results in Patients with Confirmed and Suspected DIC
- Slide Number 85
- Slide Number 86
- Comparing an Automated FM vs Manual FSP Test
- Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Slide Number 94
- Slide Number 95
- Slide Number 96
- Slide Number 97
- Slide Number 98
- Slide Number 99
- DIC Case Studies
- Case Study 1 - Presentation
- Case Study 1 ndash Lab Results
- Case Study 1 ndash Microscopy
- Case Study 1 ndash Diagnosis and Therapy
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Slide Number 110
- Slide Number 111
- Slide Number 112
- Slide Number 113
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
- Slide Number 124
- Slide Number 125
- DIC Take Home Messages
- Slide Number 127
- Slide Number 128
-
Coagulation and Fibrinolysis in DIC
Soluble fibrin Polymer
XIIIa
D-Dimer
E
Fibrin clot
Fibrin Degradation Products
Fibrinogen Thrombin
Fibrinogen Degradation
Products
D E
Plasmin
DFM + fibrinopeptides
Soluble FM ComplexesPre-throm
boticPost-throm
botic
Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis Semin Thromb Hemost 2008 34 33-8
Mechanism of DIC
THROMBOSIS
Fibrin
Blood activationEndothelial lysisTF expression
BLEEDING
FDPs
D-Dimer
Plasmin
Pathophysiology of DIC
1st step abnormal activation of coagulation Injury of vessel wall cells venous stasis release of large quantities of
thromboplastin influx of activated cells (monocytes macrophages)
Results in an intravascular deposition of fibrin
Morbidity from disseminated microthrombosis in small and midsize vessels leading to multiple organ failure
Second step Consumption and depletion of coagulation factors inhibitors (Protein C
Protein S AT) and platelets Local fibrinolytic response
bull Local plasmin generation dissolves the thrombusbull Disseminated overwhelming fibrinolytic response leading to production of
FDP and D-Dimer
Bleeding
Pathophysiology of DIC - Mechanism
Systemic activation of coagulation
Intravasculardepositionof fibrin
Thrombosis of small and midsize vessels
and organ failure
Depletion of platelets and
coagulation factors
Bleeding
Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92
Pathophysiology of DIC ndash 2 Types of Clinical pictures
Chronic = non - overt DICMay be unrecognized clinically
Acute = overt DIClife threatening bleedingor multiple organ failure
Sub-Acute and Non-Overt DIC Clinical Findings
Compensated non-overt DIC Steady low level or intermittent activation
bull Compensated by increased production of coagulation components and platelets
Few or no clinical signs or multiple microvascular thrombosis sometimes not clinically obvious
Risk of decompensation leading to overt DIC
Pathophysiology of Overt DIC
Massive activation of coagulation and fibrinolysis
Does not allow for compensatory efforts
Rapid depletion of coagulation factors inhibitors and platelets
Thrombosis multiple organ failures
Bleeding complications and shock
Physiopathology of DIC ndash Overt DIC Findings
Thrombin generation
Thrombosis
Renal liver respiratory failures coma skin necrosis gangrene venous thromboembolism hypotension edema
Cytokine and kinin generation (shock)bull Tachycardia hypotension edema
Plasmin generationHemorrhage
bull Spontaneous bruising petechiae intracranial gastrointestinal and respiratory tract bleeding persistent bleeding at venipuncture sites at surgical wounds
bull Tachycardia hypotension edema
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Pathogenesis Pathways in DIC
Cytokines
TF-mediated dysfunctional impairedthrombin anticoagulant fibrinolysisgeneration mechanism due to PAI-1 deficiency
fibrin inadequateformation fibrin removal
Fibrin deposition
Inflammation
Coagulation
Stago Celebrates Lab Week 2017
NA
Stago 247 Educational Webinar Sites
wwwstago-edvantagecomUS based KOLsPACE accredited ndash all 1 hourAccessible from mobile devicesVirtual exhibit hall
wwwstagowebinarscomMostly European KOLs30 ndash 45 min including 15 min discussion
Stago Educational Apps
HaemoscoreClinical scoring algorithmsApple and AndroidTablet or phone
iHemostasisCoagulation diagramsCase studiesApple amp AndroidTablet only
BREAK
Diagnostic and Management Approach for DIC
Diagnosis of DIC
Clinical diagnosis is obvious in cases of overt DIC
Laboratory tests are necessary To makeconfirm the diagnosis To assess stage of the patient To assess the treatment efficacy
Lab Diagnosis of DIC ndash Markers of Factor Consumption
Routinescreening assays PT APTT Platelets Fibrinogen Thrombin time
Other coagulation assays Factor assays AntithrombinGeneration of Thrombin FMFSPsGeneration of Plasmin D-dimer FDPs
Important to recognize simultaneous formation of thrombin and plasmin
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122
Lab Diagnosis of DIC ndash Screening Tests
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122
Platelet count usually decreasedPT abnormal in 70 of cases (short half-life of FVII)APTT abnormal in 50 of casesThrombin time usually prolonged in overt DIC normal in non-overt DIC and no relation with syndrome severityFibrinogen low in lt 50 of cases sensitivity 22 specificity 87 overall predictive value 64 Normal fibrinogen level should not exclude DIC diagnosis (acute phase reactant initial high
fibrinogen level) repeat testing assesses progression
Screening tests not clinically specific or sensitive for DIC
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Laboratory Changes in Overt DIC
DIC Diagnostic Practices Over Time
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
British Journal of Haematology Overt DIC Score
Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
ISTH Step by Step DIC Algorithm
Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6
US Based Validation of ISTH DIC Score
When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Differential Diagnosis in DIC
aHUS atypical hemolytic uremic syndrome
HUS hemolytic uremic syndrome
HIT heparin-induced thrombocytopenia
ITP immune thrombocytopenic purpura
TTP thrombotic thrombocytopenic purpura
DIC and MAHA
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)
When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation
DIC Management Goals
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction
DIC Management and Treatment
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)
requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)
Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia
DIC Management Strategies
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant Factor Concentrate Treatment
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis
Anticoagulant Factor Concentrate Treatment Trials
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise
Markers of Thrombin amp Plasmin Generation in DIC
D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC
Cut-off value
Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen
degradation products Sensitive assay typically with cutoff adapted for DIC
D-dimer FDPs and DIC
D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC
Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80
Follow Up of DIC State of Disease
Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8
Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility
FMD-Dimer in DIC Major Differences
onset of thrombosis
days
Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8
FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)
D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)
of Abnormal Results in Patients with Confirmed and Suspected DIC
0
20
40
60
80
100
94 85 90N = 62
Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32
Positivity of Test Results ISTH Score and Disease State
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
Red bar positive for 2 points of DIC score
Pink bar positive for 1-2 points of DIC score
HT hematopoietic tumor
IF infection
SC solid cancer
Markers in Patients with or without DIC
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
HT hematopoietic tumorIF infectionSC solid cancer
Comparing an Automated FM vs Manual FSP Test
Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71
Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)
Automated (Mitsubishi) vs Automated (Stago)
In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago
Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC
Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
Non Overt DIC Overt DIC
AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC
Trends in Markers of DIC for Different Patients
Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00
Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients
Trends in Markers of DIC for Different Patients
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes
28 day outcome survival
28 day outcome death
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines
DIC Case Studies
Case Study 1 - Presentation
18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE
WBC count 77 KμL 423 ndash 907 x KμL
RBC count 17 MμL 137 ndash 175 x MμL
Hemoglobin 67 gdL 137 ndash 175 gdL
Hematocrit 195 401 ndash 510
MCV 95 fL 790 ndash 922 fL
MPV 12 fL 94 ndash 124 fL
Platelet count 9 KμL 161 ndash 347 KμL
Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0
Lymphocytes monocytes eosinophils basophils all below normal range
PT 47 sec (corrected on mixing study) 116 ndash 152 sec
APTT 75 sec (corrected on mixing study) 253 ndash 373 sec
Fibrinogen lt 76 mgdL 177 ndash 466 mgdL
D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Microscopy
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Arrow shows giant platelets in this peripheral smear Promyelocytes apparent
Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)
DIC due to TF release by APL blasts
Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases
Transfusions to replace factors along with platelets and RBCs during APL treatment
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started
Case Study 2 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L
PT 30 sec 113 ndash 146 sec
APTT 75 sec 25 ndash 34 sec
D-dimer 078 microgml FEU lt050 microgml FEU
Fibrinogen 92 mgdl 150-400 mgdl
pH 728 738 to 742
PaO2 570 mmHg 80-100 mmHg
WBC 33 times 103mm3 40-11 times 103mm3
ALT 111 IUL 0ndash34 IUL
AST 61 IUL 0ndash34 IUL
BUN 303 mgdL 08-13 mgdL
Case Study 2 ndash Lab Results
Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures
Case Study 2 ndash Diagnosis
60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior
Case Study 3 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L
PT 228 sec 113 ndash 146 sec
APTT 45 sec 25 ndash 34 sec
D-dimer 080 microgml FEU lt050 microgmL FEU
Fibrinogen 82 mgdL 150-400 mgdL
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 134 gdL 14-16 gdL
WBC 81 times 103mm3 40-11 times 103mm3
ALT 32 IUL 0ndash34 IUL
AST 28 IUL 0ndash34 IUL
BUN 09 mgdL 08-13 mgdL
Case Study 3 ndash Lab Results
Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment
Case Study 3 ndash Diagnosis and Therapy
Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91
Case Study 4 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L
PT 28 sec 113 ndash 146 sec
APTT 71 sec 25 ndash 34 sec
D-dimer 31 microgmL FEU lt050 microgml FEU
Fibrinogen 92 mgdL 150-400 mgdl
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 158 gdL 14-16 gdL
WBC 71 times 103mm3 40-11 times 103mm3
ALT 60 IUL 0ndash34 IUL
AST 47 IUL 0ndash34 IUL
BUN 38 mgdL 08-13 mgdL
Case Study 4 ndash Lab Results
Lyme disease with DICProvide antibiotics with supportive measures
Case Study 4 ndash Diagnosis
55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis
Case Study 5 ndash Presentation
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
Case Study 5 ndash Lab Results and Time Course
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
TEST RESULT REFERENCE RANGE
Platelet count 33 x 109L 150-450 x 109L
PT 215 sec 103 ndash 128 sec
APTT 44 sec 26 ndash 36 sec
D-dimer 20 microgmL FEU lt025 microgml FEU
Fibrinogen 34 mgdL 200-375 mgdl
FII FV FVIII Low Not reported (NR)
FVII FIX FX vWF Normal NR
Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)
DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic
dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR
(C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen
(D) Illustration demonstrating repair
Case Study 5 ndash Diagnosis and Treatment
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography
Case Study 6 ndash Presentation
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
Case Study 6 ndash Lab Results
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L
PT 63 sec gt control 113 ndash 146 sec
INR 658 1 ndash 125
APTT 80 sec gt control 25 ndash 34 sec
D-dimer gt200 microgmL DDU 02 microgmL DDU
Urine exam Proteinuria and hematuria 150-400 mgdl
Albumin 28 gdL NR
Hb 58 gdL NR
LDH 1196 UL NR
SGPT 144 IU NR
SGOT 88 IU NR
Bilirubin 32 mgdL NR
DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th
day postop
Case Study 6 ndash Diagnosis and Treatment
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure
Case Study 6 ndash Discussion
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Case Study 7 ndash Lab Results vs Time
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
DIC Take Home Messages
Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation
Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers
DIC
Thank you Questions
- Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
- Learning Objectives
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Wound Sealing
- The Three Steps of Hemostasis
- Vessel Wall
- Slide Number 12
- Slide Number 13
- Platelet Structure UnactivatedActivated
- Primary Hemostasis
- Primary Hemostasis Assays
- Slide Number 17
- Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
- Slide Number 19
- Coagulation factors
- Coagulation Assay Mechanisms
- Slide Number 22
- Fibrin Formation
- Slide Number 24
- Fibrinolysis Overview
- Fibrinolysis Overview
- Slide Number 27
- Fibrinolysis Releases D-dimers
- Basic Pathophysiology of DIC
- Disseminated Intravascular Coagulation (DIC)
- Purpura Fulminans with DIC Due to Meningococcal Sepsis
- Clinical Conditions Associated With DIC
- Frequency of DIC in Selected Disease States
- Underlying Diseases in DIC Patients
- Slide Number 36
- Slide Number 37
- Slide Number 38
- Slide Number 39
- Pathophysiology of DIC
- Pathogenesis of DIC in Sepsis
- Host Response in Severe Sepsis
- Organ Failure in Severe Sepsis
- Mechanism of DIC in Organ Failure
- Interaction of Inflammation and Coagulation in Sepsis
- Slide Number 47
- Diverse and Opposing Effects of Thrombin
- Coagulation and Fibrinolysis in DIC
- Mechanism of DIC
- Pathophysiology of DIC
- Pathophysiology of DIC - Mechanism
- Pathophysiology of DIC ndash 2 Types of Clinical pictures
- Sub-Acute and Non-Overt DIC Clinical Findings
- Pathophysiology of Overt DIC
- Physiopathology of DIC ndash Overt DIC Findings
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- BREAK
- Diagnostic and Management Approach for DIC
- Diagnosis of DIC
- Lab Diagnosis of DIC ndash Markers of Factor Consumption
- Lab Diagnosis of DIC ndash Screening Tests
- Slide Number 67
- Slide Number 68
- British Journal of Haematology Overt DIC Score
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- DIC Management Goals
- DIC Management and Treatment
- DIC Management Strategies
- Anticoagulant Factor Concentrate Treatment
- Anticoagulant Factor Concentrate Treatment Trials
- Markers of Thrombin amp Plasmin Generation in DIC
- D-dimer FDPs and DIC
- D-Dimer and FDPs in DIC
- Follow Up of DIC State of Disease
- FMD-Dimer in DIC Major Differences
- of Abnormal Results in Patients with Confirmed and Suspected DIC
- Slide Number 85
- Slide Number 86
- Comparing an Automated FM vs Manual FSP Test
- Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Slide Number 94
- Slide Number 95
- Slide Number 96
- Slide Number 97
- Slide Number 98
- Slide Number 99
- DIC Case Studies
- Case Study 1 - Presentation
- Case Study 1 ndash Lab Results
- Case Study 1 ndash Microscopy
- Case Study 1 ndash Diagnosis and Therapy
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Slide Number 110
- Slide Number 111
- Slide Number 112
- Slide Number 113
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
- Slide Number 124
- Slide Number 125
- DIC Take Home Messages
- Slide Number 127
- Slide Number 128
-
Mechanism of DIC
THROMBOSIS
Fibrin
Blood activationEndothelial lysisTF expression
BLEEDING
FDPs
D-Dimer
Plasmin
Pathophysiology of DIC
1st step abnormal activation of coagulation Injury of vessel wall cells venous stasis release of large quantities of
thromboplastin influx of activated cells (monocytes macrophages)
Results in an intravascular deposition of fibrin
Morbidity from disseminated microthrombosis in small and midsize vessels leading to multiple organ failure
Second step Consumption and depletion of coagulation factors inhibitors (Protein C
Protein S AT) and platelets Local fibrinolytic response
bull Local plasmin generation dissolves the thrombusbull Disseminated overwhelming fibrinolytic response leading to production of
FDP and D-Dimer
Bleeding
Pathophysiology of DIC - Mechanism
Systemic activation of coagulation
Intravasculardepositionof fibrin
Thrombosis of small and midsize vessels
and organ failure
Depletion of platelets and
coagulation factors
Bleeding
Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92
Pathophysiology of DIC ndash 2 Types of Clinical pictures
Chronic = non - overt DICMay be unrecognized clinically
Acute = overt DIClife threatening bleedingor multiple organ failure
Sub-Acute and Non-Overt DIC Clinical Findings
Compensated non-overt DIC Steady low level or intermittent activation
bull Compensated by increased production of coagulation components and platelets
Few or no clinical signs or multiple microvascular thrombosis sometimes not clinically obvious
Risk of decompensation leading to overt DIC
Pathophysiology of Overt DIC
Massive activation of coagulation and fibrinolysis
Does not allow for compensatory efforts
Rapid depletion of coagulation factors inhibitors and platelets
Thrombosis multiple organ failures
Bleeding complications and shock
Physiopathology of DIC ndash Overt DIC Findings
Thrombin generation
Thrombosis
Renal liver respiratory failures coma skin necrosis gangrene venous thromboembolism hypotension edema
Cytokine and kinin generation (shock)bull Tachycardia hypotension edema
Plasmin generationHemorrhage
bull Spontaneous bruising petechiae intracranial gastrointestinal and respiratory tract bleeding persistent bleeding at venipuncture sites at surgical wounds
bull Tachycardia hypotension edema
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Pathogenesis Pathways in DIC
Cytokines
TF-mediated dysfunctional impairedthrombin anticoagulant fibrinolysisgeneration mechanism due to PAI-1 deficiency
fibrin inadequateformation fibrin removal
Fibrin deposition
Inflammation
Coagulation
Stago Celebrates Lab Week 2017
NA
Stago 247 Educational Webinar Sites
wwwstago-edvantagecomUS based KOLsPACE accredited ndash all 1 hourAccessible from mobile devicesVirtual exhibit hall
wwwstagowebinarscomMostly European KOLs30 ndash 45 min including 15 min discussion
Stago Educational Apps
HaemoscoreClinical scoring algorithmsApple and AndroidTablet or phone
iHemostasisCoagulation diagramsCase studiesApple amp AndroidTablet only
BREAK
Diagnostic and Management Approach for DIC
Diagnosis of DIC
Clinical diagnosis is obvious in cases of overt DIC
Laboratory tests are necessary To makeconfirm the diagnosis To assess stage of the patient To assess the treatment efficacy
Lab Diagnosis of DIC ndash Markers of Factor Consumption
Routinescreening assays PT APTT Platelets Fibrinogen Thrombin time
Other coagulation assays Factor assays AntithrombinGeneration of Thrombin FMFSPsGeneration of Plasmin D-dimer FDPs
Important to recognize simultaneous formation of thrombin and plasmin
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122
Lab Diagnosis of DIC ndash Screening Tests
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122
Platelet count usually decreasedPT abnormal in 70 of cases (short half-life of FVII)APTT abnormal in 50 of casesThrombin time usually prolonged in overt DIC normal in non-overt DIC and no relation with syndrome severityFibrinogen low in lt 50 of cases sensitivity 22 specificity 87 overall predictive value 64 Normal fibrinogen level should not exclude DIC diagnosis (acute phase reactant initial high
fibrinogen level) repeat testing assesses progression
Screening tests not clinically specific or sensitive for DIC
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Laboratory Changes in Overt DIC
DIC Diagnostic Practices Over Time
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
British Journal of Haematology Overt DIC Score
Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
ISTH Step by Step DIC Algorithm
Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6
US Based Validation of ISTH DIC Score
When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Differential Diagnosis in DIC
aHUS atypical hemolytic uremic syndrome
HUS hemolytic uremic syndrome
HIT heparin-induced thrombocytopenia
ITP immune thrombocytopenic purpura
TTP thrombotic thrombocytopenic purpura
DIC and MAHA
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)
When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation
DIC Management Goals
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction
DIC Management and Treatment
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)
requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)
Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia
DIC Management Strategies
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant Factor Concentrate Treatment
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis
Anticoagulant Factor Concentrate Treatment Trials
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise
Markers of Thrombin amp Plasmin Generation in DIC
D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC
Cut-off value
Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen
degradation products Sensitive assay typically with cutoff adapted for DIC
D-dimer FDPs and DIC
D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC
Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80
Follow Up of DIC State of Disease
Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8
Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility
FMD-Dimer in DIC Major Differences
onset of thrombosis
days
Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8
FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)
D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)
of Abnormal Results in Patients with Confirmed and Suspected DIC
0
20
40
60
80
100
94 85 90N = 62
Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32
Positivity of Test Results ISTH Score and Disease State
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
Red bar positive for 2 points of DIC score
Pink bar positive for 1-2 points of DIC score
HT hematopoietic tumor
IF infection
SC solid cancer
Markers in Patients with or without DIC
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
HT hematopoietic tumorIF infectionSC solid cancer
Comparing an Automated FM vs Manual FSP Test
Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71
Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)
Automated (Mitsubishi) vs Automated (Stago)
In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago
Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC
Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
Non Overt DIC Overt DIC
AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC
Trends in Markers of DIC for Different Patients
Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00
Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients
Trends in Markers of DIC for Different Patients
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes
28 day outcome survival
28 day outcome death
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines
DIC Case Studies
Case Study 1 - Presentation
18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE
WBC count 77 KμL 423 ndash 907 x KμL
RBC count 17 MμL 137 ndash 175 x MμL
Hemoglobin 67 gdL 137 ndash 175 gdL
Hematocrit 195 401 ndash 510
MCV 95 fL 790 ndash 922 fL
MPV 12 fL 94 ndash 124 fL
Platelet count 9 KμL 161 ndash 347 KμL
Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0
Lymphocytes monocytes eosinophils basophils all below normal range
PT 47 sec (corrected on mixing study) 116 ndash 152 sec
APTT 75 sec (corrected on mixing study) 253 ndash 373 sec
Fibrinogen lt 76 mgdL 177 ndash 466 mgdL
D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Microscopy
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Arrow shows giant platelets in this peripheral smear Promyelocytes apparent
Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)
DIC due to TF release by APL blasts
Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases
Transfusions to replace factors along with platelets and RBCs during APL treatment
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started
Case Study 2 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L
PT 30 sec 113 ndash 146 sec
APTT 75 sec 25 ndash 34 sec
D-dimer 078 microgml FEU lt050 microgml FEU
Fibrinogen 92 mgdl 150-400 mgdl
pH 728 738 to 742
PaO2 570 mmHg 80-100 mmHg
WBC 33 times 103mm3 40-11 times 103mm3
ALT 111 IUL 0ndash34 IUL
AST 61 IUL 0ndash34 IUL
BUN 303 mgdL 08-13 mgdL
Case Study 2 ndash Lab Results
Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures
Case Study 2 ndash Diagnosis
60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior
Case Study 3 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L
PT 228 sec 113 ndash 146 sec
APTT 45 sec 25 ndash 34 sec
D-dimer 080 microgml FEU lt050 microgmL FEU
Fibrinogen 82 mgdL 150-400 mgdL
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 134 gdL 14-16 gdL
WBC 81 times 103mm3 40-11 times 103mm3
ALT 32 IUL 0ndash34 IUL
AST 28 IUL 0ndash34 IUL
BUN 09 mgdL 08-13 mgdL
Case Study 3 ndash Lab Results
Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment
Case Study 3 ndash Diagnosis and Therapy
Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91
Case Study 4 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L
PT 28 sec 113 ndash 146 sec
APTT 71 sec 25 ndash 34 sec
D-dimer 31 microgmL FEU lt050 microgml FEU
Fibrinogen 92 mgdL 150-400 mgdl
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 158 gdL 14-16 gdL
WBC 71 times 103mm3 40-11 times 103mm3
ALT 60 IUL 0ndash34 IUL
AST 47 IUL 0ndash34 IUL
BUN 38 mgdL 08-13 mgdL
Case Study 4 ndash Lab Results
Lyme disease with DICProvide antibiotics with supportive measures
Case Study 4 ndash Diagnosis
55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis
Case Study 5 ndash Presentation
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
Case Study 5 ndash Lab Results and Time Course
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
TEST RESULT REFERENCE RANGE
Platelet count 33 x 109L 150-450 x 109L
PT 215 sec 103 ndash 128 sec
APTT 44 sec 26 ndash 36 sec
D-dimer 20 microgmL FEU lt025 microgml FEU
Fibrinogen 34 mgdL 200-375 mgdl
FII FV FVIII Low Not reported (NR)
FVII FIX FX vWF Normal NR
Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)
DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic
dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR
(C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen
(D) Illustration demonstrating repair
Case Study 5 ndash Diagnosis and Treatment
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography
Case Study 6 ndash Presentation
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
Case Study 6 ndash Lab Results
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L
PT 63 sec gt control 113 ndash 146 sec
INR 658 1 ndash 125
APTT 80 sec gt control 25 ndash 34 sec
D-dimer gt200 microgmL DDU 02 microgmL DDU
Urine exam Proteinuria and hematuria 150-400 mgdl
Albumin 28 gdL NR
Hb 58 gdL NR
LDH 1196 UL NR
SGPT 144 IU NR
SGOT 88 IU NR
Bilirubin 32 mgdL NR
DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th
day postop
Case Study 6 ndash Diagnosis and Treatment
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure
Case Study 6 ndash Discussion
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Case Study 7 ndash Lab Results vs Time
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
DIC Take Home Messages
Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation
Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers
DIC
Thank you Questions
- Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
- Learning Objectives
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Wound Sealing
- The Three Steps of Hemostasis
- Vessel Wall
- Slide Number 12
- Slide Number 13
- Platelet Structure UnactivatedActivated
- Primary Hemostasis
- Primary Hemostasis Assays
- Slide Number 17
- Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
- Slide Number 19
- Coagulation factors
- Coagulation Assay Mechanisms
- Slide Number 22
- Fibrin Formation
- Slide Number 24
- Fibrinolysis Overview
- Fibrinolysis Overview
- Slide Number 27
- Fibrinolysis Releases D-dimers
- Basic Pathophysiology of DIC
- Disseminated Intravascular Coagulation (DIC)
- Purpura Fulminans with DIC Due to Meningococcal Sepsis
- Clinical Conditions Associated With DIC
- Frequency of DIC in Selected Disease States
- Underlying Diseases in DIC Patients
- Slide Number 36
- Slide Number 37
- Slide Number 38
- Slide Number 39
- Pathophysiology of DIC
- Pathogenesis of DIC in Sepsis
- Host Response in Severe Sepsis
- Organ Failure in Severe Sepsis
- Mechanism of DIC in Organ Failure
- Interaction of Inflammation and Coagulation in Sepsis
- Slide Number 47
- Diverse and Opposing Effects of Thrombin
- Coagulation and Fibrinolysis in DIC
- Mechanism of DIC
- Pathophysiology of DIC
- Pathophysiology of DIC - Mechanism
- Pathophysiology of DIC ndash 2 Types of Clinical pictures
- Sub-Acute and Non-Overt DIC Clinical Findings
- Pathophysiology of Overt DIC
- Physiopathology of DIC ndash Overt DIC Findings
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- BREAK
- Diagnostic and Management Approach for DIC
- Diagnosis of DIC
- Lab Diagnosis of DIC ndash Markers of Factor Consumption
- Lab Diagnosis of DIC ndash Screening Tests
- Slide Number 67
- Slide Number 68
- British Journal of Haematology Overt DIC Score
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- DIC Management Goals
- DIC Management and Treatment
- DIC Management Strategies
- Anticoagulant Factor Concentrate Treatment
- Anticoagulant Factor Concentrate Treatment Trials
- Markers of Thrombin amp Plasmin Generation in DIC
- D-dimer FDPs and DIC
- D-Dimer and FDPs in DIC
- Follow Up of DIC State of Disease
- FMD-Dimer in DIC Major Differences
- of Abnormal Results in Patients with Confirmed and Suspected DIC
- Slide Number 85
- Slide Number 86
- Comparing an Automated FM vs Manual FSP Test
- Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Slide Number 94
- Slide Number 95
- Slide Number 96
- Slide Number 97
- Slide Number 98
- Slide Number 99
- DIC Case Studies
- Case Study 1 - Presentation
- Case Study 1 ndash Lab Results
- Case Study 1 ndash Microscopy
- Case Study 1 ndash Diagnosis and Therapy
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Slide Number 110
- Slide Number 111
- Slide Number 112
- Slide Number 113
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
- Slide Number 124
- Slide Number 125
- DIC Take Home Messages
- Slide Number 127
- Slide Number 128
-
Pathophysiology of DIC
1st step abnormal activation of coagulation Injury of vessel wall cells venous stasis release of large quantities of
thromboplastin influx of activated cells (monocytes macrophages)
Results in an intravascular deposition of fibrin
Morbidity from disseminated microthrombosis in small and midsize vessels leading to multiple organ failure
Second step Consumption and depletion of coagulation factors inhibitors (Protein C
Protein S AT) and platelets Local fibrinolytic response
bull Local plasmin generation dissolves the thrombusbull Disseminated overwhelming fibrinolytic response leading to production of
FDP and D-Dimer
Bleeding
Pathophysiology of DIC - Mechanism
Systemic activation of coagulation
Intravasculardepositionof fibrin
Thrombosis of small and midsize vessels
and organ failure
Depletion of platelets and
coagulation factors
Bleeding
Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92
Pathophysiology of DIC ndash 2 Types of Clinical pictures
Chronic = non - overt DICMay be unrecognized clinically
Acute = overt DIClife threatening bleedingor multiple organ failure
Sub-Acute and Non-Overt DIC Clinical Findings
Compensated non-overt DIC Steady low level or intermittent activation
bull Compensated by increased production of coagulation components and platelets
Few or no clinical signs or multiple microvascular thrombosis sometimes not clinically obvious
Risk of decompensation leading to overt DIC
Pathophysiology of Overt DIC
Massive activation of coagulation and fibrinolysis
Does not allow for compensatory efforts
Rapid depletion of coagulation factors inhibitors and platelets
Thrombosis multiple organ failures
Bleeding complications and shock
Physiopathology of DIC ndash Overt DIC Findings
Thrombin generation
Thrombosis
Renal liver respiratory failures coma skin necrosis gangrene venous thromboembolism hypotension edema
Cytokine and kinin generation (shock)bull Tachycardia hypotension edema
Plasmin generationHemorrhage
bull Spontaneous bruising petechiae intracranial gastrointestinal and respiratory tract bleeding persistent bleeding at venipuncture sites at surgical wounds
bull Tachycardia hypotension edema
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Pathogenesis Pathways in DIC
Cytokines
TF-mediated dysfunctional impairedthrombin anticoagulant fibrinolysisgeneration mechanism due to PAI-1 deficiency
fibrin inadequateformation fibrin removal
Fibrin deposition
Inflammation
Coagulation
Stago Celebrates Lab Week 2017
NA
Stago 247 Educational Webinar Sites
wwwstago-edvantagecomUS based KOLsPACE accredited ndash all 1 hourAccessible from mobile devicesVirtual exhibit hall
wwwstagowebinarscomMostly European KOLs30 ndash 45 min including 15 min discussion
Stago Educational Apps
HaemoscoreClinical scoring algorithmsApple and AndroidTablet or phone
iHemostasisCoagulation diagramsCase studiesApple amp AndroidTablet only
BREAK
Diagnostic and Management Approach for DIC
Diagnosis of DIC
Clinical diagnosis is obvious in cases of overt DIC
Laboratory tests are necessary To makeconfirm the diagnosis To assess stage of the patient To assess the treatment efficacy
Lab Diagnosis of DIC ndash Markers of Factor Consumption
Routinescreening assays PT APTT Platelets Fibrinogen Thrombin time
Other coagulation assays Factor assays AntithrombinGeneration of Thrombin FMFSPsGeneration of Plasmin D-dimer FDPs
Important to recognize simultaneous formation of thrombin and plasmin
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122
Lab Diagnosis of DIC ndash Screening Tests
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122
Platelet count usually decreasedPT abnormal in 70 of cases (short half-life of FVII)APTT abnormal in 50 of casesThrombin time usually prolonged in overt DIC normal in non-overt DIC and no relation with syndrome severityFibrinogen low in lt 50 of cases sensitivity 22 specificity 87 overall predictive value 64 Normal fibrinogen level should not exclude DIC diagnosis (acute phase reactant initial high
fibrinogen level) repeat testing assesses progression
Screening tests not clinically specific or sensitive for DIC
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Laboratory Changes in Overt DIC
DIC Diagnostic Practices Over Time
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
British Journal of Haematology Overt DIC Score
Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
ISTH Step by Step DIC Algorithm
Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6
US Based Validation of ISTH DIC Score
When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Differential Diagnosis in DIC
aHUS atypical hemolytic uremic syndrome
HUS hemolytic uremic syndrome
HIT heparin-induced thrombocytopenia
ITP immune thrombocytopenic purpura
TTP thrombotic thrombocytopenic purpura
DIC and MAHA
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)
When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation
DIC Management Goals
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction
DIC Management and Treatment
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)
requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)
Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia
DIC Management Strategies
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant Factor Concentrate Treatment
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis
Anticoagulant Factor Concentrate Treatment Trials
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise
Markers of Thrombin amp Plasmin Generation in DIC
D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC
Cut-off value
Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen
degradation products Sensitive assay typically with cutoff adapted for DIC
D-dimer FDPs and DIC
D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC
Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80
Follow Up of DIC State of Disease
Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8
Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility
FMD-Dimer in DIC Major Differences
onset of thrombosis
days
Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8
FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)
D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)
of Abnormal Results in Patients with Confirmed and Suspected DIC
0
20
40
60
80
100
94 85 90N = 62
Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32
Positivity of Test Results ISTH Score and Disease State
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
Red bar positive for 2 points of DIC score
Pink bar positive for 1-2 points of DIC score
HT hematopoietic tumor
IF infection
SC solid cancer
Markers in Patients with or without DIC
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
HT hematopoietic tumorIF infectionSC solid cancer
Comparing an Automated FM vs Manual FSP Test
Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71
Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)
Automated (Mitsubishi) vs Automated (Stago)
In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago
Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC
Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
Non Overt DIC Overt DIC
AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC
Trends in Markers of DIC for Different Patients
Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00
Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients
Trends in Markers of DIC for Different Patients
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes
28 day outcome survival
28 day outcome death
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines
DIC Case Studies
Case Study 1 - Presentation
18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE
WBC count 77 KμL 423 ndash 907 x KμL
RBC count 17 MμL 137 ndash 175 x MμL
Hemoglobin 67 gdL 137 ndash 175 gdL
Hematocrit 195 401 ndash 510
MCV 95 fL 790 ndash 922 fL
MPV 12 fL 94 ndash 124 fL
Platelet count 9 KμL 161 ndash 347 KμL
Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0
Lymphocytes monocytes eosinophils basophils all below normal range
PT 47 sec (corrected on mixing study) 116 ndash 152 sec
APTT 75 sec (corrected on mixing study) 253 ndash 373 sec
Fibrinogen lt 76 mgdL 177 ndash 466 mgdL
D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Microscopy
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Arrow shows giant platelets in this peripheral smear Promyelocytes apparent
Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)
DIC due to TF release by APL blasts
Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases
Transfusions to replace factors along with platelets and RBCs during APL treatment
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started
Case Study 2 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L
PT 30 sec 113 ndash 146 sec
APTT 75 sec 25 ndash 34 sec
D-dimer 078 microgml FEU lt050 microgml FEU
Fibrinogen 92 mgdl 150-400 mgdl
pH 728 738 to 742
PaO2 570 mmHg 80-100 mmHg
WBC 33 times 103mm3 40-11 times 103mm3
ALT 111 IUL 0ndash34 IUL
AST 61 IUL 0ndash34 IUL
BUN 303 mgdL 08-13 mgdL
Case Study 2 ndash Lab Results
Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures
Case Study 2 ndash Diagnosis
60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior
Case Study 3 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L
PT 228 sec 113 ndash 146 sec
APTT 45 sec 25 ndash 34 sec
D-dimer 080 microgml FEU lt050 microgmL FEU
Fibrinogen 82 mgdL 150-400 mgdL
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 134 gdL 14-16 gdL
WBC 81 times 103mm3 40-11 times 103mm3
ALT 32 IUL 0ndash34 IUL
AST 28 IUL 0ndash34 IUL
BUN 09 mgdL 08-13 mgdL
Case Study 3 ndash Lab Results
Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment
Case Study 3 ndash Diagnosis and Therapy
Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91
Case Study 4 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L
PT 28 sec 113 ndash 146 sec
APTT 71 sec 25 ndash 34 sec
D-dimer 31 microgmL FEU lt050 microgml FEU
Fibrinogen 92 mgdL 150-400 mgdl
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 158 gdL 14-16 gdL
WBC 71 times 103mm3 40-11 times 103mm3
ALT 60 IUL 0ndash34 IUL
AST 47 IUL 0ndash34 IUL
BUN 38 mgdL 08-13 mgdL
Case Study 4 ndash Lab Results
Lyme disease with DICProvide antibiotics with supportive measures
Case Study 4 ndash Diagnosis
55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis
Case Study 5 ndash Presentation
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
Case Study 5 ndash Lab Results and Time Course
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
TEST RESULT REFERENCE RANGE
Platelet count 33 x 109L 150-450 x 109L
PT 215 sec 103 ndash 128 sec
APTT 44 sec 26 ndash 36 sec
D-dimer 20 microgmL FEU lt025 microgml FEU
Fibrinogen 34 mgdL 200-375 mgdl
FII FV FVIII Low Not reported (NR)
FVII FIX FX vWF Normal NR
Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)
DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic
dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR
(C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen
(D) Illustration demonstrating repair
Case Study 5 ndash Diagnosis and Treatment
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography
Case Study 6 ndash Presentation
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
Case Study 6 ndash Lab Results
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L
PT 63 sec gt control 113 ndash 146 sec
INR 658 1 ndash 125
APTT 80 sec gt control 25 ndash 34 sec
D-dimer gt200 microgmL DDU 02 microgmL DDU
Urine exam Proteinuria and hematuria 150-400 mgdl
Albumin 28 gdL NR
Hb 58 gdL NR
LDH 1196 UL NR
SGPT 144 IU NR
SGOT 88 IU NR
Bilirubin 32 mgdL NR
DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th
day postop
Case Study 6 ndash Diagnosis and Treatment
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure
Case Study 6 ndash Discussion
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Case Study 7 ndash Lab Results vs Time
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
DIC Take Home Messages
Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation
Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers
DIC
Thank you Questions
- Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
- Learning Objectives
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Wound Sealing
- The Three Steps of Hemostasis
- Vessel Wall
- Slide Number 12
- Slide Number 13
- Platelet Structure UnactivatedActivated
- Primary Hemostasis
- Primary Hemostasis Assays
- Slide Number 17
- Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
- Slide Number 19
- Coagulation factors
- Coagulation Assay Mechanisms
- Slide Number 22
- Fibrin Formation
- Slide Number 24
- Fibrinolysis Overview
- Fibrinolysis Overview
- Slide Number 27
- Fibrinolysis Releases D-dimers
- Basic Pathophysiology of DIC
- Disseminated Intravascular Coagulation (DIC)
- Purpura Fulminans with DIC Due to Meningococcal Sepsis
- Clinical Conditions Associated With DIC
- Frequency of DIC in Selected Disease States
- Underlying Diseases in DIC Patients
- Slide Number 36
- Slide Number 37
- Slide Number 38
- Slide Number 39
- Pathophysiology of DIC
- Pathogenesis of DIC in Sepsis
- Host Response in Severe Sepsis
- Organ Failure in Severe Sepsis
- Mechanism of DIC in Organ Failure
- Interaction of Inflammation and Coagulation in Sepsis
- Slide Number 47
- Diverse and Opposing Effects of Thrombin
- Coagulation and Fibrinolysis in DIC
- Mechanism of DIC
- Pathophysiology of DIC
- Pathophysiology of DIC - Mechanism
- Pathophysiology of DIC ndash 2 Types of Clinical pictures
- Sub-Acute and Non-Overt DIC Clinical Findings
- Pathophysiology of Overt DIC
- Physiopathology of DIC ndash Overt DIC Findings
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- BREAK
- Diagnostic and Management Approach for DIC
- Diagnosis of DIC
- Lab Diagnosis of DIC ndash Markers of Factor Consumption
- Lab Diagnosis of DIC ndash Screening Tests
- Slide Number 67
- Slide Number 68
- British Journal of Haematology Overt DIC Score
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- DIC Management Goals
- DIC Management and Treatment
- DIC Management Strategies
- Anticoagulant Factor Concentrate Treatment
- Anticoagulant Factor Concentrate Treatment Trials
- Markers of Thrombin amp Plasmin Generation in DIC
- D-dimer FDPs and DIC
- D-Dimer and FDPs in DIC
- Follow Up of DIC State of Disease
- FMD-Dimer in DIC Major Differences
- of Abnormal Results in Patients with Confirmed and Suspected DIC
- Slide Number 85
- Slide Number 86
- Comparing an Automated FM vs Manual FSP Test
- Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Slide Number 94
- Slide Number 95
- Slide Number 96
- Slide Number 97
- Slide Number 98
- Slide Number 99
- DIC Case Studies
- Case Study 1 - Presentation
- Case Study 1 ndash Lab Results
- Case Study 1 ndash Microscopy
- Case Study 1 ndash Diagnosis and Therapy
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Slide Number 110
- Slide Number 111
- Slide Number 112
- Slide Number 113
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
- Slide Number 124
- Slide Number 125
- DIC Take Home Messages
- Slide Number 127
- Slide Number 128
-
Pathophysiology of DIC - Mechanism
Systemic activation of coagulation
Intravasculardepositionof fibrin
Thrombosis of small and midsize vessels
and organ failure
Depletion of platelets and
coagulation factors
Bleeding
Levi M Ten Cate H Disseminated intravascular coagulation N Engl J Med 1999 341 586-92
Pathophysiology of DIC ndash 2 Types of Clinical pictures
Chronic = non - overt DICMay be unrecognized clinically
Acute = overt DIClife threatening bleedingor multiple organ failure
Sub-Acute and Non-Overt DIC Clinical Findings
Compensated non-overt DIC Steady low level or intermittent activation
bull Compensated by increased production of coagulation components and platelets
Few or no clinical signs or multiple microvascular thrombosis sometimes not clinically obvious
Risk of decompensation leading to overt DIC
Pathophysiology of Overt DIC
Massive activation of coagulation and fibrinolysis
Does not allow for compensatory efforts
Rapid depletion of coagulation factors inhibitors and platelets
Thrombosis multiple organ failures
Bleeding complications and shock
Physiopathology of DIC ndash Overt DIC Findings
Thrombin generation
Thrombosis
Renal liver respiratory failures coma skin necrosis gangrene venous thromboembolism hypotension edema
Cytokine and kinin generation (shock)bull Tachycardia hypotension edema
Plasmin generationHemorrhage
bull Spontaneous bruising petechiae intracranial gastrointestinal and respiratory tract bleeding persistent bleeding at venipuncture sites at surgical wounds
bull Tachycardia hypotension edema
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Pathogenesis Pathways in DIC
Cytokines
TF-mediated dysfunctional impairedthrombin anticoagulant fibrinolysisgeneration mechanism due to PAI-1 deficiency
fibrin inadequateformation fibrin removal
Fibrin deposition
Inflammation
Coagulation
Stago Celebrates Lab Week 2017
NA
Stago 247 Educational Webinar Sites
wwwstago-edvantagecomUS based KOLsPACE accredited ndash all 1 hourAccessible from mobile devicesVirtual exhibit hall
wwwstagowebinarscomMostly European KOLs30 ndash 45 min including 15 min discussion
Stago Educational Apps
HaemoscoreClinical scoring algorithmsApple and AndroidTablet or phone
iHemostasisCoagulation diagramsCase studiesApple amp AndroidTablet only
BREAK
Diagnostic and Management Approach for DIC
Diagnosis of DIC
Clinical diagnosis is obvious in cases of overt DIC
Laboratory tests are necessary To makeconfirm the diagnosis To assess stage of the patient To assess the treatment efficacy
Lab Diagnosis of DIC ndash Markers of Factor Consumption
Routinescreening assays PT APTT Platelets Fibrinogen Thrombin time
Other coagulation assays Factor assays AntithrombinGeneration of Thrombin FMFSPsGeneration of Plasmin D-dimer FDPs
Important to recognize simultaneous formation of thrombin and plasmin
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122
Lab Diagnosis of DIC ndash Screening Tests
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122
Platelet count usually decreasedPT abnormal in 70 of cases (short half-life of FVII)APTT abnormal in 50 of casesThrombin time usually prolonged in overt DIC normal in non-overt DIC and no relation with syndrome severityFibrinogen low in lt 50 of cases sensitivity 22 specificity 87 overall predictive value 64 Normal fibrinogen level should not exclude DIC diagnosis (acute phase reactant initial high
fibrinogen level) repeat testing assesses progression
Screening tests not clinically specific or sensitive for DIC
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Laboratory Changes in Overt DIC
DIC Diagnostic Practices Over Time
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
British Journal of Haematology Overt DIC Score
Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
ISTH Step by Step DIC Algorithm
Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6
US Based Validation of ISTH DIC Score
When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Differential Diagnosis in DIC
aHUS atypical hemolytic uremic syndrome
HUS hemolytic uremic syndrome
HIT heparin-induced thrombocytopenia
ITP immune thrombocytopenic purpura
TTP thrombotic thrombocytopenic purpura
DIC and MAHA
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)
When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation
DIC Management Goals
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction
DIC Management and Treatment
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)
requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)
Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia
DIC Management Strategies
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant Factor Concentrate Treatment
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis
Anticoagulant Factor Concentrate Treatment Trials
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise
Markers of Thrombin amp Plasmin Generation in DIC
D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC
Cut-off value
Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen
degradation products Sensitive assay typically with cutoff adapted for DIC
D-dimer FDPs and DIC
D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC
Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80
Follow Up of DIC State of Disease
Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8
Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility
FMD-Dimer in DIC Major Differences
onset of thrombosis
days
Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8
FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)
D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)
of Abnormal Results in Patients with Confirmed and Suspected DIC
0
20
40
60
80
100
94 85 90N = 62
Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32
Positivity of Test Results ISTH Score and Disease State
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
Red bar positive for 2 points of DIC score
Pink bar positive for 1-2 points of DIC score
HT hematopoietic tumor
IF infection
SC solid cancer
Markers in Patients with or without DIC
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
HT hematopoietic tumorIF infectionSC solid cancer
Comparing an Automated FM vs Manual FSP Test
Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71
Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)
Automated (Mitsubishi) vs Automated (Stago)
In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago
Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC
Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
Non Overt DIC Overt DIC
AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC
Trends in Markers of DIC for Different Patients
Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00
Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients
Trends in Markers of DIC for Different Patients
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes
28 day outcome survival
28 day outcome death
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines
DIC Case Studies
Case Study 1 - Presentation
18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE
WBC count 77 KμL 423 ndash 907 x KμL
RBC count 17 MμL 137 ndash 175 x MμL
Hemoglobin 67 gdL 137 ndash 175 gdL
Hematocrit 195 401 ndash 510
MCV 95 fL 790 ndash 922 fL
MPV 12 fL 94 ndash 124 fL
Platelet count 9 KμL 161 ndash 347 KμL
Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0
Lymphocytes monocytes eosinophils basophils all below normal range
PT 47 sec (corrected on mixing study) 116 ndash 152 sec
APTT 75 sec (corrected on mixing study) 253 ndash 373 sec
Fibrinogen lt 76 mgdL 177 ndash 466 mgdL
D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Microscopy
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Arrow shows giant platelets in this peripheral smear Promyelocytes apparent
Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)
DIC due to TF release by APL blasts
Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases
Transfusions to replace factors along with platelets and RBCs during APL treatment
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started
Case Study 2 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L
PT 30 sec 113 ndash 146 sec
APTT 75 sec 25 ndash 34 sec
D-dimer 078 microgml FEU lt050 microgml FEU
Fibrinogen 92 mgdl 150-400 mgdl
pH 728 738 to 742
PaO2 570 mmHg 80-100 mmHg
WBC 33 times 103mm3 40-11 times 103mm3
ALT 111 IUL 0ndash34 IUL
AST 61 IUL 0ndash34 IUL
BUN 303 mgdL 08-13 mgdL
Case Study 2 ndash Lab Results
Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures
Case Study 2 ndash Diagnosis
60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior
Case Study 3 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L
PT 228 sec 113 ndash 146 sec
APTT 45 sec 25 ndash 34 sec
D-dimer 080 microgml FEU lt050 microgmL FEU
Fibrinogen 82 mgdL 150-400 mgdL
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 134 gdL 14-16 gdL
WBC 81 times 103mm3 40-11 times 103mm3
ALT 32 IUL 0ndash34 IUL
AST 28 IUL 0ndash34 IUL
BUN 09 mgdL 08-13 mgdL
Case Study 3 ndash Lab Results
Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment
Case Study 3 ndash Diagnosis and Therapy
Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91
Case Study 4 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L
PT 28 sec 113 ndash 146 sec
APTT 71 sec 25 ndash 34 sec
D-dimer 31 microgmL FEU lt050 microgml FEU
Fibrinogen 92 mgdL 150-400 mgdl
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 158 gdL 14-16 gdL
WBC 71 times 103mm3 40-11 times 103mm3
ALT 60 IUL 0ndash34 IUL
AST 47 IUL 0ndash34 IUL
BUN 38 mgdL 08-13 mgdL
Case Study 4 ndash Lab Results
Lyme disease with DICProvide antibiotics with supportive measures
Case Study 4 ndash Diagnosis
55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis
Case Study 5 ndash Presentation
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
Case Study 5 ndash Lab Results and Time Course
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
TEST RESULT REFERENCE RANGE
Platelet count 33 x 109L 150-450 x 109L
PT 215 sec 103 ndash 128 sec
APTT 44 sec 26 ndash 36 sec
D-dimer 20 microgmL FEU lt025 microgml FEU
Fibrinogen 34 mgdL 200-375 mgdl
FII FV FVIII Low Not reported (NR)
FVII FIX FX vWF Normal NR
Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)
DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic
dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR
(C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen
(D) Illustration demonstrating repair
Case Study 5 ndash Diagnosis and Treatment
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography
Case Study 6 ndash Presentation
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
Case Study 6 ndash Lab Results
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L
PT 63 sec gt control 113 ndash 146 sec
INR 658 1 ndash 125
APTT 80 sec gt control 25 ndash 34 sec
D-dimer gt200 microgmL DDU 02 microgmL DDU
Urine exam Proteinuria and hematuria 150-400 mgdl
Albumin 28 gdL NR
Hb 58 gdL NR
LDH 1196 UL NR
SGPT 144 IU NR
SGOT 88 IU NR
Bilirubin 32 mgdL NR
DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th
day postop
Case Study 6 ndash Diagnosis and Treatment
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure
Case Study 6 ndash Discussion
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Case Study 7 ndash Lab Results vs Time
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
DIC Take Home Messages
Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation
Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers
DIC
Thank you Questions
- Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
- Learning Objectives
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Wound Sealing
- The Three Steps of Hemostasis
- Vessel Wall
- Slide Number 12
- Slide Number 13
- Platelet Structure UnactivatedActivated
- Primary Hemostasis
- Primary Hemostasis Assays
- Slide Number 17
- Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
- Slide Number 19
- Coagulation factors
- Coagulation Assay Mechanisms
- Slide Number 22
- Fibrin Formation
- Slide Number 24
- Fibrinolysis Overview
- Fibrinolysis Overview
- Slide Number 27
- Fibrinolysis Releases D-dimers
- Basic Pathophysiology of DIC
- Disseminated Intravascular Coagulation (DIC)
- Purpura Fulminans with DIC Due to Meningococcal Sepsis
- Clinical Conditions Associated With DIC
- Frequency of DIC in Selected Disease States
- Underlying Diseases in DIC Patients
- Slide Number 36
- Slide Number 37
- Slide Number 38
- Slide Number 39
- Pathophysiology of DIC
- Pathogenesis of DIC in Sepsis
- Host Response in Severe Sepsis
- Organ Failure in Severe Sepsis
- Mechanism of DIC in Organ Failure
- Interaction of Inflammation and Coagulation in Sepsis
- Slide Number 47
- Diverse and Opposing Effects of Thrombin
- Coagulation and Fibrinolysis in DIC
- Mechanism of DIC
- Pathophysiology of DIC
- Pathophysiology of DIC - Mechanism
- Pathophysiology of DIC ndash 2 Types of Clinical pictures
- Sub-Acute and Non-Overt DIC Clinical Findings
- Pathophysiology of Overt DIC
- Physiopathology of DIC ndash Overt DIC Findings
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- BREAK
- Diagnostic and Management Approach for DIC
- Diagnosis of DIC
- Lab Diagnosis of DIC ndash Markers of Factor Consumption
- Lab Diagnosis of DIC ndash Screening Tests
- Slide Number 67
- Slide Number 68
- British Journal of Haematology Overt DIC Score
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- DIC Management Goals
- DIC Management and Treatment
- DIC Management Strategies
- Anticoagulant Factor Concentrate Treatment
- Anticoagulant Factor Concentrate Treatment Trials
- Markers of Thrombin amp Plasmin Generation in DIC
- D-dimer FDPs and DIC
- D-Dimer and FDPs in DIC
- Follow Up of DIC State of Disease
- FMD-Dimer in DIC Major Differences
- of Abnormal Results in Patients with Confirmed and Suspected DIC
- Slide Number 85
- Slide Number 86
- Comparing an Automated FM vs Manual FSP Test
- Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Slide Number 94
- Slide Number 95
- Slide Number 96
- Slide Number 97
- Slide Number 98
- Slide Number 99
- DIC Case Studies
- Case Study 1 - Presentation
- Case Study 1 ndash Lab Results
- Case Study 1 ndash Microscopy
- Case Study 1 ndash Diagnosis and Therapy
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Slide Number 110
- Slide Number 111
- Slide Number 112
- Slide Number 113
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
- Slide Number 124
- Slide Number 125
- DIC Take Home Messages
- Slide Number 127
- Slide Number 128
-
Pathophysiology of DIC ndash 2 Types of Clinical pictures
Chronic = non - overt DICMay be unrecognized clinically
Acute = overt DIClife threatening bleedingor multiple organ failure
Sub-Acute and Non-Overt DIC Clinical Findings
Compensated non-overt DIC Steady low level or intermittent activation
bull Compensated by increased production of coagulation components and platelets
Few or no clinical signs or multiple microvascular thrombosis sometimes not clinically obvious
Risk of decompensation leading to overt DIC
Pathophysiology of Overt DIC
Massive activation of coagulation and fibrinolysis
Does not allow for compensatory efforts
Rapid depletion of coagulation factors inhibitors and platelets
Thrombosis multiple organ failures
Bleeding complications and shock
Physiopathology of DIC ndash Overt DIC Findings
Thrombin generation
Thrombosis
Renal liver respiratory failures coma skin necrosis gangrene venous thromboembolism hypotension edema
Cytokine and kinin generation (shock)bull Tachycardia hypotension edema
Plasmin generationHemorrhage
bull Spontaneous bruising petechiae intracranial gastrointestinal and respiratory tract bleeding persistent bleeding at venipuncture sites at surgical wounds
bull Tachycardia hypotension edema
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Pathogenesis Pathways in DIC
Cytokines
TF-mediated dysfunctional impairedthrombin anticoagulant fibrinolysisgeneration mechanism due to PAI-1 deficiency
fibrin inadequateformation fibrin removal
Fibrin deposition
Inflammation
Coagulation
Stago Celebrates Lab Week 2017
NA
Stago 247 Educational Webinar Sites
wwwstago-edvantagecomUS based KOLsPACE accredited ndash all 1 hourAccessible from mobile devicesVirtual exhibit hall
wwwstagowebinarscomMostly European KOLs30 ndash 45 min including 15 min discussion
Stago Educational Apps
HaemoscoreClinical scoring algorithmsApple and AndroidTablet or phone
iHemostasisCoagulation diagramsCase studiesApple amp AndroidTablet only
BREAK
Diagnostic and Management Approach for DIC
Diagnosis of DIC
Clinical diagnosis is obvious in cases of overt DIC
Laboratory tests are necessary To makeconfirm the diagnosis To assess stage of the patient To assess the treatment efficacy
Lab Diagnosis of DIC ndash Markers of Factor Consumption
Routinescreening assays PT APTT Platelets Fibrinogen Thrombin time
Other coagulation assays Factor assays AntithrombinGeneration of Thrombin FMFSPsGeneration of Plasmin D-dimer FDPs
Important to recognize simultaneous formation of thrombin and plasmin
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122
Lab Diagnosis of DIC ndash Screening Tests
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122
Platelet count usually decreasedPT abnormal in 70 of cases (short half-life of FVII)APTT abnormal in 50 of casesThrombin time usually prolonged in overt DIC normal in non-overt DIC and no relation with syndrome severityFibrinogen low in lt 50 of cases sensitivity 22 specificity 87 overall predictive value 64 Normal fibrinogen level should not exclude DIC diagnosis (acute phase reactant initial high
fibrinogen level) repeat testing assesses progression
Screening tests not clinically specific or sensitive for DIC
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Laboratory Changes in Overt DIC
DIC Diagnostic Practices Over Time
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
British Journal of Haematology Overt DIC Score
Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
ISTH Step by Step DIC Algorithm
Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6
US Based Validation of ISTH DIC Score
When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Differential Diagnosis in DIC
aHUS atypical hemolytic uremic syndrome
HUS hemolytic uremic syndrome
HIT heparin-induced thrombocytopenia
ITP immune thrombocytopenic purpura
TTP thrombotic thrombocytopenic purpura
DIC and MAHA
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)
When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation
DIC Management Goals
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction
DIC Management and Treatment
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)
requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)
Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia
DIC Management Strategies
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant Factor Concentrate Treatment
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis
Anticoagulant Factor Concentrate Treatment Trials
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise
Markers of Thrombin amp Plasmin Generation in DIC
D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC
Cut-off value
Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen
degradation products Sensitive assay typically with cutoff adapted for DIC
D-dimer FDPs and DIC
D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC
Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80
Follow Up of DIC State of Disease
Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8
Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility
FMD-Dimer in DIC Major Differences
onset of thrombosis
days
Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8
FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)
D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)
of Abnormal Results in Patients with Confirmed and Suspected DIC
0
20
40
60
80
100
94 85 90N = 62
Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32
Positivity of Test Results ISTH Score and Disease State
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
Red bar positive for 2 points of DIC score
Pink bar positive for 1-2 points of DIC score
HT hematopoietic tumor
IF infection
SC solid cancer
Markers in Patients with or without DIC
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
HT hematopoietic tumorIF infectionSC solid cancer
Comparing an Automated FM vs Manual FSP Test
Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71
Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)
Automated (Mitsubishi) vs Automated (Stago)
In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago
Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC
Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
Non Overt DIC Overt DIC
AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC
Trends in Markers of DIC for Different Patients
Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00
Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients
Trends in Markers of DIC for Different Patients
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes
28 day outcome survival
28 day outcome death
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines
DIC Case Studies
Case Study 1 - Presentation
18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE
WBC count 77 KμL 423 ndash 907 x KμL
RBC count 17 MμL 137 ndash 175 x MμL
Hemoglobin 67 gdL 137 ndash 175 gdL
Hematocrit 195 401 ndash 510
MCV 95 fL 790 ndash 922 fL
MPV 12 fL 94 ndash 124 fL
Platelet count 9 KμL 161 ndash 347 KμL
Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0
Lymphocytes monocytes eosinophils basophils all below normal range
PT 47 sec (corrected on mixing study) 116 ndash 152 sec
APTT 75 sec (corrected on mixing study) 253 ndash 373 sec
Fibrinogen lt 76 mgdL 177 ndash 466 mgdL
D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Microscopy
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Arrow shows giant platelets in this peripheral smear Promyelocytes apparent
Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)
DIC due to TF release by APL blasts
Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases
Transfusions to replace factors along with platelets and RBCs during APL treatment
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started
Case Study 2 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L
PT 30 sec 113 ndash 146 sec
APTT 75 sec 25 ndash 34 sec
D-dimer 078 microgml FEU lt050 microgml FEU
Fibrinogen 92 mgdl 150-400 mgdl
pH 728 738 to 742
PaO2 570 mmHg 80-100 mmHg
WBC 33 times 103mm3 40-11 times 103mm3
ALT 111 IUL 0ndash34 IUL
AST 61 IUL 0ndash34 IUL
BUN 303 mgdL 08-13 mgdL
Case Study 2 ndash Lab Results
Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures
Case Study 2 ndash Diagnosis
60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior
Case Study 3 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L
PT 228 sec 113 ndash 146 sec
APTT 45 sec 25 ndash 34 sec
D-dimer 080 microgml FEU lt050 microgmL FEU
Fibrinogen 82 mgdL 150-400 mgdL
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 134 gdL 14-16 gdL
WBC 81 times 103mm3 40-11 times 103mm3
ALT 32 IUL 0ndash34 IUL
AST 28 IUL 0ndash34 IUL
BUN 09 mgdL 08-13 mgdL
Case Study 3 ndash Lab Results
Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment
Case Study 3 ndash Diagnosis and Therapy
Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91
Case Study 4 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L
PT 28 sec 113 ndash 146 sec
APTT 71 sec 25 ndash 34 sec
D-dimer 31 microgmL FEU lt050 microgml FEU
Fibrinogen 92 mgdL 150-400 mgdl
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 158 gdL 14-16 gdL
WBC 71 times 103mm3 40-11 times 103mm3
ALT 60 IUL 0ndash34 IUL
AST 47 IUL 0ndash34 IUL
BUN 38 mgdL 08-13 mgdL
Case Study 4 ndash Lab Results
Lyme disease with DICProvide antibiotics with supportive measures
Case Study 4 ndash Diagnosis
55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis
Case Study 5 ndash Presentation
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
Case Study 5 ndash Lab Results and Time Course
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
TEST RESULT REFERENCE RANGE
Platelet count 33 x 109L 150-450 x 109L
PT 215 sec 103 ndash 128 sec
APTT 44 sec 26 ndash 36 sec
D-dimer 20 microgmL FEU lt025 microgml FEU
Fibrinogen 34 mgdL 200-375 mgdl
FII FV FVIII Low Not reported (NR)
FVII FIX FX vWF Normal NR
Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)
DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic
dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR
(C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen
(D) Illustration demonstrating repair
Case Study 5 ndash Diagnosis and Treatment
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography
Case Study 6 ndash Presentation
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
Case Study 6 ndash Lab Results
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L
PT 63 sec gt control 113 ndash 146 sec
INR 658 1 ndash 125
APTT 80 sec gt control 25 ndash 34 sec
D-dimer gt200 microgmL DDU 02 microgmL DDU
Urine exam Proteinuria and hematuria 150-400 mgdl
Albumin 28 gdL NR
Hb 58 gdL NR
LDH 1196 UL NR
SGPT 144 IU NR
SGOT 88 IU NR
Bilirubin 32 mgdL NR
DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th
day postop
Case Study 6 ndash Diagnosis and Treatment
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure
Case Study 6 ndash Discussion
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Case Study 7 ndash Lab Results vs Time
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
DIC Take Home Messages
Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation
Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers
DIC
Thank you Questions
- Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
- Learning Objectives
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Wound Sealing
- The Three Steps of Hemostasis
- Vessel Wall
- Slide Number 12
- Slide Number 13
- Platelet Structure UnactivatedActivated
- Primary Hemostasis
- Primary Hemostasis Assays
- Slide Number 17
- Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
- Slide Number 19
- Coagulation factors
- Coagulation Assay Mechanisms
- Slide Number 22
- Fibrin Formation
- Slide Number 24
- Fibrinolysis Overview
- Fibrinolysis Overview
- Slide Number 27
- Fibrinolysis Releases D-dimers
- Basic Pathophysiology of DIC
- Disseminated Intravascular Coagulation (DIC)
- Purpura Fulminans with DIC Due to Meningococcal Sepsis
- Clinical Conditions Associated With DIC
- Frequency of DIC in Selected Disease States
- Underlying Diseases in DIC Patients
- Slide Number 36
- Slide Number 37
- Slide Number 38
- Slide Number 39
- Pathophysiology of DIC
- Pathogenesis of DIC in Sepsis
- Host Response in Severe Sepsis
- Organ Failure in Severe Sepsis
- Mechanism of DIC in Organ Failure
- Interaction of Inflammation and Coagulation in Sepsis
- Slide Number 47
- Diverse and Opposing Effects of Thrombin
- Coagulation and Fibrinolysis in DIC
- Mechanism of DIC
- Pathophysiology of DIC
- Pathophysiology of DIC - Mechanism
- Pathophysiology of DIC ndash 2 Types of Clinical pictures
- Sub-Acute and Non-Overt DIC Clinical Findings
- Pathophysiology of Overt DIC
- Physiopathology of DIC ndash Overt DIC Findings
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- BREAK
- Diagnostic and Management Approach for DIC
- Diagnosis of DIC
- Lab Diagnosis of DIC ndash Markers of Factor Consumption
- Lab Diagnosis of DIC ndash Screening Tests
- Slide Number 67
- Slide Number 68
- British Journal of Haematology Overt DIC Score
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- DIC Management Goals
- DIC Management and Treatment
- DIC Management Strategies
- Anticoagulant Factor Concentrate Treatment
- Anticoagulant Factor Concentrate Treatment Trials
- Markers of Thrombin amp Plasmin Generation in DIC
- D-dimer FDPs and DIC
- D-Dimer and FDPs in DIC
- Follow Up of DIC State of Disease
- FMD-Dimer in DIC Major Differences
- of Abnormal Results in Patients with Confirmed and Suspected DIC
- Slide Number 85
- Slide Number 86
- Comparing an Automated FM vs Manual FSP Test
- Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Slide Number 94
- Slide Number 95
- Slide Number 96
- Slide Number 97
- Slide Number 98
- Slide Number 99
- DIC Case Studies
- Case Study 1 - Presentation
- Case Study 1 ndash Lab Results
- Case Study 1 ndash Microscopy
- Case Study 1 ndash Diagnosis and Therapy
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Slide Number 110
- Slide Number 111
- Slide Number 112
- Slide Number 113
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
- Slide Number 124
- Slide Number 125
- DIC Take Home Messages
- Slide Number 127
- Slide Number 128
-
Sub-Acute and Non-Overt DIC Clinical Findings
Compensated non-overt DIC Steady low level or intermittent activation
bull Compensated by increased production of coagulation components and platelets
Few or no clinical signs or multiple microvascular thrombosis sometimes not clinically obvious
Risk of decompensation leading to overt DIC
Pathophysiology of Overt DIC
Massive activation of coagulation and fibrinolysis
Does not allow for compensatory efforts
Rapid depletion of coagulation factors inhibitors and platelets
Thrombosis multiple organ failures
Bleeding complications and shock
Physiopathology of DIC ndash Overt DIC Findings
Thrombin generation
Thrombosis
Renal liver respiratory failures coma skin necrosis gangrene venous thromboembolism hypotension edema
Cytokine and kinin generation (shock)bull Tachycardia hypotension edema
Plasmin generationHemorrhage
bull Spontaneous bruising petechiae intracranial gastrointestinal and respiratory tract bleeding persistent bleeding at venipuncture sites at surgical wounds
bull Tachycardia hypotension edema
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Pathogenesis Pathways in DIC
Cytokines
TF-mediated dysfunctional impairedthrombin anticoagulant fibrinolysisgeneration mechanism due to PAI-1 deficiency
fibrin inadequateformation fibrin removal
Fibrin deposition
Inflammation
Coagulation
Stago Celebrates Lab Week 2017
NA
Stago 247 Educational Webinar Sites
wwwstago-edvantagecomUS based KOLsPACE accredited ndash all 1 hourAccessible from mobile devicesVirtual exhibit hall
wwwstagowebinarscomMostly European KOLs30 ndash 45 min including 15 min discussion
Stago Educational Apps
HaemoscoreClinical scoring algorithmsApple and AndroidTablet or phone
iHemostasisCoagulation diagramsCase studiesApple amp AndroidTablet only
BREAK
Diagnostic and Management Approach for DIC
Diagnosis of DIC
Clinical diagnosis is obvious in cases of overt DIC
Laboratory tests are necessary To makeconfirm the diagnosis To assess stage of the patient To assess the treatment efficacy
Lab Diagnosis of DIC ndash Markers of Factor Consumption
Routinescreening assays PT APTT Platelets Fibrinogen Thrombin time
Other coagulation assays Factor assays AntithrombinGeneration of Thrombin FMFSPsGeneration of Plasmin D-dimer FDPs
Important to recognize simultaneous formation of thrombin and plasmin
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122
Lab Diagnosis of DIC ndash Screening Tests
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122
Platelet count usually decreasedPT abnormal in 70 of cases (short half-life of FVII)APTT abnormal in 50 of casesThrombin time usually prolonged in overt DIC normal in non-overt DIC and no relation with syndrome severityFibrinogen low in lt 50 of cases sensitivity 22 specificity 87 overall predictive value 64 Normal fibrinogen level should not exclude DIC diagnosis (acute phase reactant initial high
fibrinogen level) repeat testing assesses progression
Screening tests not clinically specific or sensitive for DIC
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Laboratory Changes in Overt DIC
DIC Diagnostic Practices Over Time
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
British Journal of Haematology Overt DIC Score
Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
ISTH Step by Step DIC Algorithm
Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6
US Based Validation of ISTH DIC Score
When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Differential Diagnosis in DIC
aHUS atypical hemolytic uremic syndrome
HUS hemolytic uremic syndrome
HIT heparin-induced thrombocytopenia
ITP immune thrombocytopenic purpura
TTP thrombotic thrombocytopenic purpura
DIC and MAHA
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)
When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation
DIC Management Goals
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction
DIC Management and Treatment
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)
requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)
Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia
DIC Management Strategies
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant Factor Concentrate Treatment
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis
Anticoagulant Factor Concentrate Treatment Trials
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise
Markers of Thrombin amp Plasmin Generation in DIC
D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC
Cut-off value
Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen
degradation products Sensitive assay typically with cutoff adapted for DIC
D-dimer FDPs and DIC
D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC
Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80
Follow Up of DIC State of Disease
Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8
Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility
FMD-Dimer in DIC Major Differences
onset of thrombosis
days
Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8
FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)
D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)
of Abnormal Results in Patients with Confirmed and Suspected DIC
0
20
40
60
80
100
94 85 90N = 62
Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32
Positivity of Test Results ISTH Score and Disease State
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
Red bar positive for 2 points of DIC score
Pink bar positive for 1-2 points of DIC score
HT hematopoietic tumor
IF infection
SC solid cancer
Markers in Patients with or without DIC
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
HT hematopoietic tumorIF infectionSC solid cancer
Comparing an Automated FM vs Manual FSP Test
Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71
Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)
Automated (Mitsubishi) vs Automated (Stago)
In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago
Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC
Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
Non Overt DIC Overt DIC
AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC
Trends in Markers of DIC for Different Patients
Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00
Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients
Trends in Markers of DIC for Different Patients
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes
28 day outcome survival
28 day outcome death
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines
DIC Case Studies
Case Study 1 - Presentation
18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE
WBC count 77 KμL 423 ndash 907 x KμL
RBC count 17 MμL 137 ndash 175 x MμL
Hemoglobin 67 gdL 137 ndash 175 gdL
Hematocrit 195 401 ndash 510
MCV 95 fL 790 ndash 922 fL
MPV 12 fL 94 ndash 124 fL
Platelet count 9 KμL 161 ndash 347 KμL
Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0
Lymphocytes monocytes eosinophils basophils all below normal range
PT 47 sec (corrected on mixing study) 116 ndash 152 sec
APTT 75 sec (corrected on mixing study) 253 ndash 373 sec
Fibrinogen lt 76 mgdL 177 ndash 466 mgdL
D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Microscopy
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Arrow shows giant platelets in this peripheral smear Promyelocytes apparent
Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)
DIC due to TF release by APL blasts
Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases
Transfusions to replace factors along with platelets and RBCs during APL treatment
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started
Case Study 2 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L
PT 30 sec 113 ndash 146 sec
APTT 75 sec 25 ndash 34 sec
D-dimer 078 microgml FEU lt050 microgml FEU
Fibrinogen 92 mgdl 150-400 mgdl
pH 728 738 to 742
PaO2 570 mmHg 80-100 mmHg
WBC 33 times 103mm3 40-11 times 103mm3
ALT 111 IUL 0ndash34 IUL
AST 61 IUL 0ndash34 IUL
BUN 303 mgdL 08-13 mgdL
Case Study 2 ndash Lab Results
Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures
Case Study 2 ndash Diagnosis
60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior
Case Study 3 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L
PT 228 sec 113 ndash 146 sec
APTT 45 sec 25 ndash 34 sec
D-dimer 080 microgml FEU lt050 microgmL FEU
Fibrinogen 82 mgdL 150-400 mgdL
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 134 gdL 14-16 gdL
WBC 81 times 103mm3 40-11 times 103mm3
ALT 32 IUL 0ndash34 IUL
AST 28 IUL 0ndash34 IUL
BUN 09 mgdL 08-13 mgdL
Case Study 3 ndash Lab Results
Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment
Case Study 3 ndash Diagnosis and Therapy
Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91
Case Study 4 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L
PT 28 sec 113 ndash 146 sec
APTT 71 sec 25 ndash 34 sec
D-dimer 31 microgmL FEU lt050 microgml FEU
Fibrinogen 92 mgdL 150-400 mgdl
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 158 gdL 14-16 gdL
WBC 71 times 103mm3 40-11 times 103mm3
ALT 60 IUL 0ndash34 IUL
AST 47 IUL 0ndash34 IUL
BUN 38 mgdL 08-13 mgdL
Case Study 4 ndash Lab Results
Lyme disease with DICProvide antibiotics with supportive measures
Case Study 4 ndash Diagnosis
55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis
Case Study 5 ndash Presentation
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
Case Study 5 ndash Lab Results and Time Course
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
TEST RESULT REFERENCE RANGE
Platelet count 33 x 109L 150-450 x 109L
PT 215 sec 103 ndash 128 sec
APTT 44 sec 26 ndash 36 sec
D-dimer 20 microgmL FEU lt025 microgml FEU
Fibrinogen 34 mgdL 200-375 mgdl
FII FV FVIII Low Not reported (NR)
FVII FIX FX vWF Normal NR
Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)
DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic
dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR
(C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen
(D) Illustration demonstrating repair
Case Study 5 ndash Diagnosis and Treatment
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography
Case Study 6 ndash Presentation
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
Case Study 6 ndash Lab Results
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L
PT 63 sec gt control 113 ndash 146 sec
INR 658 1 ndash 125
APTT 80 sec gt control 25 ndash 34 sec
D-dimer gt200 microgmL DDU 02 microgmL DDU
Urine exam Proteinuria and hematuria 150-400 mgdl
Albumin 28 gdL NR
Hb 58 gdL NR
LDH 1196 UL NR
SGPT 144 IU NR
SGOT 88 IU NR
Bilirubin 32 mgdL NR
DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th
day postop
Case Study 6 ndash Diagnosis and Treatment
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure
Case Study 6 ndash Discussion
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Case Study 7 ndash Lab Results vs Time
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
DIC Take Home Messages
Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation
Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers
DIC
Thank you Questions
- Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
- Learning Objectives
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Wound Sealing
- The Three Steps of Hemostasis
- Vessel Wall
- Slide Number 12
- Slide Number 13
- Platelet Structure UnactivatedActivated
- Primary Hemostasis
- Primary Hemostasis Assays
- Slide Number 17
- Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
- Slide Number 19
- Coagulation factors
- Coagulation Assay Mechanisms
- Slide Number 22
- Fibrin Formation
- Slide Number 24
- Fibrinolysis Overview
- Fibrinolysis Overview
- Slide Number 27
- Fibrinolysis Releases D-dimers
- Basic Pathophysiology of DIC
- Disseminated Intravascular Coagulation (DIC)
- Purpura Fulminans with DIC Due to Meningococcal Sepsis
- Clinical Conditions Associated With DIC
- Frequency of DIC in Selected Disease States
- Underlying Diseases in DIC Patients
- Slide Number 36
- Slide Number 37
- Slide Number 38
- Slide Number 39
- Pathophysiology of DIC
- Pathogenesis of DIC in Sepsis
- Host Response in Severe Sepsis
- Organ Failure in Severe Sepsis
- Mechanism of DIC in Organ Failure
- Interaction of Inflammation and Coagulation in Sepsis
- Slide Number 47
- Diverse and Opposing Effects of Thrombin
- Coagulation and Fibrinolysis in DIC
- Mechanism of DIC
- Pathophysiology of DIC
- Pathophysiology of DIC - Mechanism
- Pathophysiology of DIC ndash 2 Types of Clinical pictures
- Sub-Acute and Non-Overt DIC Clinical Findings
- Pathophysiology of Overt DIC
- Physiopathology of DIC ndash Overt DIC Findings
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- BREAK
- Diagnostic and Management Approach for DIC
- Diagnosis of DIC
- Lab Diagnosis of DIC ndash Markers of Factor Consumption
- Lab Diagnosis of DIC ndash Screening Tests
- Slide Number 67
- Slide Number 68
- British Journal of Haematology Overt DIC Score
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- DIC Management Goals
- DIC Management and Treatment
- DIC Management Strategies
- Anticoagulant Factor Concentrate Treatment
- Anticoagulant Factor Concentrate Treatment Trials
- Markers of Thrombin amp Plasmin Generation in DIC
- D-dimer FDPs and DIC
- D-Dimer and FDPs in DIC
- Follow Up of DIC State of Disease
- FMD-Dimer in DIC Major Differences
- of Abnormal Results in Patients with Confirmed and Suspected DIC
- Slide Number 85
- Slide Number 86
- Comparing an Automated FM vs Manual FSP Test
- Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Slide Number 94
- Slide Number 95
- Slide Number 96
- Slide Number 97
- Slide Number 98
- Slide Number 99
- DIC Case Studies
- Case Study 1 - Presentation
- Case Study 1 ndash Lab Results
- Case Study 1 ndash Microscopy
- Case Study 1 ndash Diagnosis and Therapy
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Slide Number 110
- Slide Number 111
- Slide Number 112
- Slide Number 113
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
- Slide Number 124
- Slide Number 125
- DIC Take Home Messages
- Slide Number 127
- Slide Number 128
-
Pathophysiology of Overt DIC
Massive activation of coagulation and fibrinolysis
Does not allow for compensatory efforts
Rapid depletion of coagulation factors inhibitors and platelets
Thrombosis multiple organ failures
Bleeding complications and shock
Physiopathology of DIC ndash Overt DIC Findings
Thrombin generation
Thrombosis
Renal liver respiratory failures coma skin necrosis gangrene venous thromboembolism hypotension edema
Cytokine and kinin generation (shock)bull Tachycardia hypotension edema
Plasmin generationHemorrhage
bull Spontaneous bruising petechiae intracranial gastrointestinal and respiratory tract bleeding persistent bleeding at venipuncture sites at surgical wounds
bull Tachycardia hypotension edema
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Pathogenesis Pathways in DIC
Cytokines
TF-mediated dysfunctional impairedthrombin anticoagulant fibrinolysisgeneration mechanism due to PAI-1 deficiency
fibrin inadequateformation fibrin removal
Fibrin deposition
Inflammation
Coagulation
Stago Celebrates Lab Week 2017
NA
Stago 247 Educational Webinar Sites
wwwstago-edvantagecomUS based KOLsPACE accredited ndash all 1 hourAccessible from mobile devicesVirtual exhibit hall
wwwstagowebinarscomMostly European KOLs30 ndash 45 min including 15 min discussion
Stago Educational Apps
HaemoscoreClinical scoring algorithmsApple and AndroidTablet or phone
iHemostasisCoagulation diagramsCase studiesApple amp AndroidTablet only
BREAK
Diagnostic and Management Approach for DIC
Diagnosis of DIC
Clinical diagnosis is obvious in cases of overt DIC
Laboratory tests are necessary To makeconfirm the diagnosis To assess stage of the patient To assess the treatment efficacy
Lab Diagnosis of DIC ndash Markers of Factor Consumption
Routinescreening assays PT APTT Platelets Fibrinogen Thrombin time
Other coagulation assays Factor assays AntithrombinGeneration of Thrombin FMFSPsGeneration of Plasmin D-dimer FDPs
Important to recognize simultaneous formation of thrombin and plasmin
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122
Lab Diagnosis of DIC ndash Screening Tests
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122
Platelet count usually decreasedPT abnormal in 70 of cases (short half-life of FVII)APTT abnormal in 50 of casesThrombin time usually prolonged in overt DIC normal in non-overt DIC and no relation with syndrome severityFibrinogen low in lt 50 of cases sensitivity 22 specificity 87 overall predictive value 64 Normal fibrinogen level should not exclude DIC diagnosis (acute phase reactant initial high
fibrinogen level) repeat testing assesses progression
Screening tests not clinically specific or sensitive for DIC
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Laboratory Changes in Overt DIC
DIC Diagnostic Practices Over Time
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
British Journal of Haematology Overt DIC Score
Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
ISTH Step by Step DIC Algorithm
Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6
US Based Validation of ISTH DIC Score
When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Differential Diagnosis in DIC
aHUS atypical hemolytic uremic syndrome
HUS hemolytic uremic syndrome
HIT heparin-induced thrombocytopenia
ITP immune thrombocytopenic purpura
TTP thrombotic thrombocytopenic purpura
DIC and MAHA
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)
When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation
DIC Management Goals
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction
DIC Management and Treatment
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)
requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)
Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia
DIC Management Strategies
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant Factor Concentrate Treatment
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis
Anticoagulant Factor Concentrate Treatment Trials
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise
Markers of Thrombin amp Plasmin Generation in DIC
D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC
Cut-off value
Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen
degradation products Sensitive assay typically with cutoff adapted for DIC
D-dimer FDPs and DIC
D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC
Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80
Follow Up of DIC State of Disease
Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8
Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility
FMD-Dimer in DIC Major Differences
onset of thrombosis
days
Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8
FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)
D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)
of Abnormal Results in Patients with Confirmed and Suspected DIC
0
20
40
60
80
100
94 85 90N = 62
Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32
Positivity of Test Results ISTH Score and Disease State
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
Red bar positive for 2 points of DIC score
Pink bar positive for 1-2 points of DIC score
HT hematopoietic tumor
IF infection
SC solid cancer
Markers in Patients with or without DIC
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
HT hematopoietic tumorIF infectionSC solid cancer
Comparing an Automated FM vs Manual FSP Test
Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71
Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)
Automated (Mitsubishi) vs Automated (Stago)
In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago
Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC
Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
Non Overt DIC Overt DIC
AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC
Trends in Markers of DIC for Different Patients
Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00
Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients
Trends in Markers of DIC for Different Patients
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes
28 day outcome survival
28 day outcome death
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines
DIC Case Studies
Case Study 1 - Presentation
18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE
WBC count 77 KμL 423 ndash 907 x KμL
RBC count 17 MμL 137 ndash 175 x MμL
Hemoglobin 67 gdL 137 ndash 175 gdL
Hematocrit 195 401 ndash 510
MCV 95 fL 790 ndash 922 fL
MPV 12 fL 94 ndash 124 fL
Platelet count 9 KμL 161 ndash 347 KμL
Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0
Lymphocytes monocytes eosinophils basophils all below normal range
PT 47 sec (corrected on mixing study) 116 ndash 152 sec
APTT 75 sec (corrected on mixing study) 253 ndash 373 sec
Fibrinogen lt 76 mgdL 177 ndash 466 mgdL
D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Microscopy
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Arrow shows giant platelets in this peripheral smear Promyelocytes apparent
Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)
DIC due to TF release by APL blasts
Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases
Transfusions to replace factors along with platelets and RBCs during APL treatment
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started
Case Study 2 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L
PT 30 sec 113 ndash 146 sec
APTT 75 sec 25 ndash 34 sec
D-dimer 078 microgml FEU lt050 microgml FEU
Fibrinogen 92 mgdl 150-400 mgdl
pH 728 738 to 742
PaO2 570 mmHg 80-100 mmHg
WBC 33 times 103mm3 40-11 times 103mm3
ALT 111 IUL 0ndash34 IUL
AST 61 IUL 0ndash34 IUL
BUN 303 mgdL 08-13 mgdL
Case Study 2 ndash Lab Results
Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures
Case Study 2 ndash Diagnosis
60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior
Case Study 3 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L
PT 228 sec 113 ndash 146 sec
APTT 45 sec 25 ndash 34 sec
D-dimer 080 microgml FEU lt050 microgmL FEU
Fibrinogen 82 mgdL 150-400 mgdL
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 134 gdL 14-16 gdL
WBC 81 times 103mm3 40-11 times 103mm3
ALT 32 IUL 0ndash34 IUL
AST 28 IUL 0ndash34 IUL
BUN 09 mgdL 08-13 mgdL
Case Study 3 ndash Lab Results
Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment
Case Study 3 ndash Diagnosis and Therapy
Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91
Case Study 4 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L
PT 28 sec 113 ndash 146 sec
APTT 71 sec 25 ndash 34 sec
D-dimer 31 microgmL FEU lt050 microgml FEU
Fibrinogen 92 mgdL 150-400 mgdl
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 158 gdL 14-16 gdL
WBC 71 times 103mm3 40-11 times 103mm3
ALT 60 IUL 0ndash34 IUL
AST 47 IUL 0ndash34 IUL
BUN 38 mgdL 08-13 mgdL
Case Study 4 ndash Lab Results
Lyme disease with DICProvide antibiotics with supportive measures
Case Study 4 ndash Diagnosis
55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis
Case Study 5 ndash Presentation
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
Case Study 5 ndash Lab Results and Time Course
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
TEST RESULT REFERENCE RANGE
Platelet count 33 x 109L 150-450 x 109L
PT 215 sec 103 ndash 128 sec
APTT 44 sec 26 ndash 36 sec
D-dimer 20 microgmL FEU lt025 microgml FEU
Fibrinogen 34 mgdL 200-375 mgdl
FII FV FVIII Low Not reported (NR)
FVII FIX FX vWF Normal NR
Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)
DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic
dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR
(C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen
(D) Illustration demonstrating repair
Case Study 5 ndash Diagnosis and Treatment
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography
Case Study 6 ndash Presentation
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
Case Study 6 ndash Lab Results
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L
PT 63 sec gt control 113 ndash 146 sec
INR 658 1 ndash 125
APTT 80 sec gt control 25 ndash 34 sec
D-dimer gt200 microgmL DDU 02 microgmL DDU
Urine exam Proteinuria and hematuria 150-400 mgdl
Albumin 28 gdL NR
Hb 58 gdL NR
LDH 1196 UL NR
SGPT 144 IU NR
SGOT 88 IU NR
Bilirubin 32 mgdL NR
DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th
day postop
Case Study 6 ndash Diagnosis and Treatment
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure
Case Study 6 ndash Discussion
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Case Study 7 ndash Lab Results vs Time
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
DIC Take Home Messages
Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation
Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers
DIC
Thank you Questions
- Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
- Learning Objectives
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Wound Sealing
- The Three Steps of Hemostasis
- Vessel Wall
- Slide Number 12
- Slide Number 13
- Platelet Structure UnactivatedActivated
- Primary Hemostasis
- Primary Hemostasis Assays
- Slide Number 17
- Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
- Slide Number 19
- Coagulation factors
- Coagulation Assay Mechanisms
- Slide Number 22
- Fibrin Formation
- Slide Number 24
- Fibrinolysis Overview
- Fibrinolysis Overview
- Slide Number 27
- Fibrinolysis Releases D-dimers
- Basic Pathophysiology of DIC
- Disseminated Intravascular Coagulation (DIC)
- Purpura Fulminans with DIC Due to Meningococcal Sepsis
- Clinical Conditions Associated With DIC
- Frequency of DIC in Selected Disease States
- Underlying Diseases in DIC Patients
- Slide Number 36
- Slide Number 37
- Slide Number 38
- Slide Number 39
- Pathophysiology of DIC
- Pathogenesis of DIC in Sepsis
- Host Response in Severe Sepsis
- Organ Failure in Severe Sepsis
- Mechanism of DIC in Organ Failure
- Interaction of Inflammation and Coagulation in Sepsis
- Slide Number 47
- Diverse and Opposing Effects of Thrombin
- Coagulation and Fibrinolysis in DIC
- Mechanism of DIC
- Pathophysiology of DIC
- Pathophysiology of DIC - Mechanism
- Pathophysiology of DIC ndash 2 Types of Clinical pictures
- Sub-Acute and Non-Overt DIC Clinical Findings
- Pathophysiology of Overt DIC
- Physiopathology of DIC ndash Overt DIC Findings
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- BREAK
- Diagnostic and Management Approach for DIC
- Diagnosis of DIC
- Lab Diagnosis of DIC ndash Markers of Factor Consumption
- Lab Diagnosis of DIC ndash Screening Tests
- Slide Number 67
- Slide Number 68
- British Journal of Haematology Overt DIC Score
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- DIC Management Goals
- DIC Management and Treatment
- DIC Management Strategies
- Anticoagulant Factor Concentrate Treatment
- Anticoagulant Factor Concentrate Treatment Trials
- Markers of Thrombin amp Plasmin Generation in DIC
- D-dimer FDPs and DIC
- D-Dimer and FDPs in DIC
- Follow Up of DIC State of Disease
- FMD-Dimer in DIC Major Differences
- of Abnormal Results in Patients with Confirmed and Suspected DIC
- Slide Number 85
- Slide Number 86
- Comparing an Automated FM vs Manual FSP Test
- Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Slide Number 94
- Slide Number 95
- Slide Number 96
- Slide Number 97
- Slide Number 98
- Slide Number 99
- DIC Case Studies
- Case Study 1 - Presentation
- Case Study 1 ndash Lab Results
- Case Study 1 ndash Microscopy
- Case Study 1 ndash Diagnosis and Therapy
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Slide Number 110
- Slide Number 111
- Slide Number 112
- Slide Number 113
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
- Slide Number 124
- Slide Number 125
- DIC Take Home Messages
- Slide Number 127
- Slide Number 128
-
Physiopathology of DIC ndash Overt DIC Findings
Thrombin generation
Thrombosis
Renal liver respiratory failures coma skin necrosis gangrene venous thromboembolism hypotension edema
Cytokine and kinin generation (shock)bull Tachycardia hypotension edema
Plasmin generationHemorrhage
bull Spontaneous bruising petechiae intracranial gastrointestinal and respiratory tract bleeding persistent bleeding at venipuncture sites at surgical wounds
bull Tachycardia hypotension edema
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Pathogenesis Pathways in DIC
Cytokines
TF-mediated dysfunctional impairedthrombin anticoagulant fibrinolysisgeneration mechanism due to PAI-1 deficiency
fibrin inadequateformation fibrin removal
Fibrin deposition
Inflammation
Coagulation
Stago Celebrates Lab Week 2017
NA
Stago 247 Educational Webinar Sites
wwwstago-edvantagecomUS based KOLsPACE accredited ndash all 1 hourAccessible from mobile devicesVirtual exhibit hall
wwwstagowebinarscomMostly European KOLs30 ndash 45 min including 15 min discussion
Stago Educational Apps
HaemoscoreClinical scoring algorithmsApple and AndroidTablet or phone
iHemostasisCoagulation diagramsCase studiesApple amp AndroidTablet only
BREAK
Diagnostic and Management Approach for DIC
Diagnosis of DIC
Clinical diagnosis is obvious in cases of overt DIC
Laboratory tests are necessary To makeconfirm the diagnosis To assess stage of the patient To assess the treatment efficacy
Lab Diagnosis of DIC ndash Markers of Factor Consumption
Routinescreening assays PT APTT Platelets Fibrinogen Thrombin time
Other coagulation assays Factor assays AntithrombinGeneration of Thrombin FMFSPsGeneration of Plasmin D-dimer FDPs
Important to recognize simultaneous formation of thrombin and plasmin
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122
Lab Diagnosis of DIC ndash Screening Tests
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122
Platelet count usually decreasedPT abnormal in 70 of cases (short half-life of FVII)APTT abnormal in 50 of casesThrombin time usually prolonged in overt DIC normal in non-overt DIC and no relation with syndrome severityFibrinogen low in lt 50 of cases sensitivity 22 specificity 87 overall predictive value 64 Normal fibrinogen level should not exclude DIC diagnosis (acute phase reactant initial high
fibrinogen level) repeat testing assesses progression
Screening tests not clinically specific or sensitive for DIC
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Laboratory Changes in Overt DIC
DIC Diagnostic Practices Over Time
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
British Journal of Haematology Overt DIC Score
Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
ISTH Step by Step DIC Algorithm
Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6
US Based Validation of ISTH DIC Score
When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Differential Diagnosis in DIC
aHUS atypical hemolytic uremic syndrome
HUS hemolytic uremic syndrome
HIT heparin-induced thrombocytopenia
ITP immune thrombocytopenic purpura
TTP thrombotic thrombocytopenic purpura
DIC and MAHA
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)
When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation
DIC Management Goals
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction
DIC Management and Treatment
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)
requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)
Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia
DIC Management Strategies
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant Factor Concentrate Treatment
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis
Anticoagulant Factor Concentrate Treatment Trials
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise
Markers of Thrombin amp Plasmin Generation in DIC
D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC
Cut-off value
Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen
degradation products Sensitive assay typically with cutoff adapted for DIC
D-dimer FDPs and DIC
D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC
Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80
Follow Up of DIC State of Disease
Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8
Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility
FMD-Dimer in DIC Major Differences
onset of thrombosis
days
Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8
FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)
D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)
of Abnormal Results in Patients with Confirmed and Suspected DIC
0
20
40
60
80
100
94 85 90N = 62
Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32
Positivity of Test Results ISTH Score and Disease State
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
Red bar positive for 2 points of DIC score
Pink bar positive for 1-2 points of DIC score
HT hematopoietic tumor
IF infection
SC solid cancer
Markers in Patients with or without DIC
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
HT hematopoietic tumorIF infectionSC solid cancer
Comparing an Automated FM vs Manual FSP Test
Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71
Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)
Automated (Mitsubishi) vs Automated (Stago)
In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago
Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC
Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
Non Overt DIC Overt DIC
AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC
Trends in Markers of DIC for Different Patients
Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00
Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients
Trends in Markers of DIC for Different Patients
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes
28 day outcome survival
28 day outcome death
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines
DIC Case Studies
Case Study 1 - Presentation
18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE
WBC count 77 KμL 423 ndash 907 x KμL
RBC count 17 MμL 137 ndash 175 x MμL
Hemoglobin 67 gdL 137 ndash 175 gdL
Hematocrit 195 401 ndash 510
MCV 95 fL 790 ndash 922 fL
MPV 12 fL 94 ndash 124 fL
Platelet count 9 KμL 161 ndash 347 KμL
Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0
Lymphocytes monocytes eosinophils basophils all below normal range
PT 47 sec (corrected on mixing study) 116 ndash 152 sec
APTT 75 sec (corrected on mixing study) 253 ndash 373 sec
Fibrinogen lt 76 mgdL 177 ndash 466 mgdL
D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Microscopy
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Arrow shows giant platelets in this peripheral smear Promyelocytes apparent
Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)
DIC due to TF release by APL blasts
Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases
Transfusions to replace factors along with platelets and RBCs during APL treatment
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started
Case Study 2 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L
PT 30 sec 113 ndash 146 sec
APTT 75 sec 25 ndash 34 sec
D-dimer 078 microgml FEU lt050 microgml FEU
Fibrinogen 92 mgdl 150-400 mgdl
pH 728 738 to 742
PaO2 570 mmHg 80-100 mmHg
WBC 33 times 103mm3 40-11 times 103mm3
ALT 111 IUL 0ndash34 IUL
AST 61 IUL 0ndash34 IUL
BUN 303 mgdL 08-13 mgdL
Case Study 2 ndash Lab Results
Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures
Case Study 2 ndash Diagnosis
60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior
Case Study 3 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L
PT 228 sec 113 ndash 146 sec
APTT 45 sec 25 ndash 34 sec
D-dimer 080 microgml FEU lt050 microgmL FEU
Fibrinogen 82 mgdL 150-400 mgdL
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 134 gdL 14-16 gdL
WBC 81 times 103mm3 40-11 times 103mm3
ALT 32 IUL 0ndash34 IUL
AST 28 IUL 0ndash34 IUL
BUN 09 mgdL 08-13 mgdL
Case Study 3 ndash Lab Results
Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment
Case Study 3 ndash Diagnosis and Therapy
Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91
Case Study 4 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L
PT 28 sec 113 ndash 146 sec
APTT 71 sec 25 ndash 34 sec
D-dimer 31 microgmL FEU lt050 microgml FEU
Fibrinogen 92 mgdL 150-400 mgdl
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 158 gdL 14-16 gdL
WBC 71 times 103mm3 40-11 times 103mm3
ALT 60 IUL 0ndash34 IUL
AST 47 IUL 0ndash34 IUL
BUN 38 mgdL 08-13 mgdL
Case Study 4 ndash Lab Results
Lyme disease with DICProvide antibiotics with supportive measures
Case Study 4 ndash Diagnosis
55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis
Case Study 5 ndash Presentation
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
Case Study 5 ndash Lab Results and Time Course
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
TEST RESULT REFERENCE RANGE
Platelet count 33 x 109L 150-450 x 109L
PT 215 sec 103 ndash 128 sec
APTT 44 sec 26 ndash 36 sec
D-dimer 20 microgmL FEU lt025 microgml FEU
Fibrinogen 34 mgdL 200-375 mgdl
FII FV FVIII Low Not reported (NR)
FVII FIX FX vWF Normal NR
Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)
DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic
dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR
(C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen
(D) Illustration demonstrating repair
Case Study 5 ndash Diagnosis and Treatment
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography
Case Study 6 ndash Presentation
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
Case Study 6 ndash Lab Results
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L
PT 63 sec gt control 113 ndash 146 sec
INR 658 1 ndash 125
APTT 80 sec gt control 25 ndash 34 sec
D-dimer gt200 microgmL DDU 02 microgmL DDU
Urine exam Proteinuria and hematuria 150-400 mgdl
Albumin 28 gdL NR
Hb 58 gdL NR
LDH 1196 UL NR
SGPT 144 IU NR
SGOT 88 IU NR
Bilirubin 32 mgdL NR
DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th
day postop
Case Study 6 ndash Diagnosis and Treatment
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure
Case Study 6 ndash Discussion
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Case Study 7 ndash Lab Results vs Time
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
DIC Take Home Messages
Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation
Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers
DIC
Thank you Questions
- Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
- Learning Objectives
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Wound Sealing
- The Three Steps of Hemostasis
- Vessel Wall
- Slide Number 12
- Slide Number 13
- Platelet Structure UnactivatedActivated
- Primary Hemostasis
- Primary Hemostasis Assays
- Slide Number 17
- Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
- Slide Number 19
- Coagulation factors
- Coagulation Assay Mechanisms
- Slide Number 22
- Fibrin Formation
- Slide Number 24
- Fibrinolysis Overview
- Fibrinolysis Overview
- Slide Number 27
- Fibrinolysis Releases D-dimers
- Basic Pathophysiology of DIC
- Disseminated Intravascular Coagulation (DIC)
- Purpura Fulminans with DIC Due to Meningococcal Sepsis
- Clinical Conditions Associated With DIC
- Frequency of DIC in Selected Disease States
- Underlying Diseases in DIC Patients
- Slide Number 36
- Slide Number 37
- Slide Number 38
- Slide Number 39
- Pathophysiology of DIC
- Pathogenesis of DIC in Sepsis
- Host Response in Severe Sepsis
- Organ Failure in Severe Sepsis
- Mechanism of DIC in Organ Failure
- Interaction of Inflammation and Coagulation in Sepsis
- Slide Number 47
- Diverse and Opposing Effects of Thrombin
- Coagulation and Fibrinolysis in DIC
- Mechanism of DIC
- Pathophysiology of DIC
- Pathophysiology of DIC - Mechanism
- Pathophysiology of DIC ndash 2 Types of Clinical pictures
- Sub-Acute and Non-Overt DIC Clinical Findings
- Pathophysiology of Overt DIC
- Physiopathology of DIC ndash Overt DIC Findings
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- BREAK
- Diagnostic and Management Approach for DIC
- Diagnosis of DIC
- Lab Diagnosis of DIC ndash Markers of Factor Consumption
- Lab Diagnosis of DIC ndash Screening Tests
- Slide Number 67
- Slide Number 68
- British Journal of Haematology Overt DIC Score
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- DIC Management Goals
- DIC Management and Treatment
- DIC Management Strategies
- Anticoagulant Factor Concentrate Treatment
- Anticoagulant Factor Concentrate Treatment Trials
- Markers of Thrombin amp Plasmin Generation in DIC
- D-dimer FDPs and DIC
- D-Dimer and FDPs in DIC
- Follow Up of DIC State of Disease
- FMD-Dimer in DIC Major Differences
- of Abnormal Results in Patients with Confirmed and Suspected DIC
- Slide Number 85
- Slide Number 86
- Comparing an Automated FM vs Manual FSP Test
- Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Slide Number 94
- Slide Number 95
- Slide Number 96
- Slide Number 97
- Slide Number 98
- Slide Number 99
- DIC Case Studies
- Case Study 1 - Presentation
- Case Study 1 ndash Lab Results
- Case Study 1 ndash Microscopy
- Case Study 1 ndash Diagnosis and Therapy
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Slide Number 110
- Slide Number 111
- Slide Number 112
- Slide Number 113
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
- Slide Number 124
- Slide Number 125
- DIC Take Home Messages
- Slide Number 127
- Slide Number 128
-
Pathogenesis Pathways in DIC
Cytokines
TF-mediated dysfunctional impairedthrombin anticoagulant fibrinolysisgeneration mechanism due to PAI-1 deficiency
fibrin inadequateformation fibrin removal
Fibrin deposition
Inflammation
Coagulation
Stago Celebrates Lab Week 2017
NA
Stago 247 Educational Webinar Sites
wwwstago-edvantagecomUS based KOLsPACE accredited ndash all 1 hourAccessible from mobile devicesVirtual exhibit hall
wwwstagowebinarscomMostly European KOLs30 ndash 45 min including 15 min discussion
Stago Educational Apps
HaemoscoreClinical scoring algorithmsApple and AndroidTablet or phone
iHemostasisCoagulation diagramsCase studiesApple amp AndroidTablet only
BREAK
Diagnostic and Management Approach for DIC
Diagnosis of DIC
Clinical diagnosis is obvious in cases of overt DIC
Laboratory tests are necessary To makeconfirm the diagnosis To assess stage of the patient To assess the treatment efficacy
Lab Diagnosis of DIC ndash Markers of Factor Consumption
Routinescreening assays PT APTT Platelets Fibrinogen Thrombin time
Other coagulation assays Factor assays AntithrombinGeneration of Thrombin FMFSPsGeneration of Plasmin D-dimer FDPs
Important to recognize simultaneous formation of thrombin and plasmin
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122
Lab Diagnosis of DIC ndash Screening Tests
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122
Platelet count usually decreasedPT abnormal in 70 of cases (short half-life of FVII)APTT abnormal in 50 of casesThrombin time usually prolonged in overt DIC normal in non-overt DIC and no relation with syndrome severityFibrinogen low in lt 50 of cases sensitivity 22 specificity 87 overall predictive value 64 Normal fibrinogen level should not exclude DIC diagnosis (acute phase reactant initial high
fibrinogen level) repeat testing assesses progression
Screening tests not clinically specific or sensitive for DIC
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Laboratory Changes in Overt DIC
DIC Diagnostic Practices Over Time
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
British Journal of Haematology Overt DIC Score
Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
ISTH Step by Step DIC Algorithm
Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6
US Based Validation of ISTH DIC Score
When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Differential Diagnosis in DIC
aHUS atypical hemolytic uremic syndrome
HUS hemolytic uremic syndrome
HIT heparin-induced thrombocytopenia
ITP immune thrombocytopenic purpura
TTP thrombotic thrombocytopenic purpura
DIC and MAHA
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)
When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation
DIC Management Goals
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction
DIC Management and Treatment
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)
requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)
Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia
DIC Management Strategies
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant Factor Concentrate Treatment
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis
Anticoagulant Factor Concentrate Treatment Trials
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise
Markers of Thrombin amp Plasmin Generation in DIC
D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC
Cut-off value
Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen
degradation products Sensitive assay typically with cutoff adapted for DIC
D-dimer FDPs and DIC
D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC
Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80
Follow Up of DIC State of Disease
Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8
Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility
FMD-Dimer in DIC Major Differences
onset of thrombosis
days
Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8
FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)
D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)
of Abnormal Results in Patients with Confirmed and Suspected DIC
0
20
40
60
80
100
94 85 90N = 62
Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32
Positivity of Test Results ISTH Score and Disease State
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
Red bar positive for 2 points of DIC score
Pink bar positive for 1-2 points of DIC score
HT hematopoietic tumor
IF infection
SC solid cancer
Markers in Patients with or without DIC
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
HT hematopoietic tumorIF infectionSC solid cancer
Comparing an Automated FM vs Manual FSP Test
Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71
Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)
Automated (Mitsubishi) vs Automated (Stago)
In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago
Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC
Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
Non Overt DIC Overt DIC
AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC
Trends in Markers of DIC for Different Patients
Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00
Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients
Trends in Markers of DIC for Different Patients
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes
28 day outcome survival
28 day outcome death
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines
DIC Case Studies
Case Study 1 - Presentation
18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE
WBC count 77 KμL 423 ndash 907 x KμL
RBC count 17 MμL 137 ndash 175 x MμL
Hemoglobin 67 gdL 137 ndash 175 gdL
Hematocrit 195 401 ndash 510
MCV 95 fL 790 ndash 922 fL
MPV 12 fL 94 ndash 124 fL
Platelet count 9 KμL 161 ndash 347 KμL
Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0
Lymphocytes monocytes eosinophils basophils all below normal range
PT 47 sec (corrected on mixing study) 116 ndash 152 sec
APTT 75 sec (corrected on mixing study) 253 ndash 373 sec
Fibrinogen lt 76 mgdL 177 ndash 466 mgdL
D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Microscopy
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Arrow shows giant platelets in this peripheral smear Promyelocytes apparent
Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)
DIC due to TF release by APL blasts
Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases
Transfusions to replace factors along with platelets and RBCs during APL treatment
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started
Case Study 2 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L
PT 30 sec 113 ndash 146 sec
APTT 75 sec 25 ndash 34 sec
D-dimer 078 microgml FEU lt050 microgml FEU
Fibrinogen 92 mgdl 150-400 mgdl
pH 728 738 to 742
PaO2 570 mmHg 80-100 mmHg
WBC 33 times 103mm3 40-11 times 103mm3
ALT 111 IUL 0ndash34 IUL
AST 61 IUL 0ndash34 IUL
BUN 303 mgdL 08-13 mgdL
Case Study 2 ndash Lab Results
Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures
Case Study 2 ndash Diagnosis
60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior
Case Study 3 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L
PT 228 sec 113 ndash 146 sec
APTT 45 sec 25 ndash 34 sec
D-dimer 080 microgml FEU lt050 microgmL FEU
Fibrinogen 82 mgdL 150-400 mgdL
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 134 gdL 14-16 gdL
WBC 81 times 103mm3 40-11 times 103mm3
ALT 32 IUL 0ndash34 IUL
AST 28 IUL 0ndash34 IUL
BUN 09 mgdL 08-13 mgdL
Case Study 3 ndash Lab Results
Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment
Case Study 3 ndash Diagnosis and Therapy
Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91
Case Study 4 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L
PT 28 sec 113 ndash 146 sec
APTT 71 sec 25 ndash 34 sec
D-dimer 31 microgmL FEU lt050 microgml FEU
Fibrinogen 92 mgdL 150-400 mgdl
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 158 gdL 14-16 gdL
WBC 71 times 103mm3 40-11 times 103mm3
ALT 60 IUL 0ndash34 IUL
AST 47 IUL 0ndash34 IUL
BUN 38 mgdL 08-13 mgdL
Case Study 4 ndash Lab Results
Lyme disease with DICProvide antibiotics with supportive measures
Case Study 4 ndash Diagnosis
55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis
Case Study 5 ndash Presentation
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
Case Study 5 ndash Lab Results and Time Course
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
TEST RESULT REFERENCE RANGE
Platelet count 33 x 109L 150-450 x 109L
PT 215 sec 103 ndash 128 sec
APTT 44 sec 26 ndash 36 sec
D-dimer 20 microgmL FEU lt025 microgml FEU
Fibrinogen 34 mgdL 200-375 mgdl
FII FV FVIII Low Not reported (NR)
FVII FIX FX vWF Normal NR
Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)
DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic
dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR
(C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen
(D) Illustration demonstrating repair
Case Study 5 ndash Diagnosis and Treatment
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography
Case Study 6 ndash Presentation
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
Case Study 6 ndash Lab Results
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L
PT 63 sec gt control 113 ndash 146 sec
INR 658 1 ndash 125
APTT 80 sec gt control 25 ndash 34 sec
D-dimer gt200 microgmL DDU 02 microgmL DDU
Urine exam Proteinuria and hematuria 150-400 mgdl
Albumin 28 gdL NR
Hb 58 gdL NR
LDH 1196 UL NR
SGPT 144 IU NR
SGOT 88 IU NR
Bilirubin 32 mgdL NR
DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th
day postop
Case Study 6 ndash Diagnosis and Treatment
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure
Case Study 6 ndash Discussion
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Case Study 7 ndash Lab Results vs Time
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
DIC Take Home Messages
Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation
Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers
DIC
Thank you Questions
- Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
- Learning Objectives
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Wound Sealing
- The Three Steps of Hemostasis
- Vessel Wall
- Slide Number 12
- Slide Number 13
- Platelet Structure UnactivatedActivated
- Primary Hemostasis
- Primary Hemostasis Assays
- Slide Number 17
- Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
- Slide Number 19
- Coagulation factors
- Coagulation Assay Mechanisms
- Slide Number 22
- Fibrin Formation
- Slide Number 24
- Fibrinolysis Overview
- Fibrinolysis Overview
- Slide Number 27
- Fibrinolysis Releases D-dimers
- Basic Pathophysiology of DIC
- Disseminated Intravascular Coagulation (DIC)
- Purpura Fulminans with DIC Due to Meningococcal Sepsis
- Clinical Conditions Associated With DIC
- Frequency of DIC in Selected Disease States
- Underlying Diseases in DIC Patients
- Slide Number 36
- Slide Number 37
- Slide Number 38
- Slide Number 39
- Pathophysiology of DIC
- Pathogenesis of DIC in Sepsis
- Host Response in Severe Sepsis
- Organ Failure in Severe Sepsis
- Mechanism of DIC in Organ Failure
- Interaction of Inflammation and Coagulation in Sepsis
- Slide Number 47
- Diverse and Opposing Effects of Thrombin
- Coagulation and Fibrinolysis in DIC
- Mechanism of DIC
- Pathophysiology of DIC
- Pathophysiology of DIC - Mechanism
- Pathophysiology of DIC ndash 2 Types of Clinical pictures
- Sub-Acute and Non-Overt DIC Clinical Findings
- Pathophysiology of Overt DIC
- Physiopathology of DIC ndash Overt DIC Findings
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- BREAK
- Diagnostic and Management Approach for DIC
- Diagnosis of DIC
- Lab Diagnosis of DIC ndash Markers of Factor Consumption
- Lab Diagnosis of DIC ndash Screening Tests
- Slide Number 67
- Slide Number 68
- British Journal of Haematology Overt DIC Score
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- DIC Management Goals
- DIC Management and Treatment
- DIC Management Strategies
- Anticoagulant Factor Concentrate Treatment
- Anticoagulant Factor Concentrate Treatment Trials
- Markers of Thrombin amp Plasmin Generation in DIC
- D-dimer FDPs and DIC
- D-Dimer and FDPs in DIC
- Follow Up of DIC State of Disease
- FMD-Dimer in DIC Major Differences
- of Abnormal Results in Patients with Confirmed and Suspected DIC
- Slide Number 85
- Slide Number 86
- Comparing an Automated FM vs Manual FSP Test
- Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Slide Number 94
- Slide Number 95
- Slide Number 96
- Slide Number 97
- Slide Number 98
- Slide Number 99
- DIC Case Studies
- Case Study 1 - Presentation
- Case Study 1 ndash Lab Results
- Case Study 1 ndash Microscopy
- Case Study 1 ndash Diagnosis and Therapy
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Slide Number 110
- Slide Number 111
- Slide Number 112
- Slide Number 113
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
- Slide Number 124
- Slide Number 125
- DIC Take Home Messages
- Slide Number 127
- Slide Number 128
-
Inflammation
Coagulation
Stago Celebrates Lab Week 2017
NA
Stago 247 Educational Webinar Sites
wwwstago-edvantagecomUS based KOLsPACE accredited ndash all 1 hourAccessible from mobile devicesVirtual exhibit hall
wwwstagowebinarscomMostly European KOLs30 ndash 45 min including 15 min discussion
Stago Educational Apps
HaemoscoreClinical scoring algorithmsApple and AndroidTablet or phone
iHemostasisCoagulation diagramsCase studiesApple amp AndroidTablet only
BREAK
Diagnostic and Management Approach for DIC
Diagnosis of DIC
Clinical diagnosis is obvious in cases of overt DIC
Laboratory tests are necessary To makeconfirm the diagnosis To assess stage of the patient To assess the treatment efficacy
Lab Diagnosis of DIC ndash Markers of Factor Consumption
Routinescreening assays PT APTT Platelets Fibrinogen Thrombin time
Other coagulation assays Factor assays AntithrombinGeneration of Thrombin FMFSPsGeneration of Plasmin D-dimer FDPs
Important to recognize simultaneous formation of thrombin and plasmin
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122
Lab Diagnosis of DIC ndash Screening Tests
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122
Platelet count usually decreasedPT abnormal in 70 of cases (short half-life of FVII)APTT abnormal in 50 of casesThrombin time usually prolonged in overt DIC normal in non-overt DIC and no relation with syndrome severityFibrinogen low in lt 50 of cases sensitivity 22 specificity 87 overall predictive value 64 Normal fibrinogen level should not exclude DIC diagnosis (acute phase reactant initial high
fibrinogen level) repeat testing assesses progression
Screening tests not clinically specific or sensitive for DIC
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Laboratory Changes in Overt DIC
DIC Diagnostic Practices Over Time
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
British Journal of Haematology Overt DIC Score
Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
ISTH Step by Step DIC Algorithm
Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6
US Based Validation of ISTH DIC Score
When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Differential Diagnosis in DIC
aHUS atypical hemolytic uremic syndrome
HUS hemolytic uremic syndrome
HIT heparin-induced thrombocytopenia
ITP immune thrombocytopenic purpura
TTP thrombotic thrombocytopenic purpura
DIC and MAHA
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)
When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation
DIC Management Goals
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction
DIC Management and Treatment
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)
requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)
Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia
DIC Management Strategies
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant Factor Concentrate Treatment
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis
Anticoagulant Factor Concentrate Treatment Trials
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise
Markers of Thrombin amp Plasmin Generation in DIC
D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC
Cut-off value
Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen
degradation products Sensitive assay typically with cutoff adapted for DIC
D-dimer FDPs and DIC
D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC
Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80
Follow Up of DIC State of Disease
Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8
Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility
FMD-Dimer in DIC Major Differences
onset of thrombosis
days
Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8
FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)
D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)
of Abnormal Results in Patients with Confirmed and Suspected DIC
0
20
40
60
80
100
94 85 90N = 62
Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32
Positivity of Test Results ISTH Score and Disease State
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
Red bar positive for 2 points of DIC score
Pink bar positive for 1-2 points of DIC score
HT hematopoietic tumor
IF infection
SC solid cancer
Markers in Patients with or without DIC
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
HT hematopoietic tumorIF infectionSC solid cancer
Comparing an Automated FM vs Manual FSP Test
Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71
Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)
Automated (Mitsubishi) vs Automated (Stago)
In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago
Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC
Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
Non Overt DIC Overt DIC
AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC
Trends in Markers of DIC for Different Patients
Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00
Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients
Trends in Markers of DIC for Different Patients
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes
28 day outcome survival
28 day outcome death
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines
DIC Case Studies
Case Study 1 - Presentation
18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE
WBC count 77 KμL 423 ndash 907 x KμL
RBC count 17 MμL 137 ndash 175 x MμL
Hemoglobin 67 gdL 137 ndash 175 gdL
Hematocrit 195 401 ndash 510
MCV 95 fL 790 ndash 922 fL
MPV 12 fL 94 ndash 124 fL
Platelet count 9 KμL 161 ndash 347 KμL
Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0
Lymphocytes monocytes eosinophils basophils all below normal range
PT 47 sec (corrected on mixing study) 116 ndash 152 sec
APTT 75 sec (corrected on mixing study) 253 ndash 373 sec
Fibrinogen lt 76 mgdL 177 ndash 466 mgdL
D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Microscopy
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Arrow shows giant platelets in this peripheral smear Promyelocytes apparent
Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)
DIC due to TF release by APL blasts
Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases
Transfusions to replace factors along with platelets and RBCs during APL treatment
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started
Case Study 2 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L
PT 30 sec 113 ndash 146 sec
APTT 75 sec 25 ndash 34 sec
D-dimer 078 microgml FEU lt050 microgml FEU
Fibrinogen 92 mgdl 150-400 mgdl
pH 728 738 to 742
PaO2 570 mmHg 80-100 mmHg
WBC 33 times 103mm3 40-11 times 103mm3
ALT 111 IUL 0ndash34 IUL
AST 61 IUL 0ndash34 IUL
BUN 303 mgdL 08-13 mgdL
Case Study 2 ndash Lab Results
Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures
Case Study 2 ndash Diagnosis
60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior
Case Study 3 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L
PT 228 sec 113 ndash 146 sec
APTT 45 sec 25 ndash 34 sec
D-dimer 080 microgml FEU lt050 microgmL FEU
Fibrinogen 82 mgdL 150-400 mgdL
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 134 gdL 14-16 gdL
WBC 81 times 103mm3 40-11 times 103mm3
ALT 32 IUL 0ndash34 IUL
AST 28 IUL 0ndash34 IUL
BUN 09 mgdL 08-13 mgdL
Case Study 3 ndash Lab Results
Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment
Case Study 3 ndash Diagnosis and Therapy
Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91
Case Study 4 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L
PT 28 sec 113 ndash 146 sec
APTT 71 sec 25 ndash 34 sec
D-dimer 31 microgmL FEU lt050 microgml FEU
Fibrinogen 92 mgdL 150-400 mgdl
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 158 gdL 14-16 gdL
WBC 71 times 103mm3 40-11 times 103mm3
ALT 60 IUL 0ndash34 IUL
AST 47 IUL 0ndash34 IUL
BUN 38 mgdL 08-13 mgdL
Case Study 4 ndash Lab Results
Lyme disease with DICProvide antibiotics with supportive measures
Case Study 4 ndash Diagnosis
55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis
Case Study 5 ndash Presentation
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
Case Study 5 ndash Lab Results and Time Course
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
TEST RESULT REFERENCE RANGE
Platelet count 33 x 109L 150-450 x 109L
PT 215 sec 103 ndash 128 sec
APTT 44 sec 26 ndash 36 sec
D-dimer 20 microgmL FEU lt025 microgml FEU
Fibrinogen 34 mgdL 200-375 mgdl
FII FV FVIII Low Not reported (NR)
FVII FIX FX vWF Normal NR
Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)
DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic
dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR
(C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen
(D) Illustration demonstrating repair
Case Study 5 ndash Diagnosis and Treatment
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography
Case Study 6 ndash Presentation
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
Case Study 6 ndash Lab Results
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L
PT 63 sec gt control 113 ndash 146 sec
INR 658 1 ndash 125
APTT 80 sec gt control 25 ndash 34 sec
D-dimer gt200 microgmL DDU 02 microgmL DDU
Urine exam Proteinuria and hematuria 150-400 mgdl
Albumin 28 gdL NR
Hb 58 gdL NR
LDH 1196 UL NR
SGPT 144 IU NR
SGOT 88 IU NR
Bilirubin 32 mgdL NR
DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th
day postop
Case Study 6 ndash Diagnosis and Treatment
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure
Case Study 6 ndash Discussion
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Case Study 7 ndash Lab Results vs Time
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
DIC Take Home Messages
Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation
Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers
DIC
Thank you Questions
- Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
- Learning Objectives
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Wound Sealing
- The Three Steps of Hemostasis
- Vessel Wall
- Slide Number 12
- Slide Number 13
- Platelet Structure UnactivatedActivated
- Primary Hemostasis
- Primary Hemostasis Assays
- Slide Number 17
- Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
- Slide Number 19
- Coagulation factors
- Coagulation Assay Mechanisms
- Slide Number 22
- Fibrin Formation
- Slide Number 24
- Fibrinolysis Overview
- Fibrinolysis Overview
- Slide Number 27
- Fibrinolysis Releases D-dimers
- Basic Pathophysiology of DIC
- Disseminated Intravascular Coagulation (DIC)
- Purpura Fulminans with DIC Due to Meningococcal Sepsis
- Clinical Conditions Associated With DIC
- Frequency of DIC in Selected Disease States
- Underlying Diseases in DIC Patients
- Slide Number 36
- Slide Number 37
- Slide Number 38
- Slide Number 39
- Pathophysiology of DIC
- Pathogenesis of DIC in Sepsis
- Host Response in Severe Sepsis
- Organ Failure in Severe Sepsis
- Mechanism of DIC in Organ Failure
- Interaction of Inflammation and Coagulation in Sepsis
- Slide Number 47
- Diverse and Opposing Effects of Thrombin
- Coagulation and Fibrinolysis in DIC
- Mechanism of DIC
- Pathophysiology of DIC
- Pathophysiology of DIC - Mechanism
- Pathophysiology of DIC ndash 2 Types of Clinical pictures
- Sub-Acute and Non-Overt DIC Clinical Findings
- Pathophysiology of Overt DIC
- Physiopathology of DIC ndash Overt DIC Findings
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- BREAK
- Diagnostic and Management Approach for DIC
- Diagnosis of DIC
- Lab Diagnosis of DIC ndash Markers of Factor Consumption
- Lab Diagnosis of DIC ndash Screening Tests
- Slide Number 67
- Slide Number 68
- British Journal of Haematology Overt DIC Score
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- DIC Management Goals
- DIC Management and Treatment
- DIC Management Strategies
- Anticoagulant Factor Concentrate Treatment
- Anticoagulant Factor Concentrate Treatment Trials
- Markers of Thrombin amp Plasmin Generation in DIC
- D-dimer FDPs and DIC
- D-Dimer and FDPs in DIC
- Follow Up of DIC State of Disease
- FMD-Dimer in DIC Major Differences
- of Abnormal Results in Patients with Confirmed and Suspected DIC
- Slide Number 85
- Slide Number 86
- Comparing an Automated FM vs Manual FSP Test
- Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Slide Number 94
- Slide Number 95
- Slide Number 96
- Slide Number 97
- Slide Number 98
- Slide Number 99
- DIC Case Studies
- Case Study 1 - Presentation
- Case Study 1 ndash Lab Results
- Case Study 1 ndash Microscopy
- Case Study 1 ndash Diagnosis and Therapy
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Slide Number 110
- Slide Number 111
- Slide Number 112
- Slide Number 113
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
- Slide Number 124
- Slide Number 125
- DIC Take Home Messages
- Slide Number 127
- Slide Number 128
-
Stago Celebrates Lab Week 2017
NA
Stago 247 Educational Webinar Sites
wwwstago-edvantagecomUS based KOLsPACE accredited ndash all 1 hourAccessible from mobile devicesVirtual exhibit hall
wwwstagowebinarscomMostly European KOLs30 ndash 45 min including 15 min discussion
Stago Educational Apps
HaemoscoreClinical scoring algorithmsApple and AndroidTablet or phone
iHemostasisCoagulation diagramsCase studiesApple amp AndroidTablet only
BREAK
Diagnostic and Management Approach for DIC
Diagnosis of DIC
Clinical diagnosis is obvious in cases of overt DIC
Laboratory tests are necessary To makeconfirm the diagnosis To assess stage of the patient To assess the treatment efficacy
Lab Diagnosis of DIC ndash Markers of Factor Consumption
Routinescreening assays PT APTT Platelets Fibrinogen Thrombin time
Other coagulation assays Factor assays AntithrombinGeneration of Thrombin FMFSPsGeneration of Plasmin D-dimer FDPs
Important to recognize simultaneous formation of thrombin and plasmin
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122
Lab Diagnosis of DIC ndash Screening Tests
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122
Platelet count usually decreasedPT abnormal in 70 of cases (short half-life of FVII)APTT abnormal in 50 of casesThrombin time usually prolonged in overt DIC normal in non-overt DIC and no relation with syndrome severityFibrinogen low in lt 50 of cases sensitivity 22 specificity 87 overall predictive value 64 Normal fibrinogen level should not exclude DIC diagnosis (acute phase reactant initial high
fibrinogen level) repeat testing assesses progression
Screening tests not clinically specific or sensitive for DIC
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Laboratory Changes in Overt DIC
DIC Diagnostic Practices Over Time
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
British Journal of Haematology Overt DIC Score
Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
ISTH Step by Step DIC Algorithm
Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6
US Based Validation of ISTH DIC Score
When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Differential Diagnosis in DIC
aHUS atypical hemolytic uremic syndrome
HUS hemolytic uremic syndrome
HIT heparin-induced thrombocytopenia
ITP immune thrombocytopenic purpura
TTP thrombotic thrombocytopenic purpura
DIC and MAHA
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)
When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation
DIC Management Goals
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction
DIC Management and Treatment
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)
requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)
Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia
DIC Management Strategies
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant Factor Concentrate Treatment
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis
Anticoagulant Factor Concentrate Treatment Trials
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise
Markers of Thrombin amp Plasmin Generation in DIC
D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC
Cut-off value
Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen
degradation products Sensitive assay typically with cutoff adapted for DIC
D-dimer FDPs and DIC
D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC
Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80
Follow Up of DIC State of Disease
Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8
Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility
FMD-Dimer in DIC Major Differences
onset of thrombosis
days
Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8
FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)
D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)
of Abnormal Results in Patients with Confirmed and Suspected DIC
0
20
40
60
80
100
94 85 90N = 62
Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32
Positivity of Test Results ISTH Score and Disease State
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
Red bar positive for 2 points of DIC score
Pink bar positive for 1-2 points of DIC score
HT hematopoietic tumor
IF infection
SC solid cancer
Markers in Patients with or without DIC
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
HT hematopoietic tumorIF infectionSC solid cancer
Comparing an Automated FM vs Manual FSP Test
Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71
Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)
Automated (Mitsubishi) vs Automated (Stago)
In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago
Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC
Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
Non Overt DIC Overt DIC
AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC
Trends in Markers of DIC for Different Patients
Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00
Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients
Trends in Markers of DIC for Different Patients
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes
28 day outcome survival
28 day outcome death
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines
DIC Case Studies
Case Study 1 - Presentation
18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE
WBC count 77 KμL 423 ndash 907 x KμL
RBC count 17 MμL 137 ndash 175 x MμL
Hemoglobin 67 gdL 137 ndash 175 gdL
Hematocrit 195 401 ndash 510
MCV 95 fL 790 ndash 922 fL
MPV 12 fL 94 ndash 124 fL
Platelet count 9 KμL 161 ndash 347 KμL
Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0
Lymphocytes monocytes eosinophils basophils all below normal range
PT 47 sec (corrected on mixing study) 116 ndash 152 sec
APTT 75 sec (corrected on mixing study) 253 ndash 373 sec
Fibrinogen lt 76 mgdL 177 ndash 466 mgdL
D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Microscopy
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Arrow shows giant platelets in this peripheral smear Promyelocytes apparent
Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)
DIC due to TF release by APL blasts
Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases
Transfusions to replace factors along with platelets and RBCs during APL treatment
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started
Case Study 2 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L
PT 30 sec 113 ndash 146 sec
APTT 75 sec 25 ndash 34 sec
D-dimer 078 microgml FEU lt050 microgml FEU
Fibrinogen 92 mgdl 150-400 mgdl
pH 728 738 to 742
PaO2 570 mmHg 80-100 mmHg
WBC 33 times 103mm3 40-11 times 103mm3
ALT 111 IUL 0ndash34 IUL
AST 61 IUL 0ndash34 IUL
BUN 303 mgdL 08-13 mgdL
Case Study 2 ndash Lab Results
Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures
Case Study 2 ndash Diagnosis
60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior
Case Study 3 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L
PT 228 sec 113 ndash 146 sec
APTT 45 sec 25 ndash 34 sec
D-dimer 080 microgml FEU lt050 microgmL FEU
Fibrinogen 82 mgdL 150-400 mgdL
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 134 gdL 14-16 gdL
WBC 81 times 103mm3 40-11 times 103mm3
ALT 32 IUL 0ndash34 IUL
AST 28 IUL 0ndash34 IUL
BUN 09 mgdL 08-13 mgdL
Case Study 3 ndash Lab Results
Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment
Case Study 3 ndash Diagnosis and Therapy
Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91
Case Study 4 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L
PT 28 sec 113 ndash 146 sec
APTT 71 sec 25 ndash 34 sec
D-dimer 31 microgmL FEU lt050 microgml FEU
Fibrinogen 92 mgdL 150-400 mgdl
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 158 gdL 14-16 gdL
WBC 71 times 103mm3 40-11 times 103mm3
ALT 60 IUL 0ndash34 IUL
AST 47 IUL 0ndash34 IUL
BUN 38 mgdL 08-13 mgdL
Case Study 4 ndash Lab Results
Lyme disease with DICProvide antibiotics with supportive measures
Case Study 4 ndash Diagnosis
55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis
Case Study 5 ndash Presentation
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
Case Study 5 ndash Lab Results and Time Course
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
TEST RESULT REFERENCE RANGE
Platelet count 33 x 109L 150-450 x 109L
PT 215 sec 103 ndash 128 sec
APTT 44 sec 26 ndash 36 sec
D-dimer 20 microgmL FEU lt025 microgml FEU
Fibrinogen 34 mgdL 200-375 mgdl
FII FV FVIII Low Not reported (NR)
FVII FIX FX vWF Normal NR
Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)
DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic
dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR
(C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen
(D) Illustration demonstrating repair
Case Study 5 ndash Diagnosis and Treatment
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography
Case Study 6 ndash Presentation
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
Case Study 6 ndash Lab Results
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L
PT 63 sec gt control 113 ndash 146 sec
INR 658 1 ndash 125
APTT 80 sec gt control 25 ndash 34 sec
D-dimer gt200 microgmL DDU 02 microgmL DDU
Urine exam Proteinuria and hematuria 150-400 mgdl
Albumin 28 gdL NR
Hb 58 gdL NR
LDH 1196 UL NR
SGPT 144 IU NR
SGOT 88 IU NR
Bilirubin 32 mgdL NR
DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th
day postop
Case Study 6 ndash Diagnosis and Treatment
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure
Case Study 6 ndash Discussion
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Case Study 7 ndash Lab Results vs Time
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
DIC Take Home Messages
Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation
Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers
DIC
Thank you Questions
- Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
- Learning Objectives
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Wound Sealing
- The Three Steps of Hemostasis
- Vessel Wall
- Slide Number 12
- Slide Number 13
- Platelet Structure UnactivatedActivated
- Primary Hemostasis
- Primary Hemostasis Assays
- Slide Number 17
- Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
- Slide Number 19
- Coagulation factors
- Coagulation Assay Mechanisms
- Slide Number 22
- Fibrin Formation
- Slide Number 24
- Fibrinolysis Overview
- Fibrinolysis Overview
- Slide Number 27
- Fibrinolysis Releases D-dimers
- Basic Pathophysiology of DIC
- Disseminated Intravascular Coagulation (DIC)
- Purpura Fulminans with DIC Due to Meningococcal Sepsis
- Clinical Conditions Associated With DIC
- Frequency of DIC in Selected Disease States
- Underlying Diseases in DIC Patients
- Slide Number 36
- Slide Number 37
- Slide Number 38
- Slide Number 39
- Pathophysiology of DIC
- Pathogenesis of DIC in Sepsis
- Host Response in Severe Sepsis
- Organ Failure in Severe Sepsis
- Mechanism of DIC in Organ Failure
- Interaction of Inflammation and Coagulation in Sepsis
- Slide Number 47
- Diverse and Opposing Effects of Thrombin
- Coagulation and Fibrinolysis in DIC
- Mechanism of DIC
- Pathophysiology of DIC
- Pathophysiology of DIC - Mechanism
- Pathophysiology of DIC ndash 2 Types of Clinical pictures
- Sub-Acute and Non-Overt DIC Clinical Findings
- Pathophysiology of Overt DIC
- Physiopathology of DIC ndash Overt DIC Findings
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- BREAK
- Diagnostic and Management Approach for DIC
- Diagnosis of DIC
- Lab Diagnosis of DIC ndash Markers of Factor Consumption
- Lab Diagnosis of DIC ndash Screening Tests
- Slide Number 67
- Slide Number 68
- British Journal of Haematology Overt DIC Score
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- DIC Management Goals
- DIC Management and Treatment
- DIC Management Strategies
- Anticoagulant Factor Concentrate Treatment
- Anticoagulant Factor Concentrate Treatment Trials
- Markers of Thrombin amp Plasmin Generation in DIC
- D-dimer FDPs and DIC
- D-Dimer and FDPs in DIC
- Follow Up of DIC State of Disease
- FMD-Dimer in DIC Major Differences
- of Abnormal Results in Patients with Confirmed and Suspected DIC
- Slide Number 85
- Slide Number 86
- Comparing an Automated FM vs Manual FSP Test
- Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Slide Number 94
- Slide Number 95
- Slide Number 96
- Slide Number 97
- Slide Number 98
- Slide Number 99
- DIC Case Studies
- Case Study 1 - Presentation
- Case Study 1 ndash Lab Results
- Case Study 1 ndash Microscopy
- Case Study 1 ndash Diagnosis and Therapy
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Slide Number 110
- Slide Number 111
- Slide Number 112
- Slide Number 113
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
- Slide Number 124
- Slide Number 125
- DIC Take Home Messages
- Slide Number 127
- Slide Number 128
-
Stago 247 Educational Webinar Sites
wwwstago-edvantagecomUS based KOLsPACE accredited ndash all 1 hourAccessible from mobile devicesVirtual exhibit hall
wwwstagowebinarscomMostly European KOLs30 ndash 45 min including 15 min discussion
Stago Educational Apps
HaemoscoreClinical scoring algorithmsApple and AndroidTablet or phone
iHemostasisCoagulation diagramsCase studiesApple amp AndroidTablet only
BREAK
Diagnostic and Management Approach for DIC
Diagnosis of DIC
Clinical diagnosis is obvious in cases of overt DIC
Laboratory tests are necessary To makeconfirm the diagnosis To assess stage of the patient To assess the treatment efficacy
Lab Diagnosis of DIC ndash Markers of Factor Consumption
Routinescreening assays PT APTT Platelets Fibrinogen Thrombin time
Other coagulation assays Factor assays AntithrombinGeneration of Thrombin FMFSPsGeneration of Plasmin D-dimer FDPs
Important to recognize simultaneous formation of thrombin and plasmin
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122
Lab Diagnosis of DIC ndash Screening Tests
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122
Platelet count usually decreasedPT abnormal in 70 of cases (short half-life of FVII)APTT abnormal in 50 of casesThrombin time usually prolonged in overt DIC normal in non-overt DIC and no relation with syndrome severityFibrinogen low in lt 50 of cases sensitivity 22 specificity 87 overall predictive value 64 Normal fibrinogen level should not exclude DIC diagnosis (acute phase reactant initial high
fibrinogen level) repeat testing assesses progression
Screening tests not clinically specific or sensitive for DIC
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Laboratory Changes in Overt DIC
DIC Diagnostic Practices Over Time
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
British Journal of Haematology Overt DIC Score
Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
ISTH Step by Step DIC Algorithm
Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6
US Based Validation of ISTH DIC Score
When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Differential Diagnosis in DIC
aHUS atypical hemolytic uremic syndrome
HUS hemolytic uremic syndrome
HIT heparin-induced thrombocytopenia
ITP immune thrombocytopenic purpura
TTP thrombotic thrombocytopenic purpura
DIC and MAHA
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)
When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation
DIC Management Goals
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction
DIC Management and Treatment
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)
requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)
Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia
DIC Management Strategies
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant Factor Concentrate Treatment
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis
Anticoagulant Factor Concentrate Treatment Trials
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise
Markers of Thrombin amp Plasmin Generation in DIC
D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC
Cut-off value
Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen
degradation products Sensitive assay typically with cutoff adapted for DIC
D-dimer FDPs and DIC
D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC
Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80
Follow Up of DIC State of Disease
Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8
Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility
FMD-Dimer in DIC Major Differences
onset of thrombosis
days
Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8
FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)
D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)
of Abnormal Results in Patients with Confirmed and Suspected DIC
0
20
40
60
80
100
94 85 90N = 62
Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32
Positivity of Test Results ISTH Score and Disease State
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
Red bar positive for 2 points of DIC score
Pink bar positive for 1-2 points of DIC score
HT hematopoietic tumor
IF infection
SC solid cancer
Markers in Patients with or without DIC
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
HT hematopoietic tumorIF infectionSC solid cancer
Comparing an Automated FM vs Manual FSP Test
Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71
Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)
Automated (Mitsubishi) vs Automated (Stago)
In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago
Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC
Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
Non Overt DIC Overt DIC
AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC
Trends in Markers of DIC for Different Patients
Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00
Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients
Trends in Markers of DIC for Different Patients
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes
28 day outcome survival
28 day outcome death
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines
DIC Case Studies
Case Study 1 - Presentation
18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE
WBC count 77 KμL 423 ndash 907 x KμL
RBC count 17 MμL 137 ndash 175 x MμL
Hemoglobin 67 gdL 137 ndash 175 gdL
Hematocrit 195 401 ndash 510
MCV 95 fL 790 ndash 922 fL
MPV 12 fL 94 ndash 124 fL
Platelet count 9 KμL 161 ndash 347 KμL
Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0
Lymphocytes monocytes eosinophils basophils all below normal range
PT 47 sec (corrected on mixing study) 116 ndash 152 sec
APTT 75 sec (corrected on mixing study) 253 ndash 373 sec
Fibrinogen lt 76 mgdL 177 ndash 466 mgdL
D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Microscopy
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Arrow shows giant platelets in this peripheral smear Promyelocytes apparent
Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)
DIC due to TF release by APL blasts
Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases
Transfusions to replace factors along with platelets and RBCs during APL treatment
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started
Case Study 2 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L
PT 30 sec 113 ndash 146 sec
APTT 75 sec 25 ndash 34 sec
D-dimer 078 microgml FEU lt050 microgml FEU
Fibrinogen 92 mgdl 150-400 mgdl
pH 728 738 to 742
PaO2 570 mmHg 80-100 mmHg
WBC 33 times 103mm3 40-11 times 103mm3
ALT 111 IUL 0ndash34 IUL
AST 61 IUL 0ndash34 IUL
BUN 303 mgdL 08-13 mgdL
Case Study 2 ndash Lab Results
Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures
Case Study 2 ndash Diagnosis
60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior
Case Study 3 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L
PT 228 sec 113 ndash 146 sec
APTT 45 sec 25 ndash 34 sec
D-dimer 080 microgml FEU lt050 microgmL FEU
Fibrinogen 82 mgdL 150-400 mgdL
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 134 gdL 14-16 gdL
WBC 81 times 103mm3 40-11 times 103mm3
ALT 32 IUL 0ndash34 IUL
AST 28 IUL 0ndash34 IUL
BUN 09 mgdL 08-13 mgdL
Case Study 3 ndash Lab Results
Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment
Case Study 3 ndash Diagnosis and Therapy
Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91
Case Study 4 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L
PT 28 sec 113 ndash 146 sec
APTT 71 sec 25 ndash 34 sec
D-dimer 31 microgmL FEU lt050 microgml FEU
Fibrinogen 92 mgdL 150-400 mgdl
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 158 gdL 14-16 gdL
WBC 71 times 103mm3 40-11 times 103mm3
ALT 60 IUL 0ndash34 IUL
AST 47 IUL 0ndash34 IUL
BUN 38 mgdL 08-13 mgdL
Case Study 4 ndash Lab Results
Lyme disease with DICProvide antibiotics with supportive measures
Case Study 4 ndash Diagnosis
55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis
Case Study 5 ndash Presentation
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
Case Study 5 ndash Lab Results and Time Course
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
TEST RESULT REFERENCE RANGE
Platelet count 33 x 109L 150-450 x 109L
PT 215 sec 103 ndash 128 sec
APTT 44 sec 26 ndash 36 sec
D-dimer 20 microgmL FEU lt025 microgml FEU
Fibrinogen 34 mgdL 200-375 mgdl
FII FV FVIII Low Not reported (NR)
FVII FIX FX vWF Normal NR
Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)
DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic
dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR
(C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen
(D) Illustration demonstrating repair
Case Study 5 ndash Diagnosis and Treatment
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography
Case Study 6 ndash Presentation
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
Case Study 6 ndash Lab Results
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L
PT 63 sec gt control 113 ndash 146 sec
INR 658 1 ndash 125
APTT 80 sec gt control 25 ndash 34 sec
D-dimer gt200 microgmL DDU 02 microgmL DDU
Urine exam Proteinuria and hematuria 150-400 mgdl
Albumin 28 gdL NR
Hb 58 gdL NR
LDH 1196 UL NR
SGPT 144 IU NR
SGOT 88 IU NR
Bilirubin 32 mgdL NR
DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th
day postop
Case Study 6 ndash Diagnosis and Treatment
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure
Case Study 6 ndash Discussion
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Case Study 7 ndash Lab Results vs Time
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
DIC Take Home Messages
Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation
Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers
DIC
Thank you Questions
- Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
- Learning Objectives
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Wound Sealing
- The Three Steps of Hemostasis
- Vessel Wall
- Slide Number 12
- Slide Number 13
- Platelet Structure UnactivatedActivated
- Primary Hemostasis
- Primary Hemostasis Assays
- Slide Number 17
- Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
- Slide Number 19
- Coagulation factors
- Coagulation Assay Mechanisms
- Slide Number 22
- Fibrin Formation
- Slide Number 24
- Fibrinolysis Overview
- Fibrinolysis Overview
- Slide Number 27
- Fibrinolysis Releases D-dimers
- Basic Pathophysiology of DIC
- Disseminated Intravascular Coagulation (DIC)
- Purpura Fulminans with DIC Due to Meningococcal Sepsis
- Clinical Conditions Associated With DIC
- Frequency of DIC in Selected Disease States
- Underlying Diseases in DIC Patients
- Slide Number 36
- Slide Number 37
- Slide Number 38
- Slide Number 39
- Pathophysiology of DIC
- Pathogenesis of DIC in Sepsis
- Host Response in Severe Sepsis
- Organ Failure in Severe Sepsis
- Mechanism of DIC in Organ Failure
- Interaction of Inflammation and Coagulation in Sepsis
- Slide Number 47
- Diverse and Opposing Effects of Thrombin
- Coagulation and Fibrinolysis in DIC
- Mechanism of DIC
- Pathophysiology of DIC
- Pathophysiology of DIC - Mechanism
- Pathophysiology of DIC ndash 2 Types of Clinical pictures
- Sub-Acute and Non-Overt DIC Clinical Findings
- Pathophysiology of Overt DIC
- Physiopathology of DIC ndash Overt DIC Findings
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- BREAK
- Diagnostic and Management Approach for DIC
- Diagnosis of DIC
- Lab Diagnosis of DIC ndash Markers of Factor Consumption
- Lab Diagnosis of DIC ndash Screening Tests
- Slide Number 67
- Slide Number 68
- British Journal of Haematology Overt DIC Score
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- DIC Management Goals
- DIC Management and Treatment
- DIC Management Strategies
- Anticoagulant Factor Concentrate Treatment
- Anticoagulant Factor Concentrate Treatment Trials
- Markers of Thrombin amp Plasmin Generation in DIC
- D-dimer FDPs and DIC
- D-Dimer and FDPs in DIC
- Follow Up of DIC State of Disease
- FMD-Dimer in DIC Major Differences
- of Abnormal Results in Patients with Confirmed and Suspected DIC
- Slide Number 85
- Slide Number 86
- Comparing an Automated FM vs Manual FSP Test
- Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Slide Number 94
- Slide Number 95
- Slide Number 96
- Slide Number 97
- Slide Number 98
- Slide Number 99
- DIC Case Studies
- Case Study 1 - Presentation
- Case Study 1 ndash Lab Results
- Case Study 1 ndash Microscopy
- Case Study 1 ndash Diagnosis and Therapy
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Slide Number 110
- Slide Number 111
- Slide Number 112
- Slide Number 113
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
- Slide Number 124
- Slide Number 125
- DIC Take Home Messages
- Slide Number 127
- Slide Number 128
-
Stago Educational Apps
HaemoscoreClinical scoring algorithmsApple and AndroidTablet or phone
iHemostasisCoagulation diagramsCase studiesApple amp AndroidTablet only
BREAK
Diagnostic and Management Approach for DIC
Diagnosis of DIC
Clinical diagnosis is obvious in cases of overt DIC
Laboratory tests are necessary To makeconfirm the diagnosis To assess stage of the patient To assess the treatment efficacy
Lab Diagnosis of DIC ndash Markers of Factor Consumption
Routinescreening assays PT APTT Platelets Fibrinogen Thrombin time
Other coagulation assays Factor assays AntithrombinGeneration of Thrombin FMFSPsGeneration of Plasmin D-dimer FDPs
Important to recognize simultaneous formation of thrombin and plasmin
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122
Lab Diagnosis of DIC ndash Screening Tests
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122
Platelet count usually decreasedPT abnormal in 70 of cases (short half-life of FVII)APTT abnormal in 50 of casesThrombin time usually prolonged in overt DIC normal in non-overt DIC and no relation with syndrome severityFibrinogen low in lt 50 of cases sensitivity 22 specificity 87 overall predictive value 64 Normal fibrinogen level should not exclude DIC diagnosis (acute phase reactant initial high
fibrinogen level) repeat testing assesses progression
Screening tests not clinically specific or sensitive for DIC
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Laboratory Changes in Overt DIC
DIC Diagnostic Practices Over Time
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
British Journal of Haematology Overt DIC Score
Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
ISTH Step by Step DIC Algorithm
Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6
US Based Validation of ISTH DIC Score
When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Differential Diagnosis in DIC
aHUS atypical hemolytic uremic syndrome
HUS hemolytic uremic syndrome
HIT heparin-induced thrombocytopenia
ITP immune thrombocytopenic purpura
TTP thrombotic thrombocytopenic purpura
DIC and MAHA
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)
When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation
DIC Management Goals
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction
DIC Management and Treatment
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)
requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)
Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia
DIC Management Strategies
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant Factor Concentrate Treatment
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis
Anticoagulant Factor Concentrate Treatment Trials
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise
Markers of Thrombin amp Plasmin Generation in DIC
D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC
Cut-off value
Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen
degradation products Sensitive assay typically with cutoff adapted for DIC
D-dimer FDPs and DIC
D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC
Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80
Follow Up of DIC State of Disease
Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8
Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility
FMD-Dimer in DIC Major Differences
onset of thrombosis
days
Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8
FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)
D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)
of Abnormal Results in Patients with Confirmed and Suspected DIC
0
20
40
60
80
100
94 85 90N = 62
Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32
Positivity of Test Results ISTH Score and Disease State
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
Red bar positive for 2 points of DIC score
Pink bar positive for 1-2 points of DIC score
HT hematopoietic tumor
IF infection
SC solid cancer
Markers in Patients with or without DIC
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
HT hematopoietic tumorIF infectionSC solid cancer
Comparing an Automated FM vs Manual FSP Test
Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71
Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)
Automated (Mitsubishi) vs Automated (Stago)
In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago
Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC
Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
Non Overt DIC Overt DIC
AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC
Trends in Markers of DIC for Different Patients
Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00
Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients
Trends in Markers of DIC for Different Patients
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes
28 day outcome survival
28 day outcome death
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines
DIC Case Studies
Case Study 1 - Presentation
18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE
WBC count 77 KμL 423 ndash 907 x KμL
RBC count 17 MμL 137 ndash 175 x MμL
Hemoglobin 67 gdL 137 ndash 175 gdL
Hematocrit 195 401 ndash 510
MCV 95 fL 790 ndash 922 fL
MPV 12 fL 94 ndash 124 fL
Platelet count 9 KμL 161 ndash 347 KμL
Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0
Lymphocytes monocytes eosinophils basophils all below normal range
PT 47 sec (corrected on mixing study) 116 ndash 152 sec
APTT 75 sec (corrected on mixing study) 253 ndash 373 sec
Fibrinogen lt 76 mgdL 177 ndash 466 mgdL
D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Microscopy
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Arrow shows giant platelets in this peripheral smear Promyelocytes apparent
Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)
DIC due to TF release by APL blasts
Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases
Transfusions to replace factors along with platelets and RBCs during APL treatment
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started
Case Study 2 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L
PT 30 sec 113 ndash 146 sec
APTT 75 sec 25 ndash 34 sec
D-dimer 078 microgml FEU lt050 microgml FEU
Fibrinogen 92 mgdl 150-400 mgdl
pH 728 738 to 742
PaO2 570 mmHg 80-100 mmHg
WBC 33 times 103mm3 40-11 times 103mm3
ALT 111 IUL 0ndash34 IUL
AST 61 IUL 0ndash34 IUL
BUN 303 mgdL 08-13 mgdL
Case Study 2 ndash Lab Results
Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures
Case Study 2 ndash Diagnosis
60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior
Case Study 3 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L
PT 228 sec 113 ndash 146 sec
APTT 45 sec 25 ndash 34 sec
D-dimer 080 microgml FEU lt050 microgmL FEU
Fibrinogen 82 mgdL 150-400 mgdL
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 134 gdL 14-16 gdL
WBC 81 times 103mm3 40-11 times 103mm3
ALT 32 IUL 0ndash34 IUL
AST 28 IUL 0ndash34 IUL
BUN 09 mgdL 08-13 mgdL
Case Study 3 ndash Lab Results
Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment
Case Study 3 ndash Diagnosis and Therapy
Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91
Case Study 4 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L
PT 28 sec 113 ndash 146 sec
APTT 71 sec 25 ndash 34 sec
D-dimer 31 microgmL FEU lt050 microgml FEU
Fibrinogen 92 mgdL 150-400 mgdl
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 158 gdL 14-16 gdL
WBC 71 times 103mm3 40-11 times 103mm3
ALT 60 IUL 0ndash34 IUL
AST 47 IUL 0ndash34 IUL
BUN 38 mgdL 08-13 mgdL
Case Study 4 ndash Lab Results
Lyme disease with DICProvide antibiotics with supportive measures
Case Study 4 ndash Diagnosis
55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis
Case Study 5 ndash Presentation
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
Case Study 5 ndash Lab Results and Time Course
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
TEST RESULT REFERENCE RANGE
Platelet count 33 x 109L 150-450 x 109L
PT 215 sec 103 ndash 128 sec
APTT 44 sec 26 ndash 36 sec
D-dimer 20 microgmL FEU lt025 microgml FEU
Fibrinogen 34 mgdL 200-375 mgdl
FII FV FVIII Low Not reported (NR)
FVII FIX FX vWF Normal NR
Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)
DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic
dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR
(C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen
(D) Illustration demonstrating repair
Case Study 5 ndash Diagnosis and Treatment
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography
Case Study 6 ndash Presentation
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
Case Study 6 ndash Lab Results
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L
PT 63 sec gt control 113 ndash 146 sec
INR 658 1 ndash 125
APTT 80 sec gt control 25 ndash 34 sec
D-dimer gt200 microgmL DDU 02 microgmL DDU
Urine exam Proteinuria and hematuria 150-400 mgdl
Albumin 28 gdL NR
Hb 58 gdL NR
LDH 1196 UL NR
SGPT 144 IU NR
SGOT 88 IU NR
Bilirubin 32 mgdL NR
DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th
day postop
Case Study 6 ndash Diagnosis and Treatment
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure
Case Study 6 ndash Discussion
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Case Study 7 ndash Lab Results vs Time
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
DIC Take Home Messages
Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation
Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers
DIC
Thank you Questions
- Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
- Learning Objectives
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Wound Sealing
- The Three Steps of Hemostasis
- Vessel Wall
- Slide Number 12
- Slide Number 13
- Platelet Structure UnactivatedActivated
- Primary Hemostasis
- Primary Hemostasis Assays
- Slide Number 17
- Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
- Slide Number 19
- Coagulation factors
- Coagulation Assay Mechanisms
- Slide Number 22
- Fibrin Formation
- Slide Number 24
- Fibrinolysis Overview
- Fibrinolysis Overview
- Slide Number 27
- Fibrinolysis Releases D-dimers
- Basic Pathophysiology of DIC
- Disseminated Intravascular Coagulation (DIC)
- Purpura Fulminans with DIC Due to Meningococcal Sepsis
- Clinical Conditions Associated With DIC
- Frequency of DIC in Selected Disease States
- Underlying Diseases in DIC Patients
- Slide Number 36
- Slide Number 37
- Slide Number 38
- Slide Number 39
- Pathophysiology of DIC
- Pathogenesis of DIC in Sepsis
- Host Response in Severe Sepsis
- Organ Failure in Severe Sepsis
- Mechanism of DIC in Organ Failure
- Interaction of Inflammation and Coagulation in Sepsis
- Slide Number 47
- Diverse and Opposing Effects of Thrombin
- Coagulation and Fibrinolysis in DIC
- Mechanism of DIC
- Pathophysiology of DIC
- Pathophysiology of DIC - Mechanism
- Pathophysiology of DIC ndash 2 Types of Clinical pictures
- Sub-Acute and Non-Overt DIC Clinical Findings
- Pathophysiology of Overt DIC
- Physiopathology of DIC ndash Overt DIC Findings
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- BREAK
- Diagnostic and Management Approach for DIC
- Diagnosis of DIC
- Lab Diagnosis of DIC ndash Markers of Factor Consumption
- Lab Diagnosis of DIC ndash Screening Tests
- Slide Number 67
- Slide Number 68
- British Journal of Haematology Overt DIC Score
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- DIC Management Goals
- DIC Management and Treatment
- DIC Management Strategies
- Anticoagulant Factor Concentrate Treatment
- Anticoagulant Factor Concentrate Treatment Trials
- Markers of Thrombin amp Plasmin Generation in DIC
- D-dimer FDPs and DIC
- D-Dimer and FDPs in DIC
- Follow Up of DIC State of Disease
- FMD-Dimer in DIC Major Differences
- of Abnormal Results in Patients with Confirmed and Suspected DIC
- Slide Number 85
- Slide Number 86
- Comparing an Automated FM vs Manual FSP Test
- Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Slide Number 94
- Slide Number 95
- Slide Number 96
- Slide Number 97
- Slide Number 98
- Slide Number 99
- DIC Case Studies
- Case Study 1 - Presentation
- Case Study 1 ndash Lab Results
- Case Study 1 ndash Microscopy
- Case Study 1 ndash Diagnosis and Therapy
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Slide Number 110
- Slide Number 111
- Slide Number 112
- Slide Number 113
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
- Slide Number 124
- Slide Number 125
- DIC Take Home Messages
- Slide Number 127
- Slide Number 128
-
BREAK
Diagnostic and Management Approach for DIC
Diagnosis of DIC
Clinical diagnosis is obvious in cases of overt DIC
Laboratory tests are necessary To makeconfirm the diagnosis To assess stage of the patient To assess the treatment efficacy
Lab Diagnosis of DIC ndash Markers of Factor Consumption
Routinescreening assays PT APTT Platelets Fibrinogen Thrombin time
Other coagulation assays Factor assays AntithrombinGeneration of Thrombin FMFSPsGeneration of Plasmin D-dimer FDPs
Important to recognize simultaneous formation of thrombin and plasmin
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122
Lab Diagnosis of DIC ndash Screening Tests
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122
Platelet count usually decreasedPT abnormal in 70 of cases (short half-life of FVII)APTT abnormal in 50 of casesThrombin time usually prolonged in overt DIC normal in non-overt DIC and no relation with syndrome severityFibrinogen low in lt 50 of cases sensitivity 22 specificity 87 overall predictive value 64 Normal fibrinogen level should not exclude DIC diagnosis (acute phase reactant initial high
fibrinogen level) repeat testing assesses progression
Screening tests not clinically specific or sensitive for DIC
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Laboratory Changes in Overt DIC
DIC Diagnostic Practices Over Time
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
British Journal of Haematology Overt DIC Score
Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
ISTH Step by Step DIC Algorithm
Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6
US Based Validation of ISTH DIC Score
When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Differential Diagnosis in DIC
aHUS atypical hemolytic uremic syndrome
HUS hemolytic uremic syndrome
HIT heparin-induced thrombocytopenia
ITP immune thrombocytopenic purpura
TTP thrombotic thrombocytopenic purpura
DIC and MAHA
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)
When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation
DIC Management Goals
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction
DIC Management and Treatment
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)
requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)
Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia
DIC Management Strategies
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant Factor Concentrate Treatment
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis
Anticoagulant Factor Concentrate Treatment Trials
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise
Markers of Thrombin amp Plasmin Generation in DIC
D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC
Cut-off value
Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen
degradation products Sensitive assay typically with cutoff adapted for DIC
D-dimer FDPs and DIC
D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC
Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80
Follow Up of DIC State of Disease
Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8
Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility
FMD-Dimer in DIC Major Differences
onset of thrombosis
days
Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8
FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)
D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)
of Abnormal Results in Patients with Confirmed and Suspected DIC
0
20
40
60
80
100
94 85 90N = 62
Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32
Positivity of Test Results ISTH Score and Disease State
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
Red bar positive for 2 points of DIC score
Pink bar positive for 1-2 points of DIC score
HT hematopoietic tumor
IF infection
SC solid cancer
Markers in Patients with or without DIC
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
HT hematopoietic tumorIF infectionSC solid cancer
Comparing an Automated FM vs Manual FSP Test
Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71
Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)
Automated (Mitsubishi) vs Automated (Stago)
In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago
Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC
Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
Non Overt DIC Overt DIC
AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC
Trends in Markers of DIC for Different Patients
Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00
Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients
Trends in Markers of DIC for Different Patients
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes
28 day outcome survival
28 day outcome death
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines
DIC Case Studies
Case Study 1 - Presentation
18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE
WBC count 77 KμL 423 ndash 907 x KμL
RBC count 17 MμL 137 ndash 175 x MμL
Hemoglobin 67 gdL 137 ndash 175 gdL
Hematocrit 195 401 ndash 510
MCV 95 fL 790 ndash 922 fL
MPV 12 fL 94 ndash 124 fL
Platelet count 9 KμL 161 ndash 347 KμL
Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0
Lymphocytes monocytes eosinophils basophils all below normal range
PT 47 sec (corrected on mixing study) 116 ndash 152 sec
APTT 75 sec (corrected on mixing study) 253 ndash 373 sec
Fibrinogen lt 76 mgdL 177 ndash 466 mgdL
D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Microscopy
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Arrow shows giant platelets in this peripheral smear Promyelocytes apparent
Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)
DIC due to TF release by APL blasts
Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases
Transfusions to replace factors along with platelets and RBCs during APL treatment
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started
Case Study 2 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L
PT 30 sec 113 ndash 146 sec
APTT 75 sec 25 ndash 34 sec
D-dimer 078 microgml FEU lt050 microgml FEU
Fibrinogen 92 mgdl 150-400 mgdl
pH 728 738 to 742
PaO2 570 mmHg 80-100 mmHg
WBC 33 times 103mm3 40-11 times 103mm3
ALT 111 IUL 0ndash34 IUL
AST 61 IUL 0ndash34 IUL
BUN 303 mgdL 08-13 mgdL
Case Study 2 ndash Lab Results
Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures
Case Study 2 ndash Diagnosis
60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior
Case Study 3 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L
PT 228 sec 113 ndash 146 sec
APTT 45 sec 25 ndash 34 sec
D-dimer 080 microgml FEU lt050 microgmL FEU
Fibrinogen 82 mgdL 150-400 mgdL
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 134 gdL 14-16 gdL
WBC 81 times 103mm3 40-11 times 103mm3
ALT 32 IUL 0ndash34 IUL
AST 28 IUL 0ndash34 IUL
BUN 09 mgdL 08-13 mgdL
Case Study 3 ndash Lab Results
Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment
Case Study 3 ndash Diagnosis and Therapy
Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91
Case Study 4 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L
PT 28 sec 113 ndash 146 sec
APTT 71 sec 25 ndash 34 sec
D-dimer 31 microgmL FEU lt050 microgml FEU
Fibrinogen 92 mgdL 150-400 mgdl
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 158 gdL 14-16 gdL
WBC 71 times 103mm3 40-11 times 103mm3
ALT 60 IUL 0ndash34 IUL
AST 47 IUL 0ndash34 IUL
BUN 38 mgdL 08-13 mgdL
Case Study 4 ndash Lab Results
Lyme disease with DICProvide antibiotics with supportive measures
Case Study 4 ndash Diagnosis
55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis
Case Study 5 ndash Presentation
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
Case Study 5 ndash Lab Results and Time Course
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
TEST RESULT REFERENCE RANGE
Platelet count 33 x 109L 150-450 x 109L
PT 215 sec 103 ndash 128 sec
APTT 44 sec 26 ndash 36 sec
D-dimer 20 microgmL FEU lt025 microgml FEU
Fibrinogen 34 mgdL 200-375 mgdl
FII FV FVIII Low Not reported (NR)
FVII FIX FX vWF Normal NR
Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)
DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic
dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR
(C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen
(D) Illustration demonstrating repair
Case Study 5 ndash Diagnosis and Treatment
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography
Case Study 6 ndash Presentation
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
Case Study 6 ndash Lab Results
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L
PT 63 sec gt control 113 ndash 146 sec
INR 658 1 ndash 125
APTT 80 sec gt control 25 ndash 34 sec
D-dimer gt200 microgmL DDU 02 microgmL DDU
Urine exam Proteinuria and hematuria 150-400 mgdl
Albumin 28 gdL NR
Hb 58 gdL NR
LDH 1196 UL NR
SGPT 144 IU NR
SGOT 88 IU NR
Bilirubin 32 mgdL NR
DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th
day postop
Case Study 6 ndash Diagnosis and Treatment
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure
Case Study 6 ndash Discussion
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Case Study 7 ndash Lab Results vs Time
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
DIC Take Home Messages
Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation
Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers
DIC
Thank you Questions
- Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
- Learning Objectives
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Wound Sealing
- The Three Steps of Hemostasis
- Vessel Wall
- Slide Number 12
- Slide Number 13
- Platelet Structure UnactivatedActivated
- Primary Hemostasis
- Primary Hemostasis Assays
- Slide Number 17
- Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
- Slide Number 19
- Coagulation factors
- Coagulation Assay Mechanisms
- Slide Number 22
- Fibrin Formation
- Slide Number 24
- Fibrinolysis Overview
- Fibrinolysis Overview
- Slide Number 27
- Fibrinolysis Releases D-dimers
- Basic Pathophysiology of DIC
- Disseminated Intravascular Coagulation (DIC)
- Purpura Fulminans with DIC Due to Meningococcal Sepsis
- Clinical Conditions Associated With DIC
- Frequency of DIC in Selected Disease States
- Underlying Diseases in DIC Patients
- Slide Number 36
- Slide Number 37
- Slide Number 38
- Slide Number 39
- Pathophysiology of DIC
- Pathogenesis of DIC in Sepsis
- Host Response in Severe Sepsis
- Organ Failure in Severe Sepsis
- Mechanism of DIC in Organ Failure
- Interaction of Inflammation and Coagulation in Sepsis
- Slide Number 47
- Diverse and Opposing Effects of Thrombin
- Coagulation and Fibrinolysis in DIC
- Mechanism of DIC
- Pathophysiology of DIC
- Pathophysiology of DIC - Mechanism
- Pathophysiology of DIC ndash 2 Types of Clinical pictures
- Sub-Acute and Non-Overt DIC Clinical Findings
- Pathophysiology of Overt DIC
- Physiopathology of DIC ndash Overt DIC Findings
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- BREAK
- Diagnostic and Management Approach for DIC
- Diagnosis of DIC
- Lab Diagnosis of DIC ndash Markers of Factor Consumption
- Lab Diagnosis of DIC ndash Screening Tests
- Slide Number 67
- Slide Number 68
- British Journal of Haematology Overt DIC Score
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- DIC Management Goals
- DIC Management and Treatment
- DIC Management Strategies
- Anticoagulant Factor Concentrate Treatment
- Anticoagulant Factor Concentrate Treatment Trials
- Markers of Thrombin amp Plasmin Generation in DIC
- D-dimer FDPs and DIC
- D-Dimer and FDPs in DIC
- Follow Up of DIC State of Disease
- FMD-Dimer in DIC Major Differences
- of Abnormal Results in Patients with Confirmed and Suspected DIC
- Slide Number 85
- Slide Number 86
- Comparing an Automated FM vs Manual FSP Test
- Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Slide Number 94
- Slide Number 95
- Slide Number 96
- Slide Number 97
- Slide Number 98
- Slide Number 99
- DIC Case Studies
- Case Study 1 - Presentation
- Case Study 1 ndash Lab Results
- Case Study 1 ndash Microscopy
- Case Study 1 ndash Diagnosis and Therapy
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Slide Number 110
- Slide Number 111
- Slide Number 112
- Slide Number 113
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
- Slide Number 124
- Slide Number 125
- DIC Take Home Messages
- Slide Number 127
- Slide Number 128
-
Diagnostic and Management Approach for DIC
Diagnosis of DIC
Clinical diagnosis is obvious in cases of overt DIC
Laboratory tests are necessary To makeconfirm the diagnosis To assess stage of the patient To assess the treatment efficacy
Lab Diagnosis of DIC ndash Markers of Factor Consumption
Routinescreening assays PT APTT Platelets Fibrinogen Thrombin time
Other coagulation assays Factor assays AntithrombinGeneration of Thrombin FMFSPsGeneration of Plasmin D-dimer FDPs
Important to recognize simultaneous formation of thrombin and plasmin
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122
Lab Diagnosis of DIC ndash Screening Tests
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122
Platelet count usually decreasedPT abnormal in 70 of cases (short half-life of FVII)APTT abnormal in 50 of casesThrombin time usually prolonged in overt DIC normal in non-overt DIC and no relation with syndrome severityFibrinogen low in lt 50 of cases sensitivity 22 specificity 87 overall predictive value 64 Normal fibrinogen level should not exclude DIC diagnosis (acute phase reactant initial high
fibrinogen level) repeat testing assesses progression
Screening tests not clinically specific or sensitive for DIC
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Laboratory Changes in Overt DIC
DIC Diagnostic Practices Over Time
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
British Journal of Haematology Overt DIC Score
Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
ISTH Step by Step DIC Algorithm
Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6
US Based Validation of ISTH DIC Score
When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Differential Diagnosis in DIC
aHUS atypical hemolytic uremic syndrome
HUS hemolytic uremic syndrome
HIT heparin-induced thrombocytopenia
ITP immune thrombocytopenic purpura
TTP thrombotic thrombocytopenic purpura
DIC and MAHA
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)
When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation
DIC Management Goals
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction
DIC Management and Treatment
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)
requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)
Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia
DIC Management Strategies
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant Factor Concentrate Treatment
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis
Anticoagulant Factor Concentrate Treatment Trials
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise
Markers of Thrombin amp Plasmin Generation in DIC
D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC
Cut-off value
Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen
degradation products Sensitive assay typically with cutoff adapted for DIC
D-dimer FDPs and DIC
D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC
Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80
Follow Up of DIC State of Disease
Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8
Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility
FMD-Dimer in DIC Major Differences
onset of thrombosis
days
Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8
FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)
D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)
of Abnormal Results in Patients with Confirmed and Suspected DIC
0
20
40
60
80
100
94 85 90N = 62
Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32
Positivity of Test Results ISTH Score and Disease State
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
Red bar positive for 2 points of DIC score
Pink bar positive for 1-2 points of DIC score
HT hematopoietic tumor
IF infection
SC solid cancer
Markers in Patients with or without DIC
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
HT hematopoietic tumorIF infectionSC solid cancer
Comparing an Automated FM vs Manual FSP Test
Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71
Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)
Automated (Mitsubishi) vs Automated (Stago)
In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago
Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC
Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
Non Overt DIC Overt DIC
AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC
Trends in Markers of DIC for Different Patients
Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00
Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients
Trends in Markers of DIC for Different Patients
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes
28 day outcome survival
28 day outcome death
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines
DIC Case Studies
Case Study 1 - Presentation
18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE
WBC count 77 KμL 423 ndash 907 x KμL
RBC count 17 MμL 137 ndash 175 x MμL
Hemoglobin 67 gdL 137 ndash 175 gdL
Hematocrit 195 401 ndash 510
MCV 95 fL 790 ndash 922 fL
MPV 12 fL 94 ndash 124 fL
Platelet count 9 KμL 161 ndash 347 KμL
Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0
Lymphocytes monocytes eosinophils basophils all below normal range
PT 47 sec (corrected on mixing study) 116 ndash 152 sec
APTT 75 sec (corrected on mixing study) 253 ndash 373 sec
Fibrinogen lt 76 mgdL 177 ndash 466 mgdL
D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Microscopy
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Arrow shows giant platelets in this peripheral smear Promyelocytes apparent
Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)
DIC due to TF release by APL blasts
Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases
Transfusions to replace factors along with platelets and RBCs during APL treatment
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started
Case Study 2 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L
PT 30 sec 113 ndash 146 sec
APTT 75 sec 25 ndash 34 sec
D-dimer 078 microgml FEU lt050 microgml FEU
Fibrinogen 92 mgdl 150-400 mgdl
pH 728 738 to 742
PaO2 570 mmHg 80-100 mmHg
WBC 33 times 103mm3 40-11 times 103mm3
ALT 111 IUL 0ndash34 IUL
AST 61 IUL 0ndash34 IUL
BUN 303 mgdL 08-13 mgdL
Case Study 2 ndash Lab Results
Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures
Case Study 2 ndash Diagnosis
60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior
Case Study 3 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L
PT 228 sec 113 ndash 146 sec
APTT 45 sec 25 ndash 34 sec
D-dimer 080 microgml FEU lt050 microgmL FEU
Fibrinogen 82 mgdL 150-400 mgdL
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 134 gdL 14-16 gdL
WBC 81 times 103mm3 40-11 times 103mm3
ALT 32 IUL 0ndash34 IUL
AST 28 IUL 0ndash34 IUL
BUN 09 mgdL 08-13 mgdL
Case Study 3 ndash Lab Results
Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment
Case Study 3 ndash Diagnosis and Therapy
Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91
Case Study 4 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L
PT 28 sec 113 ndash 146 sec
APTT 71 sec 25 ndash 34 sec
D-dimer 31 microgmL FEU lt050 microgml FEU
Fibrinogen 92 mgdL 150-400 mgdl
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 158 gdL 14-16 gdL
WBC 71 times 103mm3 40-11 times 103mm3
ALT 60 IUL 0ndash34 IUL
AST 47 IUL 0ndash34 IUL
BUN 38 mgdL 08-13 mgdL
Case Study 4 ndash Lab Results
Lyme disease with DICProvide antibiotics with supportive measures
Case Study 4 ndash Diagnosis
55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis
Case Study 5 ndash Presentation
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
Case Study 5 ndash Lab Results and Time Course
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
TEST RESULT REFERENCE RANGE
Platelet count 33 x 109L 150-450 x 109L
PT 215 sec 103 ndash 128 sec
APTT 44 sec 26 ndash 36 sec
D-dimer 20 microgmL FEU lt025 microgml FEU
Fibrinogen 34 mgdL 200-375 mgdl
FII FV FVIII Low Not reported (NR)
FVII FIX FX vWF Normal NR
Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)
DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic
dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR
(C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen
(D) Illustration demonstrating repair
Case Study 5 ndash Diagnosis and Treatment
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography
Case Study 6 ndash Presentation
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
Case Study 6 ndash Lab Results
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L
PT 63 sec gt control 113 ndash 146 sec
INR 658 1 ndash 125
APTT 80 sec gt control 25 ndash 34 sec
D-dimer gt200 microgmL DDU 02 microgmL DDU
Urine exam Proteinuria and hematuria 150-400 mgdl
Albumin 28 gdL NR
Hb 58 gdL NR
LDH 1196 UL NR
SGPT 144 IU NR
SGOT 88 IU NR
Bilirubin 32 mgdL NR
DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th
day postop
Case Study 6 ndash Diagnosis and Treatment
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure
Case Study 6 ndash Discussion
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Case Study 7 ndash Lab Results vs Time
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
DIC Take Home Messages
Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation
Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers
DIC
Thank you Questions
- Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
- Learning Objectives
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Wound Sealing
- The Three Steps of Hemostasis
- Vessel Wall
- Slide Number 12
- Slide Number 13
- Platelet Structure UnactivatedActivated
- Primary Hemostasis
- Primary Hemostasis Assays
- Slide Number 17
- Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
- Slide Number 19
- Coagulation factors
- Coagulation Assay Mechanisms
- Slide Number 22
- Fibrin Formation
- Slide Number 24
- Fibrinolysis Overview
- Fibrinolysis Overview
- Slide Number 27
- Fibrinolysis Releases D-dimers
- Basic Pathophysiology of DIC
- Disseminated Intravascular Coagulation (DIC)
- Purpura Fulminans with DIC Due to Meningococcal Sepsis
- Clinical Conditions Associated With DIC
- Frequency of DIC in Selected Disease States
- Underlying Diseases in DIC Patients
- Slide Number 36
- Slide Number 37
- Slide Number 38
- Slide Number 39
- Pathophysiology of DIC
- Pathogenesis of DIC in Sepsis
- Host Response in Severe Sepsis
- Organ Failure in Severe Sepsis
- Mechanism of DIC in Organ Failure
- Interaction of Inflammation and Coagulation in Sepsis
- Slide Number 47
- Diverse and Opposing Effects of Thrombin
- Coagulation and Fibrinolysis in DIC
- Mechanism of DIC
- Pathophysiology of DIC
- Pathophysiology of DIC - Mechanism
- Pathophysiology of DIC ndash 2 Types of Clinical pictures
- Sub-Acute and Non-Overt DIC Clinical Findings
- Pathophysiology of Overt DIC
- Physiopathology of DIC ndash Overt DIC Findings
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- BREAK
- Diagnostic and Management Approach for DIC
- Diagnosis of DIC
- Lab Diagnosis of DIC ndash Markers of Factor Consumption
- Lab Diagnosis of DIC ndash Screening Tests
- Slide Number 67
- Slide Number 68
- British Journal of Haematology Overt DIC Score
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- DIC Management Goals
- DIC Management and Treatment
- DIC Management Strategies
- Anticoagulant Factor Concentrate Treatment
- Anticoagulant Factor Concentrate Treatment Trials
- Markers of Thrombin amp Plasmin Generation in DIC
- D-dimer FDPs and DIC
- D-Dimer and FDPs in DIC
- Follow Up of DIC State of Disease
- FMD-Dimer in DIC Major Differences
- of Abnormal Results in Patients with Confirmed and Suspected DIC
- Slide Number 85
- Slide Number 86
- Comparing an Automated FM vs Manual FSP Test
- Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Slide Number 94
- Slide Number 95
- Slide Number 96
- Slide Number 97
- Slide Number 98
- Slide Number 99
- DIC Case Studies
- Case Study 1 - Presentation
- Case Study 1 ndash Lab Results
- Case Study 1 ndash Microscopy
- Case Study 1 ndash Diagnosis and Therapy
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Slide Number 110
- Slide Number 111
- Slide Number 112
- Slide Number 113
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
- Slide Number 124
- Slide Number 125
- DIC Take Home Messages
- Slide Number 127
- Slide Number 128
-
Diagnosis of DIC
Clinical diagnosis is obvious in cases of overt DIC
Laboratory tests are necessary To makeconfirm the diagnosis To assess stage of the patient To assess the treatment efficacy
Lab Diagnosis of DIC ndash Markers of Factor Consumption
Routinescreening assays PT APTT Platelets Fibrinogen Thrombin time
Other coagulation assays Factor assays AntithrombinGeneration of Thrombin FMFSPsGeneration of Plasmin D-dimer FDPs
Important to recognize simultaneous formation of thrombin and plasmin
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122
Lab Diagnosis of DIC ndash Screening Tests
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122
Platelet count usually decreasedPT abnormal in 70 of cases (short half-life of FVII)APTT abnormal in 50 of casesThrombin time usually prolonged in overt DIC normal in non-overt DIC and no relation with syndrome severityFibrinogen low in lt 50 of cases sensitivity 22 specificity 87 overall predictive value 64 Normal fibrinogen level should not exclude DIC diagnosis (acute phase reactant initial high
fibrinogen level) repeat testing assesses progression
Screening tests not clinically specific or sensitive for DIC
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Laboratory Changes in Overt DIC
DIC Diagnostic Practices Over Time
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
British Journal of Haematology Overt DIC Score
Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
ISTH Step by Step DIC Algorithm
Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6
US Based Validation of ISTH DIC Score
When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Differential Diagnosis in DIC
aHUS atypical hemolytic uremic syndrome
HUS hemolytic uremic syndrome
HIT heparin-induced thrombocytopenia
ITP immune thrombocytopenic purpura
TTP thrombotic thrombocytopenic purpura
DIC and MAHA
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)
When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation
DIC Management Goals
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction
DIC Management and Treatment
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)
requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)
Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia
DIC Management Strategies
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant Factor Concentrate Treatment
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis
Anticoagulant Factor Concentrate Treatment Trials
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise
Markers of Thrombin amp Plasmin Generation in DIC
D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC
Cut-off value
Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen
degradation products Sensitive assay typically with cutoff adapted for DIC
D-dimer FDPs and DIC
D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC
Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80
Follow Up of DIC State of Disease
Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8
Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility
FMD-Dimer in DIC Major Differences
onset of thrombosis
days
Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8
FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)
D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)
of Abnormal Results in Patients with Confirmed and Suspected DIC
0
20
40
60
80
100
94 85 90N = 62
Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32
Positivity of Test Results ISTH Score and Disease State
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
Red bar positive for 2 points of DIC score
Pink bar positive for 1-2 points of DIC score
HT hematopoietic tumor
IF infection
SC solid cancer
Markers in Patients with or without DIC
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
HT hematopoietic tumorIF infectionSC solid cancer
Comparing an Automated FM vs Manual FSP Test
Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71
Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)
Automated (Mitsubishi) vs Automated (Stago)
In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago
Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC
Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
Non Overt DIC Overt DIC
AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC
Trends in Markers of DIC for Different Patients
Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00
Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients
Trends in Markers of DIC for Different Patients
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes
28 day outcome survival
28 day outcome death
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines
DIC Case Studies
Case Study 1 - Presentation
18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE
WBC count 77 KμL 423 ndash 907 x KμL
RBC count 17 MμL 137 ndash 175 x MμL
Hemoglobin 67 gdL 137 ndash 175 gdL
Hematocrit 195 401 ndash 510
MCV 95 fL 790 ndash 922 fL
MPV 12 fL 94 ndash 124 fL
Platelet count 9 KμL 161 ndash 347 KμL
Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0
Lymphocytes monocytes eosinophils basophils all below normal range
PT 47 sec (corrected on mixing study) 116 ndash 152 sec
APTT 75 sec (corrected on mixing study) 253 ndash 373 sec
Fibrinogen lt 76 mgdL 177 ndash 466 mgdL
D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Microscopy
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Arrow shows giant platelets in this peripheral smear Promyelocytes apparent
Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)
DIC due to TF release by APL blasts
Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases
Transfusions to replace factors along with platelets and RBCs during APL treatment
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started
Case Study 2 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L
PT 30 sec 113 ndash 146 sec
APTT 75 sec 25 ndash 34 sec
D-dimer 078 microgml FEU lt050 microgml FEU
Fibrinogen 92 mgdl 150-400 mgdl
pH 728 738 to 742
PaO2 570 mmHg 80-100 mmHg
WBC 33 times 103mm3 40-11 times 103mm3
ALT 111 IUL 0ndash34 IUL
AST 61 IUL 0ndash34 IUL
BUN 303 mgdL 08-13 mgdL
Case Study 2 ndash Lab Results
Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures
Case Study 2 ndash Diagnosis
60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior
Case Study 3 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L
PT 228 sec 113 ndash 146 sec
APTT 45 sec 25 ndash 34 sec
D-dimer 080 microgml FEU lt050 microgmL FEU
Fibrinogen 82 mgdL 150-400 mgdL
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 134 gdL 14-16 gdL
WBC 81 times 103mm3 40-11 times 103mm3
ALT 32 IUL 0ndash34 IUL
AST 28 IUL 0ndash34 IUL
BUN 09 mgdL 08-13 mgdL
Case Study 3 ndash Lab Results
Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment
Case Study 3 ndash Diagnosis and Therapy
Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91
Case Study 4 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L
PT 28 sec 113 ndash 146 sec
APTT 71 sec 25 ndash 34 sec
D-dimer 31 microgmL FEU lt050 microgml FEU
Fibrinogen 92 mgdL 150-400 mgdl
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 158 gdL 14-16 gdL
WBC 71 times 103mm3 40-11 times 103mm3
ALT 60 IUL 0ndash34 IUL
AST 47 IUL 0ndash34 IUL
BUN 38 mgdL 08-13 mgdL
Case Study 4 ndash Lab Results
Lyme disease with DICProvide antibiotics with supportive measures
Case Study 4 ndash Diagnosis
55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis
Case Study 5 ndash Presentation
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
Case Study 5 ndash Lab Results and Time Course
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
TEST RESULT REFERENCE RANGE
Platelet count 33 x 109L 150-450 x 109L
PT 215 sec 103 ndash 128 sec
APTT 44 sec 26 ndash 36 sec
D-dimer 20 microgmL FEU lt025 microgml FEU
Fibrinogen 34 mgdL 200-375 mgdl
FII FV FVIII Low Not reported (NR)
FVII FIX FX vWF Normal NR
Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)
DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic
dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR
(C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen
(D) Illustration demonstrating repair
Case Study 5 ndash Diagnosis and Treatment
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography
Case Study 6 ndash Presentation
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
Case Study 6 ndash Lab Results
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L
PT 63 sec gt control 113 ndash 146 sec
INR 658 1 ndash 125
APTT 80 sec gt control 25 ndash 34 sec
D-dimer gt200 microgmL DDU 02 microgmL DDU
Urine exam Proteinuria and hematuria 150-400 mgdl
Albumin 28 gdL NR
Hb 58 gdL NR
LDH 1196 UL NR
SGPT 144 IU NR
SGOT 88 IU NR
Bilirubin 32 mgdL NR
DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th
day postop
Case Study 6 ndash Diagnosis and Treatment
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure
Case Study 6 ndash Discussion
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Case Study 7 ndash Lab Results vs Time
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
DIC Take Home Messages
Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation
Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers
DIC
Thank you Questions
- Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
- Learning Objectives
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Wound Sealing
- The Three Steps of Hemostasis
- Vessel Wall
- Slide Number 12
- Slide Number 13
- Platelet Structure UnactivatedActivated
- Primary Hemostasis
- Primary Hemostasis Assays
- Slide Number 17
- Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
- Slide Number 19
- Coagulation factors
- Coagulation Assay Mechanisms
- Slide Number 22
- Fibrin Formation
- Slide Number 24
- Fibrinolysis Overview
- Fibrinolysis Overview
- Slide Number 27
- Fibrinolysis Releases D-dimers
- Basic Pathophysiology of DIC
- Disseminated Intravascular Coagulation (DIC)
- Purpura Fulminans with DIC Due to Meningococcal Sepsis
- Clinical Conditions Associated With DIC
- Frequency of DIC in Selected Disease States
- Underlying Diseases in DIC Patients
- Slide Number 36
- Slide Number 37
- Slide Number 38
- Slide Number 39
- Pathophysiology of DIC
- Pathogenesis of DIC in Sepsis
- Host Response in Severe Sepsis
- Organ Failure in Severe Sepsis
- Mechanism of DIC in Organ Failure
- Interaction of Inflammation and Coagulation in Sepsis
- Slide Number 47
- Diverse and Opposing Effects of Thrombin
- Coagulation and Fibrinolysis in DIC
- Mechanism of DIC
- Pathophysiology of DIC
- Pathophysiology of DIC - Mechanism
- Pathophysiology of DIC ndash 2 Types of Clinical pictures
- Sub-Acute and Non-Overt DIC Clinical Findings
- Pathophysiology of Overt DIC
- Physiopathology of DIC ndash Overt DIC Findings
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- BREAK
- Diagnostic and Management Approach for DIC
- Diagnosis of DIC
- Lab Diagnosis of DIC ndash Markers of Factor Consumption
- Lab Diagnosis of DIC ndash Screening Tests
- Slide Number 67
- Slide Number 68
- British Journal of Haematology Overt DIC Score
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- DIC Management Goals
- DIC Management and Treatment
- DIC Management Strategies
- Anticoagulant Factor Concentrate Treatment
- Anticoagulant Factor Concentrate Treatment Trials
- Markers of Thrombin amp Plasmin Generation in DIC
- D-dimer FDPs and DIC
- D-Dimer and FDPs in DIC
- Follow Up of DIC State of Disease
- FMD-Dimer in DIC Major Differences
- of Abnormal Results in Patients with Confirmed and Suspected DIC
- Slide Number 85
- Slide Number 86
- Comparing an Automated FM vs Manual FSP Test
- Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Slide Number 94
- Slide Number 95
- Slide Number 96
- Slide Number 97
- Slide Number 98
- Slide Number 99
- DIC Case Studies
- Case Study 1 - Presentation
- Case Study 1 ndash Lab Results
- Case Study 1 ndash Microscopy
- Case Study 1 ndash Diagnosis and Therapy
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Slide Number 110
- Slide Number 111
- Slide Number 112
- Slide Number 113
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
- Slide Number 124
- Slide Number 125
- DIC Take Home Messages
- Slide Number 127
- Slide Number 128
-
Lab Diagnosis of DIC ndash Markers of Factor Consumption
Routinescreening assays PT APTT Platelets Fibrinogen Thrombin time
Other coagulation assays Factor assays AntithrombinGeneration of Thrombin FMFSPsGeneration of Plasmin D-dimer FDPs
Important to recognize simultaneous formation of thrombin and plasmin
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122
Lab Diagnosis of DIC ndash Screening Tests
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122
Platelet count usually decreasedPT abnormal in 70 of cases (short half-life of FVII)APTT abnormal in 50 of casesThrombin time usually prolonged in overt DIC normal in non-overt DIC and no relation with syndrome severityFibrinogen low in lt 50 of cases sensitivity 22 specificity 87 overall predictive value 64 Normal fibrinogen level should not exclude DIC diagnosis (acute phase reactant initial high
fibrinogen level) repeat testing assesses progression
Screening tests not clinically specific or sensitive for DIC
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Laboratory Changes in Overt DIC
DIC Diagnostic Practices Over Time
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
British Journal of Haematology Overt DIC Score
Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
ISTH Step by Step DIC Algorithm
Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6
US Based Validation of ISTH DIC Score
When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Differential Diagnosis in DIC
aHUS atypical hemolytic uremic syndrome
HUS hemolytic uremic syndrome
HIT heparin-induced thrombocytopenia
ITP immune thrombocytopenic purpura
TTP thrombotic thrombocytopenic purpura
DIC and MAHA
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)
When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation
DIC Management Goals
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction
DIC Management and Treatment
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)
requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)
Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia
DIC Management Strategies
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant Factor Concentrate Treatment
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis
Anticoagulant Factor Concentrate Treatment Trials
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise
Markers of Thrombin amp Plasmin Generation in DIC
D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC
Cut-off value
Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen
degradation products Sensitive assay typically with cutoff adapted for DIC
D-dimer FDPs and DIC
D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC
Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80
Follow Up of DIC State of Disease
Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8
Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility
FMD-Dimer in DIC Major Differences
onset of thrombosis
days
Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8
FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)
D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)
of Abnormal Results in Patients with Confirmed and Suspected DIC
0
20
40
60
80
100
94 85 90N = 62
Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32
Positivity of Test Results ISTH Score and Disease State
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
Red bar positive for 2 points of DIC score
Pink bar positive for 1-2 points of DIC score
HT hematopoietic tumor
IF infection
SC solid cancer
Markers in Patients with or without DIC
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
HT hematopoietic tumorIF infectionSC solid cancer
Comparing an Automated FM vs Manual FSP Test
Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71
Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)
Automated (Mitsubishi) vs Automated (Stago)
In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago
Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC
Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
Non Overt DIC Overt DIC
AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC
Trends in Markers of DIC for Different Patients
Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00
Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients
Trends in Markers of DIC for Different Patients
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes
28 day outcome survival
28 day outcome death
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines
DIC Case Studies
Case Study 1 - Presentation
18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE
WBC count 77 KμL 423 ndash 907 x KμL
RBC count 17 MμL 137 ndash 175 x MμL
Hemoglobin 67 gdL 137 ndash 175 gdL
Hematocrit 195 401 ndash 510
MCV 95 fL 790 ndash 922 fL
MPV 12 fL 94 ndash 124 fL
Platelet count 9 KμL 161 ndash 347 KμL
Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0
Lymphocytes monocytes eosinophils basophils all below normal range
PT 47 sec (corrected on mixing study) 116 ndash 152 sec
APTT 75 sec (corrected on mixing study) 253 ndash 373 sec
Fibrinogen lt 76 mgdL 177 ndash 466 mgdL
D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Microscopy
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Arrow shows giant platelets in this peripheral smear Promyelocytes apparent
Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)
DIC due to TF release by APL blasts
Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases
Transfusions to replace factors along with platelets and RBCs during APL treatment
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started
Case Study 2 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L
PT 30 sec 113 ndash 146 sec
APTT 75 sec 25 ndash 34 sec
D-dimer 078 microgml FEU lt050 microgml FEU
Fibrinogen 92 mgdl 150-400 mgdl
pH 728 738 to 742
PaO2 570 mmHg 80-100 mmHg
WBC 33 times 103mm3 40-11 times 103mm3
ALT 111 IUL 0ndash34 IUL
AST 61 IUL 0ndash34 IUL
BUN 303 mgdL 08-13 mgdL
Case Study 2 ndash Lab Results
Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures
Case Study 2 ndash Diagnosis
60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior
Case Study 3 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L
PT 228 sec 113 ndash 146 sec
APTT 45 sec 25 ndash 34 sec
D-dimer 080 microgml FEU lt050 microgmL FEU
Fibrinogen 82 mgdL 150-400 mgdL
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 134 gdL 14-16 gdL
WBC 81 times 103mm3 40-11 times 103mm3
ALT 32 IUL 0ndash34 IUL
AST 28 IUL 0ndash34 IUL
BUN 09 mgdL 08-13 mgdL
Case Study 3 ndash Lab Results
Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment
Case Study 3 ndash Diagnosis and Therapy
Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91
Case Study 4 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L
PT 28 sec 113 ndash 146 sec
APTT 71 sec 25 ndash 34 sec
D-dimer 31 microgmL FEU lt050 microgml FEU
Fibrinogen 92 mgdL 150-400 mgdl
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 158 gdL 14-16 gdL
WBC 71 times 103mm3 40-11 times 103mm3
ALT 60 IUL 0ndash34 IUL
AST 47 IUL 0ndash34 IUL
BUN 38 mgdL 08-13 mgdL
Case Study 4 ndash Lab Results
Lyme disease with DICProvide antibiotics with supportive measures
Case Study 4 ndash Diagnosis
55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis
Case Study 5 ndash Presentation
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
Case Study 5 ndash Lab Results and Time Course
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
TEST RESULT REFERENCE RANGE
Platelet count 33 x 109L 150-450 x 109L
PT 215 sec 103 ndash 128 sec
APTT 44 sec 26 ndash 36 sec
D-dimer 20 microgmL FEU lt025 microgml FEU
Fibrinogen 34 mgdL 200-375 mgdl
FII FV FVIII Low Not reported (NR)
FVII FIX FX vWF Normal NR
Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)
DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic
dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR
(C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen
(D) Illustration demonstrating repair
Case Study 5 ndash Diagnosis and Treatment
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography
Case Study 6 ndash Presentation
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
Case Study 6 ndash Lab Results
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L
PT 63 sec gt control 113 ndash 146 sec
INR 658 1 ndash 125
APTT 80 sec gt control 25 ndash 34 sec
D-dimer gt200 microgmL DDU 02 microgmL DDU
Urine exam Proteinuria and hematuria 150-400 mgdl
Albumin 28 gdL NR
Hb 58 gdL NR
LDH 1196 UL NR
SGPT 144 IU NR
SGOT 88 IU NR
Bilirubin 32 mgdL NR
DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th
day postop
Case Study 6 ndash Diagnosis and Treatment
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure
Case Study 6 ndash Discussion
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Case Study 7 ndash Lab Results vs Time
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
DIC Take Home Messages
Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation
Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers
DIC
Thank you Questions
- Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
- Learning Objectives
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Wound Sealing
- The Three Steps of Hemostasis
- Vessel Wall
- Slide Number 12
- Slide Number 13
- Platelet Structure UnactivatedActivated
- Primary Hemostasis
- Primary Hemostasis Assays
- Slide Number 17
- Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
- Slide Number 19
- Coagulation factors
- Coagulation Assay Mechanisms
- Slide Number 22
- Fibrin Formation
- Slide Number 24
- Fibrinolysis Overview
- Fibrinolysis Overview
- Slide Number 27
- Fibrinolysis Releases D-dimers
- Basic Pathophysiology of DIC
- Disseminated Intravascular Coagulation (DIC)
- Purpura Fulminans with DIC Due to Meningococcal Sepsis
- Clinical Conditions Associated With DIC
- Frequency of DIC in Selected Disease States
- Underlying Diseases in DIC Patients
- Slide Number 36
- Slide Number 37
- Slide Number 38
- Slide Number 39
- Pathophysiology of DIC
- Pathogenesis of DIC in Sepsis
- Host Response in Severe Sepsis
- Organ Failure in Severe Sepsis
- Mechanism of DIC in Organ Failure
- Interaction of Inflammation and Coagulation in Sepsis
- Slide Number 47
- Diverse and Opposing Effects of Thrombin
- Coagulation and Fibrinolysis in DIC
- Mechanism of DIC
- Pathophysiology of DIC
- Pathophysiology of DIC - Mechanism
- Pathophysiology of DIC ndash 2 Types of Clinical pictures
- Sub-Acute and Non-Overt DIC Clinical Findings
- Pathophysiology of Overt DIC
- Physiopathology of DIC ndash Overt DIC Findings
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- BREAK
- Diagnostic and Management Approach for DIC
- Diagnosis of DIC
- Lab Diagnosis of DIC ndash Markers of Factor Consumption
- Lab Diagnosis of DIC ndash Screening Tests
- Slide Number 67
- Slide Number 68
- British Journal of Haematology Overt DIC Score
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- DIC Management Goals
- DIC Management and Treatment
- DIC Management Strategies
- Anticoagulant Factor Concentrate Treatment
- Anticoagulant Factor Concentrate Treatment Trials
- Markers of Thrombin amp Plasmin Generation in DIC
- D-dimer FDPs and DIC
- D-Dimer and FDPs in DIC
- Follow Up of DIC State of Disease
- FMD-Dimer in DIC Major Differences
- of Abnormal Results in Patients with Confirmed and Suspected DIC
- Slide Number 85
- Slide Number 86
- Comparing an Automated FM vs Manual FSP Test
- Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Slide Number 94
- Slide Number 95
- Slide Number 96
- Slide Number 97
- Slide Number 98
- Slide Number 99
- DIC Case Studies
- Case Study 1 - Presentation
- Case Study 1 ndash Lab Results
- Case Study 1 ndash Microscopy
- Case Study 1 ndash Diagnosis and Therapy
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Slide Number 110
- Slide Number 111
- Slide Number 112
- Slide Number 113
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
- Slide Number 124
- Slide Number 125
- DIC Take Home Messages
- Slide Number 127
- Slide Number 128
-
Lab Diagnosis of DIC ndash Screening Tests
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 16 312 683-687Schmaier AH Laboratory evaluation of hemostatic and thrombotic disorders In Hoffman R Benz EJ Jr Shattil SJ et al eds Hoffman Hematology Basic Principles and Practice 5th ed Philadelphia Pa Churchill Livingstone Elsevier 2008chap 122
Platelet count usually decreasedPT abnormal in 70 of cases (short half-life of FVII)APTT abnormal in 50 of casesThrombin time usually prolonged in overt DIC normal in non-overt DIC and no relation with syndrome severityFibrinogen low in lt 50 of cases sensitivity 22 specificity 87 overall predictive value 64 Normal fibrinogen level should not exclude DIC diagnosis (acute phase reactant initial high
fibrinogen level) repeat testing assesses progression
Screening tests not clinically specific or sensitive for DIC
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Laboratory Changes in Overt DIC
DIC Diagnostic Practices Over Time
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
British Journal of Haematology Overt DIC Score
Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
ISTH Step by Step DIC Algorithm
Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6
US Based Validation of ISTH DIC Score
When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Differential Diagnosis in DIC
aHUS atypical hemolytic uremic syndrome
HUS hemolytic uremic syndrome
HIT heparin-induced thrombocytopenia
ITP immune thrombocytopenic purpura
TTP thrombotic thrombocytopenic purpura
DIC and MAHA
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)
When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation
DIC Management Goals
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction
DIC Management and Treatment
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)
requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)
Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia
DIC Management Strategies
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant Factor Concentrate Treatment
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis
Anticoagulant Factor Concentrate Treatment Trials
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise
Markers of Thrombin amp Plasmin Generation in DIC
D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC
Cut-off value
Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen
degradation products Sensitive assay typically with cutoff adapted for DIC
D-dimer FDPs and DIC
D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC
Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80
Follow Up of DIC State of Disease
Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8
Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility
FMD-Dimer in DIC Major Differences
onset of thrombosis
days
Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8
FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)
D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)
of Abnormal Results in Patients with Confirmed and Suspected DIC
0
20
40
60
80
100
94 85 90N = 62
Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32
Positivity of Test Results ISTH Score and Disease State
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
Red bar positive for 2 points of DIC score
Pink bar positive for 1-2 points of DIC score
HT hematopoietic tumor
IF infection
SC solid cancer
Markers in Patients with or without DIC
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
HT hematopoietic tumorIF infectionSC solid cancer
Comparing an Automated FM vs Manual FSP Test
Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71
Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)
Automated (Mitsubishi) vs Automated (Stago)
In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago
Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC
Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
Non Overt DIC Overt DIC
AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC
Trends in Markers of DIC for Different Patients
Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00
Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients
Trends in Markers of DIC for Different Patients
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes
28 day outcome survival
28 day outcome death
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines
DIC Case Studies
Case Study 1 - Presentation
18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE
WBC count 77 KμL 423 ndash 907 x KμL
RBC count 17 MμL 137 ndash 175 x MμL
Hemoglobin 67 gdL 137 ndash 175 gdL
Hematocrit 195 401 ndash 510
MCV 95 fL 790 ndash 922 fL
MPV 12 fL 94 ndash 124 fL
Platelet count 9 KμL 161 ndash 347 KμL
Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0
Lymphocytes monocytes eosinophils basophils all below normal range
PT 47 sec (corrected on mixing study) 116 ndash 152 sec
APTT 75 sec (corrected on mixing study) 253 ndash 373 sec
Fibrinogen lt 76 mgdL 177 ndash 466 mgdL
D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Microscopy
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Arrow shows giant platelets in this peripheral smear Promyelocytes apparent
Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)
DIC due to TF release by APL blasts
Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases
Transfusions to replace factors along with platelets and RBCs during APL treatment
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started
Case Study 2 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L
PT 30 sec 113 ndash 146 sec
APTT 75 sec 25 ndash 34 sec
D-dimer 078 microgml FEU lt050 microgml FEU
Fibrinogen 92 mgdl 150-400 mgdl
pH 728 738 to 742
PaO2 570 mmHg 80-100 mmHg
WBC 33 times 103mm3 40-11 times 103mm3
ALT 111 IUL 0ndash34 IUL
AST 61 IUL 0ndash34 IUL
BUN 303 mgdL 08-13 mgdL
Case Study 2 ndash Lab Results
Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures
Case Study 2 ndash Diagnosis
60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior
Case Study 3 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L
PT 228 sec 113 ndash 146 sec
APTT 45 sec 25 ndash 34 sec
D-dimer 080 microgml FEU lt050 microgmL FEU
Fibrinogen 82 mgdL 150-400 mgdL
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 134 gdL 14-16 gdL
WBC 81 times 103mm3 40-11 times 103mm3
ALT 32 IUL 0ndash34 IUL
AST 28 IUL 0ndash34 IUL
BUN 09 mgdL 08-13 mgdL
Case Study 3 ndash Lab Results
Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment
Case Study 3 ndash Diagnosis and Therapy
Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91
Case Study 4 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L
PT 28 sec 113 ndash 146 sec
APTT 71 sec 25 ndash 34 sec
D-dimer 31 microgmL FEU lt050 microgml FEU
Fibrinogen 92 mgdL 150-400 mgdl
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 158 gdL 14-16 gdL
WBC 71 times 103mm3 40-11 times 103mm3
ALT 60 IUL 0ndash34 IUL
AST 47 IUL 0ndash34 IUL
BUN 38 mgdL 08-13 mgdL
Case Study 4 ndash Lab Results
Lyme disease with DICProvide antibiotics with supportive measures
Case Study 4 ndash Diagnosis
55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis
Case Study 5 ndash Presentation
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
Case Study 5 ndash Lab Results and Time Course
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
TEST RESULT REFERENCE RANGE
Platelet count 33 x 109L 150-450 x 109L
PT 215 sec 103 ndash 128 sec
APTT 44 sec 26 ndash 36 sec
D-dimer 20 microgmL FEU lt025 microgml FEU
Fibrinogen 34 mgdL 200-375 mgdl
FII FV FVIII Low Not reported (NR)
FVII FIX FX vWF Normal NR
Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)
DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic
dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR
(C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen
(D) Illustration demonstrating repair
Case Study 5 ndash Diagnosis and Treatment
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography
Case Study 6 ndash Presentation
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
Case Study 6 ndash Lab Results
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L
PT 63 sec gt control 113 ndash 146 sec
INR 658 1 ndash 125
APTT 80 sec gt control 25 ndash 34 sec
D-dimer gt200 microgmL DDU 02 microgmL DDU
Urine exam Proteinuria and hematuria 150-400 mgdl
Albumin 28 gdL NR
Hb 58 gdL NR
LDH 1196 UL NR
SGPT 144 IU NR
SGOT 88 IU NR
Bilirubin 32 mgdL NR
DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th
day postop
Case Study 6 ndash Diagnosis and Treatment
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure
Case Study 6 ndash Discussion
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Case Study 7 ndash Lab Results vs Time
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
DIC Take Home Messages
Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation
Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers
DIC
Thank you Questions
- Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
- Learning Objectives
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Wound Sealing
- The Three Steps of Hemostasis
- Vessel Wall
- Slide Number 12
- Slide Number 13
- Platelet Structure UnactivatedActivated
- Primary Hemostasis
- Primary Hemostasis Assays
- Slide Number 17
- Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
- Slide Number 19
- Coagulation factors
- Coagulation Assay Mechanisms
- Slide Number 22
- Fibrin Formation
- Slide Number 24
- Fibrinolysis Overview
- Fibrinolysis Overview
- Slide Number 27
- Fibrinolysis Releases D-dimers
- Basic Pathophysiology of DIC
- Disseminated Intravascular Coagulation (DIC)
- Purpura Fulminans with DIC Due to Meningococcal Sepsis
- Clinical Conditions Associated With DIC
- Frequency of DIC in Selected Disease States
- Underlying Diseases in DIC Patients
- Slide Number 36
- Slide Number 37
- Slide Number 38
- Slide Number 39
- Pathophysiology of DIC
- Pathogenesis of DIC in Sepsis
- Host Response in Severe Sepsis
- Organ Failure in Severe Sepsis
- Mechanism of DIC in Organ Failure
- Interaction of Inflammation and Coagulation in Sepsis
- Slide Number 47
- Diverse and Opposing Effects of Thrombin
- Coagulation and Fibrinolysis in DIC
- Mechanism of DIC
- Pathophysiology of DIC
- Pathophysiology of DIC - Mechanism
- Pathophysiology of DIC ndash 2 Types of Clinical pictures
- Sub-Acute and Non-Overt DIC Clinical Findings
- Pathophysiology of Overt DIC
- Physiopathology of DIC ndash Overt DIC Findings
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- BREAK
- Diagnostic and Management Approach for DIC
- Diagnosis of DIC
- Lab Diagnosis of DIC ndash Markers of Factor Consumption
- Lab Diagnosis of DIC ndash Screening Tests
- Slide Number 67
- Slide Number 68
- British Journal of Haematology Overt DIC Score
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- DIC Management Goals
- DIC Management and Treatment
- DIC Management Strategies
- Anticoagulant Factor Concentrate Treatment
- Anticoagulant Factor Concentrate Treatment Trials
- Markers of Thrombin amp Plasmin Generation in DIC
- D-dimer FDPs and DIC
- D-Dimer and FDPs in DIC
- Follow Up of DIC State of Disease
- FMD-Dimer in DIC Major Differences
- of Abnormal Results in Patients with Confirmed and Suspected DIC
- Slide Number 85
- Slide Number 86
- Comparing an Automated FM vs Manual FSP Test
- Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Slide Number 94
- Slide Number 95
- Slide Number 96
- Slide Number 97
- Slide Number 98
- Slide Number 99
- DIC Case Studies
- Case Study 1 - Presentation
- Case Study 1 ndash Lab Results
- Case Study 1 ndash Microscopy
- Case Study 1 ndash Diagnosis and Therapy
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Slide Number 110
- Slide Number 111
- Slide Number 112
- Slide Number 113
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
- Slide Number 124
- Slide Number 125
- DIC Take Home Messages
- Slide Number 127
- Slide Number 128
-
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Laboratory Changes in Overt DIC
DIC Diagnostic Practices Over Time
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
British Journal of Haematology Overt DIC Score
Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
ISTH Step by Step DIC Algorithm
Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6
US Based Validation of ISTH DIC Score
When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Differential Diagnosis in DIC
aHUS atypical hemolytic uremic syndrome
HUS hemolytic uremic syndrome
HIT heparin-induced thrombocytopenia
ITP immune thrombocytopenic purpura
TTP thrombotic thrombocytopenic purpura
DIC and MAHA
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)
When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation
DIC Management Goals
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction
DIC Management and Treatment
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)
requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)
Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia
DIC Management Strategies
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant Factor Concentrate Treatment
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis
Anticoagulant Factor Concentrate Treatment Trials
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise
Markers of Thrombin amp Plasmin Generation in DIC
D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC
Cut-off value
Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen
degradation products Sensitive assay typically with cutoff adapted for DIC
D-dimer FDPs and DIC
D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC
Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80
Follow Up of DIC State of Disease
Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8
Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility
FMD-Dimer in DIC Major Differences
onset of thrombosis
days
Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8
FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)
D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)
of Abnormal Results in Patients with Confirmed and Suspected DIC
0
20
40
60
80
100
94 85 90N = 62
Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32
Positivity of Test Results ISTH Score and Disease State
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
Red bar positive for 2 points of DIC score
Pink bar positive for 1-2 points of DIC score
HT hematopoietic tumor
IF infection
SC solid cancer
Markers in Patients with or without DIC
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
HT hematopoietic tumorIF infectionSC solid cancer
Comparing an Automated FM vs Manual FSP Test
Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71
Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)
Automated (Mitsubishi) vs Automated (Stago)
In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago
Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC
Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
Non Overt DIC Overt DIC
AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC
Trends in Markers of DIC for Different Patients
Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00
Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients
Trends in Markers of DIC for Different Patients
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes
28 day outcome survival
28 day outcome death
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines
DIC Case Studies
Case Study 1 - Presentation
18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE
WBC count 77 KμL 423 ndash 907 x KμL
RBC count 17 MμL 137 ndash 175 x MμL
Hemoglobin 67 gdL 137 ndash 175 gdL
Hematocrit 195 401 ndash 510
MCV 95 fL 790 ndash 922 fL
MPV 12 fL 94 ndash 124 fL
Platelet count 9 KμL 161 ndash 347 KμL
Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0
Lymphocytes monocytes eosinophils basophils all below normal range
PT 47 sec (corrected on mixing study) 116 ndash 152 sec
APTT 75 sec (corrected on mixing study) 253 ndash 373 sec
Fibrinogen lt 76 mgdL 177 ndash 466 mgdL
D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Microscopy
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Arrow shows giant platelets in this peripheral smear Promyelocytes apparent
Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)
DIC due to TF release by APL blasts
Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases
Transfusions to replace factors along with platelets and RBCs during APL treatment
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started
Case Study 2 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L
PT 30 sec 113 ndash 146 sec
APTT 75 sec 25 ndash 34 sec
D-dimer 078 microgml FEU lt050 microgml FEU
Fibrinogen 92 mgdl 150-400 mgdl
pH 728 738 to 742
PaO2 570 mmHg 80-100 mmHg
WBC 33 times 103mm3 40-11 times 103mm3
ALT 111 IUL 0ndash34 IUL
AST 61 IUL 0ndash34 IUL
BUN 303 mgdL 08-13 mgdL
Case Study 2 ndash Lab Results
Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures
Case Study 2 ndash Diagnosis
60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior
Case Study 3 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L
PT 228 sec 113 ndash 146 sec
APTT 45 sec 25 ndash 34 sec
D-dimer 080 microgml FEU lt050 microgmL FEU
Fibrinogen 82 mgdL 150-400 mgdL
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 134 gdL 14-16 gdL
WBC 81 times 103mm3 40-11 times 103mm3
ALT 32 IUL 0ndash34 IUL
AST 28 IUL 0ndash34 IUL
BUN 09 mgdL 08-13 mgdL
Case Study 3 ndash Lab Results
Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment
Case Study 3 ndash Diagnosis and Therapy
Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91
Case Study 4 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L
PT 28 sec 113 ndash 146 sec
APTT 71 sec 25 ndash 34 sec
D-dimer 31 microgmL FEU lt050 microgml FEU
Fibrinogen 92 mgdL 150-400 mgdl
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 158 gdL 14-16 gdL
WBC 71 times 103mm3 40-11 times 103mm3
ALT 60 IUL 0ndash34 IUL
AST 47 IUL 0ndash34 IUL
BUN 38 mgdL 08-13 mgdL
Case Study 4 ndash Lab Results
Lyme disease with DICProvide antibiotics with supportive measures
Case Study 4 ndash Diagnosis
55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis
Case Study 5 ndash Presentation
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
Case Study 5 ndash Lab Results and Time Course
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
TEST RESULT REFERENCE RANGE
Platelet count 33 x 109L 150-450 x 109L
PT 215 sec 103 ndash 128 sec
APTT 44 sec 26 ndash 36 sec
D-dimer 20 microgmL FEU lt025 microgml FEU
Fibrinogen 34 mgdL 200-375 mgdl
FII FV FVIII Low Not reported (NR)
FVII FIX FX vWF Normal NR
Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)
DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic
dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR
(C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen
(D) Illustration demonstrating repair
Case Study 5 ndash Diagnosis and Treatment
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography
Case Study 6 ndash Presentation
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
Case Study 6 ndash Lab Results
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L
PT 63 sec gt control 113 ndash 146 sec
INR 658 1 ndash 125
APTT 80 sec gt control 25 ndash 34 sec
D-dimer gt200 microgmL DDU 02 microgmL DDU
Urine exam Proteinuria and hematuria 150-400 mgdl
Albumin 28 gdL NR
Hb 58 gdL NR
LDH 1196 UL NR
SGPT 144 IU NR
SGOT 88 IU NR
Bilirubin 32 mgdL NR
DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th
day postop
Case Study 6 ndash Diagnosis and Treatment
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure
Case Study 6 ndash Discussion
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Case Study 7 ndash Lab Results vs Time
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
DIC Take Home Messages
Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation
Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers
DIC
Thank you Questions
- Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
- Learning Objectives
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Wound Sealing
- The Three Steps of Hemostasis
- Vessel Wall
- Slide Number 12
- Slide Number 13
- Platelet Structure UnactivatedActivated
- Primary Hemostasis
- Primary Hemostasis Assays
- Slide Number 17
- Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
- Slide Number 19
- Coagulation factors
- Coagulation Assay Mechanisms
- Slide Number 22
- Fibrin Formation
- Slide Number 24
- Fibrinolysis Overview
- Fibrinolysis Overview
- Slide Number 27
- Fibrinolysis Releases D-dimers
- Basic Pathophysiology of DIC
- Disseminated Intravascular Coagulation (DIC)
- Purpura Fulminans with DIC Due to Meningococcal Sepsis
- Clinical Conditions Associated With DIC
- Frequency of DIC in Selected Disease States
- Underlying Diseases in DIC Patients
- Slide Number 36
- Slide Number 37
- Slide Number 38
- Slide Number 39
- Pathophysiology of DIC
- Pathogenesis of DIC in Sepsis
- Host Response in Severe Sepsis
- Organ Failure in Severe Sepsis
- Mechanism of DIC in Organ Failure
- Interaction of Inflammation and Coagulation in Sepsis
- Slide Number 47
- Diverse and Opposing Effects of Thrombin
- Coagulation and Fibrinolysis in DIC
- Mechanism of DIC
- Pathophysiology of DIC
- Pathophysiology of DIC - Mechanism
- Pathophysiology of DIC ndash 2 Types of Clinical pictures
- Sub-Acute and Non-Overt DIC Clinical Findings
- Pathophysiology of Overt DIC
- Physiopathology of DIC ndash Overt DIC Findings
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- BREAK
- Diagnostic and Management Approach for DIC
- Diagnosis of DIC
- Lab Diagnosis of DIC ndash Markers of Factor Consumption
- Lab Diagnosis of DIC ndash Screening Tests
- Slide Number 67
- Slide Number 68
- British Journal of Haematology Overt DIC Score
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- DIC Management Goals
- DIC Management and Treatment
- DIC Management Strategies
- Anticoagulant Factor Concentrate Treatment
- Anticoagulant Factor Concentrate Treatment Trials
- Markers of Thrombin amp Plasmin Generation in DIC
- D-dimer FDPs and DIC
- D-Dimer and FDPs in DIC
- Follow Up of DIC State of Disease
- FMD-Dimer in DIC Major Differences
- of Abnormal Results in Patients with Confirmed and Suspected DIC
- Slide Number 85
- Slide Number 86
- Comparing an Automated FM vs Manual FSP Test
- Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Slide Number 94
- Slide Number 95
- Slide Number 96
- Slide Number 97
- Slide Number 98
- Slide Number 99
- DIC Case Studies
- Case Study 1 - Presentation
- Case Study 1 ndash Lab Results
- Case Study 1 ndash Microscopy
- Case Study 1 ndash Diagnosis and Therapy
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Slide Number 110
- Slide Number 111
- Slide Number 112
- Slide Number 113
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
- Slide Number 124
- Slide Number 125
- DIC Take Home Messages
- Slide Number 127
- Slide Number 128
-
DIC Diagnostic Practices Over Time
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
British Journal of Haematology Overt DIC Score
Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
ISTH Step by Step DIC Algorithm
Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6
US Based Validation of ISTH DIC Score
When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Differential Diagnosis in DIC
aHUS atypical hemolytic uremic syndrome
HUS hemolytic uremic syndrome
HIT heparin-induced thrombocytopenia
ITP immune thrombocytopenic purpura
TTP thrombotic thrombocytopenic purpura
DIC and MAHA
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)
When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation
DIC Management Goals
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction
DIC Management and Treatment
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)
requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)
Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia
DIC Management Strategies
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant Factor Concentrate Treatment
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis
Anticoagulant Factor Concentrate Treatment Trials
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise
Markers of Thrombin amp Plasmin Generation in DIC
D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC
Cut-off value
Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen
degradation products Sensitive assay typically with cutoff adapted for DIC
D-dimer FDPs and DIC
D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC
Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80
Follow Up of DIC State of Disease
Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8
Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility
FMD-Dimer in DIC Major Differences
onset of thrombosis
days
Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8
FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)
D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)
of Abnormal Results in Patients with Confirmed and Suspected DIC
0
20
40
60
80
100
94 85 90N = 62
Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32
Positivity of Test Results ISTH Score and Disease State
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
Red bar positive for 2 points of DIC score
Pink bar positive for 1-2 points of DIC score
HT hematopoietic tumor
IF infection
SC solid cancer
Markers in Patients with or without DIC
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
HT hematopoietic tumorIF infectionSC solid cancer
Comparing an Automated FM vs Manual FSP Test
Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71
Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)
Automated (Mitsubishi) vs Automated (Stago)
In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago
Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC
Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
Non Overt DIC Overt DIC
AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC
Trends in Markers of DIC for Different Patients
Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00
Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients
Trends in Markers of DIC for Different Patients
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes
28 day outcome survival
28 day outcome death
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines
DIC Case Studies
Case Study 1 - Presentation
18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE
WBC count 77 KμL 423 ndash 907 x KμL
RBC count 17 MμL 137 ndash 175 x MμL
Hemoglobin 67 gdL 137 ndash 175 gdL
Hematocrit 195 401 ndash 510
MCV 95 fL 790 ndash 922 fL
MPV 12 fL 94 ndash 124 fL
Platelet count 9 KμL 161 ndash 347 KμL
Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0
Lymphocytes monocytes eosinophils basophils all below normal range
PT 47 sec (corrected on mixing study) 116 ndash 152 sec
APTT 75 sec (corrected on mixing study) 253 ndash 373 sec
Fibrinogen lt 76 mgdL 177 ndash 466 mgdL
D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Microscopy
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Arrow shows giant platelets in this peripheral smear Promyelocytes apparent
Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)
DIC due to TF release by APL blasts
Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases
Transfusions to replace factors along with platelets and RBCs during APL treatment
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started
Case Study 2 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L
PT 30 sec 113 ndash 146 sec
APTT 75 sec 25 ndash 34 sec
D-dimer 078 microgml FEU lt050 microgml FEU
Fibrinogen 92 mgdl 150-400 mgdl
pH 728 738 to 742
PaO2 570 mmHg 80-100 mmHg
WBC 33 times 103mm3 40-11 times 103mm3
ALT 111 IUL 0ndash34 IUL
AST 61 IUL 0ndash34 IUL
BUN 303 mgdL 08-13 mgdL
Case Study 2 ndash Lab Results
Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures
Case Study 2 ndash Diagnosis
60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior
Case Study 3 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L
PT 228 sec 113 ndash 146 sec
APTT 45 sec 25 ndash 34 sec
D-dimer 080 microgml FEU lt050 microgmL FEU
Fibrinogen 82 mgdL 150-400 mgdL
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 134 gdL 14-16 gdL
WBC 81 times 103mm3 40-11 times 103mm3
ALT 32 IUL 0ndash34 IUL
AST 28 IUL 0ndash34 IUL
BUN 09 mgdL 08-13 mgdL
Case Study 3 ndash Lab Results
Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment
Case Study 3 ndash Diagnosis and Therapy
Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91
Case Study 4 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L
PT 28 sec 113 ndash 146 sec
APTT 71 sec 25 ndash 34 sec
D-dimer 31 microgmL FEU lt050 microgml FEU
Fibrinogen 92 mgdL 150-400 mgdl
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 158 gdL 14-16 gdL
WBC 71 times 103mm3 40-11 times 103mm3
ALT 60 IUL 0ndash34 IUL
AST 47 IUL 0ndash34 IUL
BUN 38 mgdL 08-13 mgdL
Case Study 4 ndash Lab Results
Lyme disease with DICProvide antibiotics with supportive measures
Case Study 4 ndash Diagnosis
55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis
Case Study 5 ndash Presentation
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
Case Study 5 ndash Lab Results and Time Course
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
TEST RESULT REFERENCE RANGE
Platelet count 33 x 109L 150-450 x 109L
PT 215 sec 103 ndash 128 sec
APTT 44 sec 26 ndash 36 sec
D-dimer 20 microgmL FEU lt025 microgml FEU
Fibrinogen 34 mgdL 200-375 mgdl
FII FV FVIII Low Not reported (NR)
FVII FIX FX vWF Normal NR
Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)
DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic
dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR
(C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen
(D) Illustration demonstrating repair
Case Study 5 ndash Diagnosis and Treatment
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography
Case Study 6 ndash Presentation
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
Case Study 6 ndash Lab Results
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L
PT 63 sec gt control 113 ndash 146 sec
INR 658 1 ndash 125
APTT 80 sec gt control 25 ndash 34 sec
D-dimer gt200 microgmL DDU 02 microgmL DDU
Urine exam Proteinuria and hematuria 150-400 mgdl
Albumin 28 gdL NR
Hb 58 gdL NR
LDH 1196 UL NR
SGPT 144 IU NR
SGOT 88 IU NR
Bilirubin 32 mgdL NR
DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th
day postop
Case Study 6 ndash Diagnosis and Treatment
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure
Case Study 6 ndash Discussion
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Case Study 7 ndash Lab Results vs Time
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
DIC Take Home Messages
Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation
Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers
DIC
Thank you Questions
- Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
- Learning Objectives
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Wound Sealing
- The Three Steps of Hemostasis
- Vessel Wall
- Slide Number 12
- Slide Number 13
- Platelet Structure UnactivatedActivated
- Primary Hemostasis
- Primary Hemostasis Assays
- Slide Number 17
- Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
- Slide Number 19
- Coagulation factors
- Coagulation Assay Mechanisms
- Slide Number 22
- Fibrin Formation
- Slide Number 24
- Fibrinolysis Overview
- Fibrinolysis Overview
- Slide Number 27
- Fibrinolysis Releases D-dimers
- Basic Pathophysiology of DIC
- Disseminated Intravascular Coagulation (DIC)
- Purpura Fulminans with DIC Due to Meningococcal Sepsis
- Clinical Conditions Associated With DIC
- Frequency of DIC in Selected Disease States
- Underlying Diseases in DIC Patients
- Slide Number 36
- Slide Number 37
- Slide Number 38
- Slide Number 39
- Pathophysiology of DIC
- Pathogenesis of DIC in Sepsis
- Host Response in Severe Sepsis
- Organ Failure in Severe Sepsis
- Mechanism of DIC in Organ Failure
- Interaction of Inflammation and Coagulation in Sepsis
- Slide Number 47
- Diverse and Opposing Effects of Thrombin
- Coagulation and Fibrinolysis in DIC
- Mechanism of DIC
- Pathophysiology of DIC
- Pathophysiology of DIC - Mechanism
- Pathophysiology of DIC ndash 2 Types of Clinical pictures
- Sub-Acute and Non-Overt DIC Clinical Findings
- Pathophysiology of Overt DIC
- Physiopathology of DIC ndash Overt DIC Findings
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- BREAK
- Diagnostic and Management Approach for DIC
- Diagnosis of DIC
- Lab Diagnosis of DIC ndash Markers of Factor Consumption
- Lab Diagnosis of DIC ndash Screening Tests
- Slide Number 67
- Slide Number 68
- British Journal of Haematology Overt DIC Score
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- DIC Management Goals
- DIC Management and Treatment
- DIC Management Strategies
- Anticoagulant Factor Concentrate Treatment
- Anticoagulant Factor Concentrate Treatment Trials
- Markers of Thrombin amp Plasmin Generation in DIC
- D-dimer FDPs and DIC
- D-Dimer and FDPs in DIC
- Follow Up of DIC State of Disease
- FMD-Dimer in DIC Major Differences
- of Abnormal Results in Patients with Confirmed and Suspected DIC
- Slide Number 85
- Slide Number 86
- Comparing an Automated FM vs Manual FSP Test
- Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Slide Number 94
- Slide Number 95
- Slide Number 96
- Slide Number 97
- Slide Number 98
- Slide Number 99
- DIC Case Studies
- Case Study 1 - Presentation
- Case Study 1 ndash Lab Results
- Case Study 1 ndash Microscopy
- Case Study 1 ndash Diagnosis and Therapy
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Slide Number 110
- Slide Number 111
- Slide Number 112
- Slide Number 113
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
- Slide Number 124
- Slide Number 125
- DIC Take Home Messages
- Slide Number 127
- Slide Number 128
-
British Journal of Haematology Overt DIC Score
Levi M Toh CH Thachil J Watson HG Guidelines for the diagnosis and management of disseminatedintravascular coagulation British Journal of Haematology 145 24ndash33
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
ISTH Step by Step DIC Algorithm
Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6
US Based Validation of ISTH DIC Score
When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Differential Diagnosis in DIC
aHUS atypical hemolytic uremic syndrome
HUS hemolytic uremic syndrome
HIT heparin-induced thrombocytopenia
ITP immune thrombocytopenic purpura
TTP thrombotic thrombocytopenic purpura
DIC and MAHA
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)
When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation
DIC Management Goals
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction
DIC Management and Treatment
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)
requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)
Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia
DIC Management Strategies
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant Factor Concentrate Treatment
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis
Anticoagulant Factor Concentrate Treatment Trials
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise
Markers of Thrombin amp Plasmin Generation in DIC
D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC
Cut-off value
Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen
degradation products Sensitive assay typically with cutoff adapted for DIC
D-dimer FDPs and DIC
D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC
Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80
Follow Up of DIC State of Disease
Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8
Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility
FMD-Dimer in DIC Major Differences
onset of thrombosis
days
Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8
FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)
D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)
of Abnormal Results in Patients with Confirmed and Suspected DIC
0
20
40
60
80
100
94 85 90N = 62
Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32
Positivity of Test Results ISTH Score and Disease State
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
Red bar positive for 2 points of DIC score
Pink bar positive for 1-2 points of DIC score
HT hematopoietic tumor
IF infection
SC solid cancer
Markers in Patients with or without DIC
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
HT hematopoietic tumorIF infectionSC solid cancer
Comparing an Automated FM vs Manual FSP Test
Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71
Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)
Automated (Mitsubishi) vs Automated (Stago)
In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago
Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC
Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
Non Overt DIC Overt DIC
AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC
Trends in Markers of DIC for Different Patients
Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00
Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients
Trends in Markers of DIC for Different Patients
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes
28 day outcome survival
28 day outcome death
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines
DIC Case Studies
Case Study 1 - Presentation
18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE
WBC count 77 KμL 423 ndash 907 x KμL
RBC count 17 MμL 137 ndash 175 x MμL
Hemoglobin 67 gdL 137 ndash 175 gdL
Hematocrit 195 401 ndash 510
MCV 95 fL 790 ndash 922 fL
MPV 12 fL 94 ndash 124 fL
Platelet count 9 KμL 161 ndash 347 KμL
Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0
Lymphocytes monocytes eosinophils basophils all below normal range
PT 47 sec (corrected on mixing study) 116 ndash 152 sec
APTT 75 sec (corrected on mixing study) 253 ndash 373 sec
Fibrinogen lt 76 mgdL 177 ndash 466 mgdL
D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Microscopy
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Arrow shows giant platelets in this peripheral smear Promyelocytes apparent
Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)
DIC due to TF release by APL blasts
Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases
Transfusions to replace factors along with platelets and RBCs during APL treatment
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started
Case Study 2 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L
PT 30 sec 113 ndash 146 sec
APTT 75 sec 25 ndash 34 sec
D-dimer 078 microgml FEU lt050 microgml FEU
Fibrinogen 92 mgdl 150-400 mgdl
pH 728 738 to 742
PaO2 570 mmHg 80-100 mmHg
WBC 33 times 103mm3 40-11 times 103mm3
ALT 111 IUL 0ndash34 IUL
AST 61 IUL 0ndash34 IUL
BUN 303 mgdL 08-13 mgdL
Case Study 2 ndash Lab Results
Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures
Case Study 2 ndash Diagnosis
60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior
Case Study 3 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L
PT 228 sec 113 ndash 146 sec
APTT 45 sec 25 ndash 34 sec
D-dimer 080 microgml FEU lt050 microgmL FEU
Fibrinogen 82 mgdL 150-400 mgdL
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 134 gdL 14-16 gdL
WBC 81 times 103mm3 40-11 times 103mm3
ALT 32 IUL 0ndash34 IUL
AST 28 IUL 0ndash34 IUL
BUN 09 mgdL 08-13 mgdL
Case Study 3 ndash Lab Results
Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment
Case Study 3 ndash Diagnosis and Therapy
Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91
Case Study 4 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L
PT 28 sec 113 ndash 146 sec
APTT 71 sec 25 ndash 34 sec
D-dimer 31 microgmL FEU lt050 microgml FEU
Fibrinogen 92 mgdL 150-400 mgdl
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 158 gdL 14-16 gdL
WBC 71 times 103mm3 40-11 times 103mm3
ALT 60 IUL 0ndash34 IUL
AST 47 IUL 0ndash34 IUL
BUN 38 mgdL 08-13 mgdL
Case Study 4 ndash Lab Results
Lyme disease with DICProvide antibiotics with supportive measures
Case Study 4 ndash Diagnosis
55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis
Case Study 5 ndash Presentation
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
Case Study 5 ndash Lab Results and Time Course
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
TEST RESULT REFERENCE RANGE
Platelet count 33 x 109L 150-450 x 109L
PT 215 sec 103 ndash 128 sec
APTT 44 sec 26 ndash 36 sec
D-dimer 20 microgmL FEU lt025 microgml FEU
Fibrinogen 34 mgdL 200-375 mgdl
FII FV FVIII Low Not reported (NR)
FVII FIX FX vWF Normal NR
Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)
DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic
dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR
(C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen
(D) Illustration demonstrating repair
Case Study 5 ndash Diagnosis and Treatment
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography
Case Study 6 ndash Presentation
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
Case Study 6 ndash Lab Results
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L
PT 63 sec gt control 113 ndash 146 sec
INR 658 1 ndash 125
APTT 80 sec gt control 25 ndash 34 sec
D-dimer gt200 microgmL DDU 02 microgmL DDU
Urine exam Proteinuria and hematuria 150-400 mgdl
Albumin 28 gdL NR
Hb 58 gdL NR
LDH 1196 UL NR
SGPT 144 IU NR
SGOT 88 IU NR
Bilirubin 32 mgdL NR
DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th
day postop
Case Study 6 ndash Diagnosis and Treatment
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure
Case Study 6 ndash Discussion
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Case Study 7 ndash Lab Results vs Time
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
DIC Take Home Messages
Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation
Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers
DIC
Thank you Questions
- Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
- Learning Objectives
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Wound Sealing
- The Three Steps of Hemostasis
- Vessel Wall
- Slide Number 12
- Slide Number 13
- Platelet Structure UnactivatedActivated
- Primary Hemostasis
- Primary Hemostasis Assays
- Slide Number 17
- Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
- Slide Number 19
- Coagulation factors
- Coagulation Assay Mechanisms
- Slide Number 22
- Fibrin Formation
- Slide Number 24
- Fibrinolysis Overview
- Fibrinolysis Overview
- Slide Number 27
- Fibrinolysis Releases D-dimers
- Basic Pathophysiology of DIC
- Disseminated Intravascular Coagulation (DIC)
- Purpura Fulminans with DIC Due to Meningococcal Sepsis
- Clinical Conditions Associated With DIC
- Frequency of DIC in Selected Disease States
- Underlying Diseases in DIC Patients
- Slide Number 36
- Slide Number 37
- Slide Number 38
- Slide Number 39
- Pathophysiology of DIC
- Pathogenesis of DIC in Sepsis
- Host Response in Severe Sepsis
- Organ Failure in Severe Sepsis
- Mechanism of DIC in Organ Failure
- Interaction of Inflammation and Coagulation in Sepsis
- Slide Number 47
- Diverse and Opposing Effects of Thrombin
- Coagulation and Fibrinolysis in DIC
- Mechanism of DIC
- Pathophysiology of DIC
- Pathophysiology of DIC - Mechanism
- Pathophysiology of DIC ndash 2 Types of Clinical pictures
- Sub-Acute and Non-Overt DIC Clinical Findings
- Pathophysiology of Overt DIC
- Physiopathology of DIC ndash Overt DIC Findings
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- BREAK
- Diagnostic and Management Approach for DIC
- Diagnosis of DIC
- Lab Diagnosis of DIC ndash Markers of Factor Consumption
- Lab Diagnosis of DIC ndash Screening Tests
- Slide Number 67
- Slide Number 68
- British Journal of Haematology Overt DIC Score
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- DIC Management Goals
- DIC Management and Treatment
- DIC Management Strategies
- Anticoagulant Factor Concentrate Treatment
- Anticoagulant Factor Concentrate Treatment Trials
- Markers of Thrombin amp Plasmin Generation in DIC
- D-dimer FDPs and DIC
- D-Dimer and FDPs in DIC
- Follow Up of DIC State of Disease
- FMD-Dimer in DIC Major Differences
- of Abnormal Results in Patients with Confirmed and Suspected DIC
- Slide Number 85
- Slide Number 86
- Comparing an Automated FM vs Manual FSP Test
- Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Slide Number 94
- Slide Number 95
- Slide Number 96
- Slide Number 97
- Slide Number 98
- Slide Number 99
- DIC Case Studies
- Case Study 1 - Presentation
- Case Study 1 ndash Lab Results
- Case Study 1 ndash Microscopy
- Case Study 1 ndash Diagnosis and Therapy
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Slide Number 110
- Slide Number 111
- Slide Number 112
- Slide Number 113
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
- Slide Number 124
- Slide Number 125
- DIC Take Home Messages
- Slide Number 127
- Slide Number 128
-
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
ISTH Step by Step DIC Algorithm
Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6
US Based Validation of ISTH DIC Score
When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Differential Diagnosis in DIC
aHUS atypical hemolytic uremic syndrome
HUS hemolytic uremic syndrome
HIT heparin-induced thrombocytopenia
ITP immune thrombocytopenic purpura
TTP thrombotic thrombocytopenic purpura
DIC and MAHA
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)
When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation
DIC Management Goals
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction
DIC Management and Treatment
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)
requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)
Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia
DIC Management Strategies
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant Factor Concentrate Treatment
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis
Anticoagulant Factor Concentrate Treatment Trials
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise
Markers of Thrombin amp Plasmin Generation in DIC
D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC
Cut-off value
Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen
degradation products Sensitive assay typically with cutoff adapted for DIC
D-dimer FDPs and DIC
D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC
Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80
Follow Up of DIC State of Disease
Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8
Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility
FMD-Dimer in DIC Major Differences
onset of thrombosis
days
Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8
FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)
D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)
of Abnormal Results in Patients with Confirmed and Suspected DIC
0
20
40
60
80
100
94 85 90N = 62
Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32
Positivity of Test Results ISTH Score and Disease State
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
Red bar positive for 2 points of DIC score
Pink bar positive for 1-2 points of DIC score
HT hematopoietic tumor
IF infection
SC solid cancer
Markers in Patients with or without DIC
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
HT hematopoietic tumorIF infectionSC solid cancer
Comparing an Automated FM vs Manual FSP Test
Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71
Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)
Automated (Mitsubishi) vs Automated (Stago)
In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago
Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC
Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
Non Overt DIC Overt DIC
AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC
Trends in Markers of DIC for Different Patients
Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00
Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients
Trends in Markers of DIC for Different Patients
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes
28 day outcome survival
28 day outcome death
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines
DIC Case Studies
Case Study 1 - Presentation
18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE
WBC count 77 KμL 423 ndash 907 x KμL
RBC count 17 MμL 137 ndash 175 x MμL
Hemoglobin 67 gdL 137 ndash 175 gdL
Hematocrit 195 401 ndash 510
MCV 95 fL 790 ndash 922 fL
MPV 12 fL 94 ndash 124 fL
Platelet count 9 KμL 161 ndash 347 KμL
Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0
Lymphocytes monocytes eosinophils basophils all below normal range
PT 47 sec (corrected on mixing study) 116 ndash 152 sec
APTT 75 sec (corrected on mixing study) 253 ndash 373 sec
Fibrinogen lt 76 mgdL 177 ndash 466 mgdL
D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Microscopy
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Arrow shows giant platelets in this peripheral smear Promyelocytes apparent
Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)
DIC due to TF release by APL blasts
Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases
Transfusions to replace factors along with platelets and RBCs during APL treatment
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started
Case Study 2 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L
PT 30 sec 113 ndash 146 sec
APTT 75 sec 25 ndash 34 sec
D-dimer 078 microgml FEU lt050 microgml FEU
Fibrinogen 92 mgdl 150-400 mgdl
pH 728 738 to 742
PaO2 570 mmHg 80-100 mmHg
WBC 33 times 103mm3 40-11 times 103mm3
ALT 111 IUL 0ndash34 IUL
AST 61 IUL 0ndash34 IUL
BUN 303 mgdL 08-13 mgdL
Case Study 2 ndash Lab Results
Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures
Case Study 2 ndash Diagnosis
60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior
Case Study 3 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L
PT 228 sec 113 ndash 146 sec
APTT 45 sec 25 ndash 34 sec
D-dimer 080 microgml FEU lt050 microgmL FEU
Fibrinogen 82 mgdL 150-400 mgdL
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 134 gdL 14-16 gdL
WBC 81 times 103mm3 40-11 times 103mm3
ALT 32 IUL 0ndash34 IUL
AST 28 IUL 0ndash34 IUL
BUN 09 mgdL 08-13 mgdL
Case Study 3 ndash Lab Results
Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment
Case Study 3 ndash Diagnosis and Therapy
Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91
Case Study 4 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L
PT 28 sec 113 ndash 146 sec
APTT 71 sec 25 ndash 34 sec
D-dimer 31 microgmL FEU lt050 microgml FEU
Fibrinogen 92 mgdL 150-400 mgdl
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 158 gdL 14-16 gdL
WBC 71 times 103mm3 40-11 times 103mm3
ALT 60 IUL 0ndash34 IUL
AST 47 IUL 0ndash34 IUL
BUN 38 mgdL 08-13 mgdL
Case Study 4 ndash Lab Results
Lyme disease with DICProvide antibiotics with supportive measures
Case Study 4 ndash Diagnosis
55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis
Case Study 5 ndash Presentation
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
Case Study 5 ndash Lab Results and Time Course
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
TEST RESULT REFERENCE RANGE
Platelet count 33 x 109L 150-450 x 109L
PT 215 sec 103 ndash 128 sec
APTT 44 sec 26 ndash 36 sec
D-dimer 20 microgmL FEU lt025 microgml FEU
Fibrinogen 34 mgdL 200-375 mgdl
FII FV FVIII Low Not reported (NR)
FVII FIX FX vWF Normal NR
Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)
DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic
dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR
(C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen
(D) Illustration demonstrating repair
Case Study 5 ndash Diagnosis and Treatment
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography
Case Study 6 ndash Presentation
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
Case Study 6 ndash Lab Results
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L
PT 63 sec gt control 113 ndash 146 sec
INR 658 1 ndash 125
APTT 80 sec gt control 25 ndash 34 sec
D-dimer gt200 microgmL DDU 02 microgmL DDU
Urine exam Proteinuria and hematuria 150-400 mgdl
Albumin 28 gdL NR
Hb 58 gdL NR
LDH 1196 UL NR
SGPT 144 IU NR
SGOT 88 IU NR
Bilirubin 32 mgdL NR
DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th
day postop
Case Study 6 ndash Diagnosis and Treatment
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure
Case Study 6 ndash Discussion
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Case Study 7 ndash Lab Results vs Time
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
DIC Take Home Messages
Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation
Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers
DIC
Thank you Questions
- Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
- Learning Objectives
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Wound Sealing
- The Three Steps of Hemostasis
- Vessel Wall
- Slide Number 12
- Slide Number 13
- Platelet Structure UnactivatedActivated
- Primary Hemostasis
- Primary Hemostasis Assays
- Slide Number 17
- Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
- Slide Number 19
- Coagulation factors
- Coagulation Assay Mechanisms
- Slide Number 22
- Fibrin Formation
- Slide Number 24
- Fibrinolysis Overview
- Fibrinolysis Overview
- Slide Number 27
- Fibrinolysis Releases D-dimers
- Basic Pathophysiology of DIC
- Disseminated Intravascular Coagulation (DIC)
- Purpura Fulminans with DIC Due to Meningococcal Sepsis
- Clinical Conditions Associated With DIC
- Frequency of DIC in Selected Disease States
- Underlying Diseases in DIC Patients
- Slide Number 36
- Slide Number 37
- Slide Number 38
- Slide Number 39
- Pathophysiology of DIC
- Pathogenesis of DIC in Sepsis
- Host Response in Severe Sepsis
- Organ Failure in Severe Sepsis
- Mechanism of DIC in Organ Failure
- Interaction of Inflammation and Coagulation in Sepsis
- Slide Number 47
- Diverse and Opposing Effects of Thrombin
- Coagulation and Fibrinolysis in DIC
- Mechanism of DIC
- Pathophysiology of DIC
- Pathophysiology of DIC - Mechanism
- Pathophysiology of DIC ndash 2 Types of Clinical pictures
- Sub-Acute and Non-Overt DIC Clinical Findings
- Pathophysiology of Overt DIC
- Physiopathology of DIC ndash Overt DIC Findings
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- BREAK
- Diagnostic and Management Approach for DIC
- Diagnosis of DIC
- Lab Diagnosis of DIC ndash Markers of Factor Consumption
- Lab Diagnosis of DIC ndash Screening Tests
- Slide Number 67
- Slide Number 68
- British Journal of Haematology Overt DIC Score
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- DIC Management Goals
- DIC Management and Treatment
- DIC Management Strategies
- Anticoagulant Factor Concentrate Treatment
- Anticoagulant Factor Concentrate Treatment Trials
- Markers of Thrombin amp Plasmin Generation in DIC
- D-dimer FDPs and DIC
- D-Dimer and FDPs in DIC
- Follow Up of DIC State of Disease
- FMD-Dimer in DIC Major Differences
- of Abnormal Results in Patients with Confirmed and Suspected DIC
- Slide Number 85
- Slide Number 86
- Comparing an Automated FM vs Manual FSP Test
- Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Slide Number 94
- Slide Number 95
- Slide Number 96
- Slide Number 97
- Slide Number 98
- Slide Number 99
- DIC Case Studies
- Case Study 1 - Presentation
- Case Study 1 ndash Lab Results
- Case Study 1 ndash Microscopy
- Case Study 1 ndash Diagnosis and Therapy
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Slide Number 110
- Slide Number 111
- Slide Number 112
- Slide Number 113
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
- Slide Number 124
- Slide Number 125
- DIC Take Home Messages
- Slide Number 127
- Slide Number 128
-
Soundar EP Jariwala P Nguyen TC Eldin KW Teruya J Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients Am J Clin Pathol 2013 139 812-6
US Based Validation of ISTH DIC Score
When retrospectively comparing the ISTH score to a locally derived score in 2136 DIC panels from 130 pediatric patients the ISTH score had a higher AUC
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Differential Diagnosis in DIC
aHUS atypical hemolytic uremic syndrome
HUS hemolytic uremic syndrome
HIT heparin-induced thrombocytopenia
ITP immune thrombocytopenic purpura
TTP thrombotic thrombocytopenic purpura
DIC and MAHA
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)
When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation
DIC Management Goals
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction
DIC Management and Treatment
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)
requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)
Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia
DIC Management Strategies
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant Factor Concentrate Treatment
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis
Anticoagulant Factor Concentrate Treatment Trials
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise
Markers of Thrombin amp Plasmin Generation in DIC
D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC
Cut-off value
Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen
degradation products Sensitive assay typically with cutoff adapted for DIC
D-dimer FDPs and DIC
D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC
Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80
Follow Up of DIC State of Disease
Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8
Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility
FMD-Dimer in DIC Major Differences
onset of thrombosis
days
Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8
FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)
D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)
of Abnormal Results in Patients with Confirmed and Suspected DIC
0
20
40
60
80
100
94 85 90N = 62
Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32
Positivity of Test Results ISTH Score and Disease State
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
Red bar positive for 2 points of DIC score
Pink bar positive for 1-2 points of DIC score
HT hematopoietic tumor
IF infection
SC solid cancer
Markers in Patients with or without DIC
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
HT hematopoietic tumorIF infectionSC solid cancer
Comparing an Automated FM vs Manual FSP Test
Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71
Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)
Automated (Mitsubishi) vs Automated (Stago)
In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago
Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC
Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
Non Overt DIC Overt DIC
AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC
Trends in Markers of DIC for Different Patients
Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00
Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients
Trends in Markers of DIC for Different Patients
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes
28 day outcome survival
28 day outcome death
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines
DIC Case Studies
Case Study 1 - Presentation
18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE
WBC count 77 KμL 423 ndash 907 x KμL
RBC count 17 MμL 137 ndash 175 x MμL
Hemoglobin 67 gdL 137 ndash 175 gdL
Hematocrit 195 401 ndash 510
MCV 95 fL 790 ndash 922 fL
MPV 12 fL 94 ndash 124 fL
Platelet count 9 KμL 161 ndash 347 KμL
Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0
Lymphocytes monocytes eosinophils basophils all below normal range
PT 47 sec (corrected on mixing study) 116 ndash 152 sec
APTT 75 sec (corrected on mixing study) 253 ndash 373 sec
Fibrinogen lt 76 mgdL 177 ndash 466 mgdL
D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Microscopy
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Arrow shows giant platelets in this peripheral smear Promyelocytes apparent
Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)
DIC due to TF release by APL blasts
Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases
Transfusions to replace factors along with platelets and RBCs during APL treatment
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started
Case Study 2 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L
PT 30 sec 113 ndash 146 sec
APTT 75 sec 25 ndash 34 sec
D-dimer 078 microgml FEU lt050 microgml FEU
Fibrinogen 92 mgdl 150-400 mgdl
pH 728 738 to 742
PaO2 570 mmHg 80-100 mmHg
WBC 33 times 103mm3 40-11 times 103mm3
ALT 111 IUL 0ndash34 IUL
AST 61 IUL 0ndash34 IUL
BUN 303 mgdL 08-13 mgdL
Case Study 2 ndash Lab Results
Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures
Case Study 2 ndash Diagnosis
60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior
Case Study 3 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L
PT 228 sec 113 ndash 146 sec
APTT 45 sec 25 ndash 34 sec
D-dimer 080 microgml FEU lt050 microgmL FEU
Fibrinogen 82 mgdL 150-400 mgdL
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 134 gdL 14-16 gdL
WBC 81 times 103mm3 40-11 times 103mm3
ALT 32 IUL 0ndash34 IUL
AST 28 IUL 0ndash34 IUL
BUN 09 mgdL 08-13 mgdL
Case Study 3 ndash Lab Results
Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment
Case Study 3 ndash Diagnosis and Therapy
Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91
Case Study 4 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L
PT 28 sec 113 ndash 146 sec
APTT 71 sec 25 ndash 34 sec
D-dimer 31 microgmL FEU lt050 microgml FEU
Fibrinogen 92 mgdL 150-400 mgdl
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 158 gdL 14-16 gdL
WBC 71 times 103mm3 40-11 times 103mm3
ALT 60 IUL 0ndash34 IUL
AST 47 IUL 0ndash34 IUL
BUN 38 mgdL 08-13 mgdL
Case Study 4 ndash Lab Results
Lyme disease with DICProvide antibiotics with supportive measures
Case Study 4 ndash Diagnosis
55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis
Case Study 5 ndash Presentation
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
Case Study 5 ndash Lab Results and Time Course
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
TEST RESULT REFERENCE RANGE
Platelet count 33 x 109L 150-450 x 109L
PT 215 sec 103 ndash 128 sec
APTT 44 sec 26 ndash 36 sec
D-dimer 20 microgmL FEU lt025 microgml FEU
Fibrinogen 34 mgdL 200-375 mgdl
FII FV FVIII Low Not reported (NR)
FVII FIX FX vWF Normal NR
Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)
DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic
dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR
(C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen
(D) Illustration demonstrating repair
Case Study 5 ndash Diagnosis and Treatment
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography
Case Study 6 ndash Presentation
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
Case Study 6 ndash Lab Results
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L
PT 63 sec gt control 113 ndash 146 sec
INR 658 1 ndash 125
APTT 80 sec gt control 25 ndash 34 sec
D-dimer gt200 microgmL DDU 02 microgmL DDU
Urine exam Proteinuria and hematuria 150-400 mgdl
Albumin 28 gdL NR
Hb 58 gdL NR
LDH 1196 UL NR
SGPT 144 IU NR
SGOT 88 IU NR
Bilirubin 32 mgdL NR
DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th
day postop
Case Study 6 ndash Diagnosis and Treatment
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure
Case Study 6 ndash Discussion
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Case Study 7 ndash Lab Results vs Time
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
DIC Take Home Messages
Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation
Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers
DIC
Thank you Questions
- Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
- Learning Objectives
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Wound Sealing
- The Three Steps of Hemostasis
- Vessel Wall
- Slide Number 12
- Slide Number 13
- Platelet Structure UnactivatedActivated
- Primary Hemostasis
- Primary Hemostasis Assays
- Slide Number 17
- Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
- Slide Number 19
- Coagulation factors
- Coagulation Assay Mechanisms
- Slide Number 22
- Fibrin Formation
- Slide Number 24
- Fibrinolysis Overview
- Fibrinolysis Overview
- Slide Number 27
- Fibrinolysis Releases D-dimers
- Basic Pathophysiology of DIC
- Disseminated Intravascular Coagulation (DIC)
- Purpura Fulminans with DIC Due to Meningococcal Sepsis
- Clinical Conditions Associated With DIC
- Frequency of DIC in Selected Disease States
- Underlying Diseases in DIC Patients
- Slide Number 36
- Slide Number 37
- Slide Number 38
- Slide Number 39
- Pathophysiology of DIC
- Pathogenesis of DIC in Sepsis
- Host Response in Severe Sepsis
- Organ Failure in Severe Sepsis
- Mechanism of DIC in Organ Failure
- Interaction of Inflammation and Coagulation in Sepsis
- Slide Number 47
- Diverse and Opposing Effects of Thrombin
- Coagulation and Fibrinolysis in DIC
- Mechanism of DIC
- Pathophysiology of DIC
- Pathophysiology of DIC - Mechanism
- Pathophysiology of DIC ndash 2 Types of Clinical pictures
- Sub-Acute and Non-Overt DIC Clinical Findings
- Pathophysiology of Overt DIC
- Physiopathology of DIC ndash Overt DIC Findings
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- BREAK
- Diagnostic and Management Approach for DIC
- Diagnosis of DIC
- Lab Diagnosis of DIC ndash Markers of Factor Consumption
- Lab Diagnosis of DIC ndash Screening Tests
- Slide Number 67
- Slide Number 68
- British Journal of Haematology Overt DIC Score
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- DIC Management Goals
- DIC Management and Treatment
- DIC Management Strategies
- Anticoagulant Factor Concentrate Treatment
- Anticoagulant Factor Concentrate Treatment Trials
- Markers of Thrombin amp Plasmin Generation in DIC
- D-dimer FDPs and DIC
- D-Dimer and FDPs in DIC
- Follow Up of DIC State of Disease
- FMD-Dimer in DIC Major Differences
- of Abnormal Results in Patients with Confirmed and Suspected DIC
- Slide Number 85
- Slide Number 86
- Comparing an Automated FM vs Manual FSP Test
- Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Slide Number 94
- Slide Number 95
- Slide Number 96
- Slide Number 97
- Slide Number 98
- Slide Number 99
- DIC Case Studies
- Case Study 1 - Presentation
- Case Study 1 ndash Lab Results
- Case Study 1 ndash Microscopy
- Case Study 1 ndash Diagnosis and Therapy
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Slide Number 110
- Slide Number 111
- Slide Number 112
- Slide Number 113
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
- Slide Number 124
- Slide Number 125
- DIC Take Home Messages
- Slide Number 127
- Slide Number 128
-
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Differential Diagnosis in DIC
aHUS atypical hemolytic uremic syndrome
HUS hemolytic uremic syndrome
HIT heparin-induced thrombocytopenia
ITP immune thrombocytopenic purpura
TTP thrombotic thrombocytopenic purpura
DIC and MAHA
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)
When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation
DIC Management Goals
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction
DIC Management and Treatment
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)
requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)
Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia
DIC Management Strategies
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant Factor Concentrate Treatment
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis
Anticoagulant Factor Concentrate Treatment Trials
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise
Markers of Thrombin amp Plasmin Generation in DIC
D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC
Cut-off value
Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen
degradation products Sensitive assay typically with cutoff adapted for DIC
D-dimer FDPs and DIC
D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC
Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80
Follow Up of DIC State of Disease
Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8
Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility
FMD-Dimer in DIC Major Differences
onset of thrombosis
days
Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8
FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)
D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)
of Abnormal Results in Patients with Confirmed and Suspected DIC
0
20
40
60
80
100
94 85 90N = 62
Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32
Positivity of Test Results ISTH Score and Disease State
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
Red bar positive for 2 points of DIC score
Pink bar positive for 1-2 points of DIC score
HT hematopoietic tumor
IF infection
SC solid cancer
Markers in Patients with or without DIC
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
HT hematopoietic tumorIF infectionSC solid cancer
Comparing an Automated FM vs Manual FSP Test
Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71
Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)
Automated (Mitsubishi) vs Automated (Stago)
In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago
Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC
Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
Non Overt DIC Overt DIC
AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC
Trends in Markers of DIC for Different Patients
Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00
Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients
Trends in Markers of DIC for Different Patients
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes
28 day outcome survival
28 day outcome death
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines
DIC Case Studies
Case Study 1 - Presentation
18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE
WBC count 77 KμL 423 ndash 907 x KμL
RBC count 17 MμL 137 ndash 175 x MμL
Hemoglobin 67 gdL 137 ndash 175 gdL
Hematocrit 195 401 ndash 510
MCV 95 fL 790 ndash 922 fL
MPV 12 fL 94 ndash 124 fL
Platelet count 9 KμL 161 ndash 347 KμL
Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0
Lymphocytes monocytes eosinophils basophils all below normal range
PT 47 sec (corrected on mixing study) 116 ndash 152 sec
APTT 75 sec (corrected on mixing study) 253 ndash 373 sec
Fibrinogen lt 76 mgdL 177 ndash 466 mgdL
D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Microscopy
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Arrow shows giant platelets in this peripheral smear Promyelocytes apparent
Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)
DIC due to TF release by APL blasts
Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases
Transfusions to replace factors along with platelets and RBCs during APL treatment
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started
Case Study 2 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L
PT 30 sec 113 ndash 146 sec
APTT 75 sec 25 ndash 34 sec
D-dimer 078 microgml FEU lt050 microgml FEU
Fibrinogen 92 mgdl 150-400 mgdl
pH 728 738 to 742
PaO2 570 mmHg 80-100 mmHg
WBC 33 times 103mm3 40-11 times 103mm3
ALT 111 IUL 0ndash34 IUL
AST 61 IUL 0ndash34 IUL
BUN 303 mgdL 08-13 mgdL
Case Study 2 ndash Lab Results
Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures
Case Study 2 ndash Diagnosis
60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior
Case Study 3 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L
PT 228 sec 113 ndash 146 sec
APTT 45 sec 25 ndash 34 sec
D-dimer 080 microgml FEU lt050 microgmL FEU
Fibrinogen 82 mgdL 150-400 mgdL
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 134 gdL 14-16 gdL
WBC 81 times 103mm3 40-11 times 103mm3
ALT 32 IUL 0ndash34 IUL
AST 28 IUL 0ndash34 IUL
BUN 09 mgdL 08-13 mgdL
Case Study 3 ndash Lab Results
Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment
Case Study 3 ndash Diagnosis and Therapy
Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91
Case Study 4 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L
PT 28 sec 113 ndash 146 sec
APTT 71 sec 25 ndash 34 sec
D-dimer 31 microgmL FEU lt050 microgml FEU
Fibrinogen 92 mgdL 150-400 mgdl
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 158 gdL 14-16 gdL
WBC 71 times 103mm3 40-11 times 103mm3
ALT 60 IUL 0ndash34 IUL
AST 47 IUL 0ndash34 IUL
BUN 38 mgdL 08-13 mgdL
Case Study 4 ndash Lab Results
Lyme disease with DICProvide antibiotics with supportive measures
Case Study 4 ndash Diagnosis
55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis
Case Study 5 ndash Presentation
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
Case Study 5 ndash Lab Results and Time Course
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
TEST RESULT REFERENCE RANGE
Platelet count 33 x 109L 150-450 x 109L
PT 215 sec 103 ndash 128 sec
APTT 44 sec 26 ndash 36 sec
D-dimer 20 microgmL FEU lt025 microgml FEU
Fibrinogen 34 mgdL 200-375 mgdl
FII FV FVIII Low Not reported (NR)
FVII FIX FX vWF Normal NR
Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)
DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic
dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR
(C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen
(D) Illustration demonstrating repair
Case Study 5 ndash Diagnosis and Treatment
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography
Case Study 6 ndash Presentation
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
Case Study 6 ndash Lab Results
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L
PT 63 sec gt control 113 ndash 146 sec
INR 658 1 ndash 125
APTT 80 sec gt control 25 ndash 34 sec
D-dimer gt200 microgmL DDU 02 microgmL DDU
Urine exam Proteinuria and hematuria 150-400 mgdl
Albumin 28 gdL NR
Hb 58 gdL NR
LDH 1196 UL NR
SGPT 144 IU NR
SGOT 88 IU NR
Bilirubin 32 mgdL NR
DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th
day postop
Case Study 6 ndash Diagnosis and Treatment
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure
Case Study 6 ndash Discussion
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Case Study 7 ndash Lab Results vs Time
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
DIC Take Home Messages
Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation
Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers
DIC
Thank you Questions
- Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
- Learning Objectives
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Wound Sealing
- The Three Steps of Hemostasis
- Vessel Wall
- Slide Number 12
- Slide Number 13
- Platelet Structure UnactivatedActivated
- Primary Hemostasis
- Primary Hemostasis Assays
- Slide Number 17
- Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
- Slide Number 19
- Coagulation factors
- Coagulation Assay Mechanisms
- Slide Number 22
- Fibrin Formation
- Slide Number 24
- Fibrinolysis Overview
- Fibrinolysis Overview
- Slide Number 27
- Fibrinolysis Releases D-dimers
- Basic Pathophysiology of DIC
- Disseminated Intravascular Coagulation (DIC)
- Purpura Fulminans with DIC Due to Meningococcal Sepsis
- Clinical Conditions Associated With DIC
- Frequency of DIC in Selected Disease States
- Underlying Diseases in DIC Patients
- Slide Number 36
- Slide Number 37
- Slide Number 38
- Slide Number 39
- Pathophysiology of DIC
- Pathogenesis of DIC in Sepsis
- Host Response in Severe Sepsis
- Organ Failure in Severe Sepsis
- Mechanism of DIC in Organ Failure
- Interaction of Inflammation and Coagulation in Sepsis
- Slide Number 47
- Diverse and Opposing Effects of Thrombin
- Coagulation and Fibrinolysis in DIC
- Mechanism of DIC
- Pathophysiology of DIC
- Pathophysiology of DIC - Mechanism
- Pathophysiology of DIC ndash 2 Types of Clinical pictures
- Sub-Acute and Non-Overt DIC Clinical Findings
- Pathophysiology of Overt DIC
- Physiopathology of DIC ndash Overt DIC Findings
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- BREAK
- Diagnostic and Management Approach for DIC
- Diagnosis of DIC
- Lab Diagnosis of DIC ndash Markers of Factor Consumption
- Lab Diagnosis of DIC ndash Screening Tests
- Slide Number 67
- Slide Number 68
- British Journal of Haematology Overt DIC Score
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- DIC Management Goals
- DIC Management and Treatment
- DIC Management Strategies
- Anticoagulant Factor Concentrate Treatment
- Anticoagulant Factor Concentrate Treatment Trials
- Markers of Thrombin amp Plasmin Generation in DIC
- D-dimer FDPs and DIC
- D-Dimer and FDPs in DIC
- Follow Up of DIC State of Disease
- FMD-Dimer in DIC Major Differences
- of Abnormal Results in Patients with Confirmed and Suspected DIC
- Slide Number 85
- Slide Number 86
- Comparing an Automated FM vs Manual FSP Test
- Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Slide Number 94
- Slide Number 95
- Slide Number 96
- Slide Number 97
- Slide Number 98
- Slide Number 99
- DIC Case Studies
- Case Study 1 - Presentation
- Case Study 1 ndash Lab Results
- Case Study 1 ndash Microscopy
- Case Study 1 ndash Diagnosis and Therapy
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Slide Number 110
- Slide Number 111
- Slide Number 112
- Slide Number 113
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
- Slide Number 124
- Slide Number 125
- DIC Take Home Messages
- Slide Number 127
- Slide Number 128
-
DIC and MAHA
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
lt 3 schistocytes per high-power field considered normal gt 10 schistocytesapparent per high-power field (picture taken with oil emersion lens at x 100)
When RBCs pass through compromised vasoconstricted vessles result is microangiopathichemolytic anemia (MAHA) overt DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyteformation
DIC Management Goals
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction
DIC Management and Treatment
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)
requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)
Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia
DIC Management Strategies
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant Factor Concentrate Treatment
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis
Anticoagulant Factor Concentrate Treatment Trials
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise
Markers of Thrombin amp Plasmin Generation in DIC
D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC
Cut-off value
Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen
degradation products Sensitive assay typically with cutoff adapted for DIC
D-dimer FDPs and DIC
D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC
Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80
Follow Up of DIC State of Disease
Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8
Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility
FMD-Dimer in DIC Major Differences
onset of thrombosis
days
Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8
FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)
D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)
of Abnormal Results in Patients with Confirmed and Suspected DIC
0
20
40
60
80
100
94 85 90N = 62
Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32
Positivity of Test Results ISTH Score and Disease State
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
Red bar positive for 2 points of DIC score
Pink bar positive for 1-2 points of DIC score
HT hematopoietic tumor
IF infection
SC solid cancer
Markers in Patients with or without DIC
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
HT hematopoietic tumorIF infectionSC solid cancer
Comparing an Automated FM vs Manual FSP Test
Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71
Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)
Automated (Mitsubishi) vs Automated (Stago)
In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago
Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC
Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
Non Overt DIC Overt DIC
AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC
Trends in Markers of DIC for Different Patients
Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00
Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients
Trends in Markers of DIC for Different Patients
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes
28 day outcome survival
28 day outcome death
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines
DIC Case Studies
Case Study 1 - Presentation
18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE
WBC count 77 KμL 423 ndash 907 x KμL
RBC count 17 MμL 137 ndash 175 x MμL
Hemoglobin 67 gdL 137 ndash 175 gdL
Hematocrit 195 401 ndash 510
MCV 95 fL 790 ndash 922 fL
MPV 12 fL 94 ndash 124 fL
Platelet count 9 KμL 161 ndash 347 KμL
Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0
Lymphocytes monocytes eosinophils basophils all below normal range
PT 47 sec (corrected on mixing study) 116 ndash 152 sec
APTT 75 sec (corrected on mixing study) 253 ndash 373 sec
Fibrinogen lt 76 mgdL 177 ndash 466 mgdL
D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Microscopy
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Arrow shows giant platelets in this peripheral smear Promyelocytes apparent
Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)
DIC due to TF release by APL blasts
Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases
Transfusions to replace factors along with platelets and RBCs during APL treatment
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started
Case Study 2 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L
PT 30 sec 113 ndash 146 sec
APTT 75 sec 25 ndash 34 sec
D-dimer 078 microgml FEU lt050 microgml FEU
Fibrinogen 92 mgdl 150-400 mgdl
pH 728 738 to 742
PaO2 570 mmHg 80-100 mmHg
WBC 33 times 103mm3 40-11 times 103mm3
ALT 111 IUL 0ndash34 IUL
AST 61 IUL 0ndash34 IUL
BUN 303 mgdL 08-13 mgdL
Case Study 2 ndash Lab Results
Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures
Case Study 2 ndash Diagnosis
60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior
Case Study 3 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L
PT 228 sec 113 ndash 146 sec
APTT 45 sec 25 ndash 34 sec
D-dimer 080 microgml FEU lt050 microgmL FEU
Fibrinogen 82 mgdL 150-400 mgdL
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 134 gdL 14-16 gdL
WBC 81 times 103mm3 40-11 times 103mm3
ALT 32 IUL 0ndash34 IUL
AST 28 IUL 0ndash34 IUL
BUN 09 mgdL 08-13 mgdL
Case Study 3 ndash Lab Results
Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment
Case Study 3 ndash Diagnosis and Therapy
Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91
Case Study 4 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L
PT 28 sec 113 ndash 146 sec
APTT 71 sec 25 ndash 34 sec
D-dimer 31 microgmL FEU lt050 microgml FEU
Fibrinogen 92 mgdL 150-400 mgdl
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 158 gdL 14-16 gdL
WBC 71 times 103mm3 40-11 times 103mm3
ALT 60 IUL 0ndash34 IUL
AST 47 IUL 0ndash34 IUL
BUN 38 mgdL 08-13 mgdL
Case Study 4 ndash Lab Results
Lyme disease with DICProvide antibiotics with supportive measures
Case Study 4 ndash Diagnosis
55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis
Case Study 5 ndash Presentation
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
Case Study 5 ndash Lab Results and Time Course
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
TEST RESULT REFERENCE RANGE
Platelet count 33 x 109L 150-450 x 109L
PT 215 sec 103 ndash 128 sec
APTT 44 sec 26 ndash 36 sec
D-dimer 20 microgmL FEU lt025 microgml FEU
Fibrinogen 34 mgdL 200-375 mgdl
FII FV FVIII Low Not reported (NR)
FVII FIX FX vWF Normal NR
Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)
DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic
dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR
(C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen
(D) Illustration demonstrating repair
Case Study 5 ndash Diagnosis and Treatment
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography
Case Study 6 ndash Presentation
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
Case Study 6 ndash Lab Results
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L
PT 63 sec gt control 113 ndash 146 sec
INR 658 1 ndash 125
APTT 80 sec gt control 25 ndash 34 sec
D-dimer gt200 microgmL DDU 02 microgmL DDU
Urine exam Proteinuria and hematuria 150-400 mgdl
Albumin 28 gdL NR
Hb 58 gdL NR
LDH 1196 UL NR
SGPT 144 IU NR
SGOT 88 IU NR
Bilirubin 32 mgdL NR
DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th
day postop
Case Study 6 ndash Diagnosis and Treatment
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure
Case Study 6 ndash Discussion
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Case Study 7 ndash Lab Results vs Time
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
DIC Take Home Messages
Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation
Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers
DIC
Thank you Questions
- Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
- Learning Objectives
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Wound Sealing
- The Three Steps of Hemostasis
- Vessel Wall
- Slide Number 12
- Slide Number 13
- Platelet Structure UnactivatedActivated
- Primary Hemostasis
- Primary Hemostasis Assays
- Slide Number 17
- Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
- Slide Number 19
- Coagulation factors
- Coagulation Assay Mechanisms
- Slide Number 22
- Fibrin Formation
- Slide Number 24
- Fibrinolysis Overview
- Fibrinolysis Overview
- Slide Number 27
- Fibrinolysis Releases D-dimers
- Basic Pathophysiology of DIC
- Disseminated Intravascular Coagulation (DIC)
- Purpura Fulminans with DIC Due to Meningococcal Sepsis
- Clinical Conditions Associated With DIC
- Frequency of DIC in Selected Disease States
- Underlying Diseases in DIC Patients
- Slide Number 36
- Slide Number 37
- Slide Number 38
- Slide Number 39
- Pathophysiology of DIC
- Pathogenesis of DIC in Sepsis
- Host Response in Severe Sepsis
- Organ Failure in Severe Sepsis
- Mechanism of DIC in Organ Failure
- Interaction of Inflammation and Coagulation in Sepsis
- Slide Number 47
- Diverse and Opposing Effects of Thrombin
- Coagulation and Fibrinolysis in DIC
- Mechanism of DIC
- Pathophysiology of DIC
- Pathophysiology of DIC - Mechanism
- Pathophysiology of DIC ndash 2 Types of Clinical pictures
- Sub-Acute and Non-Overt DIC Clinical Findings
- Pathophysiology of Overt DIC
- Physiopathology of DIC ndash Overt DIC Findings
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- BREAK
- Diagnostic and Management Approach for DIC
- Diagnosis of DIC
- Lab Diagnosis of DIC ndash Markers of Factor Consumption
- Lab Diagnosis of DIC ndash Screening Tests
- Slide Number 67
- Slide Number 68
- British Journal of Haematology Overt DIC Score
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- DIC Management Goals
- DIC Management and Treatment
- DIC Management Strategies
- Anticoagulant Factor Concentrate Treatment
- Anticoagulant Factor Concentrate Treatment Trials
- Markers of Thrombin amp Plasmin Generation in DIC
- D-dimer FDPs and DIC
- D-Dimer and FDPs in DIC
- Follow Up of DIC State of Disease
- FMD-Dimer in DIC Major Differences
- of Abnormal Results in Patients with Confirmed and Suspected DIC
- Slide Number 85
- Slide Number 86
- Comparing an Automated FM vs Manual FSP Test
- Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Slide Number 94
- Slide Number 95
- Slide Number 96
- Slide Number 97
- Slide Number 98
- Slide Number 99
- DIC Case Studies
- Case Study 1 - Presentation
- Case Study 1 ndash Lab Results
- Case Study 1 ndash Microscopy
- Case Study 1 ndash Diagnosis and Therapy
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Slide Number 110
- Slide Number 111
- Slide Number 112
- Slide Number 113
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
- Slide Number 124
- Slide Number 125
- DIC Take Home Messages
- Slide Number 127
- Slide Number 128
-
DIC Management Goals
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Identify and correct the underlying causeMicroclots preventing blood flow in organs may strongly impair the biosynthesis of new coagulation factors inhibitors fibrinolysis proteins leading to severe deficienciesCorrect consumption and restore anticoagulation pathway with blood components Fresh frozen plasma (preferred) Coagulation factor concentrates fibrinogen andor cryoprecipitate Antithrombin Platelet concentrates Monitor coagulation markers for correction
DIC Management and Treatment
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)
requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)
Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia
DIC Management Strategies
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant Factor Concentrate Treatment
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis
Anticoagulant Factor Concentrate Treatment Trials
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise
Markers of Thrombin amp Plasmin Generation in DIC
D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC
Cut-off value
Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen
degradation products Sensitive assay typically with cutoff adapted for DIC
D-dimer FDPs and DIC
D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC
Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80
Follow Up of DIC State of Disease
Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8
Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility
FMD-Dimer in DIC Major Differences
onset of thrombosis
days
Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8
FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)
D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)
of Abnormal Results in Patients with Confirmed and Suspected DIC
0
20
40
60
80
100
94 85 90N = 62
Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32
Positivity of Test Results ISTH Score and Disease State
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
Red bar positive for 2 points of DIC score
Pink bar positive for 1-2 points of DIC score
HT hematopoietic tumor
IF infection
SC solid cancer
Markers in Patients with or without DIC
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
HT hematopoietic tumorIF infectionSC solid cancer
Comparing an Automated FM vs Manual FSP Test
Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71
Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)
Automated (Mitsubishi) vs Automated (Stago)
In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago
Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC
Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
Non Overt DIC Overt DIC
AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC
Trends in Markers of DIC for Different Patients
Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00
Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients
Trends in Markers of DIC for Different Patients
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes
28 day outcome survival
28 day outcome death
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines
DIC Case Studies
Case Study 1 - Presentation
18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE
WBC count 77 KμL 423 ndash 907 x KμL
RBC count 17 MμL 137 ndash 175 x MμL
Hemoglobin 67 gdL 137 ndash 175 gdL
Hematocrit 195 401 ndash 510
MCV 95 fL 790 ndash 922 fL
MPV 12 fL 94 ndash 124 fL
Platelet count 9 KμL 161 ndash 347 KμL
Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0
Lymphocytes monocytes eosinophils basophils all below normal range
PT 47 sec (corrected on mixing study) 116 ndash 152 sec
APTT 75 sec (corrected on mixing study) 253 ndash 373 sec
Fibrinogen lt 76 mgdL 177 ndash 466 mgdL
D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Microscopy
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Arrow shows giant platelets in this peripheral smear Promyelocytes apparent
Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)
DIC due to TF release by APL blasts
Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases
Transfusions to replace factors along with platelets and RBCs during APL treatment
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started
Case Study 2 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L
PT 30 sec 113 ndash 146 sec
APTT 75 sec 25 ndash 34 sec
D-dimer 078 microgml FEU lt050 microgml FEU
Fibrinogen 92 mgdl 150-400 mgdl
pH 728 738 to 742
PaO2 570 mmHg 80-100 mmHg
WBC 33 times 103mm3 40-11 times 103mm3
ALT 111 IUL 0ndash34 IUL
AST 61 IUL 0ndash34 IUL
BUN 303 mgdL 08-13 mgdL
Case Study 2 ndash Lab Results
Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures
Case Study 2 ndash Diagnosis
60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior
Case Study 3 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L
PT 228 sec 113 ndash 146 sec
APTT 45 sec 25 ndash 34 sec
D-dimer 080 microgml FEU lt050 microgmL FEU
Fibrinogen 82 mgdL 150-400 mgdL
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 134 gdL 14-16 gdL
WBC 81 times 103mm3 40-11 times 103mm3
ALT 32 IUL 0ndash34 IUL
AST 28 IUL 0ndash34 IUL
BUN 09 mgdL 08-13 mgdL
Case Study 3 ndash Lab Results
Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment
Case Study 3 ndash Diagnosis and Therapy
Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91
Case Study 4 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L
PT 28 sec 113 ndash 146 sec
APTT 71 sec 25 ndash 34 sec
D-dimer 31 microgmL FEU lt050 microgml FEU
Fibrinogen 92 mgdL 150-400 mgdl
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 158 gdL 14-16 gdL
WBC 71 times 103mm3 40-11 times 103mm3
ALT 60 IUL 0ndash34 IUL
AST 47 IUL 0ndash34 IUL
BUN 38 mgdL 08-13 mgdL
Case Study 4 ndash Lab Results
Lyme disease with DICProvide antibiotics with supportive measures
Case Study 4 ndash Diagnosis
55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis
Case Study 5 ndash Presentation
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
Case Study 5 ndash Lab Results and Time Course
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
TEST RESULT REFERENCE RANGE
Platelet count 33 x 109L 150-450 x 109L
PT 215 sec 103 ndash 128 sec
APTT 44 sec 26 ndash 36 sec
D-dimer 20 microgmL FEU lt025 microgml FEU
Fibrinogen 34 mgdL 200-375 mgdl
FII FV FVIII Low Not reported (NR)
FVII FIX FX vWF Normal NR
Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)
DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic
dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR
(C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen
(D) Illustration demonstrating repair
Case Study 5 ndash Diagnosis and Treatment
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography
Case Study 6 ndash Presentation
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
Case Study 6 ndash Lab Results
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L
PT 63 sec gt control 113 ndash 146 sec
INR 658 1 ndash 125
APTT 80 sec gt control 25 ndash 34 sec
D-dimer gt200 microgmL DDU 02 microgmL DDU
Urine exam Proteinuria and hematuria 150-400 mgdl
Albumin 28 gdL NR
Hb 58 gdL NR
LDH 1196 UL NR
SGPT 144 IU NR
SGOT 88 IU NR
Bilirubin 32 mgdL NR
DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th
day postop
Case Study 6 ndash Diagnosis and Treatment
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure
Case Study 6 ndash Discussion
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Case Study 7 ndash Lab Results vs Time
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
DIC Take Home Messages
Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation
Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers
DIC
Thank you Questions
- Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
- Learning Objectives
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Wound Sealing
- The Three Steps of Hemostasis
- Vessel Wall
- Slide Number 12
- Slide Number 13
- Platelet Structure UnactivatedActivated
- Primary Hemostasis
- Primary Hemostasis Assays
- Slide Number 17
- Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
- Slide Number 19
- Coagulation factors
- Coagulation Assay Mechanisms
- Slide Number 22
- Fibrin Formation
- Slide Number 24
- Fibrinolysis Overview
- Fibrinolysis Overview
- Slide Number 27
- Fibrinolysis Releases D-dimers
- Basic Pathophysiology of DIC
- Disseminated Intravascular Coagulation (DIC)
- Purpura Fulminans with DIC Due to Meningococcal Sepsis
- Clinical Conditions Associated With DIC
- Frequency of DIC in Selected Disease States
- Underlying Diseases in DIC Patients
- Slide Number 36
- Slide Number 37
- Slide Number 38
- Slide Number 39
- Pathophysiology of DIC
- Pathogenesis of DIC in Sepsis
- Host Response in Severe Sepsis
- Organ Failure in Severe Sepsis
- Mechanism of DIC in Organ Failure
- Interaction of Inflammation and Coagulation in Sepsis
- Slide Number 47
- Diverse and Opposing Effects of Thrombin
- Coagulation and Fibrinolysis in DIC
- Mechanism of DIC
- Pathophysiology of DIC
- Pathophysiology of DIC - Mechanism
- Pathophysiology of DIC ndash 2 Types of Clinical pictures
- Sub-Acute and Non-Overt DIC Clinical Findings
- Pathophysiology of Overt DIC
- Physiopathology of DIC ndash Overt DIC Findings
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- BREAK
- Diagnostic and Management Approach for DIC
- Diagnosis of DIC
- Lab Diagnosis of DIC ndash Markers of Factor Consumption
- Lab Diagnosis of DIC ndash Screening Tests
- Slide Number 67
- Slide Number 68
- British Journal of Haematology Overt DIC Score
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- DIC Management Goals
- DIC Management and Treatment
- DIC Management Strategies
- Anticoagulant Factor Concentrate Treatment
- Anticoagulant Factor Concentrate Treatment Trials
- Markers of Thrombin amp Plasmin Generation in DIC
- D-dimer FDPs and DIC
- D-Dimer and FDPs in DIC
- Follow Up of DIC State of Disease
- FMD-Dimer in DIC Major Differences
- of Abnormal Results in Patients with Confirmed and Suspected DIC
- Slide Number 85
- Slide Number 86
- Comparing an Automated FM vs Manual FSP Test
- Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Slide Number 94
- Slide Number 95
- Slide Number 96
- Slide Number 97
- Slide Number 98
- Slide Number 99
- DIC Case Studies
- Case Study 1 - Presentation
- Case Study 1 ndash Lab Results
- Case Study 1 ndash Microscopy
- Case Study 1 ndash Diagnosis and Therapy
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Slide Number 110
- Slide Number 111
- Slide Number 112
- Slide Number 113
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
- Slide Number 124
- Slide Number 125
- DIC Take Home Messages
- Slide Number 127
- Slide Number 128
-
DIC Management and Treatment
Baglin T Disseminated intravascular coagulation diagnosis and treatment BMJ 1996 312 683-7
Stop activation process Thrombin and plasmin inhibitors Unfractionaed heparin (UFH) amp low molecular weight heparin (LMWH)
requires adequate AT levels typically low dose Monitor with anti-Xa activity no APTT (if UFH)
Longer term once the patient stabilizes oral anticoagulantsOther supportive treatment Vitamin K for critically ill patients with acquired vitamin K deficiency Oxygen to correct hypoxia
DIC Management Strategies
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant Factor Concentrate Treatment
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis
Anticoagulant Factor Concentrate Treatment Trials
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise
Markers of Thrombin amp Plasmin Generation in DIC
D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC
Cut-off value
Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen
degradation products Sensitive assay typically with cutoff adapted for DIC
D-dimer FDPs and DIC
D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC
Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80
Follow Up of DIC State of Disease
Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8
Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility
FMD-Dimer in DIC Major Differences
onset of thrombosis
days
Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8
FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)
D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)
of Abnormal Results in Patients with Confirmed and Suspected DIC
0
20
40
60
80
100
94 85 90N = 62
Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32
Positivity of Test Results ISTH Score and Disease State
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
Red bar positive for 2 points of DIC score
Pink bar positive for 1-2 points of DIC score
HT hematopoietic tumor
IF infection
SC solid cancer
Markers in Patients with or without DIC
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
HT hematopoietic tumorIF infectionSC solid cancer
Comparing an Automated FM vs Manual FSP Test
Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71
Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)
Automated (Mitsubishi) vs Automated (Stago)
In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago
Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC
Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
Non Overt DIC Overt DIC
AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC
Trends in Markers of DIC for Different Patients
Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00
Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients
Trends in Markers of DIC for Different Patients
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes
28 day outcome survival
28 day outcome death
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines
DIC Case Studies
Case Study 1 - Presentation
18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE
WBC count 77 KμL 423 ndash 907 x KμL
RBC count 17 MμL 137 ndash 175 x MμL
Hemoglobin 67 gdL 137 ndash 175 gdL
Hematocrit 195 401 ndash 510
MCV 95 fL 790 ndash 922 fL
MPV 12 fL 94 ndash 124 fL
Platelet count 9 KμL 161 ndash 347 KμL
Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0
Lymphocytes monocytes eosinophils basophils all below normal range
PT 47 sec (corrected on mixing study) 116 ndash 152 sec
APTT 75 sec (corrected on mixing study) 253 ndash 373 sec
Fibrinogen lt 76 mgdL 177 ndash 466 mgdL
D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Microscopy
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Arrow shows giant platelets in this peripheral smear Promyelocytes apparent
Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)
DIC due to TF release by APL blasts
Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases
Transfusions to replace factors along with platelets and RBCs during APL treatment
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started
Case Study 2 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L
PT 30 sec 113 ndash 146 sec
APTT 75 sec 25 ndash 34 sec
D-dimer 078 microgml FEU lt050 microgml FEU
Fibrinogen 92 mgdl 150-400 mgdl
pH 728 738 to 742
PaO2 570 mmHg 80-100 mmHg
WBC 33 times 103mm3 40-11 times 103mm3
ALT 111 IUL 0ndash34 IUL
AST 61 IUL 0ndash34 IUL
BUN 303 mgdL 08-13 mgdL
Case Study 2 ndash Lab Results
Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures
Case Study 2 ndash Diagnosis
60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior
Case Study 3 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L
PT 228 sec 113 ndash 146 sec
APTT 45 sec 25 ndash 34 sec
D-dimer 080 microgml FEU lt050 microgmL FEU
Fibrinogen 82 mgdL 150-400 mgdL
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 134 gdL 14-16 gdL
WBC 81 times 103mm3 40-11 times 103mm3
ALT 32 IUL 0ndash34 IUL
AST 28 IUL 0ndash34 IUL
BUN 09 mgdL 08-13 mgdL
Case Study 3 ndash Lab Results
Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment
Case Study 3 ndash Diagnosis and Therapy
Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91
Case Study 4 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L
PT 28 sec 113 ndash 146 sec
APTT 71 sec 25 ndash 34 sec
D-dimer 31 microgmL FEU lt050 microgml FEU
Fibrinogen 92 mgdL 150-400 mgdl
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 158 gdL 14-16 gdL
WBC 71 times 103mm3 40-11 times 103mm3
ALT 60 IUL 0ndash34 IUL
AST 47 IUL 0ndash34 IUL
BUN 38 mgdL 08-13 mgdL
Case Study 4 ndash Lab Results
Lyme disease with DICProvide antibiotics with supportive measures
Case Study 4 ndash Diagnosis
55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis
Case Study 5 ndash Presentation
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
Case Study 5 ndash Lab Results and Time Course
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
TEST RESULT REFERENCE RANGE
Platelet count 33 x 109L 150-450 x 109L
PT 215 sec 103 ndash 128 sec
APTT 44 sec 26 ndash 36 sec
D-dimer 20 microgmL FEU lt025 microgml FEU
Fibrinogen 34 mgdL 200-375 mgdl
FII FV FVIII Low Not reported (NR)
FVII FIX FX vWF Normal NR
Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)
DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic
dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR
(C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen
(D) Illustration demonstrating repair
Case Study 5 ndash Diagnosis and Treatment
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography
Case Study 6 ndash Presentation
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
Case Study 6 ndash Lab Results
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L
PT 63 sec gt control 113 ndash 146 sec
INR 658 1 ndash 125
APTT 80 sec gt control 25 ndash 34 sec
D-dimer gt200 microgmL DDU 02 microgmL DDU
Urine exam Proteinuria and hematuria 150-400 mgdl
Albumin 28 gdL NR
Hb 58 gdL NR
LDH 1196 UL NR
SGPT 144 IU NR
SGOT 88 IU NR
Bilirubin 32 mgdL NR
DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th
day postop
Case Study 6 ndash Diagnosis and Treatment
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure
Case Study 6 ndash Discussion
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Case Study 7 ndash Lab Results vs Time
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
DIC Take Home Messages
Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation
Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers
DIC
Thank you Questions
- Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
- Learning Objectives
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Wound Sealing
- The Three Steps of Hemostasis
- Vessel Wall
- Slide Number 12
- Slide Number 13
- Platelet Structure UnactivatedActivated
- Primary Hemostasis
- Primary Hemostasis Assays
- Slide Number 17
- Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
- Slide Number 19
- Coagulation factors
- Coagulation Assay Mechanisms
- Slide Number 22
- Fibrin Formation
- Slide Number 24
- Fibrinolysis Overview
- Fibrinolysis Overview
- Slide Number 27
- Fibrinolysis Releases D-dimers
- Basic Pathophysiology of DIC
- Disseminated Intravascular Coagulation (DIC)
- Purpura Fulminans with DIC Due to Meningococcal Sepsis
- Clinical Conditions Associated With DIC
- Frequency of DIC in Selected Disease States
- Underlying Diseases in DIC Patients
- Slide Number 36
- Slide Number 37
- Slide Number 38
- Slide Number 39
- Pathophysiology of DIC
- Pathogenesis of DIC in Sepsis
- Host Response in Severe Sepsis
- Organ Failure in Severe Sepsis
- Mechanism of DIC in Organ Failure
- Interaction of Inflammation and Coagulation in Sepsis
- Slide Number 47
- Diverse and Opposing Effects of Thrombin
- Coagulation and Fibrinolysis in DIC
- Mechanism of DIC
- Pathophysiology of DIC
- Pathophysiology of DIC - Mechanism
- Pathophysiology of DIC ndash 2 Types of Clinical pictures
- Sub-Acute and Non-Overt DIC Clinical Findings
- Pathophysiology of Overt DIC
- Physiopathology of DIC ndash Overt DIC Findings
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- BREAK
- Diagnostic and Management Approach for DIC
- Diagnosis of DIC
- Lab Diagnosis of DIC ndash Markers of Factor Consumption
- Lab Diagnosis of DIC ndash Screening Tests
- Slide Number 67
- Slide Number 68
- British Journal of Haematology Overt DIC Score
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- DIC Management Goals
- DIC Management and Treatment
- DIC Management Strategies
- Anticoagulant Factor Concentrate Treatment
- Anticoagulant Factor Concentrate Treatment Trials
- Markers of Thrombin amp Plasmin Generation in DIC
- D-dimer FDPs and DIC
- D-Dimer and FDPs in DIC
- Follow Up of DIC State of Disease
- FMD-Dimer in DIC Major Differences
- of Abnormal Results in Patients with Confirmed and Suspected DIC
- Slide Number 85
- Slide Number 86
- Comparing an Automated FM vs Manual FSP Test
- Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Slide Number 94
- Slide Number 95
- Slide Number 96
- Slide Number 97
- Slide Number 98
- Slide Number 99
- DIC Case Studies
- Case Study 1 - Presentation
- Case Study 1 ndash Lab Results
- Case Study 1 ndash Microscopy
- Case Study 1 ndash Diagnosis and Therapy
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Slide Number 110
- Slide Number 111
- Slide Number 112
- Slide Number 113
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
- Slide Number 124
- Slide Number 125
- DIC Take Home Messages
- Slide Number 127
- Slide Number 128
-
DIC Management Strategies
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant Factor Concentrate Treatment
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis
Anticoagulant Factor Concentrate Treatment Trials
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise
Markers of Thrombin amp Plasmin Generation in DIC
D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC
Cut-off value
Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen
degradation products Sensitive assay typically with cutoff adapted for DIC
D-dimer FDPs and DIC
D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC
Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80
Follow Up of DIC State of Disease
Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8
Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility
FMD-Dimer in DIC Major Differences
onset of thrombosis
days
Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8
FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)
D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)
of Abnormal Results in Patients with Confirmed and Suspected DIC
0
20
40
60
80
100
94 85 90N = 62
Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32
Positivity of Test Results ISTH Score and Disease State
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
Red bar positive for 2 points of DIC score
Pink bar positive for 1-2 points of DIC score
HT hematopoietic tumor
IF infection
SC solid cancer
Markers in Patients with or without DIC
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
HT hematopoietic tumorIF infectionSC solid cancer
Comparing an Automated FM vs Manual FSP Test
Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71
Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)
Automated (Mitsubishi) vs Automated (Stago)
In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago
Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC
Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
Non Overt DIC Overt DIC
AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC
Trends in Markers of DIC for Different Patients
Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00
Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients
Trends in Markers of DIC for Different Patients
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes
28 day outcome survival
28 day outcome death
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines
DIC Case Studies
Case Study 1 - Presentation
18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE
WBC count 77 KμL 423 ndash 907 x KμL
RBC count 17 MμL 137 ndash 175 x MμL
Hemoglobin 67 gdL 137 ndash 175 gdL
Hematocrit 195 401 ndash 510
MCV 95 fL 790 ndash 922 fL
MPV 12 fL 94 ndash 124 fL
Platelet count 9 KμL 161 ndash 347 KμL
Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0
Lymphocytes monocytes eosinophils basophils all below normal range
PT 47 sec (corrected on mixing study) 116 ndash 152 sec
APTT 75 sec (corrected on mixing study) 253 ndash 373 sec
Fibrinogen lt 76 mgdL 177 ndash 466 mgdL
D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Microscopy
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Arrow shows giant platelets in this peripheral smear Promyelocytes apparent
Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)
DIC due to TF release by APL blasts
Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases
Transfusions to replace factors along with platelets and RBCs during APL treatment
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started
Case Study 2 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L
PT 30 sec 113 ndash 146 sec
APTT 75 sec 25 ndash 34 sec
D-dimer 078 microgml FEU lt050 microgml FEU
Fibrinogen 92 mgdl 150-400 mgdl
pH 728 738 to 742
PaO2 570 mmHg 80-100 mmHg
WBC 33 times 103mm3 40-11 times 103mm3
ALT 111 IUL 0ndash34 IUL
AST 61 IUL 0ndash34 IUL
BUN 303 mgdL 08-13 mgdL
Case Study 2 ndash Lab Results
Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures
Case Study 2 ndash Diagnosis
60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior
Case Study 3 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L
PT 228 sec 113 ndash 146 sec
APTT 45 sec 25 ndash 34 sec
D-dimer 080 microgml FEU lt050 microgmL FEU
Fibrinogen 82 mgdL 150-400 mgdL
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 134 gdL 14-16 gdL
WBC 81 times 103mm3 40-11 times 103mm3
ALT 32 IUL 0ndash34 IUL
AST 28 IUL 0ndash34 IUL
BUN 09 mgdL 08-13 mgdL
Case Study 3 ndash Lab Results
Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment
Case Study 3 ndash Diagnosis and Therapy
Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91
Case Study 4 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L
PT 28 sec 113 ndash 146 sec
APTT 71 sec 25 ndash 34 sec
D-dimer 31 microgmL FEU lt050 microgml FEU
Fibrinogen 92 mgdL 150-400 mgdl
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 158 gdL 14-16 gdL
WBC 71 times 103mm3 40-11 times 103mm3
ALT 60 IUL 0ndash34 IUL
AST 47 IUL 0ndash34 IUL
BUN 38 mgdL 08-13 mgdL
Case Study 4 ndash Lab Results
Lyme disease with DICProvide antibiotics with supportive measures
Case Study 4 ndash Diagnosis
55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis
Case Study 5 ndash Presentation
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
Case Study 5 ndash Lab Results and Time Course
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
TEST RESULT REFERENCE RANGE
Platelet count 33 x 109L 150-450 x 109L
PT 215 sec 103 ndash 128 sec
APTT 44 sec 26 ndash 36 sec
D-dimer 20 microgmL FEU lt025 microgml FEU
Fibrinogen 34 mgdL 200-375 mgdl
FII FV FVIII Low Not reported (NR)
FVII FIX FX vWF Normal NR
Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)
DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic
dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR
(C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen
(D) Illustration demonstrating repair
Case Study 5 ndash Diagnosis and Treatment
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography
Case Study 6 ndash Presentation
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
Case Study 6 ndash Lab Results
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L
PT 63 sec gt control 113 ndash 146 sec
INR 658 1 ndash 125
APTT 80 sec gt control 25 ndash 34 sec
D-dimer gt200 microgmL DDU 02 microgmL DDU
Urine exam Proteinuria and hematuria 150-400 mgdl
Albumin 28 gdL NR
Hb 58 gdL NR
LDH 1196 UL NR
SGPT 144 IU NR
SGOT 88 IU NR
Bilirubin 32 mgdL NR
DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th
day postop
Case Study 6 ndash Diagnosis and Treatment
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure
Case Study 6 ndash Discussion
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Case Study 7 ndash Lab Results vs Time
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
DIC Take Home Messages
Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation
Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers
DIC
Thank you Questions
- Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
- Learning Objectives
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Wound Sealing
- The Three Steps of Hemostasis
- Vessel Wall
- Slide Number 12
- Slide Number 13
- Platelet Structure UnactivatedActivated
- Primary Hemostasis
- Primary Hemostasis Assays
- Slide Number 17
- Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
- Slide Number 19
- Coagulation factors
- Coagulation Assay Mechanisms
- Slide Number 22
- Fibrin Formation
- Slide Number 24
- Fibrinolysis Overview
- Fibrinolysis Overview
- Slide Number 27
- Fibrinolysis Releases D-dimers
- Basic Pathophysiology of DIC
- Disseminated Intravascular Coagulation (DIC)
- Purpura Fulminans with DIC Due to Meningococcal Sepsis
- Clinical Conditions Associated With DIC
- Frequency of DIC in Selected Disease States
- Underlying Diseases in DIC Patients
- Slide Number 36
- Slide Number 37
- Slide Number 38
- Slide Number 39
- Pathophysiology of DIC
- Pathogenesis of DIC in Sepsis
- Host Response in Severe Sepsis
- Organ Failure in Severe Sepsis
- Mechanism of DIC in Organ Failure
- Interaction of Inflammation and Coagulation in Sepsis
- Slide Number 47
- Diverse and Opposing Effects of Thrombin
- Coagulation and Fibrinolysis in DIC
- Mechanism of DIC
- Pathophysiology of DIC
- Pathophysiology of DIC - Mechanism
- Pathophysiology of DIC ndash 2 Types of Clinical pictures
- Sub-Acute and Non-Overt DIC Clinical Findings
- Pathophysiology of Overt DIC
- Physiopathology of DIC ndash Overt DIC Findings
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- BREAK
- Diagnostic and Management Approach for DIC
- Diagnosis of DIC
- Lab Diagnosis of DIC ndash Markers of Factor Consumption
- Lab Diagnosis of DIC ndash Screening Tests
- Slide Number 67
- Slide Number 68
- British Journal of Haematology Overt DIC Score
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- DIC Management Goals
- DIC Management and Treatment
- DIC Management Strategies
- Anticoagulant Factor Concentrate Treatment
- Anticoagulant Factor Concentrate Treatment Trials
- Markers of Thrombin amp Plasmin Generation in DIC
- D-dimer FDPs and DIC
- D-Dimer and FDPs in DIC
- Follow Up of DIC State of Disease
- FMD-Dimer in DIC Major Differences
- of Abnormal Results in Patients with Confirmed and Suspected DIC
- Slide Number 85
- Slide Number 86
- Comparing an Automated FM vs Manual FSP Test
- Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Slide Number 94
- Slide Number 95
- Slide Number 96
- Slide Number 97
- Slide Number 98
- Slide Number 99
- DIC Case Studies
- Case Study 1 - Presentation
- Case Study 1 ndash Lab Results
- Case Study 1 ndash Microscopy
- Case Study 1 ndash Diagnosis and Therapy
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Slide Number 110
- Slide Number 111
- Slide Number 112
- Slide Number 113
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
- Slide Number 124
- Slide Number 125
- DIC Take Home Messages
- Slide Number 127
- Slide Number 128
-
Anticoagulant Factor Concentrate Treatment
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Anticoagulant factor concentrates (eg AT TFPI TM aPC) target sepsis with DIC before DIC emergence leads to deterioration of physiological responses maintaining homeostasis
Anticoagulant Factor Concentrate Treatment Trials
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise
Markers of Thrombin amp Plasmin Generation in DIC
D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC
Cut-off value
Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen
degradation products Sensitive assay typically with cutoff adapted for DIC
D-dimer FDPs and DIC
D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC
Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80
Follow Up of DIC State of Disease
Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8
Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility
FMD-Dimer in DIC Major Differences
onset of thrombosis
days
Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8
FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)
D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)
of Abnormal Results in Patients with Confirmed and Suspected DIC
0
20
40
60
80
100
94 85 90N = 62
Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32
Positivity of Test Results ISTH Score and Disease State
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
Red bar positive for 2 points of DIC score
Pink bar positive for 1-2 points of DIC score
HT hematopoietic tumor
IF infection
SC solid cancer
Markers in Patients with or without DIC
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
HT hematopoietic tumorIF infectionSC solid cancer
Comparing an Automated FM vs Manual FSP Test
Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71
Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)
Automated (Mitsubishi) vs Automated (Stago)
In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago
Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC
Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
Non Overt DIC Overt DIC
AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC
Trends in Markers of DIC for Different Patients
Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00
Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients
Trends in Markers of DIC for Different Patients
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes
28 day outcome survival
28 day outcome death
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines
DIC Case Studies
Case Study 1 - Presentation
18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE
WBC count 77 KμL 423 ndash 907 x KμL
RBC count 17 MμL 137 ndash 175 x MμL
Hemoglobin 67 gdL 137 ndash 175 gdL
Hematocrit 195 401 ndash 510
MCV 95 fL 790 ndash 922 fL
MPV 12 fL 94 ndash 124 fL
Platelet count 9 KμL 161 ndash 347 KμL
Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0
Lymphocytes monocytes eosinophils basophils all below normal range
PT 47 sec (corrected on mixing study) 116 ndash 152 sec
APTT 75 sec (corrected on mixing study) 253 ndash 373 sec
Fibrinogen lt 76 mgdL 177 ndash 466 mgdL
D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Microscopy
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Arrow shows giant platelets in this peripheral smear Promyelocytes apparent
Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)
DIC due to TF release by APL blasts
Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases
Transfusions to replace factors along with platelets and RBCs during APL treatment
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started
Case Study 2 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L
PT 30 sec 113 ndash 146 sec
APTT 75 sec 25 ndash 34 sec
D-dimer 078 microgml FEU lt050 microgml FEU
Fibrinogen 92 mgdl 150-400 mgdl
pH 728 738 to 742
PaO2 570 mmHg 80-100 mmHg
WBC 33 times 103mm3 40-11 times 103mm3
ALT 111 IUL 0ndash34 IUL
AST 61 IUL 0ndash34 IUL
BUN 303 mgdL 08-13 mgdL
Case Study 2 ndash Lab Results
Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures
Case Study 2 ndash Diagnosis
60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior
Case Study 3 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L
PT 228 sec 113 ndash 146 sec
APTT 45 sec 25 ndash 34 sec
D-dimer 080 microgml FEU lt050 microgmL FEU
Fibrinogen 82 mgdL 150-400 mgdL
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 134 gdL 14-16 gdL
WBC 81 times 103mm3 40-11 times 103mm3
ALT 32 IUL 0ndash34 IUL
AST 28 IUL 0ndash34 IUL
BUN 09 mgdL 08-13 mgdL
Case Study 3 ndash Lab Results
Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment
Case Study 3 ndash Diagnosis and Therapy
Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91
Case Study 4 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L
PT 28 sec 113 ndash 146 sec
APTT 71 sec 25 ndash 34 sec
D-dimer 31 microgmL FEU lt050 microgml FEU
Fibrinogen 92 mgdL 150-400 mgdl
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 158 gdL 14-16 gdL
WBC 71 times 103mm3 40-11 times 103mm3
ALT 60 IUL 0ndash34 IUL
AST 47 IUL 0ndash34 IUL
BUN 38 mgdL 08-13 mgdL
Case Study 4 ndash Lab Results
Lyme disease with DICProvide antibiotics with supportive measures
Case Study 4 ndash Diagnosis
55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis
Case Study 5 ndash Presentation
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
Case Study 5 ndash Lab Results and Time Course
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
TEST RESULT REFERENCE RANGE
Platelet count 33 x 109L 150-450 x 109L
PT 215 sec 103 ndash 128 sec
APTT 44 sec 26 ndash 36 sec
D-dimer 20 microgmL FEU lt025 microgml FEU
Fibrinogen 34 mgdL 200-375 mgdl
FII FV FVIII Low Not reported (NR)
FVII FIX FX vWF Normal NR
Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)
DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic
dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR
(C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen
(D) Illustration demonstrating repair
Case Study 5 ndash Diagnosis and Treatment
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography
Case Study 6 ndash Presentation
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
Case Study 6 ndash Lab Results
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L
PT 63 sec gt control 113 ndash 146 sec
INR 658 1 ndash 125
APTT 80 sec gt control 25 ndash 34 sec
D-dimer gt200 microgmL DDU 02 microgmL DDU
Urine exam Proteinuria and hematuria 150-400 mgdl
Albumin 28 gdL NR
Hb 58 gdL NR
LDH 1196 UL NR
SGPT 144 IU NR
SGOT 88 IU NR
Bilirubin 32 mgdL NR
DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th
day postop
Case Study 6 ndash Diagnosis and Treatment
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure
Case Study 6 ndash Discussion
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Case Study 7 ndash Lab Results vs Time
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
DIC Take Home Messages
Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation
Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers
DIC
Thank you Questions
- Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
- Learning Objectives
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Wound Sealing
- The Three Steps of Hemostasis
- Vessel Wall
- Slide Number 12
- Slide Number 13
- Platelet Structure UnactivatedActivated
- Primary Hemostasis
- Primary Hemostasis Assays
- Slide Number 17
- Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
- Slide Number 19
- Coagulation factors
- Coagulation Assay Mechanisms
- Slide Number 22
- Fibrin Formation
- Slide Number 24
- Fibrinolysis Overview
- Fibrinolysis Overview
- Slide Number 27
- Fibrinolysis Releases D-dimers
- Basic Pathophysiology of DIC
- Disseminated Intravascular Coagulation (DIC)
- Purpura Fulminans with DIC Due to Meningococcal Sepsis
- Clinical Conditions Associated With DIC
- Frequency of DIC in Selected Disease States
- Underlying Diseases in DIC Patients
- Slide Number 36
- Slide Number 37
- Slide Number 38
- Slide Number 39
- Pathophysiology of DIC
- Pathogenesis of DIC in Sepsis
- Host Response in Severe Sepsis
- Organ Failure in Severe Sepsis
- Mechanism of DIC in Organ Failure
- Interaction of Inflammation and Coagulation in Sepsis
- Slide Number 47
- Diverse and Opposing Effects of Thrombin
- Coagulation and Fibrinolysis in DIC
- Mechanism of DIC
- Pathophysiology of DIC
- Pathophysiology of DIC - Mechanism
- Pathophysiology of DIC ndash 2 Types of Clinical pictures
- Sub-Acute and Non-Overt DIC Clinical Findings
- Pathophysiology of Overt DIC
- Physiopathology of DIC ndash Overt DIC Findings
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- BREAK
- Diagnostic and Management Approach for DIC
- Diagnosis of DIC
- Lab Diagnosis of DIC ndash Markers of Factor Consumption
- Lab Diagnosis of DIC ndash Screening Tests
- Slide Number 67
- Slide Number 68
- British Journal of Haematology Overt DIC Score
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- DIC Management Goals
- DIC Management and Treatment
- DIC Management Strategies
- Anticoagulant Factor Concentrate Treatment
- Anticoagulant Factor Concentrate Treatment Trials
- Markers of Thrombin amp Plasmin Generation in DIC
- D-dimer FDPs and DIC
- D-Dimer and FDPs in DIC
- Follow Up of DIC State of Disease
- FMD-Dimer in DIC Major Differences
- of Abnormal Results in Patients with Confirmed and Suspected DIC
- Slide Number 85
- Slide Number 86
- Comparing an Automated FM vs Manual FSP Test
- Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Slide Number 94
- Slide Number 95
- Slide Number 96
- Slide Number 97
- Slide Number 98
- Slide Number 99
- DIC Case Studies
- Case Study 1 - Presentation
- Case Study 1 ndash Lab Results
- Case Study 1 ndash Microscopy
- Case Study 1 ndash Diagnosis and Therapy
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Slide Number 110
- Slide Number 111
- Slide Number 112
- Slide Number 113
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
- Slide Number 124
- Slide Number 125
- DIC Take Home Messages
- Slide Number 127
- Slide Number 128
-
Anticoagulant Factor Concentrate Treatment Trials
Gando S Levi M Toh CH Disseminated intravascular coagulation Nat Rev Dis Primers 2016 2 16037
Recombinant aPC AT and TFPI have been attempted for treatment of DIC in large clinical trials with mostly failures recombinant TM trials have shown promise
Markers of Thrombin amp Plasmin Generation in DIC
D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC
Cut-off value
Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen
degradation products Sensitive assay typically with cutoff adapted for DIC
D-dimer FDPs and DIC
D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC
Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80
Follow Up of DIC State of Disease
Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8
Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility
FMD-Dimer in DIC Major Differences
onset of thrombosis
days
Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8
FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)
D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)
of Abnormal Results in Patients with Confirmed and Suspected DIC
0
20
40
60
80
100
94 85 90N = 62
Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32
Positivity of Test Results ISTH Score and Disease State
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
Red bar positive for 2 points of DIC score
Pink bar positive for 1-2 points of DIC score
HT hematopoietic tumor
IF infection
SC solid cancer
Markers in Patients with or without DIC
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
HT hematopoietic tumorIF infectionSC solid cancer
Comparing an Automated FM vs Manual FSP Test
Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71
Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)
Automated (Mitsubishi) vs Automated (Stago)
In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago
Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC
Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
Non Overt DIC Overt DIC
AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC
Trends in Markers of DIC for Different Patients
Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00
Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients
Trends in Markers of DIC for Different Patients
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes
28 day outcome survival
28 day outcome death
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines
DIC Case Studies
Case Study 1 - Presentation
18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE
WBC count 77 KμL 423 ndash 907 x KμL
RBC count 17 MμL 137 ndash 175 x MμL
Hemoglobin 67 gdL 137 ndash 175 gdL
Hematocrit 195 401 ndash 510
MCV 95 fL 790 ndash 922 fL
MPV 12 fL 94 ndash 124 fL
Platelet count 9 KμL 161 ndash 347 KμL
Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0
Lymphocytes monocytes eosinophils basophils all below normal range
PT 47 sec (corrected on mixing study) 116 ndash 152 sec
APTT 75 sec (corrected on mixing study) 253 ndash 373 sec
Fibrinogen lt 76 mgdL 177 ndash 466 mgdL
D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Microscopy
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Arrow shows giant platelets in this peripheral smear Promyelocytes apparent
Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)
DIC due to TF release by APL blasts
Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases
Transfusions to replace factors along with platelets and RBCs during APL treatment
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started
Case Study 2 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L
PT 30 sec 113 ndash 146 sec
APTT 75 sec 25 ndash 34 sec
D-dimer 078 microgml FEU lt050 microgml FEU
Fibrinogen 92 mgdl 150-400 mgdl
pH 728 738 to 742
PaO2 570 mmHg 80-100 mmHg
WBC 33 times 103mm3 40-11 times 103mm3
ALT 111 IUL 0ndash34 IUL
AST 61 IUL 0ndash34 IUL
BUN 303 mgdL 08-13 mgdL
Case Study 2 ndash Lab Results
Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures
Case Study 2 ndash Diagnosis
60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior
Case Study 3 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L
PT 228 sec 113 ndash 146 sec
APTT 45 sec 25 ndash 34 sec
D-dimer 080 microgml FEU lt050 microgmL FEU
Fibrinogen 82 mgdL 150-400 mgdL
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 134 gdL 14-16 gdL
WBC 81 times 103mm3 40-11 times 103mm3
ALT 32 IUL 0ndash34 IUL
AST 28 IUL 0ndash34 IUL
BUN 09 mgdL 08-13 mgdL
Case Study 3 ndash Lab Results
Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment
Case Study 3 ndash Diagnosis and Therapy
Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91
Case Study 4 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L
PT 28 sec 113 ndash 146 sec
APTT 71 sec 25 ndash 34 sec
D-dimer 31 microgmL FEU lt050 microgml FEU
Fibrinogen 92 mgdL 150-400 mgdl
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 158 gdL 14-16 gdL
WBC 71 times 103mm3 40-11 times 103mm3
ALT 60 IUL 0ndash34 IUL
AST 47 IUL 0ndash34 IUL
BUN 38 mgdL 08-13 mgdL
Case Study 4 ndash Lab Results
Lyme disease with DICProvide antibiotics with supportive measures
Case Study 4 ndash Diagnosis
55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis
Case Study 5 ndash Presentation
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
Case Study 5 ndash Lab Results and Time Course
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
TEST RESULT REFERENCE RANGE
Platelet count 33 x 109L 150-450 x 109L
PT 215 sec 103 ndash 128 sec
APTT 44 sec 26 ndash 36 sec
D-dimer 20 microgmL FEU lt025 microgml FEU
Fibrinogen 34 mgdL 200-375 mgdl
FII FV FVIII Low Not reported (NR)
FVII FIX FX vWF Normal NR
Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)
DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic
dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR
(C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen
(D) Illustration demonstrating repair
Case Study 5 ndash Diagnosis and Treatment
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography
Case Study 6 ndash Presentation
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
Case Study 6 ndash Lab Results
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L
PT 63 sec gt control 113 ndash 146 sec
INR 658 1 ndash 125
APTT 80 sec gt control 25 ndash 34 sec
D-dimer gt200 microgmL DDU 02 microgmL DDU
Urine exam Proteinuria and hematuria 150-400 mgdl
Albumin 28 gdL NR
Hb 58 gdL NR
LDH 1196 UL NR
SGPT 144 IU NR
SGOT 88 IU NR
Bilirubin 32 mgdL NR
DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th
day postop
Case Study 6 ndash Diagnosis and Treatment
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure
Case Study 6 ndash Discussion
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Case Study 7 ndash Lab Results vs Time
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
DIC Take Home Messages
Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation
Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers
DIC
Thank you Questions
- Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
- Learning Objectives
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Wound Sealing
- The Three Steps of Hemostasis
- Vessel Wall
- Slide Number 12
- Slide Number 13
- Platelet Structure UnactivatedActivated
- Primary Hemostasis
- Primary Hemostasis Assays
- Slide Number 17
- Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
- Slide Number 19
- Coagulation factors
- Coagulation Assay Mechanisms
- Slide Number 22
- Fibrin Formation
- Slide Number 24
- Fibrinolysis Overview
- Fibrinolysis Overview
- Slide Number 27
- Fibrinolysis Releases D-dimers
- Basic Pathophysiology of DIC
- Disseminated Intravascular Coagulation (DIC)
- Purpura Fulminans with DIC Due to Meningococcal Sepsis
- Clinical Conditions Associated With DIC
- Frequency of DIC in Selected Disease States
- Underlying Diseases in DIC Patients
- Slide Number 36
- Slide Number 37
- Slide Number 38
- Slide Number 39
- Pathophysiology of DIC
- Pathogenesis of DIC in Sepsis
- Host Response in Severe Sepsis
- Organ Failure in Severe Sepsis
- Mechanism of DIC in Organ Failure
- Interaction of Inflammation and Coagulation in Sepsis
- Slide Number 47
- Diverse and Opposing Effects of Thrombin
- Coagulation and Fibrinolysis in DIC
- Mechanism of DIC
- Pathophysiology of DIC
- Pathophysiology of DIC - Mechanism
- Pathophysiology of DIC ndash 2 Types of Clinical pictures
- Sub-Acute and Non-Overt DIC Clinical Findings
- Pathophysiology of Overt DIC
- Physiopathology of DIC ndash Overt DIC Findings
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- BREAK
- Diagnostic and Management Approach for DIC
- Diagnosis of DIC
- Lab Diagnosis of DIC ndash Markers of Factor Consumption
- Lab Diagnosis of DIC ndash Screening Tests
- Slide Number 67
- Slide Number 68
- British Journal of Haematology Overt DIC Score
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- DIC Management Goals
- DIC Management and Treatment
- DIC Management Strategies
- Anticoagulant Factor Concentrate Treatment
- Anticoagulant Factor Concentrate Treatment Trials
- Markers of Thrombin amp Plasmin Generation in DIC
- D-dimer FDPs and DIC
- D-Dimer and FDPs in DIC
- Follow Up of DIC State of Disease
- FMD-Dimer in DIC Major Differences
- of Abnormal Results in Patients with Confirmed and Suspected DIC
- Slide Number 85
- Slide Number 86
- Comparing an Automated FM vs Manual FSP Test
- Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Slide Number 94
- Slide Number 95
- Slide Number 96
- Slide Number 97
- Slide Number 98
- Slide Number 99
- DIC Case Studies
- Case Study 1 - Presentation
- Case Study 1 ndash Lab Results
- Case Study 1 ndash Microscopy
- Case Study 1 ndash Diagnosis and Therapy
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Slide Number 110
- Slide Number 111
- Slide Number 112
- Slide Number 113
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
- Slide Number 124
- Slide Number 125
- DIC Take Home Messages
- Slide Number 127
- Slide Number 128
-
Markers of Thrombin amp Plasmin Generation in DIC
D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC
Cut-off value
Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen
degradation products Sensitive assay typically with cutoff adapted for DIC
D-dimer FDPs and DIC
D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC
Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80
Follow Up of DIC State of Disease
Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8
Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility
FMD-Dimer in DIC Major Differences
onset of thrombosis
days
Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8
FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)
D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)
of Abnormal Results in Patients with Confirmed and Suspected DIC
0
20
40
60
80
100
94 85 90N = 62
Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32
Positivity of Test Results ISTH Score and Disease State
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
Red bar positive for 2 points of DIC score
Pink bar positive for 1-2 points of DIC score
HT hematopoietic tumor
IF infection
SC solid cancer
Markers in Patients with or without DIC
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
HT hematopoietic tumorIF infectionSC solid cancer
Comparing an Automated FM vs Manual FSP Test
Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71
Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)
Automated (Mitsubishi) vs Automated (Stago)
In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago
Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC
Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
Non Overt DIC Overt DIC
AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC
Trends in Markers of DIC for Different Patients
Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00
Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients
Trends in Markers of DIC for Different Patients
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes
28 day outcome survival
28 day outcome death
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines
DIC Case Studies
Case Study 1 - Presentation
18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE
WBC count 77 KμL 423 ndash 907 x KμL
RBC count 17 MμL 137 ndash 175 x MμL
Hemoglobin 67 gdL 137 ndash 175 gdL
Hematocrit 195 401 ndash 510
MCV 95 fL 790 ndash 922 fL
MPV 12 fL 94 ndash 124 fL
Platelet count 9 KμL 161 ndash 347 KμL
Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0
Lymphocytes monocytes eosinophils basophils all below normal range
PT 47 sec (corrected on mixing study) 116 ndash 152 sec
APTT 75 sec (corrected on mixing study) 253 ndash 373 sec
Fibrinogen lt 76 mgdL 177 ndash 466 mgdL
D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Microscopy
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Arrow shows giant platelets in this peripheral smear Promyelocytes apparent
Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)
DIC due to TF release by APL blasts
Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases
Transfusions to replace factors along with platelets and RBCs during APL treatment
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started
Case Study 2 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L
PT 30 sec 113 ndash 146 sec
APTT 75 sec 25 ndash 34 sec
D-dimer 078 microgml FEU lt050 microgml FEU
Fibrinogen 92 mgdl 150-400 mgdl
pH 728 738 to 742
PaO2 570 mmHg 80-100 mmHg
WBC 33 times 103mm3 40-11 times 103mm3
ALT 111 IUL 0ndash34 IUL
AST 61 IUL 0ndash34 IUL
BUN 303 mgdL 08-13 mgdL
Case Study 2 ndash Lab Results
Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures
Case Study 2 ndash Diagnosis
60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior
Case Study 3 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L
PT 228 sec 113 ndash 146 sec
APTT 45 sec 25 ndash 34 sec
D-dimer 080 microgml FEU lt050 microgmL FEU
Fibrinogen 82 mgdL 150-400 mgdL
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 134 gdL 14-16 gdL
WBC 81 times 103mm3 40-11 times 103mm3
ALT 32 IUL 0ndash34 IUL
AST 28 IUL 0ndash34 IUL
BUN 09 mgdL 08-13 mgdL
Case Study 3 ndash Lab Results
Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment
Case Study 3 ndash Diagnosis and Therapy
Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91
Case Study 4 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L
PT 28 sec 113 ndash 146 sec
APTT 71 sec 25 ndash 34 sec
D-dimer 31 microgmL FEU lt050 microgml FEU
Fibrinogen 92 mgdL 150-400 mgdl
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 158 gdL 14-16 gdL
WBC 71 times 103mm3 40-11 times 103mm3
ALT 60 IUL 0ndash34 IUL
AST 47 IUL 0ndash34 IUL
BUN 38 mgdL 08-13 mgdL
Case Study 4 ndash Lab Results
Lyme disease with DICProvide antibiotics with supportive measures
Case Study 4 ndash Diagnosis
55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis
Case Study 5 ndash Presentation
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
Case Study 5 ndash Lab Results and Time Course
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
TEST RESULT REFERENCE RANGE
Platelet count 33 x 109L 150-450 x 109L
PT 215 sec 103 ndash 128 sec
APTT 44 sec 26 ndash 36 sec
D-dimer 20 microgmL FEU lt025 microgml FEU
Fibrinogen 34 mgdL 200-375 mgdl
FII FV FVIII Low Not reported (NR)
FVII FIX FX vWF Normal NR
Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)
DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic
dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR
(C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen
(D) Illustration demonstrating repair
Case Study 5 ndash Diagnosis and Treatment
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography
Case Study 6 ndash Presentation
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
Case Study 6 ndash Lab Results
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L
PT 63 sec gt control 113 ndash 146 sec
INR 658 1 ndash 125
APTT 80 sec gt control 25 ndash 34 sec
D-dimer gt200 microgmL DDU 02 microgmL DDU
Urine exam Proteinuria and hematuria 150-400 mgdl
Albumin 28 gdL NR
Hb 58 gdL NR
LDH 1196 UL NR
SGPT 144 IU NR
SGOT 88 IU NR
Bilirubin 32 mgdL NR
DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th
day postop
Case Study 6 ndash Diagnosis and Treatment
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure
Case Study 6 ndash Discussion
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Case Study 7 ndash Lab Results vs Time
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
DIC Take Home Messages
Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation
Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers
DIC
Thank you Questions
- Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
- Learning Objectives
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Wound Sealing
- The Three Steps of Hemostasis
- Vessel Wall
- Slide Number 12
- Slide Number 13
- Platelet Structure UnactivatedActivated
- Primary Hemostasis
- Primary Hemostasis Assays
- Slide Number 17
- Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
- Slide Number 19
- Coagulation factors
- Coagulation Assay Mechanisms
- Slide Number 22
- Fibrin Formation
- Slide Number 24
- Fibrinolysis Overview
- Fibrinolysis Overview
- Slide Number 27
- Fibrinolysis Releases D-dimers
- Basic Pathophysiology of DIC
- Disseminated Intravascular Coagulation (DIC)
- Purpura Fulminans with DIC Due to Meningococcal Sepsis
- Clinical Conditions Associated With DIC
- Frequency of DIC in Selected Disease States
- Underlying Diseases in DIC Patients
- Slide Number 36
- Slide Number 37
- Slide Number 38
- Slide Number 39
- Pathophysiology of DIC
- Pathogenesis of DIC in Sepsis
- Host Response in Severe Sepsis
- Organ Failure in Severe Sepsis
- Mechanism of DIC in Organ Failure
- Interaction of Inflammation and Coagulation in Sepsis
- Slide Number 47
- Diverse and Opposing Effects of Thrombin
- Coagulation and Fibrinolysis in DIC
- Mechanism of DIC
- Pathophysiology of DIC
- Pathophysiology of DIC - Mechanism
- Pathophysiology of DIC ndash 2 Types of Clinical pictures
- Sub-Acute and Non-Overt DIC Clinical Findings
- Pathophysiology of Overt DIC
- Physiopathology of DIC ndash Overt DIC Findings
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- BREAK
- Diagnostic and Management Approach for DIC
- Diagnosis of DIC
- Lab Diagnosis of DIC ndash Markers of Factor Consumption
- Lab Diagnosis of DIC ndash Screening Tests
- Slide Number 67
- Slide Number 68
- British Journal of Haematology Overt DIC Score
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- DIC Management Goals
- DIC Management and Treatment
- DIC Management Strategies
- Anticoagulant Factor Concentrate Treatment
- Anticoagulant Factor Concentrate Treatment Trials
- Markers of Thrombin amp Plasmin Generation in DIC
- D-dimer FDPs and DIC
- D-Dimer and FDPs in DIC
- Follow Up of DIC State of Disease
- FMD-Dimer in DIC Major Differences
- of Abnormal Results in Patients with Confirmed and Suspected DIC
- Slide Number 85
- Slide Number 86
- Comparing an Automated FM vs Manual FSP Test
- Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Slide Number 94
- Slide Number 95
- Slide Number 96
- Slide Number 97
- Slide Number 98
- Slide Number 99
- DIC Case Studies
- Case Study 1 - Presentation
- Case Study 1 ndash Lab Results
- Case Study 1 ndash Microscopy
- Case Study 1 ndash Diagnosis and Therapy
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Slide Number 110
- Slide Number 111
- Slide Number 112
- Slide Number 113
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
- Slide Number 124
- Slide Number 125
- DIC Take Home Messages
- Slide Number 127
- Slide Number 128
-
D-Dimer sensitive test for DIC but not specific Elevated D-Dimer Thrombin + Plasmin activity Negative D-Dimer low probability for DIC
Cut-off value
Fibrin monomers (FM aka soluble fibrin monomers SFM) and fibrin degradation products (FDPs aka fibrin split products FSPs) Manual FDPFSP detects both fibrin and fibrinogen
degradation products Sensitive assay typically with cutoff adapted for DIC
D-dimer FDPs and DIC
D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC
Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80
Follow Up of DIC State of Disease
Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8
Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility
FMD-Dimer in DIC Major Differences
onset of thrombosis
days
Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8
FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)
D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)
of Abnormal Results in Patients with Confirmed and Suspected DIC
0
20
40
60
80
100
94 85 90N = 62
Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32
Positivity of Test Results ISTH Score and Disease State
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
Red bar positive for 2 points of DIC score
Pink bar positive for 1-2 points of DIC score
HT hematopoietic tumor
IF infection
SC solid cancer
Markers in Patients with or without DIC
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
HT hematopoietic tumorIF infectionSC solid cancer
Comparing an Automated FM vs Manual FSP Test
Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71
Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)
Automated (Mitsubishi) vs Automated (Stago)
In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago
Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC
Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
Non Overt DIC Overt DIC
AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC
Trends in Markers of DIC for Different Patients
Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00
Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients
Trends in Markers of DIC for Different Patients
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes
28 day outcome survival
28 day outcome death
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines
DIC Case Studies
Case Study 1 - Presentation
18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE
WBC count 77 KμL 423 ndash 907 x KμL
RBC count 17 MμL 137 ndash 175 x MμL
Hemoglobin 67 gdL 137 ndash 175 gdL
Hematocrit 195 401 ndash 510
MCV 95 fL 790 ndash 922 fL
MPV 12 fL 94 ndash 124 fL
Platelet count 9 KμL 161 ndash 347 KμL
Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0
Lymphocytes monocytes eosinophils basophils all below normal range
PT 47 sec (corrected on mixing study) 116 ndash 152 sec
APTT 75 sec (corrected on mixing study) 253 ndash 373 sec
Fibrinogen lt 76 mgdL 177 ndash 466 mgdL
D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Microscopy
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Arrow shows giant platelets in this peripheral smear Promyelocytes apparent
Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)
DIC due to TF release by APL blasts
Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases
Transfusions to replace factors along with platelets and RBCs during APL treatment
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started
Case Study 2 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L
PT 30 sec 113 ndash 146 sec
APTT 75 sec 25 ndash 34 sec
D-dimer 078 microgml FEU lt050 microgml FEU
Fibrinogen 92 mgdl 150-400 mgdl
pH 728 738 to 742
PaO2 570 mmHg 80-100 mmHg
WBC 33 times 103mm3 40-11 times 103mm3
ALT 111 IUL 0ndash34 IUL
AST 61 IUL 0ndash34 IUL
BUN 303 mgdL 08-13 mgdL
Case Study 2 ndash Lab Results
Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures
Case Study 2 ndash Diagnosis
60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior
Case Study 3 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L
PT 228 sec 113 ndash 146 sec
APTT 45 sec 25 ndash 34 sec
D-dimer 080 microgml FEU lt050 microgmL FEU
Fibrinogen 82 mgdL 150-400 mgdL
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 134 gdL 14-16 gdL
WBC 81 times 103mm3 40-11 times 103mm3
ALT 32 IUL 0ndash34 IUL
AST 28 IUL 0ndash34 IUL
BUN 09 mgdL 08-13 mgdL
Case Study 3 ndash Lab Results
Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment
Case Study 3 ndash Diagnosis and Therapy
Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91
Case Study 4 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L
PT 28 sec 113 ndash 146 sec
APTT 71 sec 25 ndash 34 sec
D-dimer 31 microgmL FEU lt050 microgml FEU
Fibrinogen 92 mgdL 150-400 mgdl
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 158 gdL 14-16 gdL
WBC 71 times 103mm3 40-11 times 103mm3
ALT 60 IUL 0ndash34 IUL
AST 47 IUL 0ndash34 IUL
BUN 38 mgdL 08-13 mgdL
Case Study 4 ndash Lab Results
Lyme disease with DICProvide antibiotics with supportive measures
Case Study 4 ndash Diagnosis
55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis
Case Study 5 ndash Presentation
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
Case Study 5 ndash Lab Results and Time Course
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
TEST RESULT REFERENCE RANGE
Platelet count 33 x 109L 150-450 x 109L
PT 215 sec 103 ndash 128 sec
APTT 44 sec 26 ndash 36 sec
D-dimer 20 microgmL FEU lt025 microgml FEU
Fibrinogen 34 mgdL 200-375 mgdl
FII FV FVIII Low Not reported (NR)
FVII FIX FX vWF Normal NR
Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)
DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic
dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR
(C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen
(D) Illustration demonstrating repair
Case Study 5 ndash Diagnosis and Treatment
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography
Case Study 6 ndash Presentation
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
Case Study 6 ndash Lab Results
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L
PT 63 sec gt control 113 ndash 146 sec
INR 658 1 ndash 125
APTT 80 sec gt control 25 ndash 34 sec
D-dimer gt200 microgmL DDU 02 microgmL DDU
Urine exam Proteinuria and hematuria 150-400 mgdl
Albumin 28 gdL NR
Hb 58 gdL NR
LDH 1196 UL NR
SGPT 144 IU NR
SGOT 88 IU NR
Bilirubin 32 mgdL NR
DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th
day postop
Case Study 6 ndash Diagnosis and Treatment
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure
Case Study 6 ndash Discussion
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Case Study 7 ndash Lab Results vs Time
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
DIC Take Home Messages
Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation
Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers
DIC
Thank you Questions
- Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
- Learning Objectives
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Wound Sealing
- The Three Steps of Hemostasis
- Vessel Wall
- Slide Number 12
- Slide Number 13
- Platelet Structure UnactivatedActivated
- Primary Hemostasis
- Primary Hemostasis Assays
- Slide Number 17
- Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
- Slide Number 19
- Coagulation factors
- Coagulation Assay Mechanisms
- Slide Number 22
- Fibrin Formation
- Slide Number 24
- Fibrinolysis Overview
- Fibrinolysis Overview
- Slide Number 27
- Fibrinolysis Releases D-dimers
- Basic Pathophysiology of DIC
- Disseminated Intravascular Coagulation (DIC)
- Purpura Fulminans with DIC Due to Meningococcal Sepsis
- Clinical Conditions Associated With DIC
- Frequency of DIC in Selected Disease States
- Underlying Diseases in DIC Patients
- Slide Number 36
- Slide Number 37
- Slide Number 38
- Slide Number 39
- Pathophysiology of DIC
- Pathogenesis of DIC in Sepsis
- Host Response in Severe Sepsis
- Organ Failure in Severe Sepsis
- Mechanism of DIC in Organ Failure
- Interaction of Inflammation and Coagulation in Sepsis
- Slide Number 47
- Diverse and Opposing Effects of Thrombin
- Coagulation and Fibrinolysis in DIC
- Mechanism of DIC
- Pathophysiology of DIC
- Pathophysiology of DIC - Mechanism
- Pathophysiology of DIC ndash 2 Types of Clinical pictures
- Sub-Acute and Non-Overt DIC Clinical Findings
- Pathophysiology of Overt DIC
- Physiopathology of DIC ndash Overt DIC Findings
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- BREAK
- Diagnostic and Management Approach for DIC
- Diagnosis of DIC
- Lab Diagnosis of DIC ndash Markers of Factor Consumption
- Lab Diagnosis of DIC ndash Screening Tests
- Slide Number 67
- Slide Number 68
- British Journal of Haematology Overt DIC Score
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- DIC Management Goals
- DIC Management and Treatment
- DIC Management Strategies
- Anticoagulant Factor Concentrate Treatment
- Anticoagulant Factor Concentrate Treatment Trials
- Markers of Thrombin amp Plasmin Generation in DIC
- D-dimer FDPs and DIC
- D-Dimer and FDPs in DIC
- Follow Up of DIC State of Disease
- FMD-Dimer in DIC Major Differences
- of Abnormal Results in Patients with Confirmed and Suspected DIC
- Slide Number 85
- Slide Number 86
- Comparing an Automated FM vs Manual FSP Test
- Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Slide Number 94
- Slide Number 95
- Slide Number 96
- Slide Number 97
- Slide Number 98
- Slide Number 99
- DIC Case Studies
- Case Study 1 - Presentation
- Case Study 1 ndash Lab Results
- Case Study 1 ndash Microscopy
- Case Study 1 ndash Diagnosis and Therapy
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Slide Number 110
- Slide Number 111
- Slide Number 112
- Slide Number 113
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
- Slide Number 124
- Slide Number 125
- DIC Take Home Messages
- Slide Number 127
- Slide Number 128
-
D-Dimer and FDPs in DICDetects both fibrin and fibrinogen degradation productsSensitive cut-off adapted to DIC
Yu M Nardella A Pechet L Screening tests of disseminated intravascular coagulation guidelines for rapid and specific laboratory diagnosis Crit Care Med 2000 28 1777-80
Follow Up of DIC State of Disease
Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8
Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility
FMD-Dimer in DIC Major Differences
onset of thrombosis
days
Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8
FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)
D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)
of Abnormal Results in Patients with Confirmed and Suspected DIC
0
20
40
60
80
100
94 85 90N = 62
Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32
Positivity of Test Results ISTH Score and Disease State
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
Red bar positive for 2 points of DIC score
Pink bar positive for 1-2 points of DIC score
HT hematopoietic tumor
IF infection
SC solid cancer
Markers in Patients with or without DIC
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
HT hematopoietic tumorIF infectionSC solid cancer
Comparing an Automated FM vs Manual FSP Test
Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71
Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)
Automated (Mitsubishi) vs Automated (Stago)
In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago
Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC
Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
Non Overt DIC Overt DIC
AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC
Trends in Markers of DIC for Different Patients
Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00
Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients
Trends in Markers of DIC for Different Patients
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes
28 day outcome survival
28 day outcome death
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines
DIC Case Studies
Case Study 1 - Presentation
18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE
WBC count 77 KμL 423 ndash 907 x KμL
RBC count 17 MμL 137 ndash 175 x MμL
Hemoglobin 67 gdL 137 ndash 175 gdL
Hematocrit 195 401 ndash 510
MCV 95 fL 790 ndash 922 fL
MPV 12 fL 94 ndash 124 fL
Platelet count 9 KμL 161 ndash 347 KμL
Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0
Lymphocytes monocytes eosinophils basophils all below normal range
PT 47 sec (corrected on mixing study) 116 ndash 152 sec
APTT 75 sec (corrected on mixing study) 253 ndash 373 sec
Fibrinogen lt 76 mgdL 177 ndash 466 mgdL
D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Microscopy
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Arrow shows giant platelets in this peripheral smear Promyelocytes apparent
Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)
DIC due to TF release by APL blasts
Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases
Transfusions to replace factors along with platelets and RBCs during APL treatment
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started
Case Study 2 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L
PT 30 sec 113 ndash 146 sec
APTT 75 sec 25 ndash 34 sec
D-dimer 078 microgml FEU lt050 microgml FEU
Fibrinogen 92 mgdl 150-400 mgdl
pH 728 738 to 742
PaO2 570 mmHg 80-100 mmHg
WBC 33 times 103mm3 40-11 times 103mm3
ALT 111 IUL 0ndash34 IUL
AST 61 IUL 0ndash34 IUL
BUN 303 mgdL 08-13 mgdL
Case Study 2 ndash Lab Results
Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures
Case Study 2 ndash Diagnosis
60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior
Case Study 3 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L
PT 228 sec 113 ndash 146 sec
APTT 45 sec 25 ndash 34 sec
D-dimer 080 microgml FEU lt050 microgmL FEU
Fibrinogen 82 mgdL 150-400 mgdL
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 134 gdL 14-16 gdL
WBC 81 times 103mm3 40-11 times 103mm3
ALT 32 IUL 0ndash34 IUL
AST 28 IUL 0ndash34 IUL
BUN 09 mgdL 08-13 mgdL
Case Study 3 ndash Lab Results
Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment
Case Study 3 ndash Diagnosis and Therapy
Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91
Case Study 4 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L
PT 28 sec 113 ndash 146 sec
APTT 71 sec 25 ndash 34 sec
D-dimer 31 microgmL FEU lt050 microgml FEU
Fibrinogen 92 mgdL 150-400 mgdl
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 158 gdL 14-16 gdL
WBC 71 times 103mm3 40-11 times 103mm3
ALT 60 IUL 0ndash34 IUL
AST 47 IUL 0ndash34 IUL
BUN 38 mgdL 08-13 mgdL
Case Study 4 ndash Lab Results
Lyme disease with DICProvide antibiotics with supportive measures
Case Study 4 ndash Diagnosis
55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis
Case Study 5 ndash Presentation
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
Case Study 5 ndash Lab Results and Time Course
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
TEST RESULT REFERENCE RANGE
Platelet count 33 x 109L 150-450 x 109L
PT 215 sec 103 ndash 128 sec
APTT 44 sec 26 ndash 36 sec
D-dimer 20 microgmL FEU lt025 microgml FEU
Fibrinogen 34 mgdL 200-375 mgdl
FII FV FVIII Low Not reported (NR)
FVII FIX FX vWF Normal NR
Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)
DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic
dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR
(C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen
(D) Illustration demonstrating repair
Case Study 5 ndash Diagnosis and Treatment
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography
Case Study 6 ndash Presentation
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
Case Study 6 ndash Lab Results
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L
PT 63 sec gt control 113 ndash 146 sec
INR 658 1 ndash 125
APTT 80 sec gt control 25 ndash 34 sec
D-dimer gt200 microgmL DDU 02 microgmL DDU
Urine exam Proteinuria and hematuria 150-400 mgdl
Albumin 28 gdL NR
Hb 58 gdL NR
LDH 1196 UL NR
SGPT 144 IU NR
SGOT 88 IU NR
Bilirubin 32 mgdL NR
DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th
day postop
Case Study 6 ndash Diagnosis and Treatment
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure
Case Study 6 ndash Discussion
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Case Study 7 ndash Lab Results vs Time
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
DIC Take Home Messages
Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation
Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers
DIC
Thank you Questions
- Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
- Learning Objectives
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Wound Sealing
- The Three Steps of Hemostasis
- Vessel Wall
- Slide Number 12
- Slide Number 13
- Platelet Structure UnactivatedActivated
- Primary Hemostasis
- Primary Hemostasis Assays
- Slide Number 17
- Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
- Slide Number 19
- Coagulation factors
- Coagulation Assay Mechanisms
- Slide Number 22
- Fibrin Formation
- Slide Number 24
- Fibrinolysis Overview
- Fibrinolysis Overview
- Slide Number 27
- Fibrinolysis Releases D-dimers
- Basic Pathophysiology of DIC
- Disseminated Intravascular Coagulation (DIC)
- Purpura Fulminans with DIC Due to Meningococcal Sepsis
- Clinical Conditions Associated With DIC
- Frequency of DIC in Selected Disease States
- Underlying Diseases in DIC Patients
- Slide Number 36
- Slide Number 37
- Slide Number 38
- Slide Number 39
- Pathophysiology of DIC
- Pathogenesis of DIC in Sepsis
- Host Response in Severe Sepsis
- Organ Failure in Severe Sepsis
- Mechanism of DIC in Organ Failure
- Interaction of Inflammation and Coagulation in Sepsis
- Slide Number 47
- Diverse and Opposing Effects of Thrombin
- Coagulation and Fibrinolysis in DIC
- Mechanism of DIC
- Pathophysiology of DIC
- Pathophysiology of DIC - Mechanism
- Pathophysiology of DIC ndash 2 Types of Clinical pictures
- Sub-Acute and Non-Overt DIC Clinical Findings
- Pathophysiology of Overt DIC
- Physiopathology of DIC ndash Overt DIC Findings
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- BREAK
- Diagnostic and Management Approach for DIC
- Diagnosis of DIC
- Lab Diagnosis of DIC ndash Markers of Factor Consumption
- Lab Diagnosis of DIC ndash Screening Tests
- Slide Number 67
- Slide Number 68
- British Journal of Haematology Overt DIC Score
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- DIC Management Goals
- DIC Management and Treatment
- DIC Management Strategies
- Anticoagulant Factor Concentrate Treatment
- Anticoagulant Factor Concentrate Treatment Trials
- Markers of Thrombin amp Plasmin Generation in DIC
- D-dimer FDPs and DIC
- D-Dimer and FDPs in DIC
- Follow Up of DIC State of Disease
- FMD-Dimer in DIC Major Differences
- of Abnormal Results in Patients with Confirmed and Suspected DIC
- Slide Number 85
- Slide Number 86
- Comparing an Automated FM vs Manual FSP Test
- Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Slide Number 94
- Slide Number 95
- Slide Number 96
- Slide Number 97
- Slide Number 98
- Slide Number 99
- DIC Case Studies
- Case Study 1 - Presentation
- Case Study 1 ndash Lab Results
- Case Study 1 ndash Microscopy
- Case Study 1 ndash Diagnosis and Therapy
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Slide Number 110
- Slide Number 111
- Slide Number 112
- Slide Number 113
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
- Slide Number 124
- Slide Number 125
- DIC Take Home Messages
- Slide Number 127
- Slide Number 128
-
Follow Up of DIC State of Disease
Dhainaut JF Shorr AF Macias WL Kollef MJ Levi M Reinhart K et al Dynamic evolution of coagulopathyin the first day of severe sepsis relationship with mortality and organ failure Crit Care Med 2005 33 341-8
Coagulopathy continuing or worsening during the first day of severe sepsis (followed by PT AT and D-dimer) was associated with development of organ failure and 28 day mortaility
FMD-Dimer in DIC Major Differences
onset of thrombosis
days
Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8
FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)
D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)
of Abnormal Results in Patients with Confirmed and Suspected DIC
0
20
40
60
80
100
94 85 90N = 62
Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32
Positivity of Test Results ISTH Score and Disease State
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
Red bar positive for 2 points of DIC score
Pink bar positive for 1-2 points of DIC score
HT hematopoietic tumor
IF infection
SC solid cancer
Markers in Patients with or without DIC
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
HT hematopoietic tumorIF infectionSC solid cancer
Comparing an Automated FM vs Manual FSP Test
Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71
Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)
Automated (Mitsubishi) vs Automated (Stago)
In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago
Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC
Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
Non Overt DIC Overt DIC
AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC
Trends in Markers of DIC for Different Patients
Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00
Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients
Trends in Markers of DIC for Different Patients
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes
28 day outcome survival
28 day outcome death
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines
DIC Case Studies
Case Study 1 - Presentation
18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE
WBC count 77 KμL 423 ndash 907 x KμL
RBC count 17 MμL 137 ndash 175 x MμL
Hemoglobin 67 gdL 137 ndash 175 gdL
Hematocrit 195 401 ndash 510
MCV 95 fL 790 ndash 922 fL
MPV 12 fL 94 ndash 124 fL
Platelet count 9 KμL 161 ndash 347 KμL
Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0
Lymphocytes monocytes eosinophils basophils all below normal range
PT 47 sec (corrected on mixing study) 116 ndash 152 sec
APTT 75 sec (corrected on mixing study) 253 ndash 373 sec
Fibrinogen lt 76 mgdL 177 ndash 466 mgdL
D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Microscopy
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Arrow shows giant platelets in this peripheral smear Promyelocytes apparent
Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)
DIC due to TF release by APL blasts
Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases
Transfusions to replace factors along with platelets and RBCs during APL treatment
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started
Case Study 2 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L
PT 30 sec 113 ndash 146 sec
APTT 75 sec 25 ndash 34 sec
D-dimer 078 microgml FEU lt050 microgml FEU
Fibrinogen 92 mgdl 150-400 mgdl
pH 728 738 to 742
PaO2 570 mmHg 80-100 mmHg
WBC 33 times 103mm3 40-11 times 103mm3
ALT 111 IUL 0ndash34 IUL
AST 61 IUL 0ndash34 IUL
BUN 303 mgdL 08-13 mgdL
Case Study 2 ndash Lab Results
Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures
Case Study 2 ndash Diagnosis
60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior
Case Study 3 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L
PT 228 sec 113 ndash 146 sec
APTT 45 sec 25 ndash 34 sec
D-dimer 080 microgml FEU lt050 microgmL FEU
Fibrinogen 82 mgdL 150-400 mgdL
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 134 gdL 14-16 gdL
WBC 81 times 103mm3 40-11 times 103mm3
ALT 32 IUL 0ndash34 IUL
AST 28 IUL 0ndash34 IUL
BUN 09 mgdL 08-13 mgdL
Case Study 3 ndash Lab Results
Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment
Case Study 3 ndash Diagnosis and Therapy
Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91
Case Study 4 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L
PT 28 sec 113 ndash 146 sec
APTT 71 sec 25 ndash 34 sec
D-dimer 31 microgmL FEU lt050 microgml FEU
Fibrinogen 92 mgdL 150-400 mgdl
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 158 gdL 14-16 gdL
WBC 71 times 103mm3 40-11 times 103mm3
ALT 60 IUL 0ndash34 IUL
AST 47 IUL 0ndash34 IUL
BUN 38 mgdL 08-13 mgdL
Case Study 4 ndash Lab Results
Lyme disease with DICProvide antibiotics with supportive measures
Case Study 4 ndash Diagnosis
55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis
Case Study 5 ndash Presentation
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
Case Study 5 ndash Lab Results and Time Course
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
TEST RESULT REFERENCE RANGE
Platelet count 33 x 109L 150-450 x 109L
PT 215 sec 103 ndash 128 sec
APTT 44 sec 26 ndash 36 sec
D-dimer 20 microgmL FEU lt025 microgml FEU
Fibrinogen 34 mgdL 200-375 mgdl
FII FV FVIII Low Not reported (NR)
FVII FIX FX vWF Normal NR
Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)
DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic
dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR
(C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen
(D) Illustration demonstrating repair
Case Study 5 ndash Diagnosis and Treatment
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography
Case Study 6 ndash Presentation
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
Case Study 6 ndash Lab Results
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L
PT 63 sec gt control 113 ndash 146 sec
INR 658 1 ndash 125
APTT 80 sec gt control 25 ndash 34 sec
D-dimer gt200 microgmL DDU 02 microgmL DDU
Urine exam Proteinuria and hematuria 150-400 mgdl
Albumin 28 gdL NR
Hb 58 gdL NR
LDH 1196 UL NR
SGPT 144 IU NR
SGOT 88 IU NR
Bilirubin 32 mgdL NR
DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th
day postop
Case Study 6 ndash Diagnosis and Treatment
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure
Case Study 6 ndash Discussion
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Case Study 7 ndash Lab Results vs Time
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
DIC Take Home Messages
Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation
Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers
DIC
Thank you Questions
- Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
- Learning Objectives
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Wound Sealing
- The Three Steps of Hemostasis
- Vessel Wall
- Slide Number 12
- Slide Number 13
- Platelet Structure UnactivatedActivated
- Primary Hemostasis
- Primary Hemostasis Assays
- Slide Number 17
- Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
- Slide Number 19
- Coagulation factors
- Coagulation Assay Mechanisms
- Slide Number 22
- Fibrin Formation
- Slide Number 24
- Fibrinolysis Overview
- Fibrinolysis Overview
- Slide Number 27
- Fibrinolysis Releases D-dimers
- Basic Pathophysiology of DIC
- Disseminated Intravascular Coagulation (DIC)
- Purpura Fulminans with DIC Due to Meningococcal Sepsis
- Clinical Conditions Associated With DIC
- Frequency of DIC in Selected Disease States
- Underlying Diseases in DIC Patients
- Slide Number 36
- Slide Number 37
- Slide Number 38
- Slide Number 39
- Pathophysiology of DIC
- Pathogenesis of DIC in Sepsis
- Host Response in Severe Sepsis
- Organ Failure in Severe Sepsis
- Mechanism of DIC in Organ Failure
- Interaction of Inflammation and Coagulation in Sepsis
- Slide Number 47
- Diverse and Opposing Effects of Thrombin
- Coagulation and Fibrinolysis in DIC
- Mechanism of DIC
- Pathophysiology of DIC
- Pathophysiology of DIC - Mechanism
- Pathophysiology of DIC ndash 2 Types of Clinical pictures
- Sub-Acute and Non-Overt DIC Clinical Findings
- Pathophysiology of Overt DIC
- Physiopathology of DIC ndash Overt DIC Findings
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- BREAK
- Diagnostic and Management Approach for DIC
- Diagnosis of DIC
- Lab Diagnosis of DIC ndash Markers of Factor Consumption
- Lab Diagnosis of DIC ndash Screening Tests
- Slide Number 67
- Slide Number 68
- British Journal of Haematology Overt DIC Score
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- DIC Management Goals
- DIC Management and Treatment
- DIC Management Strategies
- Anticoagulant Factor Concentrate Treatment
- Anticoagulant Factor Concentrate Treatment Trials
- Markers of Thrombin amp Plasmin Generation in DIC
- D-dimer FDPs and DIC
- D-Dimer and FDPs in DIC
- Follow Up of DIC State of Disease
- FMD-Dimer in DIC Major Differences
- of Abnormal Results in Patients with Confirmed and Suspected DIC
- Slide Number 85
- Slide Number 86
- Comparing an Automated FM vs Manual FSP Test
- Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Slide Number 94
- Slide Number 95
- Slide Number 96
- Slide Number 97
- Slide Number 98
- Slide Number 99
- DIC Case Studies
- Case Study 1 - Presentation
- Case Study 1 ndash Lab Results
- Case Study 1 ndash Microscopy
- Case Study 1 ndash Diagnosis and Therapy
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Slide Number 110
- Slide Number 111
- Slide Number 112
- Slide Number 113
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
- Slide Number 124
- Slide Number 125
- DIC Take Home Messages
- Slide Number 127
- Slide Number 128
-
FMD-Dimer in DIC Major Differences
onset of thrombosis
days
Wada H Sakuragawa N Are fibrin-related markers useful for the diagnosis of thrombosis SeminThromb Hemost 2008 34 33-8
FM may be predictive Appear 0-3 days after the onset of thrombosis typically prethrombotic Short half-life (6 - 8 hrs)
D-Dimer (a specific FDP) well-established DIC Appear 2-10 days after the onset of thrombosis typically postthrombotic Longer half-life (4 - 11 hrs)
of Abnormal Results in Patients with Confirmed and Suspected DIC
0
20
40
60
80
100
94 85 90N = 62
Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32
Positivity of Test Results ISTH Score and Disease State
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
Red bar positive for 2 points of DIC score
Pink bar positive for 1-2 points of DIC score
HT hematopoietic tumor
IF infection
SC solid cancer
Markers in Patients with or without DIC
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
HT hematopoietic tumorIF infectionSC solid cancer
Comparing an Automated FM vs Manual FSP Test
Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71
Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)
Automated (Mitsubishi) vs Automated (Stago)
In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago
Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC
Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
Non Overt DIC Overt DIC
AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC
Trends in Markers of DIC for Different Patients
Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00
Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients
Trends in Markers of DIC for Different Patients
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes
28 day outcome survival
28 day outcome death
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines
DIC Case Studies
Case Study 1 - Presentation
18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE
WBC count 77 KμL 423 ndash 907 x KμL
RBC count 17 MμL 137 ndash 175 x MμL
Hemoglobin 67 gdL 137 ndash 175 gdL
Hematocrit 195 401 ndash 510
MCV 95 fL 790 ndash 922 fL
MPV 12 fL 94 ndash 124 fL
Platelet count 9 KμL 161 ndash 347 KμL
Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0
Lymphocytes monocytes eosinophils basophils all below normal range
PT 47 sec (corrected on mixing study) 116 ndash 152 sec
APTT 75 sec (corrected on mixing study) 253 ndash 373 sec
Fibrinogen lt 76 mgdL 177 ndash 466 mgdL
D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Microscopy
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Arrow shows giant platelets in this peripheral smear Promyelocytes apparent
Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)
DIC due to TF release by APL blasts
Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases
Transfusions to replace factors along with platelets and RBCs during APL treatment
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started
Case Study 2 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L
PT 30 sec 113 ndash 146 sec
APTT 75 sec 25 ndash 34 sec
D-dimer 078 microgml FEU lt050 microgml FEU
Fibrinogen 92 mgdl 150-400 mgdl
pH 728 738 to 742
PaO2 570 mmHg 80-100 mmHg
WBC 33 times 103mm3 40-11 times 103mm3
ALT 111 IUL 0ndash34 IUL
AST 61 IUL 0ndash34 IUL
BUN 303 mgdL 08-13 mgdL
Case Study 2 ndash Lab Results
Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures
Case Study 2 ndash Diagnosis
60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior
Case Study 3 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L
PT 228 sec 113 ndash 146 sec
APTT 45 sec 25 ndash 34 sec
D-dimer 080 microgml FEU lt050 microgmL FEU
Fibrinogen 82 mgdL 150-400 mgdL
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 134 gdL 14-16 gdL
WBC 81 times 103mm3 40-11 times 103mm3
ALT 32 IUL 0ndash34 IUL
AST 28 IUL 0ndash34 IUL
BUN 09 mgdL 08-13 mgdL
Case Study 3 ndash Lab Results
Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment
Case Study 3 ndash Diagnosis and Therapy
Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91
Case Study 4 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L
PT 28 sec 113 ndash 146 sec
APTT 71 sec 25 ndash 34 sec
D-dimer 31 microgmL FEU lt050 microgml FEU
Fibrinogen 92 mgdL 150-400 mgdl
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 158 gdL 14-16 gdL
WBC 71 times 103mm3 40-11 times 103mm3
ALT 60 IUL 0ndash34 IUL
AST 47 IUL 0ndash34 IUL
BUN 38 mgdL 08-13 mgdL
Case Study 4 ndash Lab Results
Lyme disease with DICProvide antibiotics with supportive measures
Case Study 4 ndash Diagnosis
55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis
Case Study 5 ndash Presentation
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
Case Study 5 ndash Lab Results and Time Course
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
TEST RESULT REFERENCE RANGE
Platelet count 33 x 109L 150-450 x 109L
PT 215 sec 103 ndash 128 sec
APTT 44 sec 26 ndash 36 sec
D-dimer 20 microgmL FEU lt025 microgml FEU
Fibrinogen 34 mgdL 200-375 mgdl
FII FV FVIII Low Not reported (NR)
FVII FIX FX vWF Normal NR
Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)
DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic
dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR
(C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen
(D) Illustration demonstrating repair
Case Study 5 ndash Diagnosis and Treatment
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography
Case Study 6 ndash Presentation
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
Case Study 6 ndash Lab Results
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L
PT 63 sec gt control 113 ndash 146 sec
INR 658 1 ndash 125
APTT 80 sec gt control 25 ndash 34 sec
D-dimer gt200 microgmL DDU 02 microgmL DDU
Urine exam Proteinuria and hematuria 150-400 mgdl
Albumin 28 gdL NR
Hb 58 gdL NR
LDH 1196 UL NR
SGPT 144 IU NR
SGOT 88 IU NR
Bilirubin 32 mgdL NR
DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th
day postop
Case Study 6 ndash Diagnosis and Treatment
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure
Case Study 6 ndash Discussion
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Case Study 7 ndash Lab Results vs Time
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
DIC Take Home Messages
Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation
Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers
DIC
Thank you Questions
- Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
- Learning Objectives
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Wound Sealing
- The Three Steps of Hemostasis
- Vessel Wall
- Slide Number 12
- Slide Number 13
- Platelet Structure UnactivatedActivated
- Primary Hemostasis
- Primary Hemostasis Assays
- Slide Number 17
- Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
- Slide Number 19
- Coagulation factors
- Coagulation Assay Mechanisms
- Slide Number 22
- Fibrin Formation
- Slide Number 24
- Fibrinolysis Overview
- Fibrinolysis Overview
- Slide Number 27
- Fibrinolysis Releases D-dimers
- Basic Pathophysiology of DIC
- Disseminated Intravascular Coagulation (DIC)
- Purpura Fulminans with DIC Due to Meningococcal Sepsis
- Clinical Conditions Associated With DIC
- Frequency of DIC in Selected Disease States
- Underlying Diseases in DIC Patients
- Slide Number 36
- Slide Number 37
- Slide Number 38
- Slide Number 39
- Pathophysiology of DIC
- Pathogenesis of DIC in Sepsis
- Host Response in Severe Sepsis
- Organ Failure in Severe Sepsis
- Mechanism of DIC in Organ Failure
- Interaction of Inflammation and Coagulation in Sepsis
- Slide Number 47
- Diverse and Opposing Effects of Thrombin
- Coagulation and Fibrinolysis in DIC
- Mechanism of DIC
- Pathophysiology of DIC
- Pathophysiology of DIC - Mechanism
- Pathophysiology of DIC ndash 2 Types of Clinical pictures
- Sub-Acute and Non-Overt DIC Clinical Findings
- Pathophysiology of Overt DIC
- Physiopathology of DIC ndash Overt DIC Findings
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- BREAK
- Diagnostic and Management Approach for DIC
- Diagnosis of DIC
- Lab Diagnosis of DIC ndash Markers of Factor Consumption
- Lab Diagnosis of DIC ndash Screening Tests
- Slide Number 67
- Slide Number 68
- British Journal of Haematology Overt DIC Score
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- DIC Management Goals
- DIC Management and Treatment
- DIC Management Strategies
- Anticoagulant Factor Concentrate Treatment
- Anticoagulant Factor Concentrate Treatment Trials
- Markers of Thrombin amp Plasmin Generation in DIC
- D-dimer FDPs and DIC
- D-Dimer and FDPs in DIC
- Follow Up of DIC State of Disease
- FMD-Dimer in DIC Major Differences
- of Abnormal Results in Patients with Confirmed and Suspected DIC
- Slide Number 85
- Slide Number 86
- Comparing an Automated FM vs Manual FSP Test
- Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Slide Number 94
- Slide Number 95
- Slide Number 96
- Slide Number 97
- Slide Number 98
- Slide Number 99
- DIC Case Studies
- Case Study 1 - Presentation
- Case Study 1 ndash Lab Results
- Case Study 1 ndash Microscopy
- Case Study 1 ndash Diagnosis and Therapy
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Slide Number 110
- Slide Number 111
- Slide Number 112
- Slide Number 113
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
- Slide Number 124
- Slide Number 125
- DIC Take Home Messages
- Slide Number 127
- Slide Number 128
-
of Abnormal Results in Patients with Confirmed and Suspected DIC
0
20
40
60
80
100
94 85 90N = 62
Woodhams BJ Esteve F Migaud-Fressart M Wold M Grimaux M D-dimer levels in samples from patients with disseminated intravascular coagulation (DIC) or suspected DIC using 3 different assay procedures Fibrinolysis amp Proteolysis 2000 14 Suppl 1 32
Positivity of Test Results ISTH Score and Disease State
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
Red bar positive for 2 points of DIC score
Pink bar positive for 1-2 points of DIC score
HT hematopoietic tumor
IF infection
SC solid cancer
Markers in Patients with or without DIC
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
HT hematopoietic tumorIF infectionSC solid cancer
Comparing an Automated FM vs Manual FSP Test
Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71
Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)
Automated (Mitsubishi) vs Automated (Stago)
In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago
Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC
Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
Non Overt DIC Overt DIC
AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC
Trends in Markers of DIC for Different Patients
Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00
Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients
Trends in Markers of DIC for Different Patients
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes
28 day outcome survival
28 day outcome death
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines
DIC Case Studies
Case Study 1 - Presentation
18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE
WBC count 77 KμL 423 ndash 907 x KμL
RBC count 17 MμL 137 ndash 175 x MμL
Hemoglobin 67 gdL 137 ndash 175 gdL
Hematocrit 195 401 ndash 510
MCV 95 fL 790 ndash 922 fL
MPV 12 fL 94 ndash 124 fL
Platelet count 9 KμL 161 ndash 347 KμL
Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0
Lymphocytes monocytes eosinophils basophils all below normal range
PT 47 sec (corrected on mixing study) 116 ndash 152 sec
APTT 75 sec (corrected on mixing study) 253 ndash 373 sec
Fibrinogen lt 76 mgdL 177 ndash 466 mgdL
D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Microscopy
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Arrow shows giant platelets in this peripheral smear Promyelocytes apparent
Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)
DIC due to TF release by APL blasts
Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases
Transfusions to replace factors along with platelets and RBCs during APL treatment
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started
Case Study 2 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L
PT 30 sec 113 ndash 146 sec
APTT 75 sec 25 ndash 34 sec
D-dimer 078 microgml FEU lt050 microgml FEU
Fibrinogen 92 mgdl 150-400 mgdl
pH 728 738 to 742
PaO2 570 mmHg 80-100 mmHg
WBC 33 times 103mm3 40-11 times 103mm3
ALT 111 IUL 0ndash34 IUL
AST 61 IUL 0ndash34 IUL
BUN 303 mgdL 08-13 mgdL
Case Study 2 ndash Lab Results
Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures
Case Study 2 ndash Diagnosis
60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior
Case Study 3 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L
PT 228 sec 113 ndash 146 sec
APTT 45 sec 25 ndash 34 sec
D-dimer 080 microgml FEU lt050 microgmL FEU
Fibrinogen 82 mgdL 150-400 mgdL
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 134 gdL 14-16 gdL
WBC 81 times 103mm3 40-11 times 103mm3
ALT 32 IUL 0ndash34 IUL
AST 28 IUL 0ndash34 IUL
BUN 09 mgdL 08-13 mgdL
Case Study 3 ndash Lab Results
Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment
Case Study 3 ndash Diagnosis and Therapy
Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91
Case Study 4 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L
PT 28 sec 113 ndash 146 sec
APTT 71 sec 25 ndash 34 sec
D-dimer 31 microgmL FEU lt050 microgml FEU
Fibrinogen 92 mgdL 150-400 mgdl
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 158 gdL 14-16 gdL
WBC 71 times 103mm3 40-11 times 103mm3
ALT 60 IUL 0ndash34 IUL
AST 47 IUL 0ndash34 IUL
BUN 38 mgdL 08-13 mgdL
Case Study 4 ndash Lab Results
Lyme disease with DICProvide antibiotics with supportive measures
Case Study 4 ndash Diagnosis
55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis
Case Study 5 ndash Presentation
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
Case Study 5 ndash Lab Results and Time Course
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
TEST RESULT REFERENCE RANGE
Platelet count 33 x 109L 150-450 x 109L
PT 215 sec 103 ndash 128 sec
APTT 44 sec 26 ndash 36 sec
D-dimer 20 microgmL FEU lt025 microgml FEU
Fibrinogen 34 mgdL 200-375 mgdl
FII FV FVIII Low Not reported (NR)
FVII FIX FX vWF Normal NR
Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)
DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic
dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR
(C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen
(D) Illustration demonstrating repair
Case Study 5 ndash Diagnosis and Treatment
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography
Case Study 6 ndash Presentation
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
Case Study 6 ndash Lab Results
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L
PT 63 sec gt control 113 ndash 146 sec
INR 658 1 ndash 125
APTT 80 sec gt control 25 ndash 34 sec
D-dimer gt200 microgmL DDU 02 microgmL DDU
Urine exam Proteinuria and hematuria 150-400 mgdl
Albumin 28 gdL NR
Hb 58 gdL NR
LDH 1196 UL NR
SGPT 144 IU NR
SGOT 88 IU NR
Bilirubin 32 mgdL NR
DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th
day postop
Case Study 6 ndash Diagnosis and Treatment
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure
Case Study 6 ndash Discussion
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Case Study 7 ndash Lab Results vs Time
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
DIC Take Home Messages
Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation
Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers
DIC
Thank you Questions
- Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
- Learning Objectives
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Wound Sealing
- The Three Steps of Hemostasis
- Vessel Wall
- Slide Number 12
- Slide Number 13
- Platelet Structure UnactivatedActivated
- Primary Hemostasis
- Primary Hemostasis Assays
- Slide Number 17
- Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
- Slide Number 19
- Coagulation factors
- Coagulation Assay Mechanisms
- Slide Number 22
- Fibrin Formation
- Slide Number 24
- Fibrinolysis Overview
- Fibrinolysis Overview
- Slide Number 27
- Fibrinolysis Releases D-dimers
- Basic Pathophysiology of DIC
- Disseminated Intravascular Coagulation (DIC)
- Purpura Fulminans with DIC Due to Meningococcal Sepsis
- Clinical Conditions Associated With DIC
- Frequency of DIC in Selected Disease States
- Underlying Diseases in DIC Patients
- Slide Number 36
- Slide Number 37
- Slide Number 38
- Slide Number 39
- Pathophysiology of DIC
- Pathogenesis of DIC in Sepsis
- Host Response in Severe Sepsis
- Organ Failure in Severe Sepsis
- Mechanism of DIC in Organ Failure
- Interaction of Inflammation and Coagulation in Sepsis
- Slide Number 47
- Diverse and Opposing Effects of Thrombin
- Coagulation and Fibrinolysis in DIC
- Mechanism of DIC
- Pathophysiology of DIC
- Pathophysiology of DIC - Mechanism
- Pathophysiology of DIC ndash 2 Types of Clinical pictures
- Sub-Acute and Non-Overt DIC Clinical Findings
- Pathophysiology of Overt DIC
- Physiopathology of DIC ndash Overt DIC Findings
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- BREAK
- Diagnostic and Management Approach for DIC
- Diagnosis of DIC
- Lab Diagnosis of DIC ndash Markers of Factor Consumption
- Lab Diagnosis of DIC ndash Screening Tests
- Slide Number 67
- Slide Number 68
- British Journal of Haematology Overt DIC Score
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- DIC Management Goals
- DIC Management and Treatment
- DIC Management Strategies
- Anticoagulant Factor Concentrate Treatment
- Anticoagulant Factor Concentrate Treatment Trials
- Markers of Thrombin amp Plasmin Generation in DIC
- D-dimer FDPs and DIC
- D-Dimer and FDPs in DIC
- Follow Up of DIC State of Disease
- FMD-Dimer in DIC Major Differences
- of Abnormal Results in Patients with Confirmed and Suspected DIC
- Slide Number 85
- Slide Number 86
- Comparing an Automated FM vs Manual FSP Test
- Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Slide Number 94
- Slide Number 95
- Slide Number 96
- Slide Number 97
- Slide Number 98
- Slide Number 99
- DIC Case Studies
- Case Study 1 - Presentation
- Case Study 1 ndash Lab Results
- Case Study 1 ndash Microscopy
- Case Study 1 ndash Diagnosis and Therapy
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Slide Number 110
- Slide Number 111
- Slide Number 112
- Slide Number 113
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
- Slide Number 124
- Slide Number 125
- DIC Take Home Messages
- Slide Number 127
- Slide Number 128
-
Positivity of Test Results ISTH Score and Disease State
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
Red bar positive for 2 points of DIC score
Pink bar positive for 1-2 points of DIC score
HT hematopoietic tumor
IF infection
SC solid cancer
Markers in Patients with or without DIC
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
HT hematopoietic tumorIF infectionSC solid cancer
Comparing an Automated FM vs Manual FSP Test
Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71
Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)
Automated (Mitsubishi) vs Automated (Stago)
In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago
Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC
Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
Non Overt DIC Overt DIC
AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC
Trends in Markers of DIC for Different Patients
Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00
Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients
Trends in Markers of DIC for Different Patients
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes
28 day outcome survival
28 day outcome death
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines
DIC Case Studies
Case Study 1 - Presentation
18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE
WBC count 77 KμL 423 ndash 907 x KμL
RBC count 17 MμL 137 ndash 175 x MμL
Hemoglobin 67 gdL 137 ndash 175 gdL
Hematocrit 195 401 ndash 510
MCV 95 fL 790 ndash 922 fL
MPV 12 fL 94 ndash 124 fL
Platelet count 9 KμL 161 ndash 347 KμL
Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0
Lymphocytes monocytes eosinophils basophils all below normal range
PT 47 sec (corrected on mixing study) 116 ndash 152 sec
APTT 75 sec (corrected on mixing study) 253 ndash 373 sec
Fibrinogen lt 76 mgdL 177 ndash 466 mgdL
D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Microscopy
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Arrow shows giant platelets in this peripheral smear Promyelocytes apparent
Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)
DIC due to TF release by APL blasts
Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases
Transfusions to replace factors along with platelets and RBCs during APL treatment
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started
Case Study 2 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L
PT 30 sec 113 ndash 146 sec
APTT 75 sec 25 ndash 34 sec
D-dimer 078 microgml FEU lt050 microgml FEU
Fibrinogen 92 mgdl 150-400 mgdl
pH 728 738 to 742
PaO2 570 mmHg 80-100 mmHg
WBC 33 times 103mm3 40-11 times 103mm3
ALT 111 IUL 0ndash34 IUL
AST 61 IUL 0ndash34 IUL
BUN 303 mgdL 08-13 mgdL
Case Study 2 ndash Lab Results
Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures
Case Study 2 ndash Diagnosis
60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior
Case Study 3 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L
PT 228 sec 113 ndash 146 sec
APTT 45 sec 25 ndash 34 sec
D-dimer 080 microgml FEU lt050 microgmL FEU
Fibrinogen 82 mgdL 150-400 mgdL
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 134 gdL 14-16 gdL
WBC 81 times 103mm3 40-11 times 103mm3
ALT 32 IUL 0ndash34 IUL
AST 28 IUL 0ndash34 IUL
BUN 09 mgdL 08-13 mgdL
Case Study 3 ndash Lab Results
Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment
Case Study 3 ndash Diagnosis and Therapy
Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91
Case Study 4 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L
PT 28 sec 113 ndash 146 sec
APTT 71 sec 25 ndash 34 sec
D-dimer 31 microgmL FEU lt050 microgml FEU
Fibrinogen 92 mgdL 150-400 mgdl
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 158 gdL 14-16 gdL
WBC 71 times 103mm3 40-11 times 103mm3
ALT 60 IUL 0ndash34 IUL
AST 47 IUL 0ndash34 IUL
BUN 38 mgdL 08-13 mgdL
Case Study 4 ndash Lab Results
Lyme disease with DICProvide antibiotics with supportive measures
Case Study 4 ndash Diagnosis
55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis
Case Study 5 ndash Presentation
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
Case Study 5 ndash Lab Results and Time Course
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
TEST RESULT REFERENCE RANGE
Platelet count 33 x 109L 150-450 x 109L
PT 215 sec 103 ndash 128 sec
APTT 44 sec 26 ndash 36 sec
D-dimer 20 microgmL FEU lt025 microgml FEU
Fibrinogen 34 mgdL 200-375 mgdl
FII FV FVIII Low Not reported (NR)
FVII FIX FX vWF Normal NR
Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)
DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic
dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR
(C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen
(D) Illustration demonstrating repair
Case Study 5 ndash Diagnosis and Treatment
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography
Case Study 6 ndash Presentation
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
Case Study 6 ndash Lab Results
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L
PT 63 sec gt control 113 ndash 146 sec
INR 658 1 ndash 125
APTT 80 sec gt control 25 ndash 34 sec
D-dimer gt200 microgmL DDU 02 microgmL DDU
Urine exam Proteinuria and hematuria 150-400 mgdl
Albumin 28 gdL NR
Hb 58 gdL NR
LDH 1196 UL NR
SGPT 144 IU NR
SGOT 88 IU NR
Bilirubin 32 mgdL NR
DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th
day postop
Case Study 6 ndash Diagnosis and Treatment
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure
Case Study 6 ndash Discussion
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Case Study 7 ndash Lab Results vs Time
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
DIC Take Home Messages
Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation
Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers
DIC
Thank you Questions
- Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
- Learning Objectives
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Wound Sealing
- The Three Steps of Hemostasis
- Vessel Wall
- Slide Number 12
- Slide Number 13
- Platelet Structure UnactivatedActivated
- Primary Hemostasis
- Primary Hemostasis Assays
- Slide Number 17
- Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
- Slide Number 19
- Coagulation factors
- Coagulation Assay Mechanisms
- Slide Number 22
- Fibrin Formation
- Slide Number 24
- Fibrinolysis Overview
- Fibrinolysis Overview
- Slide Number 27
- Fibrinolysis Releases D-dimers
- Basic Pathophysiology of DIC
- Disseminated Intravascular Coagulation (DIC)
- Purpura Fulminans with DIC Due to Meningococcal Sepsis
- Clinical Conditions Associated With DIC
- Frequency of DIC in Selected Disease States
- Underlying Diseases in DIC Patients
- Slide Number 36
- Slide Number 37
- Slide Number 38
- Slide Number 39
- Pathophysiology of DIC
- Pathogenesis of DIC in Sepsis
- Host Response in Severe Sepsis
- Organ Failure in Severe Sepsis
- Mechanism of DIC in Organ Failure
- Interaction of Inflammation and Coagulation in Sepsis
- Slide Number 47
- Diverse and Opposing Effects of Thrombin
- Coagulation and Fibrinolysis in DIC
- Mechanism of DIC
- Pathophysiology of DIC
- Pathophysiology of DIC - Mechanism
- Pathophysiology of DIC ndash 2 Types of Clinical pictures
- Sub-Acute and Non-Overt DIC Clinical Findings
- Pathophysiology of Overt DIC
- Physiopathology of DIC ndash Overt DIC Findings
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- BREAK
- Diagnostic and Management Approach for DIC
- Diagnosis of DIC
- Lab Diagnosis of DIC ndash Markers of Factor Consumption
- Lab Diagnosis of DIC ndash Screening Tests
- Slide Number 67
- Slide Number 68
- British Journal of Haematology Overt DIC Score
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- DIC Management Goals
- DIC Management and Treatment
- DIC Management Strategies
- Anticoagulant Factor Concentrate Treatment
- Anticoagulant Factor Concentrate Treatment Trials
- Markers of Thrombin amp Plasmin Generation in DIC
- D-dimer FDPs and DIC
- D-Dimer and FDPs in DIC
- Follow Up of DIC State of Disease
- FMD-Dimer in DIC Major Differences
- of Abnormal Results in Patients with Confirmed and Suspected DIC
- Slide Number 85
- Slide Number 86
- Comparing an Automated FM vs Manual FSP Test
- Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Slide Number 94
- Slide Number 95
- Slide Number 96
- Slide Number 97
- Slide Number 98
- Slide Number 99
- DIC Case Studies
- Case Study 1 - Presentation
- Case Study 1 ndash Lab Results
- Case Study 1 ndash Microscopy
- Case Study 1 ndash Diagnosis and Therapy
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Slide Number 110
- Slide Number 111
- Slide Number 112
- Slide Number 113
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
- Slide Number 124
- Slide Number 125
- DIC Take Home Messages
- Slide Number 127
- Slide Number 128
-
Markers in Patients with or without DIC
Wada H Matsumoto T Hatada T Diagnostic criteria and laboratory tests for disseminated intravascular coagulation Expert Rev Hematol 2012 5 643-52
HT hematopoietic tumorIF infectionSC solid cancer
Comparing an Automated FM vs Manual FSP Test
Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71
Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)
Automated (Mitsubishi) vs Automated (Stago)
In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago
Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC
Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
Non Overt DIC Overt DIC
AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC
Trends in Markers of DIC for Different Patients
Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00
Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients
Trends in Markers of DIC for Different Patients
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes
28 day outcome survival
28 day outcome death
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines
DIC Case Studies
Case Study 1 - Presentation
18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE
WBC count 77 KμL 423 ndash 907 x KμL
RBC count 17 MμL 137 ndash 175 x MμL
Hemoglobin 67 gdL 137 ndash 175 gdL
Hematocrit 195 401 ndash 510
MCV 95 fL 790 ndash 922 fL
MPV 12 fL 94 ndash 124 fL
Platelet count 9 KμL 161 ndash 347 KμL
Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0
Lymphocytes monocytes eosinophils basophils all below normal range
PT 47 sec (corrected on mixing study) 116 ndash 152 sec
APTT 75 sec (corrected on mixing study) 253 ndash 373 sec
Fibrinogen lt 76 mgdL 177 ndash 466 mgdL
D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Microscopy
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Arrow shows giant platelets in this peripheral smear Promyelocytes apparent
Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)
DIC due to TF release by APL blasts
Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases
Transfusions to replace factors along with platelets and RBCs during APL treatment
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started
Case Study 2 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L
PT 30 sec 113 ndash 146 sec
APTT 75 sec 25 ndash 34 sec
D-dimer 078 microgml FEU lt050 microgml FEU
Fibrinogen 92 mgdl 150-400 mgdl
pH 728 738 to 742
PaO2 570 mmHg 80-100 mmHg
WBC 33 times 103mm3 40-11 times 103mm3
ALT 111 IUL 0ndash34 IUL
AST 61 IUL 0ndash34 IUL
BUN 303 mgdL 08-13 mgdL
Case Study 2 ndash Lab Results
Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures
Case Study 2 ndash Diagnosis
60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior
Case Study 3 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L
PT 228 sec 113 ndash 146 sec
APTT 45 sec 25 ndash 34 sec
D-dimer 080 microgml FEU lt050 microgmL FEU
Fibrinogen 82 mgdL 150-400 mgdL
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 134 gdL 14-16 gdL
WBC 81 times 103mm3 40-11 times 103mm3
ALT 32 IUL 0ndash34 IUL
AST 28 IUL 0ndash34 IUL
BUN 09 mgdL 08-13 mgdL
Case Study 3 ndash Lab Results
Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment
Case Study 3 ndash Diagnosis and Therapy
Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91
Case Study 4 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L
PT 28 sec 113 ndash 146 sec
APTT 71 sec 25 ndash 34 sec
D-dimer 31 microgmL FEU lt050 microgml FEU
Fibrinogen 92 mgdL 150-400 mgdl
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 158 gdL 14-16 gdL
WBC 71 times 103mm3 40-11 times 103mm3
ALT 60 IUL 0ndash34 IUL
AST 47 IUL 0ndash34 IUL
BUN 38 mgdL 08-13 mgdL
Case Study 4 ndash Lab Results
Lyme disease with DICProvide antibiotics with supportive measures
Case Study 4 ndash Diagnosis
55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis
Case Study 5 ndash Presentation
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
Case Study 5 ndash Lab Results and Time Course
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
TEST RESULT REFERENCE RANGE
Platelet count 33 x 109L 150-450 x 109L
PT 215 sec 103 ndash 128 sec
APTT 44 sec 26 ndash 36 sec
D-dimer 20 microgmL FEU lt025 microgml FEU
Fibrinogen 34 mgdL 200-375 mgdl
FII FV FVIII Low Not reported (NR)
FVII FIX FX vWF Normal NR
Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)
DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic
dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR
(C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen
(D) Illustration demonstrating repair
Case Study 5 ndash Diagnosis and Treatment
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography
Case Study 6 ndash Presentation
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
Case Study 6 ndash Lab Results
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L
PT 63 sec gt control 113 ndash 146 sec
INR 658 1 ndash 125
APTT 80 sec gt control 25 ndash 34 sec
D-dimer gt200 microgmL DDU 02 microgmL DDU
Urine exam Proteinuria and hematuria 150-400 mgdl
Albumin 28 gdL NR
Hb 58 gdL NR
LDH 1196 UL NR
SGPT 144 IU NR
SGOT 88 IU NR
Bilirubin 32 mgdL NR
DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th
day postop
Case Study 6 ndash Diagnosis and Treatment
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure
Case Study 6 ndash Discussion
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Case Study 7 ndash Lab Results vs Time
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
DIC Take Home Messages
Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation
Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers
DIC
Thank you Questions
- Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
- Learning Objectives
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Wound Sealing
- The Three Steps of Hemostasis
- Vessel Wall
- Slide Number 12
- Slide Number 13
- Platelet Structure UnactivatedActivated
- Primary Hemostasis
- Primary Hemostasis Assays
- Slide Number 17
- Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
- Slide Number 19
- Coagulation factors
- Coagulation Assay Mechanisms
- Slide Number 22
- Fibrin Formation
- Slide Number 24
- Fibrinolysis Overview
- Fibrinolysis Overview
- Slide Number 27
- Fibrinolysis Releases D-dimers
- Basic Pathophysiology of DIC
- Disseminated Intravascular Coagulation (DIC)
- Purpura Fulminans with DIC Due to Meningococcal Sepsis
- Clinical Conditions Associated With DIC
- Frequency of DIC in Selected Disease States
- Underlying Diseases in DIC Patients
- Slide Number 36
- Slide Number 37
- Slide Number 38
- Slide Number 39
- Pathophysiology of DIC
- Pathogenesis of DIC in Sepsis
- Host Response in Severe Sepsis
- Organ Failure in Severe Sepsis
- Mechanism of DIC in Organ Failure
- Interaction of Inflammation and Coagulation in Sepsis
- Slide Number 47
- Diverse and Opposing Effects of Thrombin
- Coagulation and Fibrinolysis in DIC
- Mechanism of DIC
- Pathophysiology of DIC
- Pathophysiology of DIC - Mechanism
- Pathophysiology of DIC ndash 2 Types of Clinical pictures
- Sub-Acute and Non-Overt DIC Clinical Findings
- Pathophysiology of Overt DIC
- Physiopathology of DIC ndash Overt DIC Findings
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- BREAK
- Diagnostic and Management Approach for DIC
- Diagnosis of DIC
- Lab Diagnosis of DIC ndash Markers of Factor Consumption
- Lab Diagnosis of DIC ndash Screening Tests
- Slide Number 67
- Slide Number 68
- British Journal of Haematology Overt DIC Score
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- DIC Management Goals
- DIC Management and Treatment
- DIC Management Strategies
- Anticoagulant Factor Concentrate Treatment
- Anticoagulant Factor Concentrate Treatment Trials
- Markers of Thrombin amp Plasmin Generation in DIC
- D-dimer FDPs and DIC
- D-Dimer and FDPs in DIC
- Follow Up of DIC State of Disease
- FMD-Dimer in DIC Major Differences
- of Abnormal Results in Patients with Confirmed and Suspected DIC
- Slide Number 85
- Slide Number 86
- Comparing an Automated FM vs Manual FSP Test
- Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Slide Number 94
- Slide Number 95
- Slide Number 96
- Slide Number 97
- Slide Number 98
- Slide Number 99
- DIC Case Studies
- Case Study 1 - Presentation
- Case Study 1 ndash Lab Results
- Case Study 1 ndash Microscopy
- Case Study 1 ndash Diagnosis and Therapy
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Slide Number 110
- Slide Number 111
- Slide Number 112
- Slide Number 113
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
- Slide Number 124
- Slide Number 125
- DIC Take Home Messages
- Slide Number 127
- Slide Number 128
-
Comparing an Automated FM vs Manual FSP Test
Westerlund E Woodhams BJ Eintrei J Soumlderblom L Antovic JP The evaluation of two automated soluble fibrin assays for use in the routine hospital laboratory Int J Lab Hematol 2013 35 666-71
Automated (Stago) vs Manual (Stago) Automated (Mitsubishi) vs Manual (Stago)
Automated (Mitsubishi) vs Automated (Stago)
In a study of ED patients automated FM assays exhibit much better inter-assayagreement compared to automated FM vs a manual FSP assay from Stago
Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC
Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
Non Overt DIC Overt DIC
AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC
Trends in Markers of DIC for Different Patients
Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00
Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients
Trends in Markers of DIC for Different Patients
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes
28 day outcome survival
28 day outcome death
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines
DIC Case Studies
Case Study 1 - Presentation
18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE
WBC count 77 KμL 423 ndash 907 x KμL
RBC count 17 MμL 137 ndash 175 x MμL
Hemoglobin 67 gdL 137 ndash 175 gdL
Hematocrit 195 401 ndash 510
MCV 95 fL 790 ndash 922 fL
MPV 12 fL 94 ndash 124 fL
Platelet count 9 KμL 161 ndash 347 KμL
Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0
Lymphocytes monocytes eosinophils basophils all below normal range
PT 47 sec (corrected on mixing study) 116 ndash 152 sec
APTT 75 sec (corrected on mixing study) 253 ndash 373 sec
Fibrinogen lt 76 mgdL 177 ndash 466 mgdL
D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Microscopy
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Arrow shows giant platelets in this peripheral smear Promyelocytes apparent
Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)
DIC due to TF release by APL blasts
Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases
Transfusions to replace factors along with platelets and RBCs during APL treatment
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started
Case Study 2 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L
PT 30 sec 113 ndash 146 sec
APTT 75 sec 25 ndash 34 sec
D-dimer 078 microgml FEU lt050 microgml FEU
Fibrinogen 92 mgdl 150-400 mgdl
pH 728 738 to 742
PaO2 570 mmHg 80-100 mmHg
WBC 33 times 103mm3 40-11 times 103mm3
ALT 111 IUL 0ndash34 IUL
AST 61 IUL 0ndash34 IUL
BUN 303 mgdL 08-13 mgdL
Case Study 2 ndash Lab Results
Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures
Case Study 2 ndash Diagnosis
60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior
Case Study 3 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L
PT 228 sec 113 ndash 146 sec
APTT 45 sec 25 ndash 34 sec
D-dimer 080 microgml FEU lt050 microgmL FEU
Fibrinogen 82 mgdL 150-400 mgdL
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 134 gdL 14-16 gdL
WBC 81 times 103mm3 40-11 times 103mm3
ALT 32 IUL 0ndash34 IUL
AST 28 IUL 0ndash34 IUL
BUN 09 mgdL 08-13 mgdL
Case Study 3 ndash Lab Results
Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment
Case Study 3 ndash Diagnosis and Therapy
Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91
Case Study 4 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L
PT 28 sec 113 ndash 146 sec
APTT 71 sec 25 ndash 34 sec
D-dimer 31 microgmL FEU lt050 microgml FEU
Fibrinogen 92 mgdL 150-400 mgdl
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 158 gdL 14-16 gdL
WBC 71 times 103mm3 40-11 times 103mm3
ALT 60 IUL 0ndash34 IUL
AST 47 IUL 0ndash34 IUL
BUN 38 mgdL 08-13 mgdL
Case Study 4 ndash Lab Results
Lyme disease with DICProvide antibiotics with supportive measures
Case Study 4 ndash Diagnosis
55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis
Case Study 5 ndash Presentation
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
Case Study 5 ndash Lab Results and Time Course
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
TEST RESULT REFERENCE RANGE
Platelet count 33 x 109L 150-450 x 109L
PT 215 sec 103 ndash 128 sec
APTT 44 sec 26 ndash 36 sec
D-dimer 20 microgmL FEU lt025 microgml FEU
Fibrinogen 34 mgdL 200-375 mgdl
FII FV FVIII Low Not reported (NR)
FVII FIX FX vWF Normal NR
Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)
DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic
dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR
(C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen
(D) Illustration demonstrating repair
Case Study 5 ndash Diagnosis and Treatment
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography
Case Study 6 ndash Presentation
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
Case Study 6 ndash Lab Results
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L
PT 63 sec gt control 113 ndash 146 sec
INR 658 1 ndash 125
APTT 80 sec gt control 25 ndash 34 sec
D-dimer gt200 microgmL DDU 02 microgmL DDU
Urine exam Proteinuria and hematuria 150-400 mgdl
Albumin 28 gdL NR
Hb 58 gdL NR
LDH 1196 UL NR
SGPT 144 IU NR
SGOT 88 IU NR
Bilirubin 32 mgdL NR
DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th
day postop
Case Study 6 ndash Diagnosis and Treatment
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure
Case Study 6 ndash Discussion
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Case Study 7 ndash Lab Results vs Time
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
DIC Take Home Messages
Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation
Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers
DIC
Thank you Questions
- Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
- Learning Objectives
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Wound Sealing
- The Three Steps of Hemostasis
- Vessel Wall
- Slide Number 12
- Slide Number 13
- Platelet Structure UnactivatedActivated
- Primary Hemostasis
- Primary Hemostasis Assays
- Slide Number 17
- Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
- Slide Number 19
- Coagulation factors
- Coagulation Assay Mechanisms
- Slide Number 22
- Fibrin Formation
- Slide Number 24
- Fibrinolysis Overview
- Fibrinolysis Overview
- Slide Number 27
- Fibrinolysis Releases D-dimers
- Basic Pathophysiology of DIC
- Disseminated Intravascular Coagulation (DIC)
- Purpura Fulminans with DIC Due to Meningococcal Sepsis
- Clinical Conditions Associated With DIC
- Frequency of DIC in Selected Disease States
- Underlying Diseases in DIC Patients
- Slide Number 36
- Slide Number 37
- Slide Number 38
- Slide Number 39
- Pathophysiology of DIC
- Pathogenesis of DIC in Sepsis
- Host Response in Severe Sepsis
- Organ Failure in Severe Sepsis
- Mechanism of DIC in Organ Failure
- Interaction of Inflammation and Coagulation in Sepsis
- Slide Number 47
- Diverse and Opposing Effects of Thrombin
- Coagulation and Fibrinolysis in DIC
- Mechanism of DIC
- Pathophysiology of DIC
- Pathophysiology of DIC - Mechanism
- Pathophysiology of DIC ndash 2 Types of Clinical pictures
- Sub-Acute and Non-Overt DIC Clinical Findings
- Pathophysiology of Overt DIC
- Physiopathology of DIC ndash Overt DIC Findings
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- BREAK
- Diagnostic and Management Approach for DIC
- Diagnosis of DIC
- Lab Diagnosis of DIC ndash Markers of Factor Consumption
- Lab Diagnosis of DIC ndash Screening Tests
- Slide Number 67
- Slide Number 68
- British Journal of Haematology Overt DIC Score
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- DIC Management Goals
- DIC Management and Treatment
- DIC Management Strategies
- Anticoagulant Factor Concentrate Treatment
- Anticoagulant Factor Concentrate Treatment Trials
- Markers of Thrombin amp Plasmin Generation in DIC
- D-dimer FDPs and DIC
- D-Dimer and FDPs in DIC
- Follow Up of DIC State of Disease
- FMD-Dimer in DIC Major Differences
- of Abnormal Results in Patients with Confirmed and Suspected DIC
- Slide Number 85
- Slide Number 86
- Comparing an Automated FM vs Manual FSP Test
- Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Slide Number 94
- Slide Number 95
- Slide Number 96
- Slide Number 97
- Slide Number 98
- Slide Number 99
- DIC Case Studies
- Case Study 1 - Presentation
- Case Study 1 ndash Lab Results
- Case Study 1 ndash Microscopy
- Case Study 1 ndash Diagnosis and Therapy
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Slide Number 110
- Slide Number 111
- Slide Number 112
- Slide Number 113
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
- Slide Number 124
- Slide Number 125
- DIC Take Home Messages
- Slide Number 127
- Slide Number 128
-
Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC
Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
Non Overt DIC Overt DIC
AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC
Trends in Markers of DIC for Different Patients
Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00
Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients
Trends in Markers of DIC for Different Patients
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes
28 day outcome survival
28 day outcome death
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines
DIC Case Studies
Case Study 1 - Presentation
18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE
WBC count 77 KμL 423 ndash 907 x KμL
RBC count 17 MμL 137 ndash 175 x MμL
Hemoglobin 67 gdL 137 ndash 175 gdL
Hematocrit 195 401 ndash 510
MCV 95 fL 790 ndash 922 fL
MPV 12 fL 94 ndash 124 fL
Platelet count 9 KμL 161 ndash 347 KμL
Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0
Lymphocytes monocytes eosinophils basophils all below normal range
PT 47 sec (corrected on mixing study) 116 ndash 152 sec
APTT 75 sec (corrected on mixing study) 253 ndash 373 sec
Fibrinogen lt 76 mgdL 177 ndash 466 mgdL
D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Microscopy
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Arrow shows giant platelets in this peripheral smear Promyelocytes apparent
Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)
DIC due to TF release by APL blasts
Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases
Transfusions to replace factors along with platelets and RBCs during APL treatment
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started
Case Study 2 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L
PT 30 sec 113 ndash 146 sec
APTT 75 sec 25 ndash 34 sec
D-dimer 078 microgml FEU lt050 microgml FEU
Fibrinogen 92 mgdl 150-400 mgdl
pH 728 738 to 742
PaO2 570 mmHg 80-100 mmHg
WBC 33 times 103mm3 40-11 times 103mm3
ALT 111 IUL 0ndash34 IUL
AST 61 IUL 0ndash34 IUL
BUN 303 mgdL 08-13 mgdL
Case Study 2 ndash Lab Results
Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures
Case Study 2 ndash Diagnosis
60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior
Case Study 3 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L
PT 228 sec 113 ndash 146 sec
APTT 45 sec 25 ndash 34 sec
D-dimer 080 microgml FEU lt050 microgmL FEU
Fibrinogen 82 mgdL 150-400 mgdL
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 134 gdL 14-16 gdL
WBC 81 times 103mm3 40-11 times 103mm3
ALT 32 IUL 0ndash34 IUL
AST 28 IUL 0ndash34 IUL
BUN 09 mgdL 08-13 mgdL
Case Study 3 ndash Lab Results
Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment
Case Study 3 ndash Diagnosis and Therapy
Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91
Case Study 4 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L
PT 28 sec 113 ndash 146 sec
APTT 71 sec 25 ndash 34 sec
D-dimer 31 microgmL FEU lt050 microgml FEU
Fibrinogen 92 mgdL 150-400 mgdl
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 158 gdL 14-16 gdL
WBC 71 times 103mm3 40-11 times 103mm3
ALT 60 IUL 0ndash34 IUL
AST 47 IUL 0ndash34 IUL
BUN 38 mgdL 08-13 mgdL
Case Study 4 ndash Lab Results
Lyme disease with DICProvide antibiotics with supportive measures
Case Study 4 ndash Diagnosis
55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis
Case Study 5 ndash Presentation
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
Case Study 5 ndash Lab Results and Time Course
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
TEST RESULT REFERENCE RANGE
Platelet count 33 x 109L 150-450 x 109L
PT 215 sec 103 ndash 128 sec
APTT 44 sec 26 ndash 36 sec
D-dimer 20 microgmL FEU lt025 microgml FEU
Fibrinogen 34 mgdL 200-375 mgdl
FII FV FVIII Low Not reported (NR)
FVII FIX FX vWF Normal NR
Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)
DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic
dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR
(C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen
(D) Illustration demonstrating repair
Case Study 5 ndash Diagnosis and Treatment
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography
Case Study 6 ndash Presentation
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
Case Study 6 ndash Lab Results
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L
PT 63 sec gt control 113 ndash 146 sec
INR 658 1 ndash 125
APTT 80 sec gt control 25 ndash 34 sec
D-dimer gt200 microgmL DDU 02 microgmL DDU
Urine exam Proteinuria and hematuria 150-400 mgdl
Albumin 28 gdL NR
Hb 58 gdL NR
LDH 1196 UL NR
SGPT 144 IU NR
SGOT 88 IU NR
Bilirubin 32 mgdL NR
DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th
day postop
Case Study 6 ndash Diagnosis and Treatment
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure
Case Study 6 ndash Discussion
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Case Study 7 ndash Lab Results vs Time
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
DIC Take Home Messages
Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation
Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers
DIC
Thank you Questions
- Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
- Learning Objectives
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Wound Sealing
- The Three Steps of Hemostasis
- Vessel Wall
- Slide Number 12
- Slide Number 13
- Platelet Structure UnactivatedActivated
- Primary Hemostasis
- Primary Hemostasis Assays
- Slide Number 17
- Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
- Slide Number 19
- Coagulation factors
- Coagulation Assay Mechanisms
- Slide Number 22
- Fibrin Formation
- Slide Number 24
- Fibrinolysis Overview
- Fibrinolysis Overview
- Slide Number 27
- Fibrinolysis Releases D-dimers
- Basic Pathophysiology of DIC
- Disseminated Intravascular Coagulation (DIC)
- Purpura Fulminans with DIC Due to Meningococcal Sepsis
- Clinical Conditions Associated With DIC
- Frequency of DIC in Selected Disease States
- Underlying Diseases in DIC Patients
- Slide Number 36
- Slide Number 37
- Slide Number 38
- Slide Number 39
- Pathophysiology of DIC
- Pathogenesis of DIC in Sepsis
- Host Response in Severe Sepsis
- Organ Failure in Severe Sepsis
- Mechanism of DIC in Organ Failure
- Interaction of Inflammation and Coagulation in Sepsis
- Slide Number 47
- Diverse and Opposing Effects of Thrombin
- Coagulation and Fibrinolysis in DIC
- Mechanism of DIC
- Pathophysiology of DIC
- Pathophysiology of DIC - Mechanism
- Pathophysiology of DIC ndash 2 Types of Clinical pictures
- Sub-Acute and Non-Overt DIC Clinical Findings
- Pathophysiology of Overt DIC
- Physiopathology of DIC ndash Overt DIC Findings
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- BREAK
- Diagnostic and Management Approach for DIC
- Diagnosis of DIC
- Lab Diagnosis of DIC ndash Markers of Factor Consumption
- Lab Diagnosis of DIC ndash Screening Tests
- Slide Number 67
- Slide Number 68
- British Journal of Haematology Overt DIC Score
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- DIC Management Goals
- DIC Management and Treatment
- DIC Management Strategies
- Anticoagulant Factor Concentrate Treatment
- Anticoagulant Factor Concentrate Treatment Trials
- Markers of Thrombin amp Plasmin Generation in DIC
- D-dimer FDPs and DIC
- D-Dimer and FDPs in DIC
- Follow Up of DIC State of Disease
- FMD-Dimer in DIC Major Differences
- of Abnormal Results in Patients with Confirmed and Suspected DIC
- Slide Number 85
- Slide Number 86
- Comparing an Automated FM vs Manual FSP Test
- Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Slide Number 94
- Slide Number 95
- Slide Number 96
- Slide Number 97
- Slide Number 98
- Slide Number 99
- DIC Case Studies
- Case Study 1 - Presentation
- Case Study 1 ndash Lab Results
- Case Study 1 ndash Microscopy
- Case Study 1 ndash Diagnosis and Therapy
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Slide Number 110
- Slide Number 111
- Slide Number 112
- Slide Number 113
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
- Slide Number 124
- Slide Number 125
- DIC Take Home Messages
- Slide Number 127
- Slide Number 128
-
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC
Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
Non Overt DIC Overt DIC
AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC
Trends in Markers of DIC for Different Patients
Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00
Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients
Trends in Markers of DIC for Different Patients
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes
28 day outcome survival
28 day outcome death
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines
DIC Case Studies
Case Study 1 - Presentation
18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE
WBC count 77 KμL 423 ndash 907 x KμL
RBC count 17 MμL 137 ndash 175 x MμL
Hemoglobin 67 gdL 137 ndash 175 gdL
Hematocrit 195 401 ndash 510
MCV 95 fL 790 ndash 922 fL
MPV 12 fL 94 ndash 124 fL
Platelet count 9 KμL 161 ndash 347 KμL
Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0
Lymphocytes monocytes eosinophils basophils all below normal range
PT 47 sec (corrected on mixing study) 116 ndash 152 sec
APTT 75 sec (corrected on mixing study) 253 ndash 373 sec
Fibrinogen lt 76 mgdL 177 ndash 466 mgdL
D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Microscopy
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Arrow shows giant platelets in this peripheral smear Promyelocytes apparent
Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)
DIC due to TF release by APL blasts
Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases
Transfusions to replace factors along with platelets and RBCs during APL treatment
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started
Case Study 2 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L
PT 30 sec 113 ndash 146 sec
APTT 75 sec 25 ndash 34 sec
D-dimer 078 microgml FEU lt050 microgml FEU
Fibrinogen 92 mgdl 150-400 mgdl
pH 728 738 to 742
PaO2 570 mmHg 80-100 mmHg
WBC 33 times 103mm3 40-11 times 103mm3
ALT 111 IUL 0ndash34 IUL
AST 61 IUL 0ndash34 IUL
BUN 303 mgdL 08-13 mgdL
Case Study 2 ndash Lab Results
Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures
Case Study 2 ndash Diagnosis
60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior
Case Study 3 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L
PT 228 sec 113 ndash 146 sec
APTT 45 sec 25 ndash 34 sec
D-dimer 080 microgml FEU lt050 microgmL FEU
Fibrinogen 82 mgdL 150-400 mgdL
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 134 gdL 14-16 gdL
WBC 81 times 103mm3 40-11 times 103mm3
ALT 32 IUL 0ndash34 IUL
AST 28 IUL 0ndash34 IUL
BUN 09 mgdL 08-13 mgdL
Case Study 3 ndash Lab Results
Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment
Case Study 3 ndash Diagnosis and Therapy
Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91
Case Study 4 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L
PT 28 sec 113 ndash 146 sec
APTT 71 sec 25 ndash 34 sec
D-dimer 31 microgmL FEU lt050 microgml FEU
Fibrinogen 92 mgdL 150-400 mgdl
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 158 gdL 14-16 gdL
WBC 71 times 103mm3 40-11 times 103mm3
ALT 60 IUL 0ndash34 IUL
AST 47 IUL 0ndash34 IUL
BUN 38 mgdL 08-13 mgdL
Case Study 4 ndash Lab Results
Lyme disease with DICProvide antibiotics with supportive measures
Case Study 4 ndash Diagnosis
55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis
Case Study 5 ndash Presentation
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
Case Study 5 ndash Lab Results and Time Course
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
TEST RESULT REFERENCE RANGE
Platelet count 33 x 109L 150-450 x 109L
PT 215 sec 103 ndash 128 sec
APTT 44 sec 26 ndash 36 sec
D-dimer 20 microgmL FEU lt025 microgml FEU
Fibrinogen 34 mgdL 200-375 mgdl
FII FV FVIII Low Not reported (NR)
FVII FIX FX vWF Normal NR
Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)
DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic
dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR
(C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen
(D) Illustration demonstrating repair
Case Study 5 ndash Diagnosis and Treatment
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography
Case Study 6 ndash Presentation
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
Case Study 6 ndash Lab Results
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L
PT 63 sec gt control 113 ndash 146 sec
INR 658 1 ndash 125
APTT 80 sec gt control 25 ndash 34 sec
D-dimer gt200 microgmL DDU 02 microgmL DDU
Urine exam Proteinuria and hematuria 150-400 mgdl
Albumin 28 gdL NR
Hb 58 gdL NR
LDH 1196 UL NR
SGPT 144 IU NR
SGOT 88 IU NR
Bilirubin 32 mgdL NR
DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th
day postop
Case Study 6 ndash Diagnosis and Treatment
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure
Case Study 6 ndash Discussion
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Case Study 7 ndash Lab Results vs Time
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
DIC Take Home Messages
Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation
Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers
DIC
Thank you Questions
- Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
- Learning Objectives
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Wound Sealing
- The Three Steps of Hemostasis
- Vessel Wall
- Slide Number 12
- Slide Number 13
- Platelet Structure UnactivatedActivated
- Primary Hemostasis
- Primary Hemostasis Assays
- Slide Number 17
- Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
- Slide Number 19
- Coagulation factors
- Coagulation Assay Mechanisms
- Slide Number 22
- Fibrin Formation
- Slide Number 24
- Fibrinolysis Overview
- Fibrinolysis Overview
- Slide Number 27
- Fibrinolysis Releases D-dimers
- Basic Pathophysiology of DIC
- Disseminated Intravascular Coagulation (DIC)
- Purpura Fulminans with DIC Due to Meningococcal Sepsis
- Clinical Conditions Associated With DIC
- Frequency of DIC in Selected Disease States
- Underlying Diseases in DIC Patients
- Slide Number 36
- Slide Number 37
- Slide Number 38
- Slide Number 39
- Pathophysiology of DIC
- Pathogenesis of DIC in Sepsis
- Host Response in Severe Sepsis
- Organ Failure in Severe Sepsis
- Mechanism of DIC in Organ Failure
- Interaction of Inflammation and Coagulation in Sepsis
- Slide Number 47
- Diverse and Opposing Effects of Thrombin
- Coagulation and Fibrinolysis in DIC
- Mechanism of DIC
- Pathophysiology of DIC
- Pathophysiology of DIC - Mechanism
- Pathophysiology of DIC ndash 2 Types of Clinical pictures
- Sub-Acute and Non-Overt DIC Clinical Findings
- Pathophysiology of Overt DIC
- Physiopathology of DIC ndash Overt DIC Findings
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- BREAK
- Diagnostic and Management Approach for DIC
- Diagnosis of DIC
- Lab Diagnosis of DIC ndash Markers of Factor Consumption
- Lab Diagnosis of DIC ndash Screening Tests
- Slide Number 67
- Slide Number 68
- British Journal of Haematology Overt DIC Score
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- DIC Management Goals
- DIC Management and Treatment
- DIC Management Strategies
- Anticoagulant Factor Concentrate Treatment
- Anticoagulant Factor Concentrate Treatment Trials
- Markers of Thrombin amp Plasmin Generation in DIC
- D-dimer FDPs and DIC
- D-Dimer and FDPs in DIC
- Follow Up of DIC State of Disease
- FMD-Dimer in DIC Major Differences
- of Abnormal Results in Patients with Confirmed and Suspected DIC
- Slide Number 85
- Slide Number 86
- Comparing an Automated FM vs Manual FSP Test
- Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Slide Number 94
- Slide Number 95
- Slide Number 96
- Slide Number 97
- Slide Number 98
- Slide Number 99
- DIC Case Studies
- Case Study 1 - Presentation
- Case Study 1 ndash Lab Results
- Case Study 1 ndash Microscopy
- Case Study 1 ndash Diagnosis and Therapy
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Slide Number 110
- Slide Number 111
- Slide Number 112
- Slide Number 113
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
- Slide Number 124
- Slide Number 125
- DIC Take Home Messages
- Slide Number 127
- Slide Number 128
-
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Non-Overt to Non-DIC patients FM far outperforms D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC
Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
Non Overt DIC Overt DIC
AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC
Trends in Markers of DIC for Different Patients
Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00
Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients
Trends in Markers of DIC for Different Patients
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes
28 day outcome survival
28 day outcome death
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines
DIC Case Studies
Case Study 1 - Presentation
18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE
WBC count 77 KμL 423 ndash 907 x KμL
RBC count 17 MμL 137 ndash 175 x MμL
Hemoglobin 67 gdL 137 ndash 175 gdL
Hematocrit 195 401 ndash 510
MCV 95 fL 790 ndash 922 fL
MPV 12 fL 94 ndash 124 fL
Platelet count 9 KμL 161 ndash 347 KμL
Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0
Lymphocytes monocytes eosinophils basophils all below normal range
PT 47 sec (corrected on mixing study) 116 ndash 152 sec
APTT 75 sec (corrected on mixing study) 253 ndash 373 sec
Fibrinogen lt 76 mgdL 177 ndash 466 mgdL
D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Microscopy
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Arrow shows giant platelets in this peripheral smear Promyelocytes apparent
Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)
DIC due to TF release by APL blasts
Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases
Transfusions to replace factors along with platelets and RBCs during APL treatment
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started
Case Study 2 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L
PT 30 sec 113 ndash 146 sec
APTT 75 sec 25 ndash 34 sec
D-dimer 078 microgml FEU lt050 microgml FEU
Fibrinogen 92 mgdl 150-400 mgdl
pH 728 738 to 742
PaO2 570 mmHg 80-100 mmHg
WBC 33 times 103mm3 40-11 times 103mm3
ALT 111 IUL 0ndash34 IUL
AST 61 IUL 0ndash34 IUL
BUN 303 mgdL 08-13 mgdL
Case Study 2 ndash Lab Results
Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures
Case Study 2 ndash Diagnosis
60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior
Case Study 3 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L
PT 228 sec 113 ndash 146 sec
APTT 45 sec 25 ndash 34 sec
D-dimer 080 microgml FEU lt050 microgmL FEU
Fibrinogen 82 mgdL 150-400 mgdL
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 134 gdL 14-16 gdL
WBC 81 times 103mm3 40-11 times 103mm3
ALT 32 IUL 0ndash34 IUL
AST 28 IUL 0ndash34 IUL
BUN 09 mgdL 08-13 mgdL
Case Study 3 ndash Lab Results
Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment
Case Study 3 ndash Diagnosis and Therapy
Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91
Case Study 4 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L
PT 28 sec 113 ndash 146 sec
APTT 71 sec 25 ndash 34 sec
D-dimer 31 microgmL FEU lt050 microgml FEU
Fibrinogen 92 mgdL 150-400 mgdl
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 158 gdL 14-16 gdL
WBC 71 times 103mm3 40-11 times 103mm3
ALT 60 IUL 0ndash34 IUL
AST 47 IUL 0ndash34 IUL
BUN 38 mgdL 08-13 mgdL
Case Study 4 ndash Lab Results
Lyme disease with DICProvide antibiotics with supportive measures
Case Study 4 ndash Diagnosis
55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis
Case Study 5 ndash Presentation
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
Case Study 5 ndash Lab Results and Time Course
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
TEST RESULT REFERENCE RANGE
Platelet count 33 x 109L 150-450 x 109L
PT 215 sec 103 ndash 128 sec
APTT 44 sec 26 ndash 36 sec
D-dimer 20 microgmL FEU lt025 microgml FEU
Fibrinogen 34 mgdL 200-375 mgdl
FII FV FVIII Low Not reported (NR)
FVII FIX FX vWF Normal NR
Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)
DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic
dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR
(C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen
(D) Illustration demonstrating repair
Case Study 5 ndash Diagnosis and Treatment
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography
Case Study 6 ndash Presentation
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
Case Study 6 ndash Lab Results
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L
PT 63 sec gt control 113 ndash 146 sec
INR 658 1 ndash 125
APTT 80 sec gt control 25 ndash 34 sec
D-dimer gt200 microgmL DDU 02 microgmL DDU
Urine exam Proteinuria and hematuria 150-400 mgdl
Albumin 28 gdL NR
Hb 58 gdL NR
LDH 1196 UL NR
SGPT 144 IU NR
SGOT 88 IU NR
Bilirubin 32 mgdL NR
DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th
day postop
Case Study 6 ndash Diagnosis and Treatment
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure
Case Study 6 ndash Discussion
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Case Study 7 ndash Lab Results vs Time
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
DIC Take Home Messages
Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation
Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers
DIC
Thank you Questions
- Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
- Learning Objectives
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Wound Sealing
- The Three Steps of Hemostasis
- Vessel Wall
- Slide Number 12
- Slide Number 13
- Platelet Structure UnactivatedActivated
- Primary Hemostasis
- Primary Hemostasis Assays
- Slide Number 17
- Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
- Slide Number 19
- Coagulation factors
- Coagulation Assay Mechanisms
- Slide Number 22
- Fibrin Formation
- Slide Number 24
- Fibrinolysis Overview
- Fibrinolysis Overview
- Slide Number 27
- Fibrinolysis Releases D-dimers
- Basic Pathophysiology of DIC
- Disseminated Intravascular Coagulation (DIC)
- Purpura Fulminans with DIC Due to Meningococcal Sepsis
- Clinical Conditions Associated With DIC
- Frequency of DIC in Selected Disease States
- Underlying Diseases in DIC Patients
- Slide Number 36
- Slide Number 37
- Slide Number 38
- Slide Number 39
- Pathophysiology of DIC
- Pathogenesis of DIC in Sepsis
- Host Response in Severe Sepsis
- Organ Failure in Severe Sepsis
- Mechanism of DIC in Organ Failure
- Interaction of Inflammation and Coagulation in Sepsis
- Slide Number 47
- Diverse and Opposing Effects of Thrombin
- Coagulation and Fibrinolysis in DIC
- Mechanism of DIC
- Pathophysiology of DIC
- Pathophysiology of DIC - Mechanism
- Pathophysiology of DIC ndash 2 Types of Clinical pictures
- Sub-Acute and Non-Overt DIC Clinical Findings
- Pathophysiology of Overt DIC
- Physiopathology of DIC ndash Overt DIC Findings
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- BREAK
- Diagnostic and Management Approach for DIC
- Diagnosis of DIC
- Lab Diagnosis of DIC ndash Markers of Factor Consumption
- Lab Diagnosis of DIC ndash Screening Tests
- Slide Number 67
- Slide Number 68
- British Journal of Haematology Overt DIC Score
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- DIC Management Goals
- DIC Management and Treatment
- DIC Management Strategies
- Anticoagulant Factor Concentrate Treatment
- Anticoagulant Factor Concentrate Treatment Trials
- Markers of Thrombin amp Plasmin Generation in DIC
- D-dimer FDPs and DIC
- D-Dimer and FDPs in DIC
- Follow Up of DIC State of Disease
- FMD-Dimer in DIC Major Differences
- of Abnormal Results in Patients with Confirmed and Suspected DIC
- Slide Number 85
- Slide Number 86
- Comparing an Automated FM vs Manual FSP Test
- Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Slide Number 94
- Slide Number 95
- Slide Number 96
- Slide Number 97
- Slide Number 98
- Slide Number 99
- DIC Case Studies
- Case Study 1 - Presentation
- Case Study 1 ndash Lab Results
- Case Study 1 ndash Microscopy
- Case Study 1 ndash Diagnosis and Therapy
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Slide Number 110
- Slide Number 111
- Slide Number 112
- Slide Number 113
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
- Slide Number 124
- Slide Number 125
- DIC Take Home Messages
- Slide Number 127
- Slide Number 128
-
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing DIC positive to Non-Overt DIC patients D-dimer outperforms FM on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC
Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
Non Overt DIC Overt DIC
AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC
Trends in Markers of DIC for Different Patients
Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00
Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients
Trends in Markers of DIC for Different Patients
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes
28 day outcome survival
28 day outcome death
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines
DIC Case Studies
Case Study 1 - Presentation
18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE
WBC count 77 KμL 423 ndash 907 x KμL
RBC count 17 MμL 137 ndash 175 x MμL
Hemoglobin 67 gdL 137 ndash 175 gdL
Hematocrit 195 401 ndash 510
MCV 95 fL 790 ndash 922 fL
MPV 12 fL 94 ndash 124 fL
Platelet count 9 KμL 161 ndash 347 KμL
Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0
Lymphocytes monocytes eosinophils basophils all below normal range
PT 47 sec (corrected on mixing study) 116 ndash 152 sec
APTT 75 sec (corrected on mixing study) 253 ndash 373 sec
Fibrinogen lt 76 mgdL 177 ndash 466 mgdL
D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Microscopy
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Arrow shows giant platelets in this peripheral smear Promyelocytes apparent
Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)
DIC due to TF release by APL blasts
Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases
Transfusions to replace factors along with platelets and RBCs during APL treatment
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started
Case Study 2 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L
PT 30 sec 113 ndash 146 sec
APTT 75 sec 25 ndash 34 sec
D-dimer 078 microgml FEU lt050 microgml FEU
Fibrinogen 92 mgdl 150-400 mgdl
pH 728 738 to 742
PaO2 570 mmHg 80-100 mmHg
WBC 33 times 103mm3 40-11 times 103mm3
ALT 111 IUL 0ndash34 IUL
AST 61 IUL 0ndash34 IUL
BUN 303 mgdL 08-13 mgdL
Case Study 2 ndash Lab Results
Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures
Case Study 2 ndash Diagnosis
60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior
Case Study 3 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L
PT 228 sec 113 ndash 146 sec
APTT 45 sec 25 ndash 34 sec
D-dimer 080 microgml FEU lt050 microgmL FEU
Fibrinogen 82 mgdL 150-400 mgdL
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 134 gdL 14-16 gdL
WBC 81 times 103mm3 40-11 times 103mm3
ALT 32 IUL 0ndash34 IUL
AST 28 IUL 0ndash34 IUL
BUN 09 mgdL 08-13 mgdL
Case Study 3 ndash Lab Results
Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment
Case Study 3 ndash Diagnosis and Therapy
Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91
Case Study 4 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L
PT 28 sec 113 ndash 146 sec
APTT 71 sec 25 ndash 34 sec
D-dimer 31 microgmL FEU lt050 microgml FEU
Fibrinogen 92 mgdL 150-400 mgdl
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 158 gdL 14-16 gdL
WBC 71 times 103mm3 40-11 times 103mm3
ALT 60 IUL 0ndash34 IUL
AST 47 IUL 0ndash34 IUL
BUN 38 mgdL 08-13 mgdL
Case Study 4 ndash Lab Results
Lyme disease with DICProvide antibiotics with supportive measures
Case Study 4 ndash Diagnosis
55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis
Case Study 5 ndash Presentation
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
Case Study 5 ndash Lab Results and Time Course
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
TEST RESULT REFERENCE RANGE
Platelet count 33 x 109L 150-450 x 109L
PT 215 sec 103 ndash 128 sec
APTT 44 sec 26 ndash 36 sec
D-dimer 20 microgmL FEU lt025 microgml FEU
Fibrinogen 34 mgdL 200-375 mgdl
FII FV FVIII Low Not reported (NR)
FVII FIX FX vWF Normal NR
Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)
DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic
dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR
(C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen
(D) Illustration demonstrating repair
Case Study 5 ndash Diagnosis and Treatment
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography
Case Study 6 ndash Presentation
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
Case Study 6 ndash Lab Results
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L
PT 63 sec gt control 113 ndash 146 sec
INR 658 1 ndash 125
APTT 80 sec gt control 25 ndash 34 sec
D-dimer gt200 microgmL DDU 02 microgmL DDU
Urine exam Proteinuria and hematuria 150-400 mgdl
Albumin 28 gdL NR
Hb 58 gdL NR
LDH 1196 UL NR
SGPT 144 IU NR
SGOT 88 IU NR
Bilirubin 32 mgdL NR
DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th
day postop
Case Study 6 ndash Diagnosis and Treatment
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure
Case Study 6 ndash Discussion
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Case Study 7 ndash Lab Results vs Time
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
DIC Take Home Messages
Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation
Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers
DIC
Thank you Questions
- Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
- Learning Objectives
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Wound Sealing
- The Three Steps of Hemostasis
- Vessel Wall
- Slide Number 12
- Slide Number 13
- Platelet Structure UnactivatedActivated
- Primary Hemostasis
- Primary Hemostasis Assays
- Slide Number 17
- Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
- Slide Number 19
- Coagulation factors
- Coagulation Assay Mechanisms
- Slide Number 22
- Fibrin Formation
- Slide Number 24
- Fibrinolysis Overview
- Fibrinolysis Overview
- Slide Number 27
- Fibrinolysis Releases D-dimers
- Basic Pathophysiology of DIC
- Disseminated Intravascular Coagulation (DIC)
- Purpura Fulminans with DIC Due to Meningococcal Sepsis
- Clinical Conditions Associated With DIC
- Frequency of DIC in Selected Disease States
- Underlying Diseases in DIC Patients
- Slide Number 36
- Slide Number 37
- Slide Number 38
- Slide Number 39
- Pathophysiology of DIC
- Pathogenesis of DIC in Sepsis
- Host Response in Severe Sepsis
- Organ Failure in Severe Sepsis
- Mechanism of DIC in Organ Failure
- Interaction of Inflammation and Coagulation in Sepsis
- Slide Number 47
- Diverse and Opposing Effects of Thrombin
- Coagulation and Fibrinolysis in DIC
- Mechanism of DIC
- Pathophysiology of DIC
- Pathophysiology of DIC - Mechanism
- Pathophysiology of DIC ndash 2 Types of Clinical pictures
- Sub-Acute and Non-Overt DIC Clinical Findings
- Pathophysiology of Overt DIC
- Physiopathology of DIC ndash Overt DIC Findings
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- BREAK
- Diagnostic and Management Approach for DIC
- Diagnosis of DIC
- Lab Diagnosis of DIC ndash Markers of Factor Consumption
- Lab Diagnosis of DIC ndash Screening Tests
- Slide Number 67
- Slide Number 68
- British Journal of Haematology Overt DIC Score
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- DIC Management Goals
- DIC Management and Treatment
- DIC Management Strategies
- Anticoagulant Factor Concentrate Treatment
- Anticoagulant Factor Concentrate Treatment Trials
- Markers of Thrombin amp Plasmin Generation in DIC
- D-dimer FDPs and DIC
- D-Dimer and FDPs in DIC
- Follow Up of DIC State of Disease
- FMD-Dimer in DIC Major Differences
- of Abnormal Results in Patients with Confirmed and Suspected DIC
- Slide Number 85
- Slide Number 86
- Comparing an Automated FM vs Manual FSP Test
- Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Slide Number 94
- Slide Number 95
- Slide Number 96
- Slide Number 97
- Slide Number 98
- Slide Number 99
- DIC Case Studies
- Case Study 1 - Presentation
- Case Study 1 ndash Lab Results
- Case Study 1 ndash Microscopy
- Case Study 1 ndash Diagnosis and Therapy
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Slide Number 110
- Slide Number 111
- Slide Number 112
- Slide Number 113
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
- Slide Number 124
- Slide Number 125
- DIC Take Home Messages
- Slide Number 127
- Slide Number 128
-
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
In comparing Overt to Non-DIC patients FM is more comparable to D-dimer on the ROC
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC
Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
Non Overt DIC Overt DIC
AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC
Trends in Markers of DIC for Different Patients
Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00
Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients
Trends in Markers of DIC for Different Patients
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes
28 day outcome survival
28 day outcome death
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines
DIC Case Studies
Case Study 1 - Presentation
18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE
WBC count 77 KμL 423 ndash 907 x KμL
RBC count 17 MμL 137 ndash 175 x MμL
Hemoglobin 67 gdL 137 ndash 175 gdL
Hematocrit 195 401 ndash 510
MCV 95 fL 790 ndash 922 fL
MPV 12 fL 94 ndash 124 fL
Platelet count 9 KμL 161 ndash 347 KμL
Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0
Lymphocytes monocytes eosinophils basophils all below normal range
PT 47 sec (corrected on mixing study) 116 ndash 152 sec
APTT 75 sec (corrected on mixing study) 253 ndash 373 sec
Fibrinogen lt 76 mgdL 177 ndash 466 mgdL
D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Microscopy
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Arrow shows giant platelets in this peripheral smear Promyelocytes apparent
Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)
DIC due to TF release by APL blasts
Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases
Transfusions to replace factors along with platelets and RBCs during APL treatment
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started
Case Study 2 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L
PT 30 sec 113 ndash 146 sec
APTT 75 sec 25 ndash 34 sec
D-dimer 078 microgml FEU lt050 microgml FEU
Fibrinogen 92 mgdl 150-400 mgdl
pH 728 738 to 742
PaO2 570 mmHg 80-100 mmHg
WBC 33 times 103mm3 40-11 times 103mm3
ALT 111 IUL 0ndash34 IUL
AST 61 IUL 0ndash34 IUL
BUN 303 mgdL 08-13 mgdL
Case Study 2 ndash Lab Results
Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures
Case Study 2 ndash Diagnosis
60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior
Case Study 3 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L
PT 228 sec 113 ndash 146 sec
APTT 45 sec 25 ndash 34 sec
D-dimer 080 microgml FEU lt050 microgmL FEU
Fibrinogen 82 mgdL 150-400 mgdL
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 134 gdL 14-16 gdL
WBC 81 times 103mm3 40-11 times 103mm3
ALT 32 IUL 0ndash34 IUL
AST 28 IUL 0ndash34 IUL
BUN 09 mgdL 08-13 mgdL
Case Study 3 ndash Lab Results
Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment
Case Study 3 ndash Diagnosis and Therapy
Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91
Case Study 4 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L
PT 28 sec 113 ndash 146 sec
APTT 71 sec 25 ndash 34 sec
D-dimer 31 microgmL FEU lt050 microgml FEU
Fibrinogen 92 mgdL 150-400 mgdl
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 158 gdL 14-16 gdL
WBC 71 times 103mm3 40-11 times 103mm3
ALT 60 IUL 0ndash34 IUL
AST 47 IUL 0ndash34 IUL
BUN 38 mgdL 08-13 mgdL
Case Study 4 ndash Lab Results
Lyme disease with DICProvide antibiotics with supportive measures
Case Study 4 ndash Diagnosis
55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis
Case Study 5 ndash Presentation
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
Case Study 5 ndash Lab Results and Time Course
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
TEST RESULT REFERENCE RANGE
Platelet count 33 x 109L 150-450 x 109L
PT 215 sec 103 ndash 128 sec
APTT 44 sec 26 ndash 36 sec
D-dimer 20 microgmL FEU lt025 microgml FEU
Fibrinogen 34 mgdL 200-375 mgdl
FII FV FVIII Low Not reported (NR)
FVII FIX FX vWF Normal NR
Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)
DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic
dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR
(C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen
(D) Illustration demonstrating repair
Case Study 5 ndash Diagnosis and Treatment
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography
Case Study 6 ndash Presentation
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
Case Study 6 ndash Lab Results
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L
PT 63 sec gt control 113 ndash 146 sec
INR 658 1 ndash 125
APTT 80 sec gt control 25 ndash 34 sec
D-dimer gt200 microgmL DDU 02 microgmL DDU
Urine exam Proteinuria and hematuria 150-400 mgdl
Albumin 28 gdL NR
Hb 58 gdL NR
LDH 1196 UL NR
SGPT 144 IU NR
SGOT 88 IU NR
Bilirubin 32 mgdL NR
DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th
day postop
Case Study 6 ndash Diagnosis and Treatment
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure
Case Study 6 ndash Discussion
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Case Study 7 ndash Lab Results vs Time
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
DIC Take Home Messages
Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation
Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers
DIC
Thank you Questions
- Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
- Learning Objectives
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Wound Sealing
- The Three Steps of Hemostasis
- Vessel Wall
- Slide Number 12
- Slide Number 13
- Platelet Structure UnactivatedActivated
- Primary Hemostasis
- Primary Hemostasis Assays
- Slide Number 17
- Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
- Slide Number 19
- Coagulation factors
- Coagulation Assay Mechanisms
- Slide Number 22
- Fibrin Formation
- Slide Number 24
- Fibrinolysis Overview
- Fibrinolysis Overview
- Slide Number 27
- Fibrinolysis Releases D-dimers
- Basic Pathophysiology of DIC
- Disseminated Intravascular Coagulation (DIC)
- Purpura Fulminans with DIC Due to Meningococcal Sepsis
- Clinical Conditions Associated With DIC
- Frequency of DIC in Selected Disease States
- Underlying Diseases in DIC Patients
- Slide Number 36
- Slide Number 37
- Slide Number 38
- Slide Number 39
- Pathophysiology of DIC
- Pathogenesis of DIC in Sepsis
- Host Response in Severe Sepsis
- Organ Failure in Severe Sepsis
- Mechanism of DIC in Organ Failure
- Interaction of Inflammation and Coagulation in Sepsis
- Slide Number 47
- Diverse and Opposing Effects of Thrombin
- Coagulation and Fibrinolysis in DIC
- Mechanism of DIC
- Pathophysiology of DIC
- Pathophysiology of DIC - Mechanism
- Pathophysiology of DIC ndash 2 Types of Clinical pictures
- Sub-Acute and Non-Overt DIC Clinical Findings
- Pathophysiology of Overt DIC
- Physiopathology of DIC ndash Overt DIC Findings
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- BREAK
- Diagnostic and Management Approach for DIC
- Diagnosis of DIC
- Lab Diagnosis of DIC ndash Markers of Factor Consumption
- Lab Diagnosis of DIC ndash Screening Tests
- Slide Number 67
- Slide Number 68
- British Journal of Haematology Overt DIC Score
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- DIC Management Goals
- DIC Management and Treatment
- DIC Management Strategies
- Anticoagulant Factor Concentrate Treatment
- Anticoagulant Factor Concentrate Treatment Trials
- Markers of Thrombin amp Plasmin Generation in DIC
- D-dimer FDPs and DIC
- D-Dimer and FDPs in DIC
- Follow Up of DIC State of Disease
- FMD-Dimer in DIC Major Differences
- of Abnormal Results in Patients with Confirmed and Suspected DIC
- Slide Number 85
- Slide Number 86
- Comparing an Automated FM vs Manual FSP Test
- Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Slide Number 94
- Slide Number 95
- Slide Number 96
- Slide Number 97
- Slide Number 98
- Slide Number 99
- DIC Case Studies
- Case Study 1 - Presentation
- Case Study 1 ndash Lab Results
- Case Study 1 ndash Microscopy
- Case Study 1 ndash Diagnosis and Therapy
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Slide Number 110
- Slide Number 111
- Slide Number 112
- Slide Number 113
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
- Slide Number 124
- Slide Number 125
- DIC Take Home Messages
- Slide Number 127
- Slide Number 128
-
Diagnostic Performance of FM and D-dimer in DIC
Singh N Prasad Pati H Tyagi S Datt Upadhyay A Saxena R Evaluation of the Diagnostic Performanceof Fibrin Monomer in Comparison to D-Dimer in Patients With Overt and Nonovert DisseminatedIntravascular Coagulation Clin Appl ThrombHemost 2015 1-6
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC
Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
Non Overt DIC Overt DIC
AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC
Trends in Markers of DIC for Different Patients
Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00
Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients
Trends in Markers of DIC for Different Patients
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes
28 day outcome survival
28 day outcome death
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines
DIC Case Studies
Case Study 1 - Presentation
18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE
WBC count 77 KμL 423 ndash 907 x KμL
RBC count 17 MμL 137 ndash 175 x MμL
Hemoglobin 67 gdL 137 ndash 175 gdL
Hematocrit 195 401 ndash 510
MCV 95 fL 790 ndash 922 fL
MPV 12 fL 94 ndash 124 fL
Platelet count 9 KμL 161 ndash 347 KμL
Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0
Lymphocytes monocytes eosinophils basophils all below normal range
PT 47 sec (corrected on mixing study) 116 ndash 152 sec
APTT 75 sec (corrected on mixing study) 253 ndash 373 sec
Fibrinogen lt 76 mgdL 177 ndash 466 mgdL
D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Microscopy
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Arrow shows giant platelets in this peripheral smear Promyelocytes apparent
Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)
DIC due to TF release by APL blasts
Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases
Transfusions to replace factors along with platelets and RBCs during APL treatment
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started
Case Study 2 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L
PT 30 sec 113 ndash 146 sec
APTT 75 sec 25 ndash 34 sec
D-dimer 078 microgml FEU lt050 microgml FEU
Fibrinogen 92 mgdl 150-400 mgdl
pH 728 738 to 742
PaO2 570 mmHg 80-100 mmHg
WBC 33 times 103mm3 40-11 times 103mm3
ALT 111 IUL 0ndash34 IUL
AST 61 IUL 0ndash34 IUL
BUN 303 mgdL 08-13 mgdL
Case Study 2 ndash Lab Results
Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures
Case Study 2 ndash Diagnosis
60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior
Case Study 3 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L
PT 228 sec 113 ndash 146 sec
APTT 45 sec 25 ndash 34 sec
D-dimer 080 microgml FEU lt050 microgmL FEU
Fibrinogen 82 mgdL 150-400 mgdL
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 134 gdL 14-16 gdL
WBC 81 times 103mm3 40-11 times 103mm3
ALT 32 IUL 0ndash34 IUL
AST 28 IUL 0ndash34 IUL
BUN 09 mgdL 08-13 mgdL
Case Study 3 ndash Lab Results
Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment
Case Study 3 ndash Diagnosis and Therapy
Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91
Case Study 4 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L
PT 28 sec 113 ndash 146 sec
APTT 71 sec 25 ndash 34 sec
D-dimer 31 microgmL FEU lt050 microgml FEU
Fibrinogen 92 mgdL 150-400 mgdl
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 158 gdL 14-16 gdL
WBC 71 times 103mm3 40-11 times 103mm3
ALT 60 IUL 0ndash34 IUL
AST 47 IUL 0ndash34 IUL
BUN 38 mgdL 08-13 mgdL
Case Study 4 ndash Lab Results
Lyme disease with DICProvide antibiotics with supportive measures
Case Study 4 ndash Diagnosis
55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis
Case Study 5 ndash Presentation
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
Case Study 5 ndash Lab Results and Time Course
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
TEST RESULT REFERENCE RANGE
Platelet count 33 x 109L 150-450 x 109L
PT 215 sec 103 ndash 128 sec
APTT 44 sec 26 ndash 36 sec
D-dimer 20 microgmL FEU lt025 microgml FEU
Fibrinogen 34 mgdL 200-375 mgdl
FII FV FVIII Low Not reported (NR)
FVII FIX FX vWF Normal NR
Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)
DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic
dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR
(C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen
(D) Illustration demonstrating repair
Case Study 5 ndash Diagnosis and Treatment
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography
Case Study 6 ndash Presentation
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
Case Study 6 ndash Lab Results
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L
PT 63 sec gt control 113 ndash 146 sec
INR 658 1 ndash 125
APTT 80 sec gt control 25 ndash 34 sec
D-dimer gt200 microgmL DDU 02 microgmL DDU
Urine exam Proteinuria and hematuria 150-400 mgdl
Albumin 28 gdL NR
Hb 58 gdL NR
LDH 1196 UL NR
SGPT 144 IU NR
SGOT 88 IU NR
Bilirubin 32 mgdL NR
DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th
day postop
Case Study 6 ndash Diagnosis and Treatment
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure
Case Study 6 ndash Discussion
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Case Study 7 ndash Lab Results vs Time
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
DIC Take Home Messages
Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation
Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers
DIC
Thank you Questions
- Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
- Learning Objectives
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Wound Sealing
- The Three Steps of Hemostasis
- Vessel Wall
- Slide Number 12
- Slide Number 13
- Platelet Structure UnactivatedActivated
- Primary Hemostasis
- Primary Hemostasis Assays
- Slide Number 17
- Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
- Slide Number 19
- Coagulation factors
- Coagulation Assay Mechanisms
- Slide Number 22
- Fibrin Formation
- Slide Number 24
- Fibrinolysis Overview
- Fibrinolysis Overview
- Slide Number 27
- Fibrinolysis Releases D-dimers
- Basic Pathophysiology of DIC
- Disseminated Intravascular Coagulation (DIC)
- Purpura Fulminans with DIC Due to Meningococcal Sepsis
- Clinical Conditions Associated With DIC
- Frequency of DIC in Selected Disease States
- Underlying Diseases in DIC Patients
- Slide Number 36
- Slide Number 37
- Slide Number 38
- Slide Number 39
- Pathophysiology of DIC
- Pathogenesis of DIC in Sepsis
- Host Response in Severe Sepsis
- Organ Failure in Severe Sepsis
- Mechanism of DIC in Organ Failure
- Interaction of Inflammation and Coagulation in Sepsis
- Slide Number 47
- Diverse and Opposing Effects of Thrombin
- Coagulation and Fibrinolysis in DIC
- Mechanism of DIC
- Pathophysiology of DIC
- Pathophysiology of DIC - Mechanism
- Pathophysiology of DIC ndash 2 Types of Clinical pictures
- Sub-Acute and Non-Overt DIC Clinical Findings
- Pathophysiology of Overt DIC
- Physiopathology of DIC ndash Overt DIC Findings
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- BREAK
- Diagnostic and Management Approach for DIC
- Diagnosis of DIC
- Lab Diagnosis of DIC ndash Markers of Factor Consumption
- Lab Diagnosis of DIC ndash Screening Tests
- Slide Number 67
- Slide Number 68
- British Journal of Haematology Overt DIC Score
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- DIC Management Goals
- DIC Management and Treatment
- DIC Management Strategies
- Anticoagulant Factor Concentrate Treatment
- Anticoagulant Factor Concentrate Treatment Trials
- Markers of Thrombin amp Plasmin Generation in DIC
- D-dimer FDPs and DIC
- D-Dimer and FDPs in DIC
- Follow Up of DIC State of Disease
- FMD-Dimer in DIC Major Differences
- of Abnormal Results in Patients with Confirmed and Suspected DIC
- Slide Number 85
- Slide Number 86
- Comparing an Automated FM vs Manual FSP Test
- Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Slide Number 94
- Slide Number 95
- Slide Number 96
- Slide Number 97
- Slide Number 98
- Slide Number 99
- DIC Case Studies
- Case Study 1 - Presentation
- Case Study 1 ndash Lab Results
- Case Study 1 ndash Microscopy
- Case Study 1 ndash Diagnosis and Therapy
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Slide Number 110
- Slide Number 111
- Slide Number 112
- Slide Number 113
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
- Slide Number 124
- Slide Number 125
- DIC Take Home Messages
- Slide Number 127
- Slide Number 128
-
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
No DIC Non Overt DIC Overt DIC No DIC Non Overt DIC Overt DIC
Levels of D-dimer and FM generally rise going from no DIC to non-overt to overt DIC
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
Non Overt DIC Overt DIC
AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC
Trends in Markers of DIC for Different Patients
Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00
Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients
Trends in Markers of DIC for Different Patients
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes
28 day outcome survival
28 day outcome death
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines
DIC Case Studies
Case Study 1 - Presentation
18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE
WBC count 77 KμL 423 ndash 907 x KμL
RBC count 17 MμL 137 ndash 175 x MμL
Hemoglobin 67 gdL 137 ndash 175 gdL
Hematocrit 195 401 ndash 510
MCV 95 fL 790 ndash 922 fL
MPV 12 fL 94 ndash 124 fL
Platelet count 9 KμL 161 ndash 347 KμL
Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0
Lymphocytes monocytes eosinophils basophils all below normal range
PT 47 sec (corrected on mixing study) 116 ndash 152 sec
APTT 75 sec (corrected on mixing study) 253 ndash 373 sec
Fibrinogen lt 76 mgdL 177 ndash 466 mgdL
D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Microscopy
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Arrow shows giant platelets in this peripheral smear Promyelocytes apparent
Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)
DIC due to TF release by APL blasts
Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases
Transfusions to replace factors along with platelets and RBCs during APL treatment
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started
Case Study 2 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L
PT 30 sec 113 ndash 146 sec
APTT 75 sec 25 ndash 34 sec
D-dimer 078 microgml FEU lt050 microgml FEU
Fibrinogen 92 mgdl 150-400 mgdl
pH 728 738 to 742
PaO2 570 mmHg 80-100 mmHg
WBC 33 times 103mm3 40-11 times 103mm3
ALT 111 IUL 0ndash34 IUL
AST 61 IUL 0ndash34 IUL
BUN 303 mgdL 08-13 mgdL
Case Study 2 ndash Lab Results
Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures
Case Study 2 ndash Diagnosis
60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior
Case Study 3 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L
PT 228 sec 113 ndash 146 sec
APTT 45 sec 25 ndash 34 sec
D-dimer 080 microgml FEU lt050 microgmL FEU
Fibrinogen 82 mgdL 150-400 mgdL
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 134 gdL 14-16 gdL
WBC 81 times 103mm3 40-11 times 103mm3
ALT 32 IUL 0ndash34 IUL
AST 28 IUL 0ndash34 IUL
BUN 09 mgdL 08-13 mgdL
Case Study 3 ndash Lab Results
Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment
Case Study 3 ndash Diagnosis and Therapy
Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91
Case Study 4 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L
PT 28 sec 113 ndash 146 sec
APTT 71 sec 25 ndash 34 sec
D-dimer 31 microgmL FEU lt050 microgml FEU
Fibrinogen 92 mgdL 150-400 mgdl
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 158 gdL 14-16 gdL
WBC 71 times 103mm3 40-11 times 103mm3
ALT 60 IUL 0ndash34 IUL
AST 47 IUL 0ndash34 IUL
BUN 38 mgdL 08-13 mgdL
Case Study 4 ndash Lab Results
Lyme disease with DICProvide antibiotics with supportive measures
Case Study 4 ndash Diagnosis
55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis
Case Study 5 ndash Presentation
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
Case Study 5 ndash Lab Results and Time Course
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
TEST RESULT REFERENCE RANGE
Platelet count 33 x 109L 150-450 x 109L
PT 215 sec 103 ndash 128 sec
APTT 44 sec 26 ndash 36 sec
D-dimer 20 microgmL FEU lt025 microgml FEU
Fibrinogen 34 mgdL 200-375 mgdl
FII FV FVIII Low Not reported (NR)
FVII FIX FX vWF Normal NR
Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)
DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic
dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR
(C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen
(D) Illustration demonstrating repair
Case Study 5 ndash Diagnosis and Treatment
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography
Case Study 6 ndash Presentation
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
Case Study 6 ndash Lab Results
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L
PT 63 sec gt control 113 ndash 146 sec
INR 658 1 ndash 125
APTT 80 sec gt control 25 ndash 34 sec
D-dimer gt200 microgmL DDU 02 microgmL DDU
Urine exam Proteinuria and hematuria 150-400 mgdl
Albumin 28 gdL NR
Hb 58 gdL NR
LDH 1196 UL NR
SGPT 144 IU NR
SGOT 88 IU NR
Bilirubin 32 mgdL NR
DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th
day postop
Case Study 6 ndash Diagnosis and Treatment
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure
Case Study 6 ndash Discussion
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Case Study 7 ndash Lab Results vs Time
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
DIC Take Home Messages
Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation
Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers
DIC
Thank you Questions
- Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
- Learning Objectives
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Wound Sealing
- The Three Steps of Hemostasis
- Vessel Wall
- Slide Number 12
- Slide Number 13
- Platelet Structure UnactivatedActivated
- Primary Hemostasis
- Primary Hemostasis Assays
- Slide Number 17
- Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
- Slide Number 19
- Coagulation factors
- Coagulation Assay Mechanisms
- Slide Number 22
- Fibrin Formation
- Slide Number 24
- Fibrinolysis Overview
- Fibrinolysis Overview
- Slide Number 27
- Fibrinolysis Releases D-dimers
- Basic Pathophysiology of DIC
- Disseminated Intravascular Coagulation (DIC)
- Purpura Fulminans with DIC Due to Meningococcal Sepsis
- Clinical Conditions Associated With DIC
- Frequency of DIC in Selected Disease States
- Underlying Diseases in DIC Patients
- Slide Number 36
- Slide Number 37
- Slide Number 38
- Slide Number 39
- Pathophysiology of DIC
- Pathogenesis of DIC in Sepsis
- Host Response in Severe Sepsis
- Organ Failure in Severe Sepsis
- Mechanism of DIC in Organ Failure
- Interaction of Inflammation and Coagulation in Sepsis
- Slide Number 47
- Diverse and Opposing Effects of Thrombin
- Coagulation and Fibrinolysis in DIC
- Mechanism of DIC
- Pathophysiology of DIC
- Pathophysiology of DIC - Mechanism
- Pathophysiology of DIC ndash 2 Types of Clinical pictures
- Sub-Acute and Non-Overt DIC Clinical Findings
- Pathophysiology of Overt DIC
- Physiopathology of DIC ndash Overt DIC Findings
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- BREAK
- Diagnostic and Management Approach for DIC
- Diagnosis of DIC
- Lab Diagnosis of DIC ndash Markers of Factor Consumption
- Lab Diagnosis of DIC ndash Screening Tests
- Slide Number 67
- Slide Number 68
- British Journal of Haematology Overt DIC Score
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- DIC Management Goals
- DIC Management and Treatment
- DIC Management Strategies
- Anticoagulant Factor Concentrate Treatment
- Anticoagulant Factor Concentrate Treatment Trials
- Markers of Thrombin amp Plasmin Generation in DIC
- D-dimer FDPs and DIC
- D-Dimer and FDPs in DIC
- Follow Up of DIC State of Disease
- FMD-Dimer in DIC Major Differences
- of Abnormal Results in Patients with Confirmed and Suspected DIC
- Slide Number 85
- Slide Number 86
- Comparing an Automated FM vs Manual FSP Test
- Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Slide Number 94
- Slide Number 95
- Slide Number 96
- Slide Number 97
- Slide Number 98
- Slide Number 99
- DIC Case Studies
- Case Study 1 - Presentation
- Case Study 1 ndash Lab Results
- Case Study 1 ndash Microscopy
- Case Study 1 ndash Diagnosis and Therapy
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Slide Number 110
- Slide Number 111
- Slide Number 112
- Slide Number 113
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
- Slide Number 124
- Slide Number 125
- DIC Take Home Messages
- Slide Number 127
- Slide Number 128
-
Diagnostic Performance of FM and D-dimer in DIC
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
Non Overt DIC Overt DIC
AUC in the ROC was higher for D-dimer (dashed line) in Non-overt but higher for FM (solidline) in Overt DIC
Trends in Markers of DIC for Different Patients
Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00
Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients
Trends in Markers of DIC for Different Patients
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes
28 day outcome survival
28 day outcome death
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines
DIC Case Studies
Case Study 1 - Presentation
18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE
WBC count 77 KμL 423 ndash 907 x KμL
RBC count 17 MμL 137 ndash 175 x MμL
Hemoglobin 67 gdL 137 ndash 175 gdL
Hematocrit 195 401 ndash 510
MCV 95 fL 790 ndash 922 fL
MPV 12 fL 94 ndash 124 fL
Platelet count 9 KμL 161 ndash 347 KμL
Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0
Lymphocytes monocytes eosinophils basophils all below normal range
PT 47 sec (corrected on mixing study) 116 ndash 152 sec
APTT 75 sec (corrected on mixing study) 253 ndash 373 sec
Fibrinogen lt 76 mgdL 177 ndash 466 mgdL
D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Microscopy
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Arrow shows giant platelets in this peripheral smear Promyelocytes apparent
Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)
DIC due to TF release by APL blasts
Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases
Transfusions to replace factors along with platelets and RBCs during APL treatment
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started
Case Study 2 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L
PT 30 sec 113 ndash 146 sec
APTT 75 sec 25 ndash 34 sec
D-dimer 078 microgml FEU lt050 microgml FEU
Fibrinogen 92 mgdl 150-400 mgdl
pH 728 738 to 742
PaO2 570 mmHg 80-100 mmHg
WBC 33 times 103mm3 40-11 times 103mm3
ALT 111 IUL 0ndash34 IUL
AST 61 IUL 0ndash34 IUL
BUN 303 mgdL 08-13 mgdL
Case Study 2 ndash Lab Results
Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures
Case Study 2 ndash Diagnosis
60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior
Case Study 3 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L
PT 228 sec 113 ndash 146 sec
APTT 45 sec 25 ndash 34 sec
D-dimer 080 microgml FEU lt050 microgmL FEU
Fibrinogen 82 mgdL 150-400 mgdL
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 134 gdL 14-16 gdL
WBC 81 times 103mm3 40-11 times 103mm3
ALT 32 IUL 0ndash34 IUL
AST 28 IUL 0ndash34 IUL
BUN 09 mgdL 08-13 mgdL
Case Study 3 ndash Lab Results
Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment
Case Study 3 ndash Diagnosis and Therapy
Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91
Case Study 4 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L
PT 28 sec 113 ndash 146 sec
APTT 71 sec 25 ndash 34 sec
D-dimer 31 microgmL FEU lt050 microgml FEU
Fibrinogen 92 mgdL 150-400 mgdl
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 158 gdL 14-16 gdL
WBC 71 times 103mm3 40-11 times 103mm3
ALT 60 IUL 0ndash34 IUL
AST 47 IUL 0ndash34 IUL
BUN 38 mgdL 08-13 mgdL
Case Study 4 ndash Lab Results
Lyme disease with DICProvide antibiotics with supportive measures
Case Study 4 ndash Diagnosis
55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis
Case Study 5 ndash Presentation
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
Case Study 5 ndash Lab Results and Time Course
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
TEST RESULT REFERENCE RANGE
Platelet count 33 x 109L 150-450 x 109L
PT 215 sec 103 ndash 128 sec
APTT 44 sec 26 ndash 36 sec
D-dimer 20 microgmL FEU lt025 microgml FEU
Fibrinogen 34 mgdL 200-375 mgdl
FII FV FVIII Low Not reported (NR)
FVII FIX FX vWF Normal NR
Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)
DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic
dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR
(C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen
(D) Illustration demonstrating repair
Case Study 5 ndash Diagnosis and Treatment
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography
Case Study 6 ndash Presentation
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
Case Study 6 ndash Lab Results
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L
PT 63 sec gt control 113 ndash 146 sec
INR 658 1 ndash 125
APTT 80 sec gt control 25 ndash 34 sec
D-dimer gt200 microgmL DDU 02 microgmL DDU
Urine exam Proteinuria and hematuria 150-400 mgdl
Albumin 28 gdL NR
Hb 58 gdL NR
LDH 1196 UL NR
SGPT 144 IU NR
SGOT 88 IU NR
Bilirubin 32 mgdL NR
DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th
day postop
Case Study 6 ndash Diagnosis and Treatment
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure
Case Study 6 ndash Discussion
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Case Study 7 ndash Lab Results vs Time
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
DIC Take Home Messages
Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation
Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers
DIC
Thank you Questions
- Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
- Learning Objectives
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Wound Sealing
- The Three Steps of Hemostasis
- Vessel Wall
- Slide Number 12
- Slide Number 13
- Platelet Structure UnactivatedActivated
- Primary Hemostasis
- Primary Hemostasis Assays
- Slide Number 17
- Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
- Slide Number 19
- Coagulation factors
- Coagulation Assay Mechanisms
- Slide Number 22
- Fibrin Formation
- Slide Number 24
- Fibrinolysis Overview
- Fibrinolysis Overview
- Slide Number 27
- Fibrinolysis Releases D-dimers
- Basic Pathophysiology of DIC
- Disseminated Intravascular Coagulation (DIC)
- Purpura Fulminans with DIC Due to Meningococcal Sepsis
- Clinical Conditions Associated With DIC
- Frequency of DIC in Selected Disease States
- Underlying Diseases in DIC Patients
- Slide Number 36
- Slide Number 37
- Slide Number 38
- Slide Number 39
- Pathophysiology of DIC
- Pathogenesis of DIC in Sepsis
- Host Response in Severe Sepsis
- Organ Failure in Severe Sepsis
- Mechanism of DIC in Organ Failure
- Interaction of Inflammation and Coagulation in Sepsis
- Slide Number 47
- Diverse and Opposing Effects of Thrombin
- Coagulation and Fibrinolysis in DIC
- Mechanism of DIC
- Pathophysiology of DIC
- Pathophysiology of DIC - Mechanism
- Pathophysiology of DIC ndash 2 Types of Clinical pictures
- Sub-Acute and Non-Overt DIC Clinical Findings
- Pathophysiology of Overt DIC
- Physiopathology of DIC ndash Overt DIC Findings
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- BREAK
- Diagnostic and Management Approach for DIC
- Diagnosis of DIC
- Lab Diagnosis of DIC ndash Markers of Factor Consumption
- Lab Diagnosis of DIC ndash Screening Tests
- Slide Number 67
- Slide Number 68
- British Journal of Haematology Overt DIC Score
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- DIC Management Goals
- DIC Management and Treatment
- DIC Management Strategies
- Anticoagulant Factor Concentrate Treatment
- Anticoagulant Factor Concentrate Treatment Trials
- Markers of Thrombin amp Plasmin Generation in DIC
- D-dimer FDPs and DIC
- D-Dimer and FDPs in DIC
- Follow Up of DIC State of Disease
- FMD-Dimer in DIC Major Differences
- of Abnormal Results in Patients with Confirmed and Suspected DIC
- Slide Number 85
- Slide Number 86
- Comparing an Automated FM vs Manual FSP Test
- Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Slide Number 94
- Slide Number 95
- Slide Number 96
- Slide Number 97
- Slide Number 98
- Slide Number 99
- DIC Case Studies
- Case Study 1 - Presentation
- Case Study 1 ndash Lab Results
- Case Study 1 ndash Microscopy
- Case Study 1 ndash Diagnosis and Therapy
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Slide Number 110
- Slide Number 111
- Slide Number 112
- Slide Number 113
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
- Slide Number 124
- Slide Number 125
- DIC Take Home Messages
- Slide Number 127
- Slide Number 128
-
Trends in Markers of DIC for Different Patients
Toh JMH Ken-Drorb G Downeyd C Abram ST The clinical utility of fibrin-related biomarkers in sepsisBlood Coagulation and Fibrinolysis 2013 2400ndash00
Sepsis patients have much higher levels of FDP FM and D-dimer compared to normal and systemic inflammatory response syndrome (SIRS) patients
Trends in Markers of DIC for Different Patients
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes
28 day outcome survival
28 day outcome death
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines
DIC Case Studies
Case Study 1 - Presentation
18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE
WBC count 77 KμL 423 ndash 907 x KμL
RBC count 17 MμL 137 ndash 175 x MμL
Hemoglobin 67 gdL 137 ndash 175 gdL
Hematocrit 195 401 ndash 510
MCV 95 fL 790 ndash 922 fL
MPV 12 fL 94 ndash 124 fL
Platelet count 9 KμL 161 ndash 347 KμL
Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0
Lymphocytes monocytes eosinophils basophils all below normal range
PT 47 sec (corrected on mixing study) 116 ndash 152 sec
APTT 75 sec (corrected on mixing study) 253 ndash 373 sec
Fibrinogen lt 76 mgdL 177 ndash 466 mgdL
D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Microscopy
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Arrow shows giant platelets in this peripheral smear Promyelocytes apparent
Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)
DIC due to TF release by APL blasts
Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases
Transfusions to replace factors along with platelets and RBCs during APL treatment
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started
Case Study 2 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L
PT 30 sec 113 ndash 146 sec
APTT 75 sec 25 ndash 34 sec
D-dimer 078 microgml FEU lt050 microgml FEU
Fibrinogen 92 mgdl 150-400 mgdl
pH 728 738 to 742
PaO2 570 mmHg 80-100 mmHg
WBC 33 times 103mm3 40-11 times 103mm3
ALT 111 IUL 0ndash34 IUL
AST 61 IUL 0ndash34 IUL
BUN 303 mgdL 08-13 mgdL
Case Study 2 ndash Lab Results
Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures
Case Study 2 ndash Diagnosis
60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior
Case Study 3 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L
PT 228 sec 113 ndash 146 sec
APTT 45 sec 25 ndash 34 sec
D-dimer 080 microgml FEU lt050 microgmL FEU
Fibrinogen 82 mgdL 150-400 mgdL
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 134 gdL 14-16 gdL
WBC 81 times 103mm3 40-11 times 103mm3
ALT 32 IUL 0ndash34 IUL
AST 28 IUL 0ndash34 IUL
BUN 09 mgdL 08-13 mgdL
Case Study 3 ndash Lab Results
Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment
Case Study 3 ndash Diagnosis and Therapy
Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91
Case Study 4 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L
PT 28 sec 113 ndash 146 sec
APTT 71 sec 25 ndash 34 sec
D-dimer 31 microgmL FEU lt050 microgml FEU
Fibrinogen 92 mgdL 150-400 mgdl
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 158 gdL 14-16 gdL
WBC 71 times 103mm3 40-11 times 103mm3
ALT 60 IUL 0ndash34 IUL
AST 47 IUL 0ndash34 IUL
BUN 38 mgdL 08-13 mgdL
Case Study 4 ndash Lab Results
Lyme disease with DICProvide antibiotics with supportive measures
Case Study 4 ndash Diagnosis
55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis
Case Study 5 ndash Presentation
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
Case Study 5 ndash Lab Results and Time Course
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
TEST RESULT REFERENCE RANGE
Platelet count 33 x 109L 150-450 x 109L
PT 215 sec 103 ndash 128 sec
APTT 44 sec 26 ndash 36 sec
D-dimer 20 microgmL FEU lt025 microgml FEU
Fibrinogen 34 mgdL 200-375 mgdl
FII FV FVIII Low Not reported (NR)
FVII FIX FX vWF Normal NR
Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)
DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic
dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR
(C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen
(D) Illustration demonstrating repair
Case Study 5 ndash Diagnosis and Treatment
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography
Case Study 6 ndash Presentation
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
Case Study 6 ndash Lab Results
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L
PT 63 sec gt control 113 ndash 146 sec
INR 658 1 ndash 125
APTT 80 sec gt control 25 ndash 34 sec
D-dimer gt200 microgmL DDU 02 microgmL DDU
Urine exam Proteinuria and hematuria 150-400 mgdl
Albumin 28 gdL NR
Hb 58 gdL NR
LDH 1196 UL NR
SGPT 144 IU NR
SGOT 88 IU NR
Bilirubin 32 mgdL NR
DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th
day postop
Case Study 6 ndash Diagnosis and Treatment
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure
Case Study 6 ndash Discussion
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Case Study 7 ndash Lab Results vs Time
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
DIC Take Home Messages
Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation
Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers
DIC
Thank you Questions
- Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
- Learning Objectives
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Wound Sealing
- The Three Steps of Hemostasis
- Vessel Wall
- Slide Number 12
- Slide Number 13
- Platelet Structure UnactivatedActivated
- Primary Hemostasis
- Primary Hemostasis Assays
- Slide Number 17
- Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
- Slide Number 19
- Coagulation factors
- Coagulation Assay Mechanisms
- Slide Number 22
- Fibrin Formation
- Slide Number 24
- Fibrinolysis Overview
- Fibrinolysis Overview
- Slide Number 27
- Fibrinolysis Releases D-dimers
- Basic Pathophysiology of DIC
- Disseminated Intravascular Coagulation (DIC)
- Purpura Fulminans with DIC Due to Meningococcal Sepsis
- Clinical Conditions Associated With DIC
- Frequency of DIC in Selected Disease States
- Underlying Diseases in DIC Patients
- Slide Number 36
- Slide Number 37
- Slide Number 38
- Slide Number 39
- Pathophysiology of DIC
- Pathogenesis of DIC in Sepsis
- Host Response in Severe Sepsis
- Organ Failure in Severe Sepsis
- Mechanism of DIC in Organ Failure
- Interaction of Inflammation and Coagulation in Sepsis
- Slide Number 47
- Diverse and Opposing Effects of Thrombin
- Coagulation and Fibrinolysis in DIC
- Mechanism of DIC
- Pathophysiology of DIC
- Pathophysiology of DIC - Mechanism
- Pathophysiology of DIC ndash 2 Types of Clinical pictures
- Sub-Acute and Non-Overt DIC Clinical Findings
- Pathophysiology of Overt DIC
- Physiopathology of DIC ndash Overt DIC Findings
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- BREAK
- Diagnostic and Management Approach for DIC
- Diagnosis of DIC
- Lab Diagnosis of DIC ndash Markers of Factor Consumption
- Lab Diagnosis of DIC ndash Screening Tests
- Slide Number 67
- Slide Number 68
- British Journal of Haematology Overt DIC Score
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- DIC Management Goals
- DIC Management and Treatment
- DIC Management Strategies
- Anticoagulant Factor Concentrate Treatment
- Anticoagulant Factor Concentrate Treatment Trials
- Markers of Thrombin amp Plasmin Generation in DIC
- D-dimer FDPs and DIC
- D-Dimer and FDPs in DIC
- Follow Up of DIC State of Disease
- FMD-Dimer in DIC Major Differences
- of Abnormal Results in Patients with Confirmed and Suspected DIC
- Slide Number 85
- Slide Number 86
- Comparing an Automated FM vs Manual FSP Test
- Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Slide Number 94
- Slide Number 95
- Slide Number 96
- Slide Number 97
- Slide Number 98
- Slide Number 99
- DIC Case Studies
- Case Study 1 - Presentation
- Case Study 1 ndash Lab Results
- Case Study 1 ndash Microscopy
- Case Study 1 ndash Diagnosis and Therapy
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Slide Number 110
- Slide Number 111
- Slide Number 112
- Slide Number 113
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
- Slide Number 124
- Slide Number 125
- DIC Take Home Messages
- Slide Number 127
- Slide Number 128
-
Trends in Markers of DIC for Different Patients
Park KJ Kwon EH Kim HJ Kim SH Evaluation of the diagnostic performance of fibrin monomer in disseminated intravascular coagulation Korean J Lab Med 2011 31 143-7
FDP FM and D-dimer all increase for patients with survival outcomes compared to thosewith death outcomes
28 day outcome survival
28 day outcome death
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines
DIC Case Studies
Case Study 1 - Presentation
18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE
WBC count 77 KμL 423 ndash 907 x KμL
RBC count 17 MμL 137 ndash 175 x MμL
Hemoglobin 67 gdL 137 ndash 175 gdL
Hematocrit 195 401 ndash 510
MCV 95 fL 790 ndash 922 fL
MPV 12 fL 94 ndash 124 fL
Platelet count 9 KμL 161 ndash 347 KμL
Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0
Lymphocytes monocytes eosinophils basophils all below normal range
PT 47 sec (corrected on mixing study) 116 ndash 152 sec
APTT 75 sec (corrected on mixing study) 253 ndash 373 sec
Fibrinogen lt 76 mgdL 177 ndash 466 mgdL
D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Microscopy
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Arrow shows giant platelets in this peripheral smear Promyelocytes apparent
Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)
DIC due to TF release by APL blasts
Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases
Transfusions to replace factors along with platelets and RBCs during APL treatment
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started
Case Study 2 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L
PT 30 sec 113 ndash 146 sec
APTT 75 sec 25 ndash 34 sec
D-dimer 078 microgml FEU lt050 microgml FEU
Fibrinogen 92 mgdl 150-400 mgdl
pH 728 738 to 742
PaO2 570 mmHg 80-100 mmHg
WBC 33 times 103mm3 40-11 times 103mm3
ALT 111 IUL 0ndash34 IUL
AST 61 IUL 0ndash34 IUL
BUN 303 mgdL 08-13 mgdL
Case Study 2 ndash Lab Results
Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures
Case Study 2 ndash Diagnosis
60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior
Case Study 3 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L
PT 228 sec 113 ndash 146 sec
APTT 45 sec 25 ndash 34 sec
D-dimer 080 microgml FEU lt050 microgmL FEU
Fibrinogen 82 mgdL 150-400 mgdL
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 134 gdL 14-16 gdL
WBC 81 times 103mm3 40-11 times 103mm3
ALT 32 IUL 0ndash34 IUL
AST 28 IUL 0ndash34 IUL
BUN 09 mgdL 08-13 mgdL
Case Study 3 ndash Lab Results
Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment
Case Study 3 ndash Diagnosis and Therapy
Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91
Case Study 4 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L
PT 28 sec 113 ndash 146 sec
APTT 71 sec 25 ndash 34 sec
D-dimer 31 microgmL FEU lt050 microgml FEU
Fibrinogen 92 mgdL 150-400 mgdl
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 158 gdL 14-16 gdL
WBC 71 times 103mm3 40-11 times 103mm3
ALT 60 IUL 0ndash34 IUL
AST 47 IUL 0ndash34 IUL
BUN 38 mgdL 08-13 mgdL
Case Study 4 ndash Lab Results
Lyme disease with DICProvide antibiotics with supportive measures
Case Study 4 ndash Diagnosis
55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis
Case Study 5 ndash Presentation
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
Case Study 5 ndash Lab Results and Time Course
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
TEST RESULT REFERENCE RANGE
Platelet count 33 x 109L 150-450 x 109L
PT 215 sec 103 ndash 128 sec
APTT 44 sec 26 ndash 36 sec
D-dimer 20 microgmL FEU lt025 microgml FEU
Fibrinogen 34 mgdL 200-375 mgdl
FII FV FVIII Low Not reported (NR)
FVII FIX FX vWF Normal NR
Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)
DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic
dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR
(C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen
(D) Illustration demonstrating repair
Case Study 5 ndash Diagnosis and Treatment
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography
Case Study 6 ndash Presentation
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
Case Study 6 ndash Lab Results
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L
PT 63 sec gt control 113 ndash 146 sec
INR 658 1 ndash 125
APTT 80 sec gt control 25 ndash 34 sec
D-dimer gt200 microgmL DDU 02 microgmL DDU
Urine exam Proteinuria and hematuria 150-400 mgdl
Albumin 28 gdL NR
Hb 58 gdL NR
LDH 1196 UL NR
SGPT 144 IU NR
SGOT 88 IU NR
Bilirubin 32 mgdL NR
DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th
day postop
Case Study 6 ndash Diagnosis and Treatment
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure
Case Study 6 ndash Discussion
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Case Study 7 ndash Lab Results vs Time
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
DIC Take Home Messages
Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation
Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers
DIC
Thank you Questions
- Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
- Learning Objectives
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Wound Sealing
- The Three Steps of Hemostasis
- Vessel Wall
- Slide Number 12
- Slide Number 13
- Platelet Structure UnactivatedActivated
- Primary Hemostasis
- Primary Hemostasis Assays
- Slide Number 17
- Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
- Slide Number 19
- Coagulation factors
- Coagulation Assay Mechanisms
- Slide Number 22
- Fibrin Formation
- Slide Number 24
- Fibrinolysis Overview
- Fibrinolysis Overview
- Slide Number 27
- Fibrinolysis Releases D-dimers
- Basic Pathophysiology of DIC
- Disseminated Intravascular Coagulation (DIC)
- Purpura Fulminans with DIC Due to Meningococcal Sepsis
- Clinical Conditions Associated With DIC
- Frequency of DIC in Selected Disease States
- Underlying Diseases in DIC Patients
- Slide Number 36
- Slide Number 37
- Slide Number 38
- Slide Number 39
- Pathophysiology of DIC
- Pathogenesis of DIC in Sepsis
- Host Response in Severe Sepsis
- Organ Failure in Severe Sepsis
- Mechanism of DIC in Organ Failure
- Interaction of Inflammation and Coagulation in Sepsis
- Slide Number 47
- Diverse and Opposing Effects of Thrombin
- Coagulation and Fibrinolysis in DIC
- Mechanism of DIC
- Pathophysiology of DIC
- Pathophysiology of DIC - Mechanism
- Pathophysiology of DIC ndash 2 Types of Clinical pictures
- Sub-Acute and Non-Overt DIC Clinical Findings
- Pathophysiology of Overt DIC
- Physiopathology of DIC ndash Overt DIC Findings
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- BREAK
- Diagnostic and Management Approach for DIC
- Diagnosis of DIC
- Lab Diagnosis of DIC ndash Markers of Factor Consumption
- Lab Diagnosis of DIC ndash Screening Tests
- Slide Number 67
- Slide Number 68
- British Journal of Haematology Overt DIC Score
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- DIC Management Goals
- DIC Management and Treatment
- DIC Management Strategies
- Anticoagulant Factor Concentrate Treatment
- Anticoagulant Factor Concentrate Treatment Trials
- Markers of Thrombin amp Plasmin Generation in DIC
- D-dimer FDPs and DIC
- D-Dimer and FDPs in DIC
- Follow Up of DIC State of Disease
- FMD-Dimer in DIC Major Differences
- of Abnormal Results in Patients with Confirmed and Suspected DIC
- Slide Number 85
- Slide Number 86
- Comparing an Automated FM vs Manual FSP Test
- Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Slide Number 94
- Slide Number 95
- Slide Number 96
- Slide Number 97
- Slide Number 98
- Slide Number 99
- DIC Case Studies
- Case Study 1 - Presentation
- Case Study 1 ndash Lab Results
- Case Study 1 ndash Microscopy
- Case Study 1 ndash Diagnosis and Therapy
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Slide Number 110
- Slide Number 111
- Slide Number 112
- Slide Number 113
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
- Slide Number 124
- Slide Number 125
- DIC Take Home Messages
- Slide Number 127
- Slide Number 128
-
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines
DIC Case Studies
Case Study 1 - Presentation
18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE
WBC count 77 KμL 423 ndash 907 x KμL
RBC count 17 MμL 137 ndash 175 x MμL
Hemoglobin 67 gdL 137 ndash 175 gdL
Hematocrit 195 401 ndash 510
MCV 95 fL 790 ndash 922 fL
MPV 12 fL 94 ndash 124 fL
Platelet count 9 KμL 161 ndash 347 KμL
Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0
Lymphocytes monocytes eosinophils basophils all below normal range
PT 47 sec (corrected on mixing study) 116 ndash 152 sec
APTT 75 sec (corrected on mixing study) 253 ndash 373 sec
Fibrinogen lt 76 mgdL 177 ndash 466 mgdL
D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Microscopy
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Arrow shows giant platelets in this peripheral smear Promyelocytes apparent
Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)
DIC due to TF release by APL blasts
Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases
Transfusions to replace factors along with platelets and RBCs during APL treatment
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started
Case Study 2 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L
PT 30 sec 113 ndash 146 sec
APTT 75 sec 25 ndash 34 sec
D-dimer 078 microgml FEU lt050 microgml FEU
Fibrinogen 92 mgdl 150-400 mgdl
pH 728 738 to 742
PaO2 570 mmHg 80-100 mmHg
WBC 33 times 103mm3 40-11 times 103mm3
ALT 111 IUL 0ndash34 IUL
AST 61 IUL 0ndash34 IUL
BUN 303 mgdL 08-13 mgdL
Case Study 2 ndash Lab Results
Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures
Case Study 2 ndash Diagnosis
60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior
Case Study 3 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L
PT 228 sec 113 ndash 146 sec
APTT 45 sec 25 ndash 34 sec
D-dimer 080 microgml FEU lt050 microgmL FEU
Fibrinogen 82 mgdL 150-400 mgdL
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 134 gdL 14-16 gdL
WBC 81 times 103mm3 40-11 times 103mm3
ALT 32 IUL 0ndash34 IUL
AST 28 IUL 0ndash34 IUL
BUN 09 mgdL 08-13 mgdL
Case Study 3 ndash Lab Results
Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment
Case Study 3 ndash Diagnosis and Therapy
Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91
Case Study 4 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L
PT 28 sec 113 ndash 146 sec
APTT 71 sec 25 ndash 34 sec
D-dimer 31 microgmL FEU lt050 microgml FEU
Fibrinogen 92 mgdL 150-400 mgdl
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 158 gdL 14-16 gdL
WBC 71 times 103mm3 40-11 times 103mm3
ALT 60 IUL 0ndash34 IUL
AST 47 IUL 0ndash34 IUL
BUN 38 mgdL 08-13 mgdL
Case Study 4 ndash Lab Results
Lyme disease with DICProvide antibiotics with supportive measures
Case Study 4 ndash Diagnosis
55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis
Case Study 5 ndash Presentation
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
Case Study 5 ndash Lab Results and Time Course
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
TEST RESULT REFERENCE RANGE
Platelet count 33 x 109L 150-450 x 109L
PT 215 sec 103 ndash 128 sec
APTT 44 sec 26 ndash 36 sec
D-dimer 20 microgmL FEU lt025 microgml FEU
Fibrinogen 34 mgdL 200-375 mgdl
FII FV FVIII Low Not reported (NR)
FVII FIX FX vWF Normal NR
Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)
DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic
dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR
(C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen
(D) Illustration demonstrating repair
Case Study 5 ndash Diagnosis and Treatment
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography
Case Study 6 ndash Presentation
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
Case Study 6 ndash Lab Results
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L
PT 63 sec gt control 113 ndash 146 sec
INR 658 1 ndash 125
APTT 80 sec gt control 25 ndash 34 sec
D-dimer gt200 microgmL DDU 02 microgmL DDU
Urine exam Proteinuria and hematuria 150-400 mgdl
Albumin 28 gdL NR
Hb 58 gdL NR
LDH 1196 UL NR
SGPT 144 IU NR
SGOT 88 IU NR
Bilirubin 32 mgdL NR
DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th
day postop
Case Study 6 ndash Diagnosis and Treatment
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure
Case Study 6 ndash Discussion
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Case Study 7 ndash Lab Results vs Time
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
DIC Take Home Messages
Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation
Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers
DIC
Thank you Questions
- Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
- Learning Objectives
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Wound Sealing
- The Three Steps of Hemostasis
- Vessel Wall
- Slide Number 12
- Slide Number 13
- Platelet Structure UnactivatedActivated
- Primary Hemostasis
- Primary Hemostasis Assays
- Slide Number 17
- Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
- Slide Number 19
- Coagulation factors
- Coagulation Assay Mechanisms
- Slide Number 22
- Fibrin Formation
- Slide Number 24
- Fibrinolysis Overview
- Fibrinolysis Overview
- Slide Number 27
- Fibrinolysis Releases D-dimers
- Basic Pathophysiology of DIC
- Disseminated Intravascular Coagulation (DIC)
- Purpura Fulminans with DIC Due to Meningococcal Sepsis
- Clinical Conditions Associated With DIC
- Frequency of DIC in Selected Disease States
- Underlying Diseases in DIC Patients
- Slide Number 36
- Slide Number 37
- Slide Number 38
- Slide Number 39
- Pathophysiology of DIC
- Pathogenesis of DIC in Sepsis
- Host Response in Severe Sepsis
- Organ Failure in Severe Sepsis
- Mechanism of DIC in Organ Failure
- Interaction of Inflammation and Coagulation in Sepsis
- Slide Number 47
- Diverse and Opposing Effects of Thrombin
- Coagulation and Fibrinolysis in DIC
- Mechanism of DIC
- Pathophysiology of DIC
- Pathophysiology of DIC - Mechanism
- Pathophysiology of DIC ndash 2 Types of Clinical pictures
- Sub-Acute and Non-Overt DIC Clinical Findings
- Pathophysiology of Overt DIC
- Physiopathology of DIC ndash Overt DIC Findings
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- BREAK
- Diagnostic and Management Approach for DIC
- Diagnosis of DIC
- Lab Diagnosis of DIC ndash Markers of Factor Consumption
- Lab Diagnosis of DIC ndash Screening Tests
- Slide Number 67
- Slide Number 68
- British Journal of Haematology Overt DIC Score
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- DIC Management Goals
- DIC Management and Treatment
- DIC Management Strategies
- Anticoagulant Factor Concentrate Treatment
- Anticoagulant Factor Concentrate Treatment Trials
- Markers of Thrombin amp Plasmin Generation in DIC
- D-dimer FDPs and DIC
- D-Dimer and FDPs in DIC
- Follow Up of DIC State of Disease
- FMD-Dimer in DIC Major Differences
- of Abnormal Results in Patients with Confirmed and Suspected DIC
- Slide Number 85
- Slide Number 86
- Comparing an Automated FM vs Manual FSP Test
- Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Slide Number 94
- Slide Number 95
- Slide Number 96
- Slide Number 97
- Slide Number 98
- Slide Number 99
- DIC Case Studies
- Case Study 1 - Presentation
- Case Study 1 ndash Lab Results
- Case Study 1 ndash Microscopy
- Case Study 1 ndash Diagnosis and Therapy
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Slide Number 110
- Slide Number 111
- Slide Number 112
- Slide Number 113
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
- Slide Number 124
- Slide Number 125
- DIC Take Home Messages
- Slide Number 127
- Slide Number 128
-
Determination of Cutoffs of FM and D-dimer in DIC
Hatada T Wada H Kawasugi K Okamoto K Uchiyama T Kushimoto S et al Japanese Society of Thrombosis HemostasisDIC subcommittee Analysis of the cutoff values in fibrin-related markers for the diagnosis of overt DIC Clin Appl Thromb Hemost 2012 18 495-500
Analysis of D-dimer FDP and FM in DIC patients and classifying by outcome enablescutoff values to be determined in concordance with ISTH guidelines
DIC Case Studies
Case Study 1 - Presentation
18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE
WBC count 77 KμL 423 ndash 907 x KμL
RBC count 17 MμL 137 ndash 175 x MμL
Hemoglobin 67 gdL 137 ndash 175 gdL
Hematocrit 195 401 ndash 510
MCV 95 fL 790 ndash 922 fL
MPV 12 fL 94 ndash 124 fL
Platelet count 9 KμL 161 ndash 347 KμL
Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0
Lymphocytes monocytes eosinophils basophils all below normal range
PT 47 sec (corrected on mixing study) 116 ndash 152 sec
APTT 75 sec (corrected on mixing study) 253 ndash 373 sec
Fibrinogen lt 76 mgdL 177 ndash 466 mgdL
D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Microscopy
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Arrow shows giant platelets in this peripheral smear Promyelocytes apparent
Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)
DIC due to TF release by APL blasts
Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases
Transfusions to replace factors along with platelets and RBCs during APL treatment
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started
Case Study 2 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L
PT 30 sec 113 ndash 146 sec
APTT 75 sec 25 ndash 34 sec
D-dimer 078 microgml FEU lt050 microgml FEU
Fibrinogen 92 mgdl 150-400 mgdl
pH 728 738 to 742
PaO2 570 mmHg 80-100 mmHg
WBC 33 times 103mm3 40-11 times 103mm3
ALT 111 IUL 0ndash34 IUL
AST 61 IUL 0ndash34 IUL
BUN 303 mgdL 08-13 mgdL
Case Study 2 ndash Lab Results
Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures
Case Study 2 ndash Diagnosis
60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior
Case Study 3 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L
PT 228 sec 113 ndash 146 sec
APTT 45 sec 25 ndash 34 sec
D-dimer 080 microgml FEU lt050 microgmL FEU
Fibrinogen 82 mgdL 150-400 mgdL
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 134 gdL 14-16 gdL
WBC 81 times 103mm3 40-11 times 103mm3
ALT 32 IUL 0ndash34 IUL
AST 28 IUL 0ndash34 IUL
BUN 09 mgdL 08-13 mgdL
Case Study 3 ndash Lab Results
Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment
Case Study 3 ndash Diagnosis and Therapy
Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91
Case Study 4 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L
PT 28 sec 113 ndash 146 sec
APTT 71 sec 25 ndash 34 sec
D-dimer 31 microgmL FEU lt050 microgml FEU
Fibrinogen 92 mgdL 150-400 mgdl
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 158 gdL 14-16 gdL
WBC 71 times 103mm3 40-11 times 103mm3
ALT 60 IUL 0ndash34 IUL
AST 47 IUL 0ndash34 IUL
BUN 38 mgdL 08-13 mgdL
Case Study 4 ndash Lab Results
Lyme disease with DICProvide antibiotics with supportive measures
Case Study 4 ndash Diagnosis
55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis
Case Study 5 ndash Presentation
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
Case Study 5 ndash Lab Results and Time Course
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
TEST RESULT REFERENCE RANGE
Platelet count 33 x 109L 150-450 x 109L
PT 215 sec 103 ndash 128 sec
APTT 44 sec 26 ndash 36 sec
D-dimer 20 microgmL FEU lt025 microgml FEU
Fibrinogen 34 mgdL 200-375 mgdl
FII FV FVIII Low Not reported (NR)
FVII FIX FX vWF Normal NR
Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)
DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic
dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR
(C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen
(D) Illustration demonstrating repair
Case Study 5 ndash Diagnosis and Treatment
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography
Case Study 6 ndash Presentation
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
Case Study 6 ndash Lab Results
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L
PT 63 sec gt control 113 ndash 146 sec
INR 658 1 ndash 125
APTT 80 sec gt control 25 ndash 34 sec
D-dimer gt200 microgmL DDU 02 microgmL DDU
Urine exam Proteinuria and hematuria 150-400 mgdl
Albumin 28 gdL NR
Hb 58 gdL NR
LDH 1196 UL NR
SGPT 144 IU NR
SGOT 88 IU NR
Bilirubin 32 mgdL NR
DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th
day postop
Case Study 6 ndash Diagnosis and Treatment
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure
Case Study 6 ndash Discussion
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Case Study 7 ndash Lab Results vs Time
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
DIC Take Home Messages
Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation
Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers
DIC
Thank you Questions
- Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
- Learning Objectives
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Wound Sealing
- The Three Steps of Hemostasis
- Vessel Wall
- Slide Number 12
- Slide Number 13
- Platelet Structure UnactivatedActivated
- Primary Hemostasis
- Primary Hemostasis Assays
- Slide Number 17
- Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
- Slide Number 19
- Coagulation factors
- Coagulation Assay Mechanisms
- Slide Number 22
- Fibrin Formation
- Slide Number 24
- Fibrinolysis Overview
- Fibrinolysis Overview
- Slide Number 27
- Fibrinolysis Releases D-dimers
- Basic Pathophysiology of DIC
- Disseminated Intravascular Coagulation (DIC)
- Purpura Fulminans with DIC Due to Meningococcal Sepsis
- Clinical Conditions Associated With DIC
- Frequency of DIC in Selected Disease States
- Underlying Diseases in DIC Patients
- Slide Number 36
- Slide Number 37
- Slide Number 38
- Slide Number 39
- Pathophysiology of DIC
- Pathogenesis of DIC in Sepsis
- Host Response in Severe Sepsis
- Organ Failure in Severe Sepsis
- Mechanism of DIC in Organ Failure
- Interaction of Inflammation and Coagulation in Sepsis
- Slide Number 47
- Diverse and Opposing Effects of Thrombin
- Coagulation and Fibrinolysis in DIC
- Mechanism of DIC
- Pathophysiology of DIC
- Pathophysiology of DIC - Mechanism
- Pathophysiology of DIC ndash 2 Types of Clinical pictures
- Sub-Acute and Non-Overt DIC Clinical Findings
- Pathophysiology of Overt DIC
- Physiopathology of DIC ndash Overt DIC Findings
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- BREAK
- Diagnostic and Management Approach for DIC
- Diagnosis of DIC
- Lab Diagnosis of DIC ndash Markers of Factor Consumption
- Lab Diagnosis of DIC ndash Screening Tests
- Slide Number 67
- Slide Number 68
- British Journal of Haematology Overt DIC Score
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- DIC Management Goals
- DIC Management and Treatment
- DIC Management Strategies
- Anticoagulant Factor Concentrate Treatment
- Anticoagulant Factor Concentrate Treatment Trials
- Markers of Thrombin amp Plasmin Generation in DIC
- D-dimer FDPs and DIC
- D-Dimer and FDPs in DIC
- Follow Up of DIC State of Disease
- FMD-Dimer in DIC Major Differences
- of Abnormal Results in Patients with Confirmed and Suspected DIC
- Slide Number 85
- Slide Number 86
- Comparing an Automated FM vs Manual FSP Test
- Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Slide Number 94
- Slide Number 95
- Slide Number 96
- Slide Number 97
- Slide Number 98
- Slide Number 99
- DIC Case Studies
- Case Study 1 - Presentation
- Case Study 1 ndash Lab Results
- Case Study 1 ndash Microscopy
- Case Study 1 ndash Diagnosis and Therapy
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Slide Number 110
- Slide Number 111
- Slide Number 112
- Slide Number 113
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
- Slide Number 124
- Slide Number 125
- DIC Take Home Messages
- Slide Number 127
- Slide Number 128
-
DIC Case Studies
Case Study 1 - Presentation
18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE
WBC count 77 KμL 423 ndash 907 x KμL
RBC count 17 MμL 137 ndash 175 x MμL
Hemoglobin 67 gdL 137 ndash 175 gdL
Hematocrit 195 401 ndash 510
MCV 95 fL 790 ndash 922 fL
MPV 12 fL 94 ndash 124 fL
Platelet count 9 KμL 161 ndash 347 KμL
Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0
Lymphocytes monocytes eosinophils basophils all below normal range
PT 47 sec (corrected on mixing study) 116 ndash 152 sec
APTT 75 sec (corrected on mixing study) 253 ndash 373 sec
Fibrinogen lt 76 mgdL 177 ndash 466 mgdL
D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Microscopy
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Arrow shows giant platelets in this peripheral smear Promyelocytes apparent
Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)
DIC due to TF release by APL blasts
Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases
Transfusions to replace factors along with platelets and RBCs during APL treatment
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started
Case Study 2 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L
PT 30 sec 113 ndash 146 sec
APTT 75 sec 25 ndash 34 sec
D-dimer 078 microgml FEU lt050 microgml FEU
Fibrinogen 92 mgdl 150-400 mgdl
pH 728 738 to 742
PaO2 570 mmHg 80-100 mmHg
WBC 33 times 103mm3 40-11 times 103mm3
ALT 111 IUL 0ndash34 IUL
AST 61 IUL 0ndash34 IUL
BUN 303 mgdL 08-13 mgdL
Case Study 2 ndash Lab Results
Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures
Case Study 2 ndash Diagnosis
60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior
Case Study 3 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L
PT 228 sec 113 ndash 146 sec
APTT 45 sec 25 ndash 34 sec
D-dimer 080 microgml FEU lt050 microgmL FEU
Fibrinogen 82 mgdL 150-400 mgdL
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 134 gdL 14-16 gdL
WBC 81 times 103mm3 40-11 times 103mm3
ALT 32 IUL 0ndash34 IUL
AST 28 IUL 0ndash34 IUL
BUN 09 mgdL 08-13 mgdL
Case Study 3 ndash Lab Results
Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment
Case Study 3 ndash Diagnosis and Therapy
Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91
Case Study 4 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L
PT 28 sec 113 ndash 146 sec
APTT 71 sec 25 ndash 34 sec
D-dimer 31 microgmL FEU lt050 microgml FEU
Fibrinogen 92 mgdL 150-400 mgdl
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 158 gdL 14-16 gdL
WBC 71 times 103mm3 40-11 times 103mm3
ALT 60 IUL 0ndash34 IUL
AST 47 IUL 0ndash34 IUL
BUN 38 mgdL 08-13 mgdL
Case Study 4 ndash Lab Results
Lyme disease with DICProvide antibiotics with supportive measures
Case Study 4 ndash Diagnosis
55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis
Case Study 5 ndash Presentation
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
Case Study 5 ndash Lab Results and Time Course
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
TEST RESULT REFERENCE RANGE
Platelet count 33 x 109L 150-450 x 109L
PT 215 sec 103 ndash 128 sec
APTT 44 sec 26 ndash 36 sec
D-dimer 20 microgmL FEU lt025 microgml FEU
Fibrinogen 34 mgdL 200-375 mgdl
FII FV FVIII Low Not reported (NR)
FVII FIX FX vWF Normal NR
Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)
DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic
dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR
(C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen
(D) Illustration demonstrating repair
Case Study 5 ndash Diagnosis and Treatment
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography
Case Study 6 ndash Presentation
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
Case Study 6 ndash Lab Results
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L
PT 63 sec gt control 113 ndash 146 sec
INR 658 1 ndash 125
APTT 80 sec gt control 25 ndash 34 sec
D-dimer gt200 microgmL DDU 02 microgmL DDU
Urine exam Proteinuria and hematuria 150-400 mgdl
Albumin 28 gdL NR
Hb 58 gdL NR
LDH 1196 UL NR
SGPT 144 IU NR
SGOT 88 IU NR
Bilirubin 32 mgdL NR
DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th
day postop
Case Study 6 ndash Diagnosis and Treatment
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure
Case Study 6 ndash Discussion
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Case Study 7 ndash Lab Results vs Time
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
DIC Take Home Messages
Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation
Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers
DIC
Thank you Questions
- Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
- Learning Objectives
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Wound Sealing
- The Three Steps of Hemostasis
- Vessel Wall
- Slide Number 12
- Slide Number 13
- Platelet Structure UnactivatedActivated
- Primary Hemostasis
- Primary Hemostasis Assays
- Slide Number 17
- Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
- Slide Number 19
- Coagulation factors
- Coagulation Assay Mechanisms
- Slide Number 22
- Fibrin Formation
- Slide Number 24
- Fibrinolysis Overview
- Fibrinolysis Overview
- Slide Number 27
- Fibrinolysis Releases D-dimers
- Basic Pathophysiology of DIC
- Disseminated Intravascular Coagulation (DIC)
- Purpura Fulminans with DIC Due to Meningococcal Sepsis
- Clinical Conditions Associated With DIC
- Frequency of DIC in Selected Disease States
- Underlying Diseases in DIC Patients
- Slide Number 36
- Slide Number 37
- Slide Number 38
- Slide Number 39
- Pathophysiology of DIC
- Pathogenesis of DIC in Sepsis
- Host Response in Severe Sepsis
- Organ Failure in Severe Sepsis
- Mechanism of DIC in Organ Failure
- Interaction of Inflammation and Coagulation in Sepsis
- Slide Number 47
- Diverse and Opposing Effects of Thrombin
- Coagulation and Fibrinolysis in DIC
- Mechanism of DIC
- Pathophysiology of DIC
- Pathophysiology of DIC - Mechanism
- Pathophysiology of DIC ndash 2 Types of Clinical pictures
- Sub-Acute and Non-Overt DIC Clinical Findings
- Pathophysiology of Overt DIC
- Physiopathology of DIC ndash Overt DIC Findings
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- BREAK
- Diagnostic and Management Approach for DIC
- Diagnosis of DIC
- Lab Diagnosis of DIC ndash Markers of Factor Consumption
- Lab Diagnosis of DIC ndash Screening Tests
- Slide Number 67
- Slide Number 68
- British Journal of Haematology Overt DIC Score
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- DIC Management Goals
- DIC Management and Treatment
- DIC Management Strategies
- Anticoagulant Factor Concentrate Treatment
- Anticoagulant Factor Concentrate Treatment Trials
- Markers of Thrombin amp Plasmin Generation in DIC
- D-dimer FDPs and DIC
- D-Dimer and FDPs in DIC
- Follow Up of DIC State of Disease
- FMD-Dimer in DIC Major Differences
- of Abnormal Results in Patients with Confirmed and Suspected DIC
- Slide Number 85
- Slide Number 86
- Comparing an Automated FM vs Manual FSP Test
- Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Slide Number 94
- Slide Number 95
- Slide Number 96
- Slide Number 97
- Slide Number 98
- Slide Number 99
- DIC Case Studies
- Case Study 1 - Presentation
- Case Study 1 ndash Lab Results
- Case Study 1 ndash Microscopy
- Case Study 1 ndash Diagnosis and Therapy
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Slide Number 110
- Slide Number 111
- Slide Number 112
- Slide Number 113
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
- Slide Number 124
- Slide Number 125
- DIC Take Home Messages
- Slide Number 127
- Slide Number 128
-
Case Study 1 - Presentation
18 year old male presented to the ED after 3 weeks of nosebleeds and increasing levels of severe fatigue No medical history born at term all developmental milestones achieved No family history of bleeding or thrombosis No medications denies recreational drugsalcohol Physical exam finds blood clots in both nostrils and petechial hemorrhages in mouth and lower extremities Bleeding subsided but lab results were monitored closely during hospitalization while blood products were administered
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE
WBC count 77 KμL 423 ndash 907 x KμL
RBC count 17 MμL 137 ndash 175 x MμL
Hemoglobin 67 gdL 137 ndash 175 gdL
Hematocrit 195 401 ndash 510
MCV 95 fL 790 ndash 922 fL
MPV 12 fL 94 ndash 124 fL
Platelet count 9 KμL 161 ndash 347 KμL
Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0
Lymphocytes monocytes eosinophils basophils all below normal range
PT 47 sec (corrected on mixing study) 116 ndash 152 sec
APTT 75 sec (corrected on mixing study) 253 ndash 373 sec
Fibrinogen lt 76 mgdL 177 ndash 466 mgdL
D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Microscopy
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Arrow shows giant platelets in this peripheral smear Promyelocytes apparent
Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)
DIC due to TF release by APL blasts
Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases
Transfusions to replace factors along with platelets and RBCs during APL treatment
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started
Case Study 2 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L
PT 30 sec 113 ndash 146 sec
APTT 75 sec 25 ndash 34 sec
D-dimer 078 microgml FEU lt050 microgml FEU
Fibrinogen 92 mgdl 150-400 mgdl
pH 728 738 to 742
PaO2 570 mmHg 80-100 mmHg
WBC 33 times 103mm3 40-11 times 103mm3
ALT 111 IUL 0ndash34 IUL
AST 61 IUL 0ndash34 IUL
BUN 303 mgdL 08-13 mgdL
Case Study 2 ndash Lab Results
Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures
Case Study 2 ndash Diagnosis
60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior
Case Study 3 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L
PT 228 sec 113 ndash 146 sec
APTT 45 sec 25 ndash 34 sec
D-dimer 080 microgml FEU lt050 microgmL FEU
Fibrinogen 82 mgdL 150-400 mgdL
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 134 gdL 14-16 gdL
WBC 81 times 103mm3 40-11 times 103mm3
ALT 32 IUL 0ndash34 IUL
AST 28 IUL 0ndash34 IUL
BUN 09 mgdL 08-13 mgdL
Case Study 3 ndash Lab Results
Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment
Case Study 3 ndash Diagnosis and Therapy
Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91
Case Study 4 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L
PT 28 sec 113 ndash 146 sec
APTT 71 sec 25 ndash 34 sec
D-dimer 31 microgmL FEU lt050 microgml FEU
Fibrinogen 92 mgdL 150-400 mgdl
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 158 gdL 14-16 gdL
WBC 71 times 103mm3 40-11 times 103mm3
ALT 60 IUL 0ndash34 IUL
AST 47 IUL 0ndash34 IUL
BUN 38 mgdL 08-13 mgdL
Case Study 4 ndash Lab Results
Lyme disease with DICProvide antibiotics with supportive measures
Case Study 4 ndash Diagnosis
55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis
Case Study 5 ndash Presentation
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
Case Study 5 ndash Lab Results and Time Course
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
TEST RESULT REFERENCE RANGE
Platelet count 33 x 109L 150-450 x 109L
PT 215 sec 103 ndash 128 sec
APTT 44 sec 26 ndash 36 sec
D-dimer 20 microgmL FEU lt025 microgml FEU
Fibrinogen 34 mgdL 200-375 mgdl
FII FV FVIII Low Not reported (NR)
FVII FIX FX vWF Normal NR
Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)
DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic
dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR
(C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen
(D) Illustration demonstrating repair
Case Study 5 ndash Diagnosis and Treatment
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography
Case Study 6 ndash Presentation
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
Case Study 6 ndash Lab Results
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L
PT 63 sec gt control 113 ndash 146 sec
INR 658 1 ndash 125
APTT 80 sec gt control 25 ndash 34 sec
D-dimer gt200 microgmL DDU 02 microgmL DDU
Urine exam Proteinuria and hematuria 150-400 mgdl
Albumin 28 gdL NR
Hb 58 gdL NR
LDH 1196 UL NR
SGPT 144 IU NR
SGOT 88 IU NR
Bilirubin 32 mgdL NR
DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th
day postop
Case Study 6 ndash Diagnosis and Treatment
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure
Case Study 6 ndash Discussion
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Case Study 7 ndash Lab Results vs Time
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
DIC Take Home Messages
Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation
Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers
DIC
Thank you Questions
- Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
- Learning Objectives
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Wound Sealing
- The Three Steps of Hemostasis
- Vessel Wall
- Slide Number 12
- Slide Number 13
- Platelet Structure UnactivatedActivated
- Primary Hemostasis
- Primary Hemostasis Assays
- Slide Number 17
- Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
- Slide Number 19
- Coagulation factors
- Coagulation Assay Mechanisms
- Slide Number 22
- Fibrin Formation
- Slide Number 24
- Fibrinolysis Overview
- Fibrinolysis Overview
- Slide Number 27
- Fibrinolysis Releases D-dimers
- Basic Pathophysiology of DIC
- Disseminated Intravascular Coagulation (DIC)
- Purpura Fulminans with DIC Due to Meningococcal Sepsis
- Clinical Conditions Associated With DIC
- Frequency of DIC in Selected Disease States
- Underlying Diseases in DIC Patients
- Slide Number 36
- Slide Number 37
- Slide Number 38
- Slide Number 39
- Pathophysiology of DIC
- Pathogenesis of DIC in Sepsis
- Host Response in Severe Sepsis
- Organ Failure in Severe Sepsis
- Mechanism of DIC in Organ Failure
- Interaction of Inflammation and Coagulation in Sepsis
- Slide Number 47
- Diverse and Opposing Effects of Thrombin
- Coagulation and Fibrinolysis in DIC
- Mechanism of DIC
- Pathophysiology of DIC
- Pathophysiology of DIC - Mechanism
- Pathophysiology of DIC ndash 2 Types of Clinical pictures
- Sub-Acute and Non-Overt DIC Clinical Findings
- Pathophysiology of Overt DIC
- Physiopathology of DIC ndash Overt DIC Findings
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- BREAK
- Diagnostic and Management Approach for DIC
- Diagnosis of DIC
- Lab Diagnosis of DIC ndash Markers of Factor Consumption
- Lab Diagnosis of DIC ndash Screening Tests
- Slide Number 67
- Slide Number 68
- British Journal of Haematology Overt DIC Score
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- DIC Management Goals
- DIC Management and Treatment
- DIC Management Strategies
- Anticoagulant Factor Concentrate Treatment
- Anticoagulant Factor Concentrate Treatment Trials
- Markers of Thrombin amp Plasmin Generation in DIC
- D-dimer FDPs and DIC
- D-Dimer and FDPs in DIC
- Follow Up of DIC State of Disease
- FMD-Dimer in DIC Major Differences
- of Abnormal Results in Patients with Confirmed and Suspected DIC
- Slide Number 85
- Slide Number 86
- Comparing an Automated FM vs Manual FSP Test
- Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Slide Number 94
- Slide Number 95
- Slide Number 96
- Slide Number 97
- Slide Number 98
- Slide Number 99
- DIC Case Studies
- Case Study 1 - Presentation
- Case Study 1 ndash Lab Results
- Case Study 1 ndash Microscopy
- Case Study 1 ndash Diagnosis and Therapy
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Slide Number 110
- Slide Number 111
- Slide Number 112
- Slide Number 113
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
- Slide Number 124
- Slide Number 125
- DIC Take Home Messages
- Slide Number 127
- Slide Number 128
-
Case Study 1 ndash Lab ResultsTEST RESULT REFERENCE RANGE
WBC count 77 KμL 423 ndash 907 x KμL
RBC count 17 MμL 137 ndash 175 x MμL
Hemoglobin 67 gdL 137 ndash 175 gdL
Hematocrit 195 401 ndash 510
MCV 95 fL 790 ndash 922 fL
MPV 12 fL 94 ndash 124 fL
Platelet count 9 KμL 161 ndash 347 KμL
Metamyelocytes promyelocytes myelocytes myeloblasts all elevated above normal level of 0
Lymphocytes monocytes eosinophils basophils all below normal range
PT 47 sec (corrected on mixing study) 116 ndash 152 sec
APTT 75 sec (corrected on mixing study) 253 ndash 373 sec
Fibrinogen lt 76 mgdL 177 ndash 466 mgdL
D-dimer 900 μgmL FEU 0 ndash 050 μgmL FEU
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Case Study 1 ndash Microscopy
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Arrow shows giant platelets in this peripheral smear Promyelocytes apparent
Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)
DIC due to TF release by APL blasts
Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases
Transfusions to replace factors along with platelets and RBCs during APL treatment
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started
Case Study 2 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L
PT 30 sec 113 ndash 146 sec
APTT 75 sec 25 ndash 34 sec
D-dimer 078 microgml FEU lt050 microgml FEU
Fibrinogen 92 mgdl 150-400 mgdl
pH 728 738 to 742
PaO2 570 mmHg 80-100 mmHg
WBC 33 times 103mm3 40-11 times 103mm3
ALT 111 IUL 0ndash34 IUL
AST 61 IUL 0ndash34 IUL
BUN 303 mgdL 08-13 mgdL
Case Study 2 ndash Lab Results
Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures
Case Study 2 ndash Diagnosis
60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior
Case Study 3 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L
PT 228 sec 113 ndash 146 sec
APTT 45 sec 25 ndash 34 sec
D-dimer 080 microgml FEU lt050 microgmL FEU
Fibrinogen 82 mgdL 150-400 mgdL
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 134 gdL 14-16 gdL
WBC 81 times 103mm3 40-11 times 103mm3
ALT 32 IUL 0ndash34 IUL
AST 28 IUL 0ndash34 IUL
BUN 09 mgdL 08-13 mgdL
Case Study 3 ndash Lab Results
Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment
Case Study 3 ndash Diagnosis and Therapy
Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91
Case Study 4 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L
PT 28 sec 113 ndash 146 sec
APTT 71 sec 25 ndash 34 sec
D-dimer 31 microgmL FEU lt050 microgml FEU
Fibrinogen 92 mgdL 150-400 mgdl
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 158 gdL 14-16 gdL
WBC 71 times 103mm3 40-11 times 103mm3
ALT 60 IUL 0ndash34 IUL
AST 47 IUL 0ndash34 IUL
BUN 38 mgdL 08-13 mgdL
Case Study 4 ndash Lab Results
Lyme disease with DICProvide antibiotics with supportive measures
Case Study 4 ndash Diagnosis
55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis
Case Study 5 ndash Presentation
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
Case Study 5 ndash Lab Results and Time Course
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
TEST RESULT REFERENCE RANGE
Platelet count 33 x 109L 150-450 x 109L
PT 215 sec 103 ndash 128 sec
APTT 44 sec 26 ndash 36 sec
D-dimer 20 microgmL FEU lt025 microgml FEU
Fibrinogen 34 mgdL 200-375 mgdl
FII FV FVIII Low Not reported (NR)
FVII FIX FX vWF Normal NR
Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)
DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic
dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR
(C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen
(D) Illustration demonstrating repair
Case Study 5 ndash Diagnosis and Treatment
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography
Case Study 6 ndash Presentation
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
Case Study 6 ndash Lab Results
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L
PT 63 sec gt control 113 ndash 146 sec
INR 658 1 ndash 125
APTT 80 sec gt control 25 ndash 34 sec
D-dimer gt200 microgmL DDU 02 microgmL DDU
Urine exam Proteinuria and hematuria 150-400 mgdl
Albumin 28 gdL NR
Hb 58 gdL NR
LDH 1196 UL NR
SGPT 144 IU NR
SGOT 88 IU NR
Bilirubin 32 mgdL NR
DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th
day postop
Case Study 6 ndash Diagnosis and Treatment
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure
Case Study 6 ndash Discussion
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Case Study 7 ndash Lab Results vs Time
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
DIC Take Home Messages
Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation
Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers
DIC
Thank you Questions
- Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
- Learning Objectives
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Wound Sealing
- The Three Steps of Hemostasis
- Vessel Wall
- Slide Number 12
- Slide Number 13
- Platelet Structure UnactivatedActivated
- Primary Hemostasis
- Primary Hemostasis Assays
- Slide Number 17
- Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
- Slide Number 19
- Coagulation factors
- Coagulation Assay Mechanisms
- Slide Number 22
- Fibrin Formation
- Slide Number 24
- Fibrinolysis Overview
- Fibrinolysis Overview
- Slide Number 27
- Fibrinolysis Releases D-dimers
- Basic Pathophysiology of DIC
- Disseminated Intravascular Coagulation (DIC)
- Purpura Fulminans with DIC Due to Meningococcal Sepsis
- Clinical Conditions Associated With DIC
- Frequency of DIC in Selected Disease States
- Underlying Diseases in DIC Patients
- Slide Number 36
- Slide Number 37
- Slide Number 38
- Slide Number 39
- Pathophysiology of DIC
- Pathogenesis of DIC in Sepsis
- Host Response in Severe Sepsis
- Organ Failure in Severe Sepsis
- Mechanism of DIC in Organ Failure
- Interaction of Inflammation and Coagulation in Sepsis
- Slide Number 47
- Diverse and Opposing Effects of Thrombin
- Coagulation and Fibrinolysis in DIC
- Mechanism of DIC
- Pathophysiology of DIC
- Pathophysiology of DIC - Mechanism
- Pathophysiology of DIC ndash 2 Types of Clinical pictures
- Sub-Acute and Non-Overt DIC Clinical Findings
- Pathophysiology of Overt DIC
- Physiopathology of DIC ndash Overt DIC Findings
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- BREAK
- Diagnostic and Management Approach for DIC
- Diagnosis of DIC
- Lab Diagnosis of DIC ndash Markers of Factor Consumption
- Lab Diagnosis of DIC ndash Screening Tests
- Slide Number 67
- Slide Number 68
- British Journal of Haematology Overt DIC Score
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- DIC Management Goals
- DIC Management and Treatment
- DIC Management Strategies
- Anticoagulant Factor Concentrate Treatment
- Anticoagulant Factor Concentrate Treatment Trials
- Markers of Thrombin amp Plasmin Generation in DIC
- D-dimer FDPs and DIC
- D-Dimer and FDPs in DIC
- Follow Up of DIC State of Disease
- FMD-Dimer in DIC Major Differences
- of Abnormal Results in Patients with Confirmed and Suspected DIC
- Slide Number 85
- Slide Number 86
- Comparing an Automated FM vs Manual FSP Test
- Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Slide Number 94
- Slide Number 95
- Slide Number 96
- Slide Number 97
- Slide Number 98
- Slide Number 99
- DIC Case Studies
- Case Study 1 - Presentation
- Case Study 1 ndash Lab Results
- Case Study 1 ndash Microscopy
- Case Study 1 ndash Diagnosis and Therapy
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Slide Number 110
- Slide Number 111
- Slide Number 112
- Slide Number 113
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
- Slide Number 124
- Slide Number 125
- DIC Take Home Messages
- Slide Number 127
- Slide Number 128
-
Case Study 1 ndash Microscopy
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
Arrow shows giant platelets in this peripheral smear Promyelocytes apparent
Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)
DIC due to TF release by APL blasts
Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases
Transfusions to replace factors along with platelets and RBCs during APL treatment
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started
Case Study 2 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L
PT 30 sec 113 ndash 146 sec
APTT 75 sec 25 ndash 34 sec
D-dimer 078 microgml FEU lt050 microgml FEU
Fibrinogen 92 mgdl 150-400 mgdl
pH 728 738 to 742
PaO2 570 mmHg 80-100 mmHg
WBC 33 times 103mm3 40-11 times 103mm3
ALT 111 IUL 0ndash34 IUL
AST 61 IUL 0ndash34 IUL
BUN 303 mgdL 08-13 mgdL
Case Study 2 ndash Lab Results
Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures
Case Study 2 ndash Diagnosis
60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior
Case Study 3 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L
PT 228 sec 113 ndash 146 sec
APTT 45 sec 25 ndash 34 sec
D-dimer 080 microgml FEU lt050 microgmL FEU
Fibrinogen 82 mgdL 150-400 mgdL
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 134 gdL 14-16 gdL
WBC 81 times 103mm3 40-11 times 103mm3
ALT 32 IUL 0ndash34 IUL
AST 28 IUL 0ndash34 IUL
BUN 09 mgdL 08-13 mgdL
Case Study 3 ndash Lab Results
Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment
Case Study 3 ndash Diagnosis and Therapy
Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91
Case Study 4 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L
PT 28 sec 113 ndash 146 sec
APTT 71 sec 25 ndash 34 sec
D-dimer 31 microgmL FEU lt050 microgml FEU
Fibrinogen 92 mgdL 150-400 mgdl
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 158 gdL 14-16 gdL
WBC 71 times 103mm3 40-11 times 103mm3
ALT 60 IUL 0ndash34 IUL
AST 47 IUL 0ndash34 IUL
BUN 38 mgdL 08-13 mgdL
Case Study 4 ndash Lab Results
Lyme disease with DICProvide antibiotics with supportive measures
Case Study 4 ndash Diagnosis
55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis
Case Study 5 ndash Presentation
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
Case Study 5 ndash Lab Results and Time Course
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
TEST RESULT REFERENCE RANGE
Platelet count 33 x 109L 150-450 x 109L
PT 215 sec 103 ndash 128 sec
APTT 44 sec 26 ndash 36 sec
D-dimer 20 microgmL FEU lt025 microgml FEU
Fibrinogen 34 mgdL 200-375 mgdl
FII FV FVIII Low Not reported (NR)
FVII FIX FX vWF Normal NR
Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)
DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic
dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR
(C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen
(D) Illustration demonstrating repair
Case Study 5 ndash Diagnosis and Treatment
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography
Case Study 6 ndash Presentation
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
Case Study 6 ndash Lab Results
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L
PT 63 sec gt control 113 ndash 146 sec
INR 658 1 ndash 125
APTT 80 sec gt control 25 ndash 34 sec
D-dimer gt200 microgmL DDU 02 microgmL DDU
Urine exam Proteinuria and hematuria 150-400 mgdl
Albumin 28 gdL NR
Hb 58 gdL NR
LDH 1196 UL NR
SGPT 144 IU NR
SGOT 88 IU NR
Bilirubin 32 mgdL NR
DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th
day postop
Case Study 6 ndash Diagnosis and Treatment
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure
Case Study 6 ndash Discussion
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Case Study 7 ndash Lab Results vs Time
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
DIC Take Home Messages
Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation
Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers
DIC
Thank you Questions
- Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
- Learning Objectives
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Wound Sealing
- The Three Steps of Hemostasis
- Vessel Wall
- Slide Number 12
- Slide Number 13
- Platelet Structure UnactivatedActivated
- Primary Hemostasis
- Primary Hemostasis Assays
- Slide Number 17
- Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
- Slide Number 19
- Coagulation factors
- Coagulation Assay Mechanisms
- Slide Number 22
- Fibrin Formation
- Slide Number 24
- Fibrinolysis Overview
- Fibrinolysis Overview
- Slide Number 27
- Fibrinolysis Releases D-dimers
- Basic Pathophysiology of DIC
- Disseminated Intravascular Coagulation (DIC)
- Purpura Fulminans with DIC Due to Meningococcal Sepsis
- Clinical Conditions Associated With DIC
- Frequency of DIC in Selected Disease States
- Underlying Diseases in DIC Patients
- Slide Number 36
- Slide Number 37
- Slide Number 38
- Slide Number 39
- Pathophysiology of DIC
- Pathogenesis of DIC in Sepsis
- Host Response in Severe Sepsis
- Organ Failure in Severe Sepsis
- Mechanism of DIC in Organ Failure
- Interaction of Inflammation and Coagulation in Sepsis
- Slide Number 47
- Diverse and Opposing Effects of Thrombin
- Coagulation and Fibrinolysis in DIC
- Mechanism of DIC
- Pathophysiology of DIC
- Pathophysiology of DIC - Mechanism
- Pathophysiology of DIC ndash 2 Types of Clinical pictures
- Sub-Acute and Non-Overt DIC Clinical Findings
- Pathophysiology of Overt DIC
- Physiopathology of DIC ndash Overt DIC Findings
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- BREAK
- Diagnostic and Management Approach for DIC
- Diagnosis of DIC
- Lab Diagnosis of DIC ndash Markers of Factor Consumption
- Lab Diagnosis of DIC ndash Screening Tests
- Slide Number 67
- Slide Number 68
- British Journal of Haematology Overt DIC Score
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- DIC Management Goals
- DIC Management and Treatment
- DIC Management Strategies
- Anticoagulant Factor Concentrate Treatment
- Anticoagulant Factor Concentrate Treatment Trials
- Markers of Thrombin amp Plasmin Generation in DIC
- D-dimer FDPs and DIC
- D-Dimer and FDPs in DIC
- Follow Up of DIC State of Disease
- FMD-Dimer in DIC Major Differences
- of Abnormal Results in Patients with Confirmed and Suspected DIC
- Slide Number 85
- Slide Number 86
- Comparing an Automated FM vs Manual FSP Test
- Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Slide Number 94
- Slide Number 95
- Slide Number 96
- Slide Number 97
- Slide Number 98
- Slide Number 99
- DIC Case Studies
- Case Study 1 - Presentation
- Case Study 1 ndash Lab Results
- Case Study 1 ndash Microscopy
- Case Study 1 ndash Diagnosis and Therapy
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Slide Number 110
- Slide Number 111
- Slide Number 112
- Slide Number 113
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
- Slide Number 124
- Slide Number 125
- DIC Take Home Messages
- Slide Number 127
- Slide Number 128
-
Case Study 1 ndash Diagnosis and TherapyProfound anemia significant reticulocytosis and increased mean corpuscular volume (MCV) decreased platelets with increased mean platelet volume (MPV) numerous promyelocytes High D-dimer with PTAPTT correcting on mixing study along with low fibrinogen indicate disseminated intravascular coagulation (DIC) secondary to acute myelogenous leukemia (AML) most likely acute promyelocytic leukemia (APL)
DIC due to TF release by APL blasts
Molecular studies of PML-retinoic acid receptor-alpha (RARA) gene fusion was positive occurs in gt95 of APL cases
Transfusions to replace factors along with platelets and RBCs during APL treatment
Fisher VR Scott MK Tremblay CA Beaulieu GP Ward DC Byrne KM Disseminated Intravascular Coagulation Laboratory Support for Management and Treatment Lab Med 2013 Spring Supplement e10-e14
20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started
Case Study 2 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L
PT 30 sec 113 ndash 146 sec
APTT 75 sec 25 ndash 34 sec
D-dimer 078 microgml FEU lt050 microgml FEU
Fibrinogen 92 mgdl 150-400 mgdl
pH 728 738 to 742
PaO2 570 mmHg 80-100 mmHg
WBC 33 times 103mm3 40-11 times 103mm3
ALT 111 IUL 0ndash34 IUL
AST 61 IUL 0ndash34 IUL
BUN 303 mgdL 08-13 mgdL
Case Study 2 ndash Lab Results
Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures
Case Study 2 ndash Diagnosis
60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior
Case Study 3 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L
PT 228 sec 113 ndash 146 sec
APTT 45 sec 25 ndash 34 sec
D-dimer 080 microgml FEU lt050 microgmL FEU
Fibrinogen 82 mgdL 150-400 mgdL
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 134 gdL 14-16 gdL
WBC 81 times 103mm3 40-11 times 103mm3
ALT 32 IUL 0ndash34 IUL
AST 28 IUL 0ndash34 IUL
BUN 09 mgdL 08-13 mgdL
Case Study 3 ndash Lab Results
Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment
Case Study 3 ndash Diagnosis and Therapy
Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91
Case Study 4 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L
PT 28 sec 113 ndash 146 sec
APTT 71 sec 25 ndash 34 sec
D-dimer 31 microgmL FEU lt050 microgml FEU
Fibrinogen 92 mgdL 150-400 mgdl
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 158 gdL 14-16 gdL
WBC 71 times 103mm3 40-11 times 103mm3
ALT 60 IUL 0ndash34 IUL
AST 47 IUL 0ndash34 IUL
BUN 38 mgdL 08-13 mgdL
Case Study 4 ndash Lab Results
Lyme disease with DICProvide antibiotics with supportive measures
Case Study 4 ndash Diagnosis
55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis
Case Study 5 ndash Presentation
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
Case Study 5 ndash Lab Results and Time Course
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
TEST RESULT REFERENCE RANGE
Platelet count 33 x 109L 150-450 x 109L
PT 215 sec 103 ndash 128 sec
APTT 44 sec 26 ndash 36 sec
D-dimer 20 microgmL FEU lt025 microgml FEU
Fibrinogen 34 mgdL 200-375 mgdl
FII FV FVIII Low Not reported (NR)
FVII FIX FX vWF Normal NR
Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)
DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic
dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR
(C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen
(D) Illustration demonstrating repair
Case Study 5 ndash Diagnosis and Treatment
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography
Case Study 6 ndash Presentation
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
Case Study 6 ndash Lab Results
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L
PT 63 sec gt control 113 ndash 146 sec
INR 658 1 ndash 125
APTT 80 sec gt control 25 ndash 34 sec
D-dimer gt200 microgmL DDU 02 microgmL DDU
Urine exam Proteinuria and hematuria 150-400 mgdl
Albumin 28 gdL NR
Hb 58 gdL NR
LDH 1196 UL NR
SGPT 144 IU NR
SGOT 88 IU NR
Bilirubin 32 mgdL NR
DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th
day postop
Case Study 6 ndash Diagnosis and Treatment
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure
Case Study 6 ndash Discussion
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Case Study 7 ndash Lab Results vs Time
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
DIC Take Home Messages
Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation
Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers
DIC
Thank you Questions
- Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
- Learning Objectives
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Wound Sealing
- The Three Steps of Hemostasis
- Vessel Wall
- Slide Number 12
- Slide Number 13
- Platelet Structure UnactivatedActivated
- Primary Hemostasis
- Primary Hemostasis Assays
- Slide Number 17
- Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
- Slide Number 19
- Coagulation factors
- Coagulation Assay Mechanisms
- Slide Number 22
- Fibrin Formation
- Slide Number 24
- Fibrinolysis Overview
- Fibrinolysis Overview
- Slide Number 27
- Fibrinolysis Releases D-dimers
- Basic Pathophysiology of DIC
- Disseminated Intravascular Coagulation (DIC)
- Purpura Fulminans with DIC Due to Meningococcal Sepsis
- Clinical Conditions Associated With DIC
- Frequency of DIC in Selected Disease States
- Underlying Diseases in DIC Patients
- Slide Number 36
- Slide Number 37
- Slide Number 38
- Slide Number 39
- Pathophysiology of DIC
- Pathogenesis of DIC in Sepsis
- Host Response in Severe Sepsis
- Organ Failure in Severe Sepsis
- Mechanism of DIC in Organ Failure
- Interaction of Inflammation and Coagulation in Sepsis
- Slide Number 47
- Diverse and Opposing Effects of Thrombin
- Coagulation and Fibrinolysis in DIC
- Mechanism of DIC
- Pathophysiology of DIC
- Pathophysiology of DIC - Mechanism
- Pathophysiology of DIC ndash 2 Types of Clinical pictures
- Sub-Acute and Non-Overt DIC Clinical Findings
- Pathophysiology of Overt DIC
- Physiopathology of DIC ndash Overt DIC Findings
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- BREAK
- Diagnostic and Management Approach for DIC
- Diagnosis of DIC
- Lab Diagnosis of DIC ndash Markers of Factor Consumption
- Lab Diagnosis of DIC ndash Screening Tests
- Slide Number 67
- Slide Number 68
- British Journal of Haematology Overt DIC Score
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- DIC Management Goals
- DIC Management and Treatment
- DIC Management Strategies
- Anticoagulant Factor Concentrate Treatment
- Anticoagulant Factor Concentrate Treatment Trials
- Markers of Thrombin amp Plasmin Generation in DIC
- D-dimer FDPs and DIC
- D-Dimer and FDPs in DIC
- Follow Up of DIC State of Disease
- FMD-Dimer in DIC Major Differences
- of Abnormal Results in Patients with Confirmed and Suspected DIC
- Slide Number 85
- Slide Number 86
- Comparing an Automated FM vs Manual FSP Test
- Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Slide Number 94
- Slide Number 95
- Slide Number 96
- Slide Number 97
- Slide Number 98
- Slide Number 99
- DIC Case Studies
- Case Study 1 - Presentation
- Case Study 1 ndash Lab Results
- Case Study 1 ndash Microscopy
- Case Study 1 ndash Diagnosis and Therapy
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Slide Number 110
- Slide Number 111
- Slide Number 112
- Slide Number 113
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
- Slide Number 124
- Slide Number 125
- DIC Take Home Messages
- Slide Number 127
- Slide Number 128
-
20-year-old male college student presenting to EDGeneral malaise hypotension (9060 mmHg) high-grade fever purplish discoloration on his body pain in both legs vomiting and diarrhea on the preceding dayFacial discoloration developed rapidly during the time from when he left house to the time he arrived at the emergency roomBlood cultures started
Case Study 2 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L
PT 30 sec 113 ndash 146 sec
APTT 75 sec 25 ndash 34 sec
D-dimer 078 microgml FEU lt050 microgml FEU
Fibrinogen 92 mgdl 150-400 mgdl
pH 728 738 to 742
PaO2 570 mmHg 80-100 mmHg
WBC 33 times 103mm3 40-11 times 103mm3
ALT 111 IUL 0ndash34 IUL
AST 61 IUL 0ndash34 IUL
BUN 303 mgdL 08-13 mgdL
Case Study 2 ndash Lab Results
Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures
Case Study 2 ndash Diagnosis
60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior
Case Study 3 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L
PT 228 sec 113 ndash 146 sec
APTT 45 sec 25 ndash 34 sec
D-dimer 080 microgml FEU lt050 microgmL FEU
Fibrinogen 82 mgdL 150-400 mgdL
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 134 gdL 14-16 gdL
WBC 81 times 103mm3 40-11 times 103mm3
ALT 32 IUL 0ndash34 IUL
AST 28 IUL 0ndash34 IUL
BUN 09 mgdL 08-13 mgdL
Case Study 3 ndash Lab Results
Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment
Case Study 3 ndash Diagnosis and Therapy
Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91
Case Study 4 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L
PT 28 sec 113 ndash 146 sec
APTT 71 sec 25 ndash 34 sec
D-dimer 31 microgmL FEU lt050 microgml FEU
Fibrinogen 92 mgdL 150-400 mgdl
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 158 gdL 14-16 gdL
WBC 71 times 103mm3 40-11 times 103mm3
ALT 60 IUL 0ndash34 IUL
AST 47 IUL 0ndash34 IUL
BUN 38 mgdL 08-13 mgdL
Case Study 4 ndash Lab Results
Lyme disease with DICProvide antibiotics with supportive measures
Case Study 4 ndash Diagnosis
55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis
Case Study 5 ndash Presentation
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
Case Study 5 ndash Lab Results and Time Course
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
TEST RESULT REFERENCE RANGE
Platelet count 33 x 109L 150-450 x 109L
PT 215 sec 103 ndash 128 sec
APTT 44 sec 26 ndash 36 sec
D-dimer 20 microgmL FEU lt025 microgml FEU
Fibrinogen 34 mgdL 200-375 mgdl
FII FV FVIII Low Not reported (NR)
FVII FIX FX vWF Normal NR
Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)
DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic
dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR
(C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen
(D) Illustration demonstrating repair
Case Study 5 ndash Diagnosis and Treatment
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography
Case Study 6 ndash Presentation
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
Case Study 6 ndash Lab Results
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L
PT 63 sec gt control 113 ndash 146 sec
INR 658 1 ndash 125
APTT 80 sec gt control 25 ndash 34 sec
D-dimer gt200 microgmL DDU 02 microgmL DDU
Urine exam Proteinuria and hematuria 150-400 mgdl
Albumin 28 gdL NR
Hb 58 gdL NR
LDH 1196 UL NR
SGPT 144 IU NR
SGOT 88 IU NR
Bilirubin 32 mgdL NR
DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th
day postop
Case Study 6 ndash Diagnosis and Treatment
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure
Case Study 6 ndash Discussion
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Case Study 7 ndash Lab Results vs Time
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
DIC Take Home Messages
Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation
Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers
DIC
Thank you Questions
- Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
- Learning Objectives
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Wound Sealing
- The Three Steps of Hemostasis
- Vessel Wall
- Slide Number 12
- Slide Number 13
- Platelet Structure UnactivatedActivated
- Primary Hemostasis
- Primary Hemostasis Assays
- Slide Number 17
- Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
- Slide Number 19
- Coagulation factors
- Coagulation Assay Mechanisms
- Slide Number 22
- Fibrin Formation
- Slide Number 24
- Fibrinolysis Overview
- Fibrinolysis Overview
- Slide Number 27
- Fibrinolysis Releases D-dimers
- Basic Pathophysiology of DIC
- Disseminated Intravascular Coagulation (DIC)
- Purpura Fulminans with DIC Due to Meningococcal Sepsis
- Clinical Conditions Associated With DIC
- Frequency of DIC in Selected Disease States
- Underlying Diseases in DIC Patients
- Slide Number 36
- Slide Number 37
- Slide Number 38
- Slide Number 39
- Pathophysiology of DIC
- Pathogenesis of DIC in Sepsis
- Host Response in Severe Sepsis
- Organ Failure in Severe Sepsis
- Mechanism of DIC in Organ Failure
- Interaction of Inflammation and Coagulation in Sepsis
- Slide Number 47
- Diverse and Opposing Effects of Thrombin
- Coagulation and Fibrinolysis in DIC
- Mechanism of DIC
- Pathophysiology of DIC
- Pathophysiology of DIC - Mechanism
- Pathophysiology of DIC ndash 2 Types of Clinical pictures
- Sub-Acute and Non-Overt DIC Clinical Findings
- Pathophysiology of Overt DIC
- Physiopathology of DIC ndash Overt DIC Findings
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- BREAK
- Diagnostic and Management Approach for DIC
- Diagnosis of DIC
- Lab Diagnosis of DIC ndash Markers of Factor Consumption
- Lab Diagnosis of DIC ndash Screening Tests
- Slide Number 67
- Slide Number 68
- British Journal of Haematology Overt DIC Score
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- DIC Management Goals
- DIC Management and Treatment
- DIC Management Strategies
- Anticoagulant Factor Concentrate Treatment
- Anticoagulant Factor Concentrate Treatment Trials
- Markers of Thrombin amp Plasmin Generation in DIC
- D-dimer FDPs and DIC
- D-Dimer and FDPs in DIC
- Follow Up of DIC State of Disease
- FMD-Dimer in DIC Major Differences
- of Abnormal Results in Patients with Confirmed and Suspected DIC
- Slide Number 85
- Slide Number 86
- Comparing an Automated FM vs Manual FSP Test
- Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Slide Number 94
- Slide Number 95
- Slide Number 96
- Slide Number 97
- Slide Number 98
- Slide Number 99
- DIC Case Studies
- Case Study 1 - Presentation
- Case Study 1 ndash Lab Results
- Case Study 1 ndash Microscopy
- Case Study 1 ndash Diagnosis and Therapy
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Slide Number 110
- Slide Number 111
- Slide Number 112
- Slide Number 113
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
- Slide Number 124
- Slide Number 125
- DIC Take Home Messages
- Slide Number 127
- Slide Number 128
-
TEST RESULT REFERENCE RANGEPlatelet count 67 x 109L 150-400 x 109L
PT 30 sec 113 ndash 146 sec
APTT 75 sec 25 ndash 34 sec
D-dimer 078 microgml FEU lt050 microgml FEU
Fibrinogen 92 mgdl 150-400 mgdl
pH 728 738 to 742
PaO2 570 mmHg 80-100 mmHg
WBC 33 times 103mm3 40-11 times 103mm3
ALT 111 IUL 0ndash34 IUL
AST 61 IUL 0ndash34 IUL
BUN 303 mgdL 08-13 mgdL
Case Study 2 ndash Lab Results
Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures
Case Study 2 ndash Diagnosis
60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior
Case Study 3 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L
PT 228 sec 113 ndash 146 sec
APTT 45 sec 25 ndash 34 sec
D-dimer 080 microgml FEU lt050 microgmL FEU
Fibrinogen 82 mgdL 150-400 mgdL
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 134 gdL 14-16 gdL
WBC 81 times 103mm3 40-11 times 103mm3
ALT 32 IUL 0ndash34 IUL
AST 28 IUL 0ndash34 IUL
BUN 09 mgdL 08-13 mgdL
Case Study 3 ndash Lab Results
Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment
Case Study 3 ndash Diagnosis and Therapy
Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91
Case Study 4 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L
PT 28 sec 113 ndash 146 sec
APTT 71 sec 25 ndash 34 sec
D-dimer 31 microgmL FEU lt050 microgml FEU
Fibrinogen 92 mgdL 150-400 mgdl
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 158 gdL 14-16 gdL
WBC 71 times 103mm3 40-11 times 103mm3
ALT 60 IUL 0ndash34 IUL
AST 47 IUL 0ndash34 IUL
BUN 38 mgdL 08-13 mgdL
Case Study 4 ndash Lab Results
Lyme disease with DICProvide antibiotics with supportive measures
Case Study 4 ndash Diagnosis
55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis
Case Study 5 ndash Presentation
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
Case Study 5 ndash Lab Results and Time Course
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
TEST RESULT REFERENCE RANGE
Platelet count 33 x 109L 150-450 x 109L
PT 215 sec 103 ndash 128 sec
APTT 44 sec 26 ndash 36 sec
D-dimer 20 microgmL FEU lt025 microgml FEU
Fibrinogen 34 mgdL 200-375 mgdl
FII FV FVIII Low Not reported (NR)
FVII FIX FX vWF Normal NR
Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)
DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic
dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR
(C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen
(D) Illustration demonstrating repair
Case Study 5 ndash Diagnosis and Treatment
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography
Case Study 6 ndash Presentation
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
Case Study 6 ndash Lab Results
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L
PT 63 sec gt control 113 ndash 146 sec
INR 658 1 ndash 125
APTT 80 sec gt control 25 ndash 34 sec
D-dimer gt200 microgmL DDU 02 microgmL DDU
Urine exam Proteinuria and hematuria 150-400 mgdl
Albumin 28 gdL NR
Hb 58 gdL NR
LDH 1196 UL NR
SGPT 144 IU NR
SGOT 88 IU NR
Bilirubin 32 mgdL NR
DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th
day postop
Case Study 6 ndash Diagnosis and Treatment
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure
Case Study 6 ndash Discussion
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Case Study 7 ndash Lab Results vs Time
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
DIC Take Home Messages
Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation
Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers
DIC
Thank you Questions
- Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
- Learning Objectives
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Wound Sealing
- The Three Steps of Hemostasis
- Vessel Wall
- Slide Number 12
- Slide Number 13
- Platelet Structure UnactivatedActivated
- Primary Hemostasis
- Primary Hemostasis Assays
- Slide Number 17
- Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
- Slide Number 19
- Coagulation factors
- Coagulation Assay Mechanisms
- Slide Number 22
- Fibrin Formation
- Slide Number 24
- Fibrinolysis Overview
- Fibrinolysis Overview
- Slide Number 27
- Fibrinolysis Releases D-dimers
- Basic Pathophysiology of DIC
- Disseminated Intravascular Coagulation (DIC)
- Purpura Fulminans with DIC Due to Meningococcal Sepsis
- Clinical Conditions Associated With DIC
- Frequency of DIC in Selected Disease States
- Underlying Diseases in DIC Patients
- Slide Number 36
- Slide Number 37
- Slide Number 38
- Slide Number 39
- Pathophysiology of DIC
- Pathogenesis of DIC in Sepsis
- Host Response in Severe Sepsis
- Organ Failure in Severe Sepsis
- Mechanism of DIC in Organ Failure
- Interaction of Inflammation and Coagulation in Sepsis
- Slide Number 47
- Diverse and Opposing Effects of Thrombin
- Coagulation and Fibrinolysis in DIC
- Mechanism of DIC
- Pathophysiology of DIC
- Pathophysiology of DIC - Mechanism
- Pathophysiology of DIC ndash 2 Types of Clinical pictures
- Sub-Acute and Non-Overt DIC Clinical Findings
- Pathophysiology of Overt DIC
- Physiopathology of DIC ndash Overt DIC Findings
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- BREAK
- Diagnostic and Management Approach for DIC
- Diagnosis of DIC
- Lab Diagnosis of DIC ndash Markers of Factor Consumption
- Lab Diagnosis of DIC ndash Screening Tests
- Slide Number 67
- Slide Number 68
- British Journal of Haematology Overt DIC Score
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- DIC Management Goals
- DIC Management and Treatment
- DIC Management Strategies
- Anticoagulant Factor Concentrate Treatment
- Anticoagulant Factor Concentrate Treatment Trials
- Markers of Thrombin amp Plasmin Generation in DIC
- D-dimer FDPs and DIC
- D-Dimer and FDPs in DIC
- Follow Up of DIC State of Disease
- FMD-Dimer in DIC Major Differences
- of Abnormal Results in Patients with Confirmed and Suspected DIC
- Slide Number 85
- Slide Number 86
- Comparing an Automated FM vs Manual FSP Test
- Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Slide Number 94
- Slide Number 95
- Slide Number 96
- Slide Number 97
- Slide Number 98
- Slide Number 99
- DIC Case Studies
- Case Study 1 - Presentation
- Case Study 1 ndash Lab Results
- Case Study 1 ndash Microscopy
- Case Study 1 ndash Diagnosis and Therapy
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Slide Number 110
- Slide Number 111
- Slide Number 112
- Slide Number 113
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
- Slide Number 124
- Slide Number 125
- DIC Take Home Messages
- Slide Number 127
- Slide Number 128
-
Pneumococcal infectionWaterhouse-Friderichsen Syndrome with DICProvide antibiotics with supportive measures
Case Study 2 ndash Diagnosis
60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior
Case Study 3 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L
PT 228 sec 113 ndash 146 sec
APTT 45 sec 25 ndash 34 sec
D-dimer 080 microgml FEU lt050 microgmL FEU
Fibrinogen 82 mgdL 150-400 mgdL
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 134 gdL 14-16 gdL
WBC 81 times 103mm3 40-11 times 103mm3
ALT 32 IUL 0ndash34 IUL
AST 28 IUL 0ndash34 IUL
BUN 09 mgdL 08-13 mgdL
Case Study 3 ndash Lab Results
Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment
Case Study 3 ndash Diagnosis and Therapy
Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91
Case Study 4 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L
PT 28 sec 113 ndash 146 sec
APTT 71 sec 25 ndash 34 sec
D-dimer 31 microgmL FEU lt050 microgml FEU
Fibrinogen 92 mgdL 150-400 mgdl
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 158 gdL 14-16 gdL
WBC 71 times 103mm3 40-11 times 103mm3
ALT 60 IUL 0ndash34 IUL
AST 47 IUL 0ndash34 IUL
BUN 38 mgdL 08-13 mgdL
Case Study 4 ndash Lab Results
Lyme disease with DICProvide antibiotics with supportive measures
Case Study 4 ndash Diagnosis
55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis
Case Study 5 ndash Presentation
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
Case Study 5 ndash Lab Results and Time Course
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
TEST RESULT REFERENCE RANGE
Platelet count 33 x 109L 150-450 x 109L
PT 215 sec 103 ndash 128 sec
APTT 44 sec 26 ndash 36 sec
D-dimer 20 microgmL FEU lt025 microgml FEU
Fibrinogen 34 mgdL 200-375 mgdl
FII FV FVIII Low Not reported (NR)
FVII FIX FX vWF Normal NR
Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)
DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic
dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR
(C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen
(D) Illustration demonstrating repair
Case Study 5 ndash Diagnosis and Treatment
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography
Case Study 6 ndash Presentation
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
Case Study 6 ndash Lab Results
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L
PT 63 sec gt control 113 ndash 146 sec
INR 658 1 ndash 125
APTT 80 sec gt control 25 ndash 34 sec
D-dimer gt200 microgmL DDU 02 microgmL DDU
Urine exam Proteinuria and hematuria 150-400 mgdl
Albumin 28 gdL NR
Hb 58 gdL NR
LDH 1196 UL NR
SGPT 144 IU NR
SGOT 88 IU NR
Bilirubin 32 mgdL NR
DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th
day postop
Case Study 6 ndash Diagnosis and Treatment
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure
Case Study 6 ndash Discussion
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Case Study 7 ndash Lab Results vs Time
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
DIC Take Home Messages
Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation
Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers
DIC
Thank you Questions
- Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
- Learning Objectives
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Wound Sealing
- The Three Steps of Hemostasis
- Vessel Wall
- Slide Number 12
- Slide Number 13
- Platelet Structure UnactivatedActivated
- Primary Hemostasis
- Primary Hemostasis Assays
- Slide Number 17
- Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
- Slide Number 19
- Coagulation factors
- Coagulation Assay Mechanisms
- Slide Number 22
- Fibrin Formation
- Slide Number 24
- Fibrinolysis Overview
- Fibrinolysis Overview
- Slide Number 27
- Fibrinolysis Releases D-dimers
- Basic Pathophysiology of DIC
- Disseminated Intravascular Coagulation (DIC)
- Purpura Fulminans with DIC Due to Meningococcal Sepsis
- Clinical Conditions Associated With DIC
- Frequency of DIC in Selected Disease States
- Underlying Diseases in DIC Patients
- Slide Number 36
- Slide Number 37
- Slide Number 38
- Slide Number 39
- Pathophysiology of DIC
- Pathogenesis of DIC in Sepsis
- Host Response in Severe Sepsis
- Organ Failure in Severe Sepsis
- Mechanism of DIC in Organ Failure
- Interaction of Inflammation and Coagulation in Sepsis
- Slide Number 47
- Diverse and Opposing Effects of Thrombin
- Coagulation and Fibrinolysis in DIC
- Mechanism of DIC
- Pathophysiology of DIC
- Pathophysiology of DIC - Mechanism
- Pathophysiology of DIC ndash 2 Types of Clinical pictures
- Sub-Acute and Non-Overt DIC Clinical Findings
- Pathophysiology of Overt DIC
- Physiopathology of DIC ndash Overt DIC Findings
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- BREAK
- Diagnostic and Management Approach for DIC
- Diagnosis of DIC
- Lab Diagnosis of DIC ndash Markers of Factor Consumption
- Lab Diagnosis of DIC ndash Screening Tests
- Slide Number 67
- Slide Number 68
- British Journal of Haematology Overt DIC Score
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- DIC Management Goals
- DIC Management and Treatment
- DIC Management Strategies
- Anticoagulant Factor Concentrate Treatment
- Anticoagulant Factor Concentrate Treatment Trials
- Markers of Thrombin amp Plasmin Generation in DIC
- D-dimer FDPs and DIC
- D-Dimer and FDPs in DIC
- Follow Up of DIC State of Disease
- FMD-Dimer in DIC Major Differences
- of Abnormal Results in Patients with Confirmed and Suspected DIC
- Slide Number 85
- Slide Number 86
- Comparing an Automated FM vs Manual FSP Test
- Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Slide Number 94
- Slide Number 95
- Slide Number 96
- Slide Number 97
- Slide Number 98
- Slide Number 99
- DIC Case Studies
- Case Study 1 - Presentation
- Case Study 1 ndash Lab Results
- Case Study 1 ndash Microscopy
- Case Study 1 ndash Diagnosis and Therapy
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Slide Number 110
- Slide Number 111
- Slide Number 112
- Slide Number 113
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
- Slide Number 124
- Slide Number 125
- DIC Take Home Messages
- Slide Number 127
- Slide Number 128
-
60-year-old male 4 day history of bleeding from the gums diffuse spontaneous ecchymoses mild fatigue and bone pain6-month history of pain localized to his right thigh with extension to the posterior part of his right legPast medical history included atrial fibrillation hypercholesterolemia and hypertension all well controlled with medicationNo history of smoking moderate alcohol consumption until 1 year prior
Case Study 3 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L
PT 228 sec 113 ndash 146 sec
APTT 45 sec 25 ndash 34 sec
D-dimer 080 microgml FEU lt050 microgmL FEU
Fibrinogen 82 mgdL 150-400 mgdL
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 134 gdL 14-16 gdL
WBC 81 times 103mm3 40-11 times 103mm3
ALT 32 IUL 0ndash34 IUL
AST 28 IUL 0ndash34 IUL
BUN 09 mgdL 08-13 mgdL
Case Study 3 ndash Lab Results
Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment
Case Study 3 ndash Diagnosis and Therapy
Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91
Case Study 4 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L
PT 28 sec 113 ndash 146 sec
APTT 71 sec 25 ndash 34 sec
D-dimer 31 microgmL FEU lt050 microgml FEU
Fibrinogen 92 mgdL 150-400 mgdl
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 158 gdL 14-16 gdL
WBC 71 times 103mm3 40-11 times 103mm3
ALT 60 IUL 0ndash34 IUL
AST 47 IUL 0ndash34 IUL
BUN 38 mgdL 08-13 mgdL
Case Study 4 ndash Lab Results
Lyme disease with DICProvide antibiotics with supportive measures
Case Study 4 ndash Diagnosis
55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis
Case Study 5 ndash Presentation
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
Case Study 5 ndash Lab Results and Time Course
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
TEST RESULT REFERENCE RANGE
Platelet count 33 x 109L 150-450 x 109L
PT 215 sec 103 ndash 128 sec
APTT 44 sec 26 ndash 36 sec
D-dimer 20 microgmL FEU lt025 microgml FEU
Fibrinogen 34 mgdL 200-375 mgdl
FII FV FVIII Low Not reported (NR)
FVII FIX FX vWF Normal NR
Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)
DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic
dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR
(C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen
(D) Illustration demonstrating repair
Case Study 5 ndash Diagnosis and Treatment
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography
Case Study 6 ndash Presentation
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
Case Study 6 ndash Lab Results
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L
PT 63 sec gt control 113 ndash 146 sec
INR 658 1 ndash 125
APTT 80 sec gt control 25 ndash 34 sec
D-dimer gt200 microgmL DDU 02 microgmL DDU
Urine exam Proteinuria and hematuria 150-400 mgdl
Albumin 28 gdL NR
Hb 58 gdL NR
LDH 1196 UL NR
SGPT 144 IU NR
SGOT 88 IU NR
Bilirubin 32 mgdL NR
DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th
day postop
Case Study 6 ndash Diagnosis and Treatment
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure
Case Study 6 ndash Discussion
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Case Study 7 ndash Lab Results vs Time
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
DIC Take Home Messages
Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation
Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers
DIC
Thank you Questions
- Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
- Learning Objectives
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Wound Sealing
- The Three Steps of Hemostasis
- Vessel Wall
- Slide Number 12
- Slide Number 13
- Platelet Structure UnactivatedActivated
- Primary Hemostasis
- Primary Hemostasis Assays
- Slide Number 17
- Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
- Slide Number 19
- Coagulation factors
- Coagulation Assay Mechanisms
- Slide Number 22
- Fibrin Formation
- Slide Number 24
- Fibrinolysis Overview
- Fibrinolysis Overview
- Slide Number 27
- Fibrinolysis Releases D-dimers
- Basic Pathophysiology of DIC
- Disseminated Intravascular Coagulation (DIC)
- Purpura Fulminans with DIC Due to Meningococcal Sepsis
- Clinical Conditions Associated With DIC
- Frequency of DIC in Selected Disease States
- Underlying Diseases in DIC Patients
- Slide Number 36
- Slide Number 37
- Slide Number 38
- Slide Number 39
- Pathophysiology of DIC
- Pathogenesis of DIC in Sepsis
- Host Response in Severe Sepsis
- Organ Failure in Severe Sepsis
- Mechanism of DIC in Organ Failure
- Interaction of Inflammation and Coagulation in Sepsis
- Slide Number 47
- Diverse and Opposing Effects of Thrombin
- Coagulation and Fibrinolysis in DIC
- Mechanism of DIC
- Pathophysiology of DIC
- Pathophysiology of DIC - Mechanism
- Pathophysiology of DIC ndash 2 Types of Clinical pictures
- Sub-Acute and Non-Overt DIC Clinical Findings
- Pathophysiology of Overt DIC
- Physiopathology of DIC ndash Overt DIC Findings
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- BREAK
- Diagnostic and Management Approach for DIC
- Diagnosis of DIC
- Lab Diagnosis of DIC ndash Markers of Factor Consumption
- Lab Diagnosis of DIC ndash Screening Tests
- Slide Number 67
- Slide Number 68
- British Journal of Haematology Overt DIC Score
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- DIC Management Goals
- DIC Management and Treatment
- DIC Management Strategies
- Anticoagulant Factor Concentrate Treatment
- Anticoagulant Factor Concentrate Treatment Trials
- Markers of Thrombin amp Plasmin Generation in DIC
- D-dimer FDPs and DIC
- D-Dimer and FDPs in DIC
- Follow Up of DIC State of Disease
- FMD-Dimer in DIC Major Differences
- of Abnormal Results in Patients with Confirmed and Suspected DIC
- Slide Number 85
- Slide Number 86
- Comparing an Automated FM vs Manual FSP Test
- Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Slide Number 94
- Slide Number 95
- Slide Number 96
- Slide Number 97
- Slide Number 98
- Slide Number 99
- DIC Case Studies
- Case Study 1 - Presentation
- Case Study 1 ndash Lab Results
- Case Study 1 ndash Microscopy
- Case Study 1 ndash Diagnosis and Therapy
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Slide Number 110
- Slide Number 111
- Slide Number 112
- Slide Number 113
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
- Slide Number 124
- Slide Number 125
- DIC Take Home Messages
- Slide Number 127
- Slide Number 128
-
TEST RESULT REFERENCE RANGEPlatelet count 107 x 109L 150-400 x 109L
PT 228 sec 113 ndash 146 sec
APTT 45 sec 25 ndash 34 sec
D-dimer 080 microgml FEU lt050 microgmL FEU
Fibrinogen 82 mgdL 150-400 mgdL
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 134 gdL 14-16 gdL
WBC 81 times 103mm3 40-11 times 103mm3
ALT 32 IUL 0ndash34 IUL
AST 28 IUL 0ndash34 IUL
BUN 09 mgdL 08-13 mgdL
Case Study 3 ndash Lab Results
Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment
Case Study 3 ndash Diagnosis and Therapy
Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91
Case Study 4 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L
PT 28 sec 113 ndash 146 sec
APTT 71 sec 25 ndash 34 sec
D-dimer 31 microgmL FEU lt050 microgml FEU
Fibrinogen 92 mgdL 150-400 mgdl
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 158 gdL 14-16 gdL
WBC 71 times 103mm3 40-11 times 103mm3
ALT 60 IUL 0ndash34 IUL
AST 47 IUL 0ndash34 IUL
BUN 38 mgdL 08-13 mgdL
Case Study 4 ndash Lab Results
Lyme disease with DICProvide antibiotics with supportive measures
Case Study 4 ndash Diagnosis
55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis
Case Study 5 ndash Presentation
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
Case Study 5 ndash Lab Results and Time Course
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
TEST RESULT REFERENCE RANGE
Platelet count 33 x 109L 150-450 x 109L
PT 215 sec 103 ndash 128 sec
APTT 44 sec 26 ndash 36 sec
D-dimer 20 microgmL FEU lt025 microgml FEU
Fibrinogen 34 mgdL 200-375 mgdl
FII FV FVIII Low Not reported (NR)
FVII FIX FX vWF Normal NR
Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)
DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic
dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR
(C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen
(D) Illustration demonstrating repair
Case Study 5 ndash Diagnosis and Treatment
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography
Case Study 6 ndash Presentation
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
Case Study 6 ndash Lab Results
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L
PT 63 sec gt control 113 ndash 146 sec
INR 658 1 ndash 125
APTT 80 sec gt control 25 ndash 34 sec
D-dimer gt200 microgmL DDU 02 microgmL DDU
Urine exam Proteinuria and hematuria 150-400 mgdl
Albumin 28 gdL NR
Hb 58 gdL NR
LDH 1196 UL NR
SGPT 144 IU NR
SGOT 88 IU NR
Bilirubin 32 mgdL NR
DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th
day postop
Case Study 6 ndash Diagnosis and Treatment
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure
Case Study 6 ndash Discussion
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Case Study 7 ndash Lab Results vs Time
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
DIC Take Home Messages
Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation
Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers
DIC
Thank you Questions
- Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
- Learning Objectives
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Wound Sealing
- The Three Steps of Hemostasis
- Vessel Wall
- Slide Number 12
- Slide Number 13
- Platelet Structure UnactivatedActivated
- Primary Hemostasis
- Primary Hemostasis Assays
- Slide Number 17
- Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
- Slide Number 19
- Coagulation factors
- Coagulation Assay Mechanisms
- Slide Number 22
- Fibrin Formation
- Slide Number 24
- Fibrinolysis Overview
- Fibrinolysis Overview
- Slide Number 27
- Fibrinolysis Releases D-dimers
- Basic Pathophysiology of DIC
- Disseminated Intravascular Coagulation (DIC)
- Purpura Fulminans with DIC Due to Meningococcal Sepsis
- Clinical Conditions Associated With DIC
- Frequency of DIC in Selected Disease States
- Underlying Diseases in DIC Patients
- Slide Number 36
- Slide Number 37
- Slide Number 38
- Slide Number 39
- Pathophysiology of DIC
- Pathogenesis of DIC in Sepsis
- Host Response in Severe Sepsis
- Organ Failure in Severe Sepsis
- Mechanism of DIC in Organ Failure
- Interaction of Inflammation and Coagulation in Sepsis
- Slide Number 47
- Diverse and Opposing Effects of Thrombin
- Coagulation and Fibrinolysis in DIC
- Mechanism of DIC
- Pathophysiology of DIC
- Pathophysiology of DIC - Mechanism
- Pathophysiology of DIC ndash 2 Types of Clinical pictures
- Sub-Acute and Non-Overt DIC Clinical Findings
- Pathophysiology of Overt DIC
- Physiopathology of DIC ndash Overt DIC Findings
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- BREAK
- Diagnostic and Management Approach for DIC
- Diagnosis of DIC
- Lab Diagnosis of DIC ndash Markers of Factor Consumption
- Lab Diagnosis of DIC ndash Screening Tests
- Slide Number 67
- Slide Number 68
- British Journal of Haematology Overt DIC Score
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- DIC Management Goals
- DIC Management and Treatment
- DIC Management Strategies
- Anticoagulant Factor Concentrate Treatment
- Anticoagulant Factor Concentrate Treatment Trials
- Markers of Thrombin amp Plasmin Generation in DIC
- D-dimer FDPs and DIC
- D-Dimer and FDPs in DIC
- Follow Up of DIC State of Disease
- FMD-Dimer in DIC Major Differences
- of Abnormal Results in Patients with Confirmed and Suspected DIC
- Slide Number 85
- Slide Number 86
- Comparing an Automated FM vs Manual FSP Test
- Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Slide Number 94
- Slide Number 95
- Slide Number 96
- Slide Number 97
- Slide Number 98
- Slide Number 99
- DIC Case Studies
- Case Study 1 - Presentation
- Case Study 1 ndash Lab Results
- Case Study 1 ndash Microscopy
- Case Study 1 ndash Diagnosis and Therapy
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Slide Number 110
- Slide Number 111
- Slide Number 112
- Slide Number 113
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
- Slide Number 124
- Slide Number 125
- DIC Take Home Messages
- Slide Number 127
- Slide Number 128
-
Acute promyelocytic leukemia with DICTransfusions to replace platelets and RBCs during APL treatment
Case Study 3 ndash Diagnosis and Therapy
Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91
Case Study 4 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L
PT 28 sec 113 ndash 146 sec
APTT 71 sec 25 ndash 34 sec
D-dimer 31 microgmL FEU lt050 microgml FEU
Fibrinogen 92 mgdL 150-400 mgdl
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 158 gdL 14-16 gdL
WBC 71 times 103mm3 40-11 times 103mm3
ALT 60 IUL 0ndash34 IUL
AST 47 IUL 0ndash34 IUL
BUN 38 mgdL 08-13 mgdL
Case Study 4 ndash Lab Results
Lyme disease with DICProvide antibiotics with supportive measures
Case Study 4 ndash Diagnosis
55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis
Case Study 5 ndash Presentation
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
Case Study 5 ndash Lab Results and Time Course
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
TEST RESULT REFERENCE RANGE
Platelet count 33 x 109L 150-450 x 109L
PT 215 sec 103 ndash 128 sec
APTT 44 sec 26 ndash 36 sec
D-dimer 20 microgmL FEU lt025 microgml FEU
Fibrinogen 34 mgdL 200-375 mgdl
FII FV FVIII Low Not reported (NR)
FVII FIX FX vWF Normal NR
Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)
DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic
dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR
(C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen
(D) Illustration demonstrating repair
Case Study 5 ndash Diagnosis and Treatment
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography
Case Study 6 ndash Presentation
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
Case Study 6 ndash Lab Results
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L
PT 63 sec gt control 113 ndash 146 sec
INR 658 1 ndash 125
APTT 80 sec gt control 25 ndash 34 sec
D-dimer gt200 microgmL DDU 02 microgmL DDU
Urine exam Proteinuria and hematuria 150-400 mgdl
Albumin 28 gdL NR
Hb 58 gdL NR
LDH 1196 UL NR
SGPT 144 IU NR
SGOT 88 IU NR
Bilirubin 32 mgdL NR
DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th
day postop
Case Study 6 ndash Diagnosis and Treatment
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure
Case Study 6 ndash Discussion
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Case Study 7 ndash Lab Results vs Time
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
DIC Take Home Messages
Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation
Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers
DIC
Thank you Questions
- Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
- Learning Objectives
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Wound Sealing
- The Three Steps of Hemostasis
- Vessel Wall
- Slide Number 12
- Slide Number 13
- Platelet Structure UnactivatedActivated
- Primary Hemostasis
- Primary Hemostasis Assays
- Slide Number 17
- Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
- Slide Number 19
- Coagulation factors
- Coagulation Assay Mechanisms
- Slide Number 22
- Fibrin Formation
- Slide Number 24
- Fibrinolysis Overview
- Fibrinolysis Overview
- Slide Number 27
- Fibrinolysis Releases D-dimers
- Basic Pathophysiology of DIC
- Disseminated Intravascular Coagulation (DIC)
- Purpura Fulminans with DIC Due to Meningococcal Sepsis
- Clinical Conditions Associated With DIC
- Frequency of DIC in Selected Disease States
- Underlying Diseases in DIC Patients
- Slide Number 36
- Slide Number 37
- Slide Number 38
- Slide Number 39
- Pathophysiology of DIC
- Pathogenesis of DIC in Sepsis
- Host Response in Severe Sepsis
- Organ Failure in Severe Sepsis
- Mechanism of DIC in Organ Failure
- Interaction of Inflammation and Coagulation in Sepsis
- Slide Number 47
- Diverse and Opposing Effects of Thrombin
- Coagulation and Fibrinolysis in DIC
- Mechanism of DIC
- Pathophysiology of DIC
- Pathophysiology of DIC - Mechanism
- Pathophysiology of DIC ndash 2 Types of Clinical pictures
- Sub-Acute and Non-Overt DIC Clinical Findings
- Pathophysiology of Overt DIC
- Physiopathology of DIC ndash Overt DIC Findings
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- BREAK
- Diagnostic and Management Approach for DIC
- Diagnosis of DIC
- Lab Diagnosis of DIC ndash Markers of Factor Consumption
- Lab Diagnosis of DIC ndash Screening Tests
- Slide Number 67
- Slide Number 68
- British Journal of Haematology Overt DIC Score
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- DIC Management Goals
- DIC Management and Treatment
- DIC Management Strategies
- Anticoagulant Factor Concentrate Treatment
- Anticoagulant Factor Concentrate Treatment Trials
- Markers of Thrombin amp Plasmin Generation in DIC
- D-dimer FDPs and DIC
- D-Dimer and FDPs in DIC
- Follow Up of DIC State of Disease
- FMD-Dimer in DIC Major Differences
- of Abnormal Results in Patients with Confirmed and Suspected DIC
- Slide Number 85
- Slide Number 86
- Comparing an Automated FM vs Manual FSP Test
- Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Slide Number 94
- Slide Number 95
- Slide Number 96
- Slide Number 97
- Slide Number 98
- Slide Number 99
- DIC Case Studies
- Case Study 1 - Presentation
- Case Study 1 ndash Lab Results
- Case Study 1 ndash Microscopy
- Case Study 1 ndash Diagnosis and Therapy
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Slide Number 110
- Slide Number 111
- Slide Number 112
- Slide Number 113
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
- Slide Number 124
- Slide Number 125
- DIC Take Home Messages
- Slide Number 127
- Slide Number 128
-
Critical care transport arranged for 48 year old male admitted to the local hospital 3 days prior with weakness and hypotension Four days prior insect bite while hiking large hematoma on left armNo prior medical history no drug allergies no current medicationsUpon arrival patient is awake and alert in moderate respiratory distress oozing blood from both vascular access sites nose and urinary catheter skin is cool and mildly jaundicedVital signs heart rate 110 beats per minute blood pressure 9244 slightly labored respiratory rate 22 breaths per minute pulse oximetry 91
Case Study 4 ndash Presentation
TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L
PT 28 sec 113 ndash 146 sec
APTT 71 sec 25 ndash 34 sec
D-dimer 31 microgmL FEU lt050 microgml FEU
Fibrinogen 92 mgdL 150-400 mgdl
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 158 gdL 14-16 gdL
WBC 71 times 103mm3 40-11 times 103mm3
ALT 60 IUL 0ndash34 IUL
AST 47 IUL 0ndash34 IUL
BUN 38 mgdL 08-13 mgdL
Case Study 4 ndash Lab Results
Lyme disease with DICProvide antibiotics with supportive measures
Case Study 4 ndash Diagnosis
55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis
Case Study 5 ndash Presentation
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
Case Study 5 ndash Lab Results and Time Course
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
TEST RESULT REFERENCE RANGE
Platelet count 33 x 109L 150-450 x 109L
PT 215 sec 103 ndash 128 sec
APTT 44 sec 26 ndash 36 sec
D-dimer 20 microgmL FEU lt025 microgml FEU
Fibrinogen 34 mgdL 200-375 mgdl
FII FV FVIII Low Not reported (NR)
FVII FIX FX vWF Normal NR
Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)
DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic
dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR
(C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen
(D) Illustration demonstrating repair
Case Study 5 ndash Diagnosis and Treatment
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography
Case Study 6 ndash Presentation
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
Case Study 6 ndash Lab Results
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L
PT 63 sec gt control 113 ndash 146 sec
INR 658 1 ndash 125
APTT 80 sec gt control 25 ndash 34 sec
D-dimer gt200 microgmL DDU 02 microgmL DDU
Urine exam Proteinuria and hematuria 150-400 mgdl
Albumin 28 gdL NR
Hb 58 gdL NR
LDH 1196 UL NR
SGPT 144 IU NR
SGOT 88 IU NR
Bilirubin 32 mgdL NR
DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th
day postop
Case Study 6 ndash Diagnosis and Treatment
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure
Case Study 6 ndash Discussion
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Case Study 7 ndash Lab Results vs Time
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
DIC Take Home Messages
Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation
Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers
DIC
Thank you Questions
- Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
- Learning Objectives
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Wound Sealing
- The Three Steps of Hemostasis
- Vessel Wall
- Slide Number 12
- Slide Number 13
- Platelet Structure UnactivatedActivated
- Primary Hemostasis
- Primary Hemostasis Assays
- Slide Number 17
- Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
- Slide Number 19
- Coagulation factors
- Coagulation Assay Mechanisms
- Slide Number 22
- Fibrin Formation
- Slide Number 24
- Fibrinolysis Overview
- Fibrinolysis Overview
- Slide Number 27
- Fibrinolysis Releases D-dimers
- Basic Pathophysiology of DIC
- Disseminated Intravascular Coagulation (DIC)
- Purpura Fulminans with DIC Due to Meningococcal Sepsis
- Clinical Conditions Associated With DIC
- Frequency of DIC in Selected Disease States
- Underlying Diseases in DIC Patients
- Slide Number 36
- Slide Number 37
- Slide Number 38
- Slide Number 39
- Pathophysiology of DIC
- Pathogenesis of DIC in Sepsis
- Host Response in Severe Sepsis
- Organ Failure in Severe Sepsis
- Mechanism of DIC in Organ Failure
- Interaction of Inflammation and Coagulation in Sepsis
- Slide Number 47
- Diverse and Opposing Effects of Thrombin
- Coagulation and Fibrinolysis in DIC
- Mechanism of DIC
- Pathophysiology of DIC
- Pathophysiology of DIC - Mechanism
- Pathophysiology of DIC ndash 2 Types of Clinical pictures
- Sub-Acute and Non-Overt DIC Clinical Findings
- Pathophysiology of Overt DIC
- Physiopathology of DIC ndash Overt DIC Findings
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- BREAK
- Diagnostic and Management Approach for DIC
- Diagnosis of DIC
- Lab Diagnosis of DIC ndash Markers of Factor Consumption
- Lab Diagnosis of DIC ndash Screening Tests
- Slide Number 67
- Slide Number 68
- British Journal of Haematology Overt DIC Score
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- DIC Management Goals
- DIC Management and Treatment
- DIC Management Strategies
- Anticoagulant Factor Concentrate Treatment
- Anticoagulant Factor Concentrate Treatment Trials
- Markers of Thrombin amp Plasmin Generation in DIC
- D-dimer FDPs and DIC
- D-Dimer and FDPs in DIC
- Follow Up of DIC State of Disease
- FMD-Dimer in DIC Major Differences
- of Abnormal Results in Patients with Confirmed and Suspected DIC
- Slide Number 85
- Slide Number 86
- Comparing an Automated FM vs Manual FSP Test
- Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Slide Number 94
- Slide Number 95
- Slide Number 96
- Slide Number 97
- Slide Number 98
- Slide Number 99
- DIC Case Studies
- Case Study 1 - Presentation
- Case Study 1 ndash Lab Results
- Case Study 1 ndash Microscopy
- Case Study 1 ndash Diagnosis and Therapy
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Slide Number 110
- Slide Number 111
- Slide Number 112
- Slide Number 113
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
- Slide Number 124
- Slide Number 125
- DIC Take Home Messages
- Slide Number 127
- Slide Number 128
-
TEST RESULT REFERENCE RANGEPlatelet count 70 x 109L 150-400 x 109L
PT 28 sec 113 ndash 146 sec
APTT 71 sec 25 ndash 34 sec
D-dimer 31 microgmL FEU lt050 microgml FEU
Fibrinogen 92 mgdL 150-400 mgdl
FV Normal 70-120
FVII Normal 55-170
FVIII Normal 60-150
Protein C Normal 70-130
Hb 158 gdL 14-16 gdL
WBC 71 times 103mm3 40-11 times 103mm3
ALT 60 IUL 0ndash34 IUL
AST 47 IUL 0ndash34 IUL
BUN 38 mgdL 08-13 mgdL
Case Study 4 ndash Lab Results
Lyme disease with DICProvide antibiotics with supportive measures
Case Study 4 ndash Diagnosis
55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis
Case Study 5 ndash Presentation
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
Case Study 5 ndash Lab Results and Time Course
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
TEST RESULT REFERENCE RANGE
Platelet count 33 x 109L 150-450 x 109L
PT 215 sec 103 ndash 128 sec
APTT 44 sec 26 ndash 36 sec
D-dimer 20 microgmL FEU lt025 microgml FEU
Fibrinogen 34 mgdL 200-375 mgdl
FII FV FVIII Low Not reported (NR)
FVII FIX FX vWF Normal NR
Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)
DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic
dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR
(C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen
(D) Illustration demonstrating repair
Case Study 5 ndash Diagnosis and Treatment
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography
Case Study 6 ndash Presentation
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
Case Study 6 ndash Lab Results
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L
PT 63 sec gt control 113 ndash 146 sec
INR 658 1 ndash 125
APTT 80 sec gt control 25 ndash 34 sec
D-dimer gt200 microgmL DDU 02 microgmL DDU
Urine exam Proteinuria and hematuria 150-400 mgdl
Albumin 28 gdL NR
Hb 58 gdL NR
LDH 1196 UL NR
SGPT 144 IU NR
SGOT 88 IU NR
Bilirubin 32 mgdL NR
DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th
day postop
Case Study 6 ndash Diagnosis and Treatment
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure
Case Study 6 ndash Discussion
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Case Study 7 ndash Lab Results vs Time
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
DIC Take Home Messages
Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation
Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers
DIC
Thank you Questions
- Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
- Learning Objectives
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Wound Sealing
- The Three Steps of Hemostasis
- Vessel Wall
- Slide Number 12
- Slide Number 13
- Platelet Structure UnactivatedActivated
- Primary Hemostasis
- Primary Hemostasis Assays
- Slide Number 17
- Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
- Slide Number 19
- Coagulation factors
- Coagulation Assay Mechanisms
- Slide Number 22
- Fibrin Formation
- Slide Number 24
- Fibrinolysis Overview
- Fibrinolysis Overview
- Slide Number 27
- Fibrinolysis Releases D-dimers
- Basic Pathophysiology of DIC
- Disseminated Intravascular Coagulation (DIC)
- Purpura Fulminans with DIC Due to Meningococcal Sepsis
- Clinical Conditions Associated With DIC
- Frequency of DIC in Selected Disease States
- Underlying Diseases in DIC Patients
- Slide Number 36
- Slide Number 37
- Slide Number 38
- Slide Number 39
- Pathophysiology of DIC
- Pathogenesis of DIC in Sepsis
- Host Response in Severe Sepsis
- Organ Failure in Severe Sepsis
- Mechanism of DIC in Organ Failure
- Interaction of Inflammation and Coagulation in Sepsis
- Slide Number 47
- Diverse and Opposing Effects of Thrombin
- Coagulation and Fibrinolysis in DIC
- Mechanism of DIC
- Pathophysiology of DIC
- Pathophysiology of DIC - Mechanism
- Pathophysiology of DIC ndash 2 Types of Clinical pictures
- Sub-Acute and Non-Overt DIC Clinical Findings
- Pathophysiology of Overt DIC
- Physiopathology of DIC ndash Overt DIC Findings
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- BREAK
- Diagnostic and Management Approach for DIC
- Diagnosis of DIC
- Lab Diagnosis of DIC ndash Markers of Factor Consumption
- Lab Diagnosis of DIC ndash Screening Tests
- Slide Number 67
- Slide Number 68
- British Journal of Haematology Overt DIC Score
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- DIC Management Goals
- DIC Management and Treatment
- DIC Management Strategies
- Anticoagulant Factor Concentrate Treatment
- Anticoagulant Factor Concentrate Treatment Trials
- Markers of Thrombin amp Plasmin Generation in DIC
- D-dimer FDPs and DIC
- D-Dimer and FDPs in DIC
- Follow Up of DIC State of Disease
- FMD-Dimer in DIC Major Differences
- of Abnormal Results in Patients with Confirmed and Suspected DIC
- Slide Number 85
- Slide Number 86
- Comparing an Automated FM vs Manual FSP Test
- Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Slide Number 94
- Slide Number 95
- Slide Number 96
- Slide Number 97
- Slide Number 98
- Slide Number 99
- DIC Case Studies
- Case Study 1 - Presentation
- Case Study 1 ndash Lab Results
- Case Study 1 ndash Microscopy
- Case Study 1 ndash Diagnosis and Therapy
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Slide Number 110
- Slide Number 111
- Slide Number 112
- Slide Number 113
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
- Slide Number 124
- Slide Number 125
- DIC Take Home Messages
- Slide Number 127
- Slide Number 128
-
Lyme disease with DICProvide antibiotics with supportive measures
Case Study 4 ndash Diagnosis
55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis
Case Study 5 ndash Presentation
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
Case Study 5 ndash Lab Results and Time Course
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
TEST RESULT REFERENCE RANGE
Platelet count 33 x 109L 150-450 x 109L
PT 215 sec 103 ndash 128 sec
APTT 44 sec 26 ndash 36 sec
D-dimer 20 microgmL FEU lt025 microgml FEU
Fibrinogen 34 mgdL 200-375 mgdl
FII FV FVIII Low Not reported (NR)
FVII FIX FX vWF Normal NR
Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)
DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic
dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR
(C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen
(D) Illustration demonstrating repair
Case Study 5 ndash Diagnosis and Treatment
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography
Case Study 6 ndash Presentation
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
Case Study 6 ndash Lab Results
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L
PT 63 sec gt control 113 ndash 146 sec
INR 658 1 ndash 125
APTT 80 sec gt control 25 ndash 34 sec
D-dimer gt200 microgmL DDU 02 microgmL DDU
Urine exam Proteinuria and hematuria 150-400 mgdl
Albumin 28 gdL NR
Hb 58 gdL NR
LDH 1196 UL NR
SGPT 144 IU NR
SGOT 88 IU NR
Bilirubin 32 mgdL NR
DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th
day postop
Case Study 6 ndash Diagnosis and Treatment
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure
Case Study 6 ndash Discussion
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Case Study 7 ndash Lab Results vs Time
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
DIC Take Home Messages
Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation
Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers
DIC
Thank you Questions
- Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
- Learning Objectives
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Wound Sealing
- The Three Steps of Hemostasis
- Vessel Wall
- Slide Number 12
- Slide Number 13
- Platelet Structure UnactivatedActivated
- Primary Hemostasis
- Primary Hemostasis Assays
- Slide Number 17
- Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
- Slide Number 19
- Coagulation factors
- Coagulation Assay Mechanisms
- Slide Number 22
- Fibrin Formation
- Slide Number 24
- Fibrinolysis Overview
- Fibrinolysis Overview
- Slide Number 27
- Fibrinolysis Releases D-dimers
- Basic Pathophysiology of DIC
- Disseminated Intravascular Coagulation (DIC)
- Purpura Fulminans with DIC Due to Meningococcal Sepsis
- Clinical Conditions Associated With DIC
- Frequency of DIC in Selected Disease States
- Underlying Diseases in DIC Patients
- Slide Number 36
- Slide Number 37
- Slide Number 38
- Slide Number 39
- Pathophysiology of DIC
- Pathogenesis of DIC in Sepsis
- Host Response in Severe Sepsis
- Organ Failure in Severe Sepsis
- Mechanism of DIC in Organ Failure
- Interaction of Inflammation and Coagulation in Sepsis
- Slide Number 47
- Diverse and Opposing Effects of Thrombin
- Coagulation and Fibrinolysis in DIC
- Mechanism of DIC
- Pathophysiology of DIC
- Pathophysiology of DIC - Mechanism
- Pathophysiology of DIC ndash 2 Types of Clinical pictures
- Sub-Acute and Non-Overt DIC Clinical Findings
- Pathophysiology of Overt DIC
- Physiopathology of DIC ndash Overt DIC Findings
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- BREAK
- Diagnostic and Management Approach for DIC
- Diagnosis of DIC
- Lab Diagnosis of DIC ndash Markers of Factor Consumption
- Lab Diagnosis of DIC ndash Screening Tests
- Slide Number 67
- Slide Number 68
- British Journal of Haematology Overt DIC Score
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- DIC Management Goals
- DIC Management and Treatment
- DIC Management Strategies
- Anticoagulant Factor Concentrate Treatment
- Anticoagulant Factor Concentrate Treatment Trials
- Markers of Thrombin amp Plasmin Generation in DIC
- D-dimer FDPs and DIC
- D-Dimer and FDPs in DIC
- Follow Up of DIC State of Disease
- FMD-Dimer in DIC Major Differences
- of Abnormal Results in Patients with Confirmed and Suspected DIC
- Slide Number 85
- Slide Number 86
- Comparing an Automated FM vs Manual FSP Test
- Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Slide Number 94
- Slide Number 95
- Slide Number 96
- Slide Number 97
- Slide Number 98
- Slide Number 99
- DIC Case Studies
- Case Study 1 - Presentation
- Case Study 1 ndash Lab Results
- Case Study 1 ndash Microscopy
- Case Study 1 ndash Diagnosis and Therapy
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Slide Number 110
- Slide Number 111
- Slide Number 112
- Slide Number 113
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
- Slide Number 124
- Slide Number 125
- DIC Take Home Messages
- Slide Number 127
- Slide Number 128
-
55-year-old man 10 following months after thoracic endovascular aortic repair (TEVAR) multiple ecchymoses diffusely distributed in his torso along with upper and lower extremitiesChronic type B aortic dissection and descending thoracic aortic aneurysmPersistent retrograde flow in false lumen with stable aneurysm diameterFalse lumen embolized with multiple Amplatzer plugs which promoted false lumen thrombosis
Case Study 5 ndash Presentation
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
Case Study 5 ndash Lab Results and Time Course
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
TEST RESULT REFERENCE RANGE
Platelet count 33 x 109L 150-450 x 109L
PT 215 sec 103 ndash 128 sec
APTT 44 sec 26 ndash 36 sec
D-dimer 20 microgmL FEU lt025 microgml FEU
Fibrinogen 34 mgdL 200-375 mgdl
FII FV FVIII Low Not reported (NR)
FVII FIX FX vWF Normal NR
Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)
DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic
dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR
(C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen
(D) Illustration demonstrating repair
Case Study 5 ndash Diagnosis and Treatment
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography
Case Study 6 ndash Presentation
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
Case Study 6 ndash Lab Results
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L
PT 63 sec gt control 113 ndash 146 sec
INR 658 1 ndash 125
APTT 80 sec gt control 25 ndash 34 sec
D-dimer gt200 microgmL DDU 02 microgmL DDU
Urine exam Proteinuria and hematuria 150-400 mgdl
Albumin 28 gdL NR
Hb 58 gdL NR
LDH 1196 UL NR
SGPT 144 IU NR
SGOT 88 IU NR
Bilirubin 32 mgdL NR
DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th
day postop
Case Study 6 ndash Diagnosis and Treatment
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure
Case Study 6 ndash Discussion
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Case Study 7 ndash Lab Results vs Time
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
DIC Take Home Messages
Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation
Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers
DIC
Thank you Questions
- Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
- Learning Objectives
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Wound Sealing
- The Three Steps of Hemostasis
- Vessel Wall
- Slide Number 12
- Slide Number 13
- Platelet Structure UnactivatedActivated
- Primary Hemostasis
- Primary Hemostasis Assays
- Slide Number 17
- Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
- Slide Number 19
- Coagulation factors
- Coagulation Assay Mechanisms
- Slide Number 22
- Fibrin Formation
- Slide Number 24
- Fibrinolysis Overview
- Fibrinolysis Overview
- Slide Number 27
- Fibrinolysis Releases D-dimers
- Basic Pathophysiology of DIC
- Disseminated Intravascular Coagulation (DIC)
- Purpura Fulminans with DIC Due to Meningococcal Sepsis
- Clinical Conditions Associated With DIC
- Frequency of DIC in Selected Disease States
- Underlying Diseases in DIC Patients
- Slide Number 36
- Slide Number 37
- Slide Number 38
- Slide Number 39
- Pathophysiology of DIC
- Pathogenesis of DIC in Sepsis
- Host Response in Severe Sepsis
- Organ Failure in Severe Sepsis
- Mechanism of DIC in Organ Failure
- Interaction of Inflammation and Coagulation in Sepsis
- Slide Number 47
- Diverse and Opposing Effects of Thrombin
- Coagulation and Fibrinolysis in DIC
- Mechanism of DIC
- Pathophysiology of DIC
- Pathophysiology of DIC - Mechanism
- Pathophysiology of DIC ndash 2 Types of Clinical pictures
- Sub-Acute and Non-Overt DIC Clinical Findings
- Pathophysiology of Overt DIC
- Physiopathology of DIC ndash Overt DIC Findings
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- BREAK
- Diagnostic and Management Approach for DIC
- Diagnosis of DIC
- Lab Diagnosis of DIC ndash Markers of Factor Consumption
- Lab Diagnosis of DIC ndash Screening Tests
- Slide Number 67
- Slide Number 68
- British Journal of Haematology Overt DIC Score
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- DIC Management Goals
- DIC Management and Treatment
- DIC Management Strategies
- Anticoagulant Factor Concentrate Treatment
- Anticoagulant Factor Concentrate Treatment Trials
- Markers of Thrombin amp Plasmin Generation in DIC
- D-dimer FDPs and DIC
- D-Dimer and FDPs in DIC
- Follow Up of DIC State of Disease
- FMD-Dimer in DIC Major Differences
- of Abnormal Results in Patients with Confirmed and Suspected DIC
- Slide Number 85
- Slide Number 86
- Comparing an Automated FM vs Manual FSP Test
- Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Slide Number 94
- Slide Number 95
- Slide Number 96
- Slide Number 97
- Slide Number 98
- Slide Number 99
- DIC Case Studies
- Case Study 1 - Presentation
- Case Study 1 ndash Lab Results
- Case Study 1 ndash Microscopy
- Case Study 1 ndash Diagnosis and Therapy
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Slide Number 110
- Slide Number 111
- Slide Number 112
- Slide Number 113
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
- Slide Number 124
- Slide Number 125
- DIC Take Home Messages
- Slide Number 127
- Slide Number 128
-
Case Study 5 ndash Lab Results and Time Course
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
TEST RESULT REFERENCE RANGE
Platelet count 33 x 109L 150-450 x 109L
PT 215 sec 103 ndash 128 sec
APTT 44 sec 26 ndash 36 sec
D-dimer 20 microgmL FEU lt025 microgml FEU
Fibrinogen 34 mgdL 200-375 mgdl
FII FV FVIII Low Not reported (NR)
FVII FIX FX vWF Normal NR
Improvement in Pltand Fib after false lumen embolization with multiple endovascular plugs(arrows)
DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic
dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR
(C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen
(D) Illustration demonstrating repair
Case Study 5 ndash Diagnosis and Treatment
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography
Case Study 6 ndash Presentation
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
Case Study 6 ndash Lab Results
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L
PT 63 sec gt control 113 ndash 146 sec
INR 658 1 ndash 125
APTT 80 sec gt control 25 ndash 34 sec
D-dimer gt200 microgmL DDU 02 microgmL DDU
Urine exam Proteinuria and hematuria 150-400 mgdl
Albumin 28 gdL NR
Hb 58 gdL NR
LDH 1196 UL NR
SGPT 144 IU NR
SGOT 88 IU NR
Bilirubin 32 mgdL NR
DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th
day postop
Case Study 6 ndash Diagnosis and Treatment
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure
Case Study 6 ndash Discussion
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Case Study 7 ndash Lab Results vs Time
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
DIC Take Home Messages
Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation
Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers
DIC
Thank you Questions
- Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
- Learning Objectives
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Wound Sealing
- The Three Steps of Hemostasis
- Vessel Wall
- Slide Number 12
- Slide Number 13
- Platelet Structure UnactivatedActivated
- Primary Hemostasis
- Primary Hemostasis Assays
- Slide Number 17
- Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
- Slide Number 19
- Coagulation factors
- Coagulation Assay Mechanisms
- Slide Number 22
- Fibrin Formation
- Slide Number 24
- Fibrinolysis Overview
- Fibrinolysis Overview
- Slide Number 27
- Fibrinolysis Releases D-dimers
- Basic Pathophysiology of DIC
- Disseminated Intravascular Coagulation (DIC)
- Purpura Fulminans with DIC Due to Meningococcal Sepsis
- Clinical Conditions Associated With DIC
- Frequency of DIC in Selected Disease States
- Underlying Diseases in DIC Patients
- Slide Number 36
- Slide Number 37
- Slide Number 38
- Slide Number 39
- Pathophysiology of DIC
- Pathogenesis of DIC in Sepsis
- Host Response in Severe Sepsis
- Organ Failure in Severe Sepsis
- Mechanism of DIC in Organ Failure
- Interaction of Inflammation and Coagulation in Sepsis
- Slide Number 47
- Diverse and Opposing Effects of Thrombin
- Coagulation and Fibrinolysis in DIC
- Mechanism of DIC
- Pathophysiology of DIC
- Pathophysiology of DIC - Mechanism
- Pathophysiology of DIC ndash 2 Types of Clinical pictures
- Sub-Acute and Non-Overt DIC Clinical Findings
- Pathophysiology of Overt DIC
- Physiopathology of DIC ndash Overt DIC Findings
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- BREAK
- Diagnostic and Management Approach for DIC
- Diagnosis of DIC
- Lab Diagnosis of DIC ndash Markers of Factor Consumption
- Lab Diagnosis of DIC ndash Screening Tests
- Slide Number 67
- Slide Number 68
- British Journal of Haematology Overt DIC Score
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- DIC Management Goals
- DIC Management and Treatment
- DIC Management Strategies
- Anticoagulant Factor Concentrate Treatment
- Anticoagulant Factor Concentrate Treatment Trials
- Markers of Thrombin amp Plasmin Generation in DIC
- D-dimer FDPs and DIC
- D-Dimer and FDPs in DIC
- Follow Up of DIC State of Disease
- FMD-Dimer in DIC Major Differences
- of Abnormal Results in Patients with Confirmed and Suspected DIC
- Slide Number 85
- Slide Number 86
- Comparing an Automated FM vs Manual FSP Test
- Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Slide Number 94
- Slide Number 95
- Slide Number 96
- Slide Number 97
- Slide Number 98
- Slide Number 99
- DIC Case Studies
- Case Study 1 - Presentation
- Case Study 1 ndash Lab Results
- Case Study 1 ndash Microscopy
- Case Study 1 ndash Diagnosis and Therapy
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Slide Number 110
- Slide Number 111
- Slide Number 112
- Slide Number 113
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
- Slide Number 124
- Slide Number 125
- DIC Take Home Messages
- Slide Number 127
- Slide Number 128
-
DIC secondary to large type Ib endoleakUFH infusion cryoprecipitate partial improvement in platelet count and fibrinogenRare case of DIC following TEVAR (A) 3D CT reconstruction (B) Illustration demonstrating chronic type B aortic
dissection with associated aneurysmal dilatation of the descending thoracic aorta patient treated with TEVAR
(C) Completion angiogram demonstrated patent supra-aortic vessels and thoracic stent-graft no evidence of an antegrade endoleak but persistent distal type Ib endoleak (black arrow) into false lumen
(D) Illustration demonstrating repair
Case Study 5 ndash Diagnosis and Treatment
Mendes BC Oderich GS Erben Y Reed NR Pruthi RK False Lumen Embolization to Treat Disseminated Intravascular Coagulation After Thoracic Endovascular Aortic Repair of Type B Aortic Dissection Journal of Endovascular Therapy 2015 22 938ndash41
29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography
Case Study 6 ndash Presentation
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
Case Study 6 ndash Lab Results
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L
PT 63 sec gt control 113 ndash 146 sec
INR 658 1 ndash 125
APTT 80 sec gt control 25 ndash 34 sec
D-dimer gt200 microgmL DDU 02 microgmL DDU
Urine exam Proteinuria and hematuria 150-400 mgdl
Albumin 28 gdL NR
Hb 58 gdL NR
LDH 1196 UL NR
SGPT 144 IU NR
SGOT 88 IU NR
Bilirubin 32 mgdL NR
DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th
day postop
Case Study 6 ndash Diagnosis and Treatment
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure
Case Study 6 ndash Discussion
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Case Study 7 ndash Lab Results vs Time
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
DIC Take Home Messages
Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation
Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers
DIC
Thank you Questions
- Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
- Learning Objectives
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Wound Sealing
- The Three Steps of Hemostasis
- Vessel Wall
- Slide Number 12
- Slide Number 13
- Platelet Structure UnactivatedActivated
- Primary Hemostasis
- Primary Hemostasis Assays
- Slide Number 17
- Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
- Slide Number 19
- Coagulation factors
- Coagulation Assay Mechanisms
- Slide Number 22
- Fibrin Formation
- Slide Number 24
- Fibrinolysis Overview
- Fibrinolysis Overview
- Slide Number 27
- Fibrinolysis Releases D-dimers
- Basic Pathophysiology of DIC
- Disseminated Intravascular Coagulation (DIC)
- Purpura Fulminans with DIC Due to Meningococcal Sepsis
- Clinical Conditions Associated With DIC
- Frequency of DIC in Selected Disease States
- Underlying Diseases in DIC Patients
- Slide Number 36
- Slide Number 37
- Slide Number 38
- Slide Number 39
- Pathophysiology of DIC
- Pathogenesis of DIC in Sepsis
- Host Response in Severe Sepsis
- Organ Failure in Severe Sepsis
- Mechanism of DIC in Organ Failure
- Interaction of Inflammation and Coagulation in Sepsis
- Slide Number 47
- Diverse and Opposing Effects of Thrombin
- Coagulation and Fibrinolysis in DIC
- Mechanism of DIC
- Pathophysiology of DIC
- Pathophysiology of DIC - Mechanism
- Pathophysiology of DIC ndash 2 Types of Clinical pictures
- Sub-Acute and Non-Overt DIC Clinical Findings
- Pathophysiology of Overt DIC
- Physiopathology of DIC ndash Overt DIC Findings
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- BREAK
- Diagnostic and Management Approach for DIC
- Diagnosis of DIC
- Lab Diagnosis of DIC ndash Markers of Factor Consumption
- Lab Diagnosis of DIC ndash Screening Tests
- Slide Number 67
- Slide Number 68
- British Journal of Haematology Overt DIC Score
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- DIC Management Goals
- DIC Management and Treatment
- DIC Management Strategies
- Anticoagulant Factor Concentrate Treatment
- Anticoagulant Factor Concentrate Treatment Trials
- Markers of Thrombin amp Plasmin Generation in DIC
- D-dimer FDPs and DIC
- D-Dimer and FDPs in DIC
- Follow Up of DIC State of Disease
- FMD-Dimer in DIC Major Differences
- of Abnormal Results in Patients with Confirmed and Suspected DIC
- Slide Number 85
- Slide Number 86
- Comparing an Automated FM vs Manual FSP Test
- Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Slide Number 94
- Slide Number 95
- Slide Number 96
- Slide Number 97
- Slide Number 98
- Slide Number 99
- DIC Case Studies
- Case Study 1 - Presentation
- Case Study 1 ndash Lab Results
- Case Study 1 ndash Microscopy
- Case Study 1 ndash Diagnosis and Therapy
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Slide Number 110
- Slide Number 111
- Slide Number 112
- Slide Number 113
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
- Slide Number 124
- Slide Number 125
- DIC Take Home Messages
- Slide Number 127
- Slide Number 128
-
29 year old female 50 kg hematuria and epistaxis pregnant 37 weeks no prior prenatal check ups hematuria 10 days priorOn examination blood pressure 200160 started on α-methyldopaShe developed profuse epistaxis controlled after bilateral nasal packinNo history of blurring of vision or epigastric pain denied history of prior abnormal bleeding episodes ingestion of any medication except α-methyldopaExamination revealed pallor and pedal edema controlled with three 5 mg boluses of intravenous labetalolTrachea was electively intubated under midazolam sedation for protection of airway and patient placed on ventilation with oxygen supplementationBaby was monitored using cardiotocography and Doppler ultrasonography
Case Study 6 ndash Presentation
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
Case Study 6 ndash Lab Results
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L
PT 63 sec gt control 113 ndash 146 sec
INR 658 1 ndash 125
APTT 80 sec gt control 25 ndash 34 sec
D-dimer gt200 microgmL DDU 02 microgmL DDU
Urine exam Proteinuria and hematuria 150-400 mgdl
Albumin 28 gdL NR
Hb 58 gdL NR
LDH 1196 UL NR
SGPT 144 IU NR
SGOT 88 IU NR
Bilirubin 32 mgdL NR
DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th
day postop
Case Study 6 ndash Diagnosis and Treatment
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure
Case Study 6 ndash Discussion
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Case Study 7 ndash Lab Results vs Time
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
DIC Take Home Messages
Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation
Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers
DIC
Thank you Questions
- Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
- Learning Objectives
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Wound Sealing
- The Three Steps of Hemostasis
- Vessel Wall
- Slide Number 12
- Slide Number 13
- Platelet Structure UnactivatedActivated
- Primary Hemostasis
- Primary Hemostasis Assays
- Slide Number 17
- Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
- Slide Number 19
- Coagulation factors
- Coagulation Assay Mechanisms
- Slide Number 22
- Fibrin Formation
- Slide Number 24
- Fibrinolysis Overview
- Fibrinolysis Overview
- Slide Number 27
- Fibrinolysis Releases D-dimers
- Basic Pathophysiology of DIC
- Disseminated Intravascular Coagulation (DIC)
- Purpura Fulminans with DIC Due to Meningococcal Sepsis
- Clinical Conditions Associated With DIC
- Frequency of DIC in Selected Disease States
- Underlying Diseases in DIC Patients
- Slide Number 36
- Slide Number 37
- Slide Number 38
- Slide Number 39
- Pathophysiology of DIC
- Pathogenesis of DIC in Sepsis
- Host Response in Severe Sepsis
- Organ Failure in Severe Sepsis
- Mechanism of DIC in Organ Failure
- Interaction of Inflammation and Coagulation in Sepsis
- Slide Number 47
- Diverse and Opposing Effects of Thrombin
- Coagulation and Fibrinolysis in DIC
- Mechanism of DIC
- Pathophysiology of DIC
- Pathophysiology of DIC - Mechanism
- Pathophysiology of DIC ndash 2 Types of Clinical pictures
- Sub-Acute and Non-Overt DIC Clinical Findings
- Pathophysiology of Overt DIC
- Physiopathology of DIC ndash Overt DIC Findings
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- BREAK
- Diagnostic and Management Approach for DIC
- Diagnosis of DIC
- Lab Diagnosis of DIC ndash Markers of Factor Consumption
- Lab Diagnosis of DIC ndash Screening Tests
- Slide Number 67
- Slide Number 68
- British Journal of Haematology Overt DIC Score
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- DIC Management Goals
- DIC Management and Treatment
- DIC Management Strategies
- Anticoagulant Factor Concentrate Treatment
- Anticoagulant Factor Concentrate Treatment Trials
- Markers of Thrombin amp Plasmin Generation in DIC
- D-dimer FDPs and DIC
- D-Dimer and FDPs in DIC
- Follow Up of DIC State of Disease
- FMD-Dimer in DIC Major Differences
- of Abnormal Results in Patients with Confirmed and Suspected DIC
- Slide Number 85
- Slide Number 86
- Comparing an Automated FM vs Manual FSP Test
- Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Slide Number 94
- Slide Number 95
- Slide Number 96
- Slide Number 97
- Slide Number 98
- Slide Number 99
- DIC Case Studies
- Case Study 1 - Presentation
- Case Study 1 ndash Lab Results
- Case Study 1 ndash Microscopy
- Case Study 1 ndash Diagnosis and Therapy
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Slide Number 110
- Slide Number 111
- Slide Number 112
- Slide Number 113
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
- Slide Number 124
- Slide Number 125
- DIC Take Home Messages
- Slide Number 127
- Slide Number 128
-
Case Study 6 ndash Lab Results
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
TEST RESULT REFERENCE RANGEPlatelet count 109 x 109L 150-400 x 109L
PT 63 sec gt control 113 ndash 146 sec
INR 658 1 ndash 125
APTT 80 sec gt control 25 ndash 34 sec
D-dimer gt200 microgmL DDU 02 microgmL DDU
Urine exam Proteinuria and hematuria 150-400 mgdl
Albumin 28 gdL NR
Hb 58 gdL NR
LDH 1196 UL NR
SGPT 144 IU NR
SGOT 88 IU NR
Bilirubin 32 mgdL NR
DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th
day postop
Case Study 6 ndash Diagnosis and Treatment
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure
Case Study 6 ndash Discussion
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Case Study 7 ndash Lab Results vs Time
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
DIC Take Home Messages
Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation
Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers
DIC
Thank you Questions
- Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
- Learning Objectives
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Wound Sealing
- The Three Steps of Hemostasis
- Vessel Wall
- Slide Number 12
- Slide Number 13
- Platelet Structure UnactivatedActivated
- Primary Hemostasis
- Primary Hemostasis Assays
- Slide Number 17
- Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
- Slide Number 19
- Coagulation factors
- Coagulation Assay Mechanisms
- Slide Number 22
- Fibrin Formation
- Slide Number 24
- Fibrinolysis Overview
- Fibrinolysis Overview
- Slide Number 27
- Fibrinolysis Releases D-dimers
- Basic Pathophysiology of DIC
- Disseminated Intravascular Coagulation (DIC)
- Purpura Fulminans with DIC Due to Meningococcal Sepsis
- Clinical Conditions Associated With DIC
- Frequency of DIC in Selected Disease States
- Underlying Diseases in DIC Patients
- Slide Number 36
- Slide Number 37
- Slide Number 38
- Slide Number 39
- Pathophysiology of DIC
- Pathogenesis of DIC in Sepsis
- Host Response in Severe Sepsis
- Organ Failure in Severe Sepsis
- Mechanism of DIC in Organ Failure
- Interaction of Inflammation and Coagulation in Sepsis
- Slide Number 47
- Diverse and Opposing Effects of Thrombin
- Coagulation and Fibrinolysis in DIC
- Mechanism of DIC
- Pathophysiology of DIC
- Pathophysiology of DIC - Mechanism
- Pathophysiology of DIC ndash 2 Types of Clinical pictures
- Sub-Acute and Non-Overt DIC Clinical Findings
- Pathophysiology of Overt DIC
- Physiopathology of DIC ndash Overt DIC Findings
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- BREAK
- Diagnostic and Management Approach for DIC
- Diagnosis of DIC
- Lab Diagnosis of DIC ndash Markers of Factor Consumption
- Lab Diagnosis of DIC ndash Screening Tests
- Slide Number 67
- Slide Number 68
- British Journal of Haematology Overt DIC Score
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- DIC Management Goals
- DIC Management and Treatment
- DIC Management Strategies
- Anticoagulant Factor Concentrate Treatment
- Anticoagulant Factor Concentrate Treatment Trials
- Markers of Thrombin amp Plasmin Generation in DIC
- D-dimer FDPs and DIC
- D-Dimer and FDPs in DIC
- Follow Up of DIC State of Disease
- FMD-Dimer in DIC Major Differences
- of Abnormal Results in Patients with Confirmed and Suspected DIC
- Slide Number 85
- Slide Number 86
- Comparing an Automated FM vs Manual FSP Test
- Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Slide Number 94
- Slide Number 95
- Slide Number 96
- Slide Number 97
- Slide Number 98
- Slide Number 99
- DIC Case Studies
- Case Study 1 - Presentation
- Case Study 1 ndash Lab Results
- Case Study 1 ndash Microscopy
- Case Study 1 ndash Diagnosis and Therapy
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Slide Number 110
- Slide Number 111
- Slide Number 112
- Slide Number 113
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
- Slide Number 124
- Slide Number 125
- DIC Take Home Messages
- Slide Number 127
- Slide Number 128
-
DIC complicating hemolysis elevated liver enzymes and low platelets (HELLP) syndrome in preeclampsia was made and C section plannedIntraoperative blood loss replaced with FFP packed red blood cells (RBC) hexastarch and crystalloidsBaby delivered successfullyPostop vaginal bleeding treated with intravenous TXA platelets and FFPPatient remained haemodynamically stable and disharged on the 10th
day postop
Case Study 6 ndash Diagnosis and Treatment
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure
Case Study 6 ndash Discussion
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Case Study 7 ndash Lab Results vs Time
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
DIC Take Home Messages
Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation
Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers
DIC
Thank you Questions
- Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
- Learning Objectives
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Wound Sealing
- The Three Steps of Hemostasis
- Vessel Wall
- Slide Number 12
- Slide Number 13
- Platelet Structure UnactivatedActivated
- Primary Hemostasis
- Primary Hemostasis Assays
- Slide Number 17
- Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
- Slide Number 19
- Coagulation factors
- Coagulation Assay Mechanisms
- Slide Number 22
- Fibrin Formation
- Slide Number 24
- Fibrinolysis Overview
- Fibrinolysis Overview
- Slide Number 27
- Fibrinolysis Releases D-dimers
- Basic Pathophysiology of DIC
- Disseminated Intravascular Coagulation (DIC)
- Purpura Fulminans with DIC Due to Meningococcal Sepsis
- Clinical Conditions Associated With DIC
- Frequency of DIC in Selected Disease States
- Underlying Diseases in DIC Patients
- Slide Number 36
- Slide Number 37
- Slide Number 38
- Slide Number 39
- Pathophysiology of DIC
- Pathogenesis of DIC in Sepsis
- Host Response in Severe Sepsis
- Organ Failure in Severe Sepsis
- Mechanism of DIC in Organ Failure
- Interaction of Inflammation and Coagulation in Sepsis
- Slide Number 47
- Diverse and Opposing Effects of Thrombin
- Coagulation and Fibrinolysis in DIC
- Mechanism of DIC
- Pathophysiology of DIC
- Pathophysiology of DIC - Mechanism
- Pathophysiology of DIC ndash 2 Types of Clinical pictures
- Sub-Acute and Non-Overt DIC Clinical Findings
- Pathophysiology of Overt DIC
- Physiopathology of DIC ndash Overt DIC Findings
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- BREAK
- Diagnostic and Management Approach for DIC
- Diagnosis of DIC
- Lab Diagnosis of DIC ndash Markers of Factor Consumption
- Lab Diagnosis of DIC ndash Screening Tests
- Slide Number 67
- Slide Number 68
- British Journal of Haematology Overt DIC Score
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- DIC Management Goals
- DIC Management and Treatment
- DIC Management Strategies
- Anticoagulant Factor Concentrate Treatment
- Anticoagulant Factor Concentrate Treatment Trials
- Markers of Thrombin amp Plasmin Generation in DIC
- D-dimer FDPs and DIC
- D-Dimer and FDPs in DIC
- Follow Up of DIC State of Disease
- FMD-Dimer in DIC Major Differences
- of Abnormal Results in Patients with Confirmed and Suspected DIC
- Slide Number 85
- Slide Number 86
- Comparing an Automated FM vs Manual FSP Test
- Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Slide Number 94
- Slide Number 95
- Slide Number 96
- Slide Number 97
- Slide Number 98
- Slide Number 99
- DIC Case Studies
- Case Study 1 - Presentation
- Case Study 1 ndash Lab Results
- Case Study 1 ndash Microscopy
- Case Study 1 ndash Diagnosis and Therapy
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Slide Number 110
- Slide Number 111
- Slide Number 112
- Slide Number 113
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
- Slide Number 124
- Slide Number 125
- DIC Take Home Messages
- Slide Number 127
- Slide Number 128
-
HELLP syndrome complicates 02 ndash06 of all pregnancies 4ndash12 of cases with severe preeclampsia and 30ndash50 of eclamptic gravidasMaternal and neonatal mortality 2ndash24 and 3ndash39 respectively HELLP syndrome may progress to DIC in 15ndash38 of patientsPatients with HELLP syndrome are at increased risk of abruptio placentae pulmonary edema ruptured liver hematoma acute renal failure cerebrovascular accident and multiorgan failure
Case Study 6 ndash Discussion
Garg R Nath MP Bhalla AP Kuma A Unusual association of diseasessymptoms Disseminated intravascular coagulation complicating HELLP syndrome perioperative management BMJ Case Rep 2009 2009 bcr1020081027
44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Case Study 7 ndash Lab Results vs Time
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
DIC Take Home Messages
Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation
Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers
DIC
Thank you Questions
- Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
- Learning Objectives
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Wound Sealing
- The Three Steps of Hemostasis
- Vessel Wall
- Slide Number 12
- Slide Number 13
- Platelet Structure UnactivatedActivated
- Primary Hemostasis
- Primary Hemostasis Assays
- Slide Number 17
- Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
- Slide Number 19
- Coagulation factors
- Coagulation Assay Mechanisms
- Slide Number 22
- Fibrin Formation
- Slide Number 24
- Fibrinolysis Overview
- Fibrinolysis Overview
- Slide Number 27
- Fibrinolysis Releases D-dimers
- Basic Pathophysiology of DIC
- Disseminated Intravascular Coagulation (DIC)
- Purpura Fulminans with DIC Due to Meningococcal Sepsis
- Clinical Conditions Associated With DIC
- Frequency of DIC in Selected Disease States
- Underlying Diseases in DIC Patients
- Slide Number 36
- Slide Number 37
- Slide Number 38
- Slide Number 39
- Pathophysiology of DIC
- Pathogenesis of DIC in Sepsis
- Host Response in Severe Sepsis
- Organ Failure in Severe Sepsis
- Mechanism of DIC in Organ Failure
- Interaction of Inflammation and Coagulation in Sepsis
- Slide Number 47
- Diverse and Opposing Effects of Thrombin
- Coagulation and Fibrinolysis in DIC
- Mechanism of DIC
- Pathophysiology of DIC
- Pathophysiology of DIC - Mechanism
- Pathophysiology of DIC ndash 2 Types of Clinical pictures
- Sub-Acute and Non-Overt DIC Clinical Findings
- Pathophysiology of Overt DIC
- Physiopathology of DIC ndash Overt DIC Findings
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- BREAK
- Diagnostic and Management Approach for DIC
- Diagnosis of DIC
- Lab Diagnosis of DIC ndash Markers of Factor Consumption
- Lab Diagnosis of DIC ndash Screening Tests
- Slide Number 67
- Slide Number 68
- British Journal of Haematology Overt DIC Score
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- DIC Management Goals
- DIC Management and Treatment
- DIC Management Strategies
- Anticoagulant Factor Concentrate Treatment
- Anticoagulant Factor Concentrate Treatment Trials
- Markers of Thrombin amp Plasmin Generation in DIC
- D-dimer FDPs and DIC
- D-Dimer and FDPs in DIC
- Follow Up of DIC State of Disease
- FMD-Dimer in DIC Major Differences
- of Abnormal Results in Patients with Confirmed and Suspected DIC
- Slide Number 85
- Slide Number 86
- Comparing an Automated FM vs Manual FSP Test
- Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Slide Number 94
- Slide Number 95
- Slide Number 96
- Slide Number 97
- Slide Number 98
- Slide Number 99
- DIC Case Studies
- Case Study 1 - Presentation
- Case Study 1 ndash Lab Results
- Case Study 1 ndash Microscopy
- Case Study 1 ndash Diagnosis and Therapy
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Slide Number 110
- Slide Number 111
- Slide Number 112
- Slide Number 113
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
- Slide Number 124
- Slide Number 125
- DIC Take Home Messages
- Slide Number 127
- Slide Number 128
-
44-year-old man with history of hepatitis C cirrhosis and chronic kidney disease presents to ED for altered mental status and ammonia level gt 500 mM (RR 11-51 mM)Patient was given lactulose however his mental status worsened to require intubationVital signs on admission to ICU on Oct 23 BP 12084 heart rate 107 beatsmin respiratory rate 18min temperature 978 degF
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Case Study 7 ndash Lab Results vs Time
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
DIC Take Home Messages
Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation
Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers
DIC
Thank you Questions
- Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
- Learning Objectives
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Wound Sealing
- The Three Steps of Hemostasis
- Vessel Wall
- Slide Number 12
- Slide Number 13
- Platelet Structure UnactivatedActivated
- Primary Hemostasis
- Primary Hemostasis Assays
- Slide Number 17
- Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
- Slide Number 19
- Coagulation factors
- Coagulation Assay Mechanisms
- Slide Number 22
- Fibrin Formation
- Slide Number 24
- Fibrinolysis Overview
- Fibrinolysis Overview
- Slide Number 27
- Fibrinolysis Releases D-dimers
- Basic Pathophysiology of DIC
- Disseminated Intravascular Coagulation (DIC)
- Purpura Fulminans with DIC Due to Meningococcal Sepsis
- Clinical Conditions Associated With DIC
- Frequency of DIC in Selected Disease States
- Underlying Diseases in DIC Patients
- Slide Number 36
- Slide Number 37
- Slide Number 38
- Slide Number 39
- Pathophysiology of DIC
- Pathogenesis of DIC in Sepsis
- Host Response in Severe Sepsis
- Organ Failure in Severe Sepsis
- Mechanism of DIC in Organ Failure
- Interaction of Inflammation and Coagulation in Sepsis
- Slide Number 47
- Diverse and Opposing Effects of Thrombin
- Coagulation and Fibrinolysis in DIC
- Mechanism of DIC
- Pathophysiology of DIC
- Pathophysiology of DIC - Mechanism
- Pathophysiology of DIC ndash 2 Types of Clinical pictures
- Sub-Acute and Non-Overt DIC Clinical Findings
- Pathophysiology of Overt DIC
- Physiopathology of DIC ndash Overt DIC Findings
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- BREAK
- Diagnostic and Management Approach for DIC
- Diagnosis of DIC
- Lab Diagnosis of DIC ndash Markers of Factor Consumption
- Lab Diagnosis of DIC ndash Screening Tests
- Slide Number 67
- Slide Number 68
- British Journal of Haematology Overt DIC Score
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- DIC Management Goals
- DIC Management and Treatment
- DIC Management Strategies
- Anticoagulant Factor Concentrate Treatment
- Anticoagulant Factor Concentrate Treatment Trials
- Markers of Thrombin amp Plasmin Generation in DIC
- D-dimer FDPs and DIC
- D-Dimer and FDPs in DIC
- Follow Up of DIC State of Disease
- FMD-Dimer in DIC Major Differences
- of Abnormal Results in Patients with Confirmed and Suspected DIC
- Slide Number 85
- Slide Number 86
- Comparing an Automated FM vs Manual FSP Test
- Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Slide Number 94
- Slide Number 95
- Slide Number 96
- Slide Number 97
- Slide Number 98
- Slide Number 99
- DIC Case Studies
- Case Study 1 - Presentation
- Case Study 1 ndash Lab Results
- Case Study 1 ndash Microscopy
- Case Study 1 ndash Diagnosis and Therapy
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Slide Number 110
- Slide Number 111
- Slide Number 112
- Slide Number 113
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
- Slide Number 124
- Slide Number 125
- DIC Take Home Messages
- Slide Number 127
- Slide Number 128
-
On Oct 23 patient started on vancomycin piperacillintazobactam and fluids because of concern for sepsis associated with systemic inflammatory response syndrome (SIRS) and multiorgan failure as well as laboratory values showing a high WBC count and elevated lactate of 8 mM (RR 05-16mmolL)Vital signs worsened over next 24 hours became hypotensive requiring treatment with norepinephrine and 6 L of normal saline on Oct 24Renal function continued to decline received continuous renal replacement therapy on Oct 25
Case Study 7 ndash Presentation
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Case Study 7 ndash Lab Results vs Time
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
DIC Take Home Messages
Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation
Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers
DIC
Thank you Questions
- Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
- Learning Objectives
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Wound Sealing
- The Three Steps of Hemostasis
- Vessel Wall
- Slide Number 12
- Slide Number 13
- Platelet Structure UnactivatedActivated
- Primary Hemostasis
- Primary Hemostasis Assays
- Slide Number 17
- Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
- Slide Number 19
- Coagulation factors
- Coagulation Assay Mechanisms
- Slide Number 22
- Fibrin Formation
- Slide Number 24
- Fibrinolysis Overview
- Fibrinolysis Overview
- Slide Number 27
- Fibrinolysis Releases D-dimers
- Basic Pathophysiology of DIC
- Disseminated Intravascular Coagulation (DIC)
- Purpura Fulminans with DIC Due to Meningococcal Sepsis
- Clinical Conditions Associated With DIC
- Frequency of DIC in Selected Disease States
- Underlying Diseases in DIC Patients
- Slide Number 36
- Slide Number 37
- Slide Number 38
- Slide Number 39
- Pathophysiology of DIC
- Pathogenesis of DIC in Sepsis
- Host Response in Severe Sepsis
- Organ Failure in Severe Sepsis
- Mechanism of DIC in Organ Failure
- Interaction of Inflammation and Coagulation in Sepsis
- Slide Number 47
- Diverse and Opposing Effects of Thrombin
- Coagulation and Fibrinolysis in DIC
- Mechanism of DIC
- Pathophysiology of DIC
- Pathophysiology of DIC - Mechanism
- Pathophysiology of DIC ndash 2 Types of Clinical pictures
- Sub-Acute and Non-Overt DIC Clinical Findings
- Pathophysiology of Overt DIC
- Physiopathology of DIC ndash Overt DIC Findings
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- BREAK
- Diagnostic and Management Approach for DIC
- Diagnosis of DIC
- Lab Diagnosis of DIC ndash Markers of Factor Consumption
- Lab Diagnosis of DIC ndash Screening Tests
- Slide Number 67
- Slide Number 68
- British Journal of Haematology Overt DIC Score
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- DIC Management Goals
- DIC Management and Treatment
- DIC Management Strategies
- Anticoagulant Factor Concentrate Treatment
- Anticoagulant Factor Concentrate Treatment Trials
- Markers of Thrombin amp Plasmin Generation in DIC
- D-dimer FDPs and DIC
- D-Dimer and FDPs in DIC
- Follow Up of DIC State of Disease
- FMD-Dimer in DIC Major Differences
- of Abnormal Results in Patients with Confirmed and Suspected DIC
- Slide Number 85
- Slide Number 86
- Comparing an Automated FM vs Manual FSP Test
- Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Slide Number 94
- Slide Number 95
- Slide Number 96
- Slide Number 97
- Slide Number 98
- Slide Number 99
- DIC Case Studies
- Case Study 1 - Presentation
- Case Study 1 ndash Lab Results
- Case Study 1 ndash Microscopy
- Case Study 1 ndash Diagnosis and Therapy
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Slide Number 110
- Slide Number 111
- Slide Number 112
- Slide Number 113
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
- Slide Number 124
- Slide Number 125
- DIC Take Home Messages
- Slide Number 127
- Slide Number 128
-
Case Study 7 ndash Lab Results vs Time
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
DIC Take Home Messages
Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation
Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers
DIC
Thank you Questions
- Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
- Learning Objectives
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Wound Sealing
- The Three Steps of Hemostasis
- Vessel Wall
- Slide Number 12
- Slide Number 13
- Platelet Structure UnactivatedActivated
- Primary Hemostasis
- Primary Hemostasis Assays
- Slide Number 17
- Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
- Slide Number 19
- Coagulation factors
- Coagulation Assay Mechanisms
- Slide Number 22
- Fibrin Formation
- Slide Number 24
- Fibrinolysis Overview
- Fibrinolysis Overview
- Slide Number 27
- Fibrinolysis Releases D-dimers
- Basic Pathophysiology of DIC
- Disseminated Intravascular Coagulation (DIC)
- Purpura Fulminans with DIC Due to Meningococcal Sepsis
- Clinical Conditions Associated With DIC
- Frequency of DIC in Selected Disease States
- Underlying Diseases in DIC Patients
- Slide Number 36
- Slide Number 37
- Slide Number 38
- Slide Number 39
- Pathophysiology of DIC
- Pathogenesis of DIC in Sepsis
- Host Response in Severe Sepsis
- Organ Failure in Severe Sepsis
- Mechanism of DIC in Organ Failure
- Interaction of Inflammation and Coagulation in Sepsis
- Slide Number 47
- Diverse and Opposing Effects of Thrombin
- Coagulation and Fibrinolysis in DIC
- Mechanism of DIC
- Pathophysiology of DIC
- Pathophysiology of DIC - Mechanism
- Pathophysiology of DIC ndash 2 Types of Clinical pictures
- Sub-Acute and Non-Overt DIC Clinical Findings
- Pathophysiology of Overt DIC
- Physiopathology of DIC ndash Overt DIC Findings
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- BREAK
- Diagnostic and Management Approach for DIC
- Diagnosis of DIC
- Lab Diagnosis of DIC ndash Markers of Factor Consumption
- Lab Diagnosis of DIC ndash Screening Tests
- Slide Number 67
- Slide Number 68
- British Journal of Haematology Overt DIC Score
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- DIC Management Goals
- DIC Management and Treatment
- DIC Management Strategies
- Anticoagulant Factor Concentrate Treatment
- Anticoagulant Factor Concentrate Treatment Trials
- Markers of Thrombin amp Plasmin Generation in DIC
- D-dimer FDPs and DIC
- D-Dimer and FDPs in DIC
- Follow Up of DIC State of Disease
- FMD-Dimer in DIC Major Differences
- of Abnormal Results in Patients with Confirmed and Suspected DIC
- Slide Number 85
- Slide Number 86
- Comparing an Automated FM vs Manual FSP Test
- Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Slide Number 94
- Slide Number 95
- Slide Number 96
- Slide Number 97
- Slide Number 98
- Slide Number 99
- DIC Case Studies
- Case Study 1 - Presentation
- Case Study 1 ndash Lab Results
- Case Study 1 ndash Microscopy
- Case Study 1 ndash Diagnosis and Therapy
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Slide Number 110
- Slide Number 111
- Slide Number 112
- Slide Number 113
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
- Slide Number 124
- Slide Number 125
- DIC Take Home Messages
- Slide Number 127
- Slide Number 128
-
Lab values from Oct 25 consistent with DIC given packed RBCs FFP cryo plts and vit K to treat peritoneal bleeding which stopped by Oct 26Over next few days continued to require norepinephrine but eventually vital signs and laboratory values stabilizedDuring next few days improvement was apparent but found to have multiple infections including vancomycin-resistant enterococcus (VRE) along with Stenotrophomonas maltophilia peritoneal fluid growing Acinetobacter and urinalysis growing Candida glabrata
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
DIC Take Home Messages
Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation
Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers
DIC
Thank you Questions
- Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
- Learning Objectives
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Wound Sealing
- The Three Steps of Hemostasis
- Vessel Wall
- Slide Number 12
- Slide Number 13
- Platelet Structure UnactivatedActivated
- Primary Hemostasis
- Primary Hemostasis Assays
- Slide Number 17
- Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
- Slide Number 19
- Coagulation factors
- Coagulation Assay Mechanisms
- Slide Number 22
- Fibrin Formation
- Slide Number 24
- Fibrinolysis Overview
- Fibrinolysis Overview
- Slide Number 27
- Fibrinolysis Releases D-dimers
- Basic Pathophysiology of DIC
- Disseminated Intravascular Coagulation (DIC)
- Purpura Fulminans with DIC Due to Meningococcal Sepsis
- Clinical Conditions Associated With DIC
- Frequency of DIC in Selected Disease States
- Underlying Diseases in DIC Patients
- Slide Number 36
- Slide Number 37
- Slide Number 38
- Slide Number 39
- Pathophysiology of DIC
- Pathogenesis of DIC in Sepsis
- Host Response in Severe Sepsis
- Organ Failure in Severe Sepsis
- Mechanism of DIC in Organ Failure
- Interaction of Inflammation and Coagulation in Sepsis
- Slide Number 47
- Diverse and Opposing Effects of Thrombin
- Coagulation and Fibrinolysis in DIC
- Mechanism of DIC
- Pathophysiology of DIC
- Pathophysiology of DIC - Mechanism
- Pathophysiology of DIC ndash 2 Types of Clinical pictures
- Sub-Acute and Non-Overt DIC Clinical Findings
- Pathophysiology of Overt DIC
- Physiopathology of DIC ndash Overt DIC Findings
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- BREAK
- Diagnostic and Management Approach for DIC
- Diagnosis of DIC
- Lab Diagnosis of DIC ndash Markers of Factor Consumption
- Lab Diagnosis of DIC ndash Screening Tests
- Slide Number 67
- Slide Number 68
- British Journal of Haematology Overt DIC Score
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- DIC Management Goals
- DIC Management and Treatment
- DIC Management Strategies
- Anticoagulant Factor Concentrate Treatment
- Anticoagulant Factor Concentrate Treatment Trials
- Markers of Thrombin amp Plasmin Generation in DIC
- D-dimer FDPs and DIC
- D-Dimer and FDPs in DIC
- Follow Up of DIC State of Disease
- FMD-Dimer in DIC Major Differences
- of Abnormal Results in Patients with Confirmed and Suspected DIC
- Slide Number 85
- Slide Number 86
- Comparing an Automated FM vs Manual FSP Test
- Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Slide Number 94
- Slide Number 95
- Slide Number 96
- Slide Number 97
- Slide Number 98
- Slide Number 99
- DIC Case Studies
- Case Study 1 - Presentation
- Case Study 1 ndash Lab Results
- Case Study 1 ndash Microscopy
- Case Study 1 ndash Diagnosis and Therapy
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Slide Number 110
- Slide Number 111
- Slide Number 112
- Slide Number 113
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
- Slide Number 124
- Slide Number 125
- DIC Take Home Messages
- Slide Number 127
- Slide Number 128
-
On Oct 29 started on daptomycin linezolid trimethoprimsulfamethoxazole and fluconazole vancomycin and piperacillintazobactam were discontinuedHemodynamically stable taken off pressors and extubated on Nov 1In process of transfer from ICU became obtunded and hypotensive onFFP cryo platelets and packed RBCs were ordered but patient went into cardiac arrest and passed away
Case Study 7 ndash Diagnosis and Treatment
Boral BM Williams DJ Boral LI Disseminated Intravascular Coagulation Am J Clin Pathol 2016 146 670-80
DIC Take Home Messages
Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation
Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers
DIC
Thank you Questions
- Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
- Learning Objectives
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Wound Sealing
- The Three Steps of Hemostasis
- Vessel Wall
- Slide Number 12
- Slide Number 13
- Platelet Structure UnactivatedActivated
- Primary Hemostasis
- Primary Hemostasis Assays
- Slide Number 17
- Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
- Slide Number 19
- Coagulation factors
- Coagulation Assay Mechanisms
- Slide Number 22
- Fibrin Formation
- Slide Number 24
- Fibrinolysis Overview
- Fibrinolysis Overview
- Slide Number 27
- Fibrinolysis Releases D-dimers
- Basic Pathophysiology of DIC
- Disseminated Intravascular Coagulation (DIC)
- Purpura Fulminans with DIC Due to Meningococcal Sepsis
- Clinical Conditions Associated With DIC
- Frequency of DIC in Selected Disease States
- Underlying Diseases in DIC Patients
- Slide Number 36
- Slide Number 37
- Slide Number 38
- Slide Number 39
- Pathophysiology of DIC
- Pathogenesis of DIC in Sepsis
- Host Response in Severe Sepsis
- Organ Failure in Severe Sepsis
- Mechanism of DIC in Organ Failure
- Interaction of Inflammation and Coagulation in Sepsis
- Slide Number 47
- Diverse and Opposing Effects of Thrombin
- Coagulation and Fibrinolysis in DIC
- Mechanism of DIC
- Pathophysiology of DIC
- Pathophysiology of DIC - Mechanism
- Pathophysiology of DIC ndash 2 Types of Clinical pictures
- Sub-Acute and Non-Overt DIC Clinical Findings
- Pathophysiology of Overt DIC
- Physiopathology of DIC ndash Overt DIC Findings
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- BREAK
- Diagnostic and Management Approach for DIC
- Diagnosis of DIC
- Lab Diagnosis of DIC ndash Markers of Factor Consumption
- Lab Diagnosis of DIC ndash Screening Tests
- Slide Number 67
- Slide Number 68
- British Journal of Haematology Overt DIC Score
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- DIC Management Goals
- DIC Management and Treatment
- DIC Management Strategies
- Anticoagulant Factor Concentrate Treatment
- Anticoagulant Factor Concentrate Treatment Trials
- Markers of Thrombin amp Plasmin Generation in DIC
- D-dimer FDPs and DIC
- D-Dimer and FDPs in DIC
- Follow Up of DIC State of Disease
- FMD-Dimer in DIC Major Differences
- of Abnormal Results in Patients with Confirmed and Suspected DIC
- Slide Number 85
- Slide Number 86
- Comparing an Automated FM vs Manual FSP Test
- Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Slide Number 94
- Slide Number 95
- Slide Number 96
- Slide Number 97
- Slide Number 98
- Slide Number 99
- DIC Case Studies
- Case Study 1 - Presentation
- Case Study 1 ndash Lab Results
- Case Study 1 ndash Microscopy
- Case Study 1 ndash Diagnosis and Therapy
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Slide Number 110
- Slide Number 111
- Slide Number 112
- Slide Number 113
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
- Slide Number 124
- Slide Number 125
- DIC Take Home Messages
- Slide Number 127
- Slide Number 128
-
DIC Take Home Messages
Heterogeneous rapidly fatal syndromeEtiology sepsis tumors injuries or obstetric complicationsSimultaneous activation of coagulation and fibrinolysis Consumption of factors anticoagulant proteins fibrinogen and plateletsDiagnosis not with a single test panel including activation markers Screening coags platelets FMFS and D-dimer 1st consideration treat the critical symptoms and underlying issue 2nd consideration compensation for the consumption and sometimes anticoagulation
Monitor efficacy of therapy Activation markers (D-Dimer FMFSP) Normalization of coagulation markers
DIC
Thank you Questions
- Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
- Learning Objectives
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Wound Sealing
- The Three Steps of Hemostasis
- Vessel Wall
- Slide Number 12
- Slide Number 13
- Platelet Structure UnactivatedActivated
- Primary Hemostasis
- Primary Hemostasis Assays
- Slide Number 17
- Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
- Slide Number 19
- Coagulation factors
- Coagulation Assay Mechanisms
- Slide Number 22
- Fibrin Formation
- Slide Number 24
- Fibrinolysis Overview
- Fibrinolysis Overview
- Slide Number 27
- Fibrinolysis Releases D-dimers
- Basic Pathophysiology of DIC
- Disseminated Intravascular Coagulation (DIC)
- Purpura Fulminans with DIC Due to Meningococcal Sepsis
- Clinical Conditions Associated With DIC
- Frequency of DIC in Selected Disease States
- Underlying Diseases in DIC Patients
- Slide Number 36
- Slide Number 37
- Slide Number 38
- Slide Number 39
- Pathophysiology of DIC
- Pathogenesis of DIC in Sepsis
- Host Response in Severe Sepsis
- Organ Failure in Severe Sepsis
- Mechanism of DIC in Organ Failure
- Interaction of Inflammation and Coagulation in Sepsis
- Slide Number 47
- Diverse and Opposing Effects of Thrombin
- Coagulation and Fibrinolysis in DIC
- Mechanism of DIC
- Pathophysiology of DIC
- Pathophysiology of DIC - Mechanism
- Pathophysiology of DIC ndash 2 Types of Clinical pictures
- Sub-Acute and Non-Overt DIC Clinical Findings
- Pathophysiology of Overt DIC
- Physiopathology of DIC ndash Overt DIC Findings
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- BREAK
- Diagnostic and Management Approach for DIC
- Diagnosis of DIC
- Lab Diagnosis of DIC ndash Markers of Factor Consumption
- Lab Diagnosis of DIC ndash Screening Tests
- Slide Number 67
- Slide Number 68
- British Journal of Haematology Overt DIC Score
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- DIC Management Goals
- DIC Management and Treatment
- DIC Management Strategies
- Anticoagulant Factor Concentrate Treatment
- Anticoagulant Factor Concentrate Treatment Trials
- Markers of Thrombin amp Plasmin Generation in DIC
- D-dimer FDPs and DIC
- D-Dimer and FDPs in DIC
- Follow Up of DIC State of Disease
- FMD-Dimer in DIC Major Differences
- of Abnormal Results in Patients with Confirmed and Suspected DIC
- Slide Number 85
- Slide Number 86
- Comparing an Automated FM vs Manual FSP Test
- Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Slide Number 94
- Slide Number 95
- Slide Number 96
- Slide Number 97
- Slide Number 98
- Slide Number 99
- DIC Case Studies
- Case Study 1 - Presentation
- Case Study 1 ndash Lab Results
- Case Study 1 ndash Microscopy
- Case Study 1 ndash Diagnosis and Therapy
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Slide Number 110
- Slide Number 111
- Slide Number 112
- Slide Number 113
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
- Slide Number 124
- Slide Number 125
- DIC Take Home Messages
- Slide Number 127
- Slide Number 128
-
DIC
Thank you Questions
- Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
- Learning Objectives
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Wound Sealing
- The Three Steps of Hemostasis
- Vessel Wall
- Slide Number 12
- Slide Number 13
- Platelet Structure UnactivatedActivated
- Primary Hemostasis
- Primary Hemostasis Assays
- Slide Number 17
- Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
- Slide Number 19
- Coagulation factors
- Coagulation Assay Mechanisms
- Slide Number 22
- Fibrin Formation
- Slide Number 24
- Fibrinolysis Overview
- Fibrinolysis Overview
- Slide Number 27
- Fibrinolysis Releases D-dimers
- Basic Pathophysiology of DIC
- Disseminated Intravascular Coagulation (DIC)
- Purpura Fulminans with DIC Due to Meningococcal Sepsis
- Clinical Conditions Associated With DIC
- Frequency of DIC in Selected Disease States
- Underlying Diseases in DIC Patients
- Slide Number 36
- Slide Number 37
- Slide Number 38
- Slide Number 39
- Pathophysiology of DIC
- Pathogenesis of DIC in Sepsis
- Host Response in Severe Sepsis
- Organ Failure in Severe Sepsis
- Mechanism of DIC in Organ Failure
- Interaction of Inflammation and Coagulation in Sepsis
- Slide Number 47
- Diverse and Opposing Effects of Thrombin
- Coagulation and Fibrinolysis in DIC
- Mechanism of DIC
- Pathophysiology of DIC
- Pathophysiology of DIC - Mechanism
- Pathophysiology of DIC ndash 2 Types of Clinical pictures
- Sub-Acute and Non-Overt DIC Clinical Findings
- Pathophysiology of Overt DIC
- Physiopathology of DIC ndash Overt DIC Findings
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- BREAK
- Diagnostic and Management Approach for DIC
- Diagnosis of DIC
- Lab Diagnosis of DIC ndash Markers of Factor Consumption
- Lab Diagnosis of DIC ndash Screening Tests
- Slide Number 67
- Slide Number 68
- British Journal of Haematology Overt DIC Score
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- DIC Management Goals
- DIC Management and Treatment
- DIC Management Strategies
- Anticoagulant Factor Concentrate Treatment
- Anticoagulant Factor Concentrate Treatment Trials
- Markers of Thrombin amp Plasmin Generation in DIC
- D-dimer FDPs and DIC
- D-Dimer and FDPs in DIC
- Follow Up of DIC State of Disease
- FMD-Dimer in DIC Major Differences
- of Abnormal Results in Patients with Confirmed and Suspected DIC
- Slide Number 85
- Slide Number 86
- Comparing an Automated FM vs Manual FSP Test
- Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Slide Number 94
- Slide Number 95
- Slide Number 96
- Slide Number 97
- Slide Number 98
- Slide Number 99
- DIC Case Studies
- Case Study 1 - Presentation
- Case Study 1 ndash Lab Results
- Case Study 1 ndash Microscopy
- Case Study 1 ndash Diagnosis and Therapy
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Slide Number 110
- Slide Number 111
- Slide Number 112
- Slide Number 113
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
- Slide Number 124
- Slide Number 125
- DIC Take Home Messages
- Slide Number 127
- Slide Number 128
-
Thank you Questions
- Disseminated Intravascular Coagulation (DIC) and Thrombosis The Critical Role of the Lab
- Learning Objectives
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Wound Sealing
- The Three Steps of Hemostasis
- Vessel Wall
- Slide Number 12
- Slide Number 13
- Platelet Structure UnactivatedActivated
- Primary Hemostasis
- Primary Hemostasis Assays
- Slide Number 17
- Coagulation is a balance between pro- amp anti-coagulant mechanisms bleed amp clot hemorrhage amp thrombosis
- Slide Number 19
- Coagulation factors
- Coagulation Assay Mechanisms
- Slide Number 22
- Fibrin Formation
- Slide Number 24
- Fibrinolysis Overview
- Fibrinolysis Overview
- Slide Number 27
- Fibrinolysis Releases D-dimers
- Basic Pathophysiology of DIC
- Disseminated Intravascular Coagulation (DIC)
- Purpura Fulminans with DIC Due to Meningococcal Sepsis
- Clinical Conditions Associated With DIC
- Frequency of DIC in Selected Disease States
- Underlying Diseases in DIC Patients
- Slide Number 36
- Slide Number 37
- Slide Number 38
- Slide Number 39
- Pathophysiology of DIC
- Pathogenesis of DIC in Sepsis
- Host Response in Severe Sepsis
- Organ Failure in Severe Sepsis
- Mechanism of DIC in Organ Failure
- Interaction of Inflammation and Coagulation in Sepsis
- Slide Number 47
- Diverse and Opposing Effects of Thrombin
- Coagulation and Fibrinolysis in DIC
- Mechanism of DIC
- Pathophysiology of DIC
- Pathophysiology of DIC - Mechanism
- Pathophysiology of DIC ndash 2 Types of Clinical pictures
- Sub-Acute and Non-Overt DIC Clinical Findings
- Pathophysiology of Overt DIC
- Physiopathology of DIC ndash Overt DIC Findings
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- BREAK
- Diagnostic and Management Approach for DIC
- Diagnosis of DIC
- Lab Diagnosis of DIC ndash Markers of Factor Consumption
- Lab Diagnosis of DIC ndash Screening Tests
- Slide Number 67
- Slide Number 68
- British Journal of Haematology Overt DIC Score
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- DIC Management Goals
- DIC Management and Treatment
- DIC Management Strategies
- Anticoagulant Factor Concentrate Treatment
- Anticoagulant Factor Concentrate Treatment Trials
- Markers of Thrombin amp Plasmin Generation in DIC
- D-dimer FDPs and DIC
- D-Dimer and FDPs in DIC
- Follow Up of DIC State of Disease
- FMD-Dimer in DIC Major Differences
- of Abnormal Results in Patients with Confirmed and Suspected DIC
- Slide Number 85
- Slide Number 86
- Comparing an Automated FM vs Manual FSP Test
- Baseline Characteristics in Study of Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Diagnostic Performance of FM and D-dimer in DIC
- Slide Number 94
- Slide Number 95
- Slide Number 96
- Slide Number 97
- Slide Number 98
- Slide Number 99
- DIC Case Studies
- Case Study 1 - Presentation
- Case Study 1 ndash Lab Results
- Case Study 1 ndash Microscopy
- Case Study 1 ndash Diagnosis and Therapy
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Slide Number 110
- Slide Number 111
- Slide Number 112
- Slide Number 113
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
- Slide Number 124
- Slide Number 125
- DIC Take Home Messages
- Slide Number 127
- Slide Number 128
-