Sepsis and coagulation

Christian Fenger-Eriksen

Center for Haemophilia and Thrombosis, Department of Anaesthesiology,Aarhus University Hospital, Denmarkchfen@dadlnet.dk

Outline of presentation

Normal Haemostasiso Coagulopathy of sepsis

o Disseminated Intravascular Coagulationo Mechanismo Diagnosiso Treatment

o Dilutional coagulopathyo Hyperfibrinolysiso Anaemiao Acidose/Hypotermi

The Haemostatic System anno 2009Primary haemostasis

= von Willebrand Factor

= platelet = activated platelet

= fibrinogen

The Haemostatic System anno 2009Secondary haemostasis

Tissue factor-FVIIa

Thrombin

Fibrinogen Fibrin

FVIIIa-FIXaIntrinsic tenase

FVa-FXaProthrombinnase

FXFXa

FXIII

Thrombophilia Bleeding tendencyHealthy

HaemostasisBalance versus imbalance

Thrombophilia

• DIC

• Tissue factor induced activation

• Bedrest

• Cancer

• Brain damage

Bleeding tendency

• DIC

• Consumption

• Hyperfibrinolyse

• Colloids

• Anaemia

• Hypotermia

HaemostasisThrombophilia versus bleeding

Clinical picture Sepsis

Coagulopathy of sepsisInflammation and coagulation Close relation between inflammtory response and

coagulation activation

Monocytes and microparticles express tissue factor

LPS Activates FXII Interaction with endothelial cells – Tissue factor Activates platelets

Result: Imbalance between intravascular fibrin formation and its removal

Coagulopathy of sepsisActivation

Tissue factor-FVIIa

Thrombin

Fibrinogen Fibrin

Fibrinogen split products

Coagulopathy of sepsisRegulatory mechanism of activation

Antithrombin, The protein C system, Tissue factor pathway inhibitor

Coagulopathy of sepsisSystemic anticoagulation

Thrombin Fibrin Tissue factor-FVIIa

Activated Protein C

Antithrombin – TAT•Rapid clearance of TAT•Antithrombin negative acute phase protein

TFPI•Plasma/endothelial cells

Thrombomodulin

Dissemineret intravascular coagulationDefinition Intravascular activation and imbalance of

inhibition and fibrinolysis

Microthrombosis Brain (delirium/coma) Skin (necrosis) Kidney (oliguri/renal failure) Lungs (ARDS) Multi Organ Dysfunction Syndrome Bleeding

Dissemineret intravascular coagulationDiagnose Clinical diagnose Biochemistry:

Activation: Platelets low/decreasing FII, VII and FX low Fibrinogen low/decreasing (acute phase)

Fibrinolysis: D-dimer high

Consumption of inhibitors: Antithrombin low Protein C normal TAT high

DIC score IOvert DIC Does the patient have an underlying disorder known to

be associated with overt DIC, YES?

Platelet count (10*9/l): (>100 = 0; 50-100 = 1;<50 = 2)Fibrin-related marker: (No increase = 0; Moderate increase = 2; Strong increase = 3)Prolonged prothrombin time: (<3 s = 0; 3-6 s = 1; >6 s = 2)Fibrinogen: (>1.0 g/l = 0; <1.0 g/l: 1)

If the sum is ≥5, the patient status is compatible with overt DIC.

XII XIIa

XI XIa

IX IXa

X Xa

ProthrombinThrombin

Fibrinogen Fibrin

TFVIIa

TFVII

Va

VIIIa

The coagulation cascadeSecondary haemostasis

Intrinsic pathway Extrinsic pathway

DIC-screen•Platelets•APTT•PT relativ•Thrombintime•Fibrin d-dimer•Antithrombin•Fibrinogen

PTrelativAPTT

Heparin induced thrombocytopenia

Beware: Isolated Thrombocytopenia without other

affection Thrombosis during heparing treatment

Incidens: UFH; 0.5-5% LMH; 0,05-0,5%

Patogenesis: Antibody formation against platelets

(activation) + tissue factor release from monocytes

5-10 days after institution of treatment

Heparin induced thrombocytopenia

Christoffersen C., Ugeskr Læger 2009;171(8):612

Coagulopathy of sepsisTreatment

Thrombin Fibrin Tissue factor-FVIIa

Activated Protein C

Antithrombin – TAT•Rapid clearance of TAT•Antithrombin negative acute phase protein

TFPI•Plasma/endothelial cells

Thrombomodulin

Antithrombin

Small clinical trials: improvement of a DIC score shortening of the duration of DIC improvement in organ function

Randomized, controlled clinical trial, 2314 patients with severe sepsis (Kybersept trial9 Identical mortality between treatment with

antithrombin for 4 days versus placebo

Trend; Decreased mortality in subgroup of patients who did not receive heparinM Levi M, Schouten M, van der Poll T. Semin Thromb Hemost. 2008 Nov;34(8):742-6. Review.

Tissue factor pathway inhibitor

TFPI has been shown to attenuate IL-6 and IL-8 release in an animal model

A large RCT failed to show a reduced mortality in patients with severe sepsis

Levi M Crit Care. 2005;9(6):624-5.

Activated Protein CXigris Recombinant protein Indication:

Severe sepsis MODS

Evidens: 28 day mortality APC vs. Placebo Mortality 24,7% (APC) vs. 30,8% (Placebo)

E Tønnesen Ugeskr Læger 2004;166(11):1002Bernard GR, Vincent JL, Laterre PF et al. N Engl J Med 2001;344:699-709.

Activated Protein CXigris Drug approval based on a single study

Side effects: Serious bleeding events APC (3.5%) vs.

placebo (2.0%), p=0.06 First part of study

720 patients inrolled – no effect of APC treatment

Monitorering / duration of treatment Mode of action

Eichacker PQ. Crit Care Med. 2003 Jan;31(1 Suppl):S94-6. Review. Costa V et al.BMC Anesthesiol. 2007 Jun 25;7:5.

Dissemineret intravascular coagulationTreatment Treat underlying disease

Fresh frozen plasma

Platelets pool – only thrombocytopenia induced bleeding

Fibrinogen concentrate – only during massive bleeding and afibrinogenaemia

Xigris

Consult: Local coagulation lab.

Hyperfibrinolysis Increased breakdown of the clot formed

Induced by Release of fibrinolytic agents from damaged

endothelial cells Hypoperfusion

Massive bleeding Obstetric Urology Severe trauma (ISS <25)

Hyperfibrinolysis Treatment; tranexamic acid 15 mg/kg

Remember to substitute consumptioned fibrinogen

CRASH II study 20,000 trauma patients Ongoeing bleeding or significant risk for

bleeding RCT; tranexamic acid or placebo End-points; Death and transfusion

requirementsBrohi K et al J Trauma. 2008 May;64(5):1211-7; WWW.CRASH2.LSHTM.AC.UK

Anaemia

• Changes flow conditions• Haematocrit correlates inverse with bleeding time

Valeri R et al. Transfusion. 2001;41:(8):977-983

Dilutional cogulopathyDefinition

Ongoing Bleeding+ Intravenously fluid resuscitation

= Haemodilution

Dilutional coagulopathyCrystalloids vs colloids

• Porcine model of bleeding

– 30 pigs, removal of 60% of blood volume

– Substitution with:• Hypertonic saline + HES 200/0.65 (HyperHaes)• HES 130/0.4 (Voluven)• Gelatine (Gelofusin)

– Hepatic incision

Dilutional coagulopathyCrystalloids vs colloids, Blood loss

• Hypertonic saline + HES 200/0.65 (HyperHaes)– 725 (375 - 900) ml

• HES 130/0.4 (Voluven)– 1600 (1500 - 1800) ml

• Gelatine (Gelofusin)– 1625 (1275 -1950) ml

Colloid induced coagulopathyAquired fibrinogen deficiency

– Dys-functional fibrinogen with compromised polymerization induced by hydroxyethyl starch plasma expanders

– Reduces clot strength

– Increases bleeding

Fries et al. Br J Anaest 95(2):172-7 (2005)Fenger-Eriksen et al. Br J Anaest 94(3)324-29 (2005) E de Jonge et al. Crit Care Med 2001 Vol 29 1261-67Haas T et al Anesth Analg 2008 Apr; 106(4):1078-86Hiippala ST et al., Anesth Analg. 1995 Aug;81(2):360-5

Coagulopathy of the bleeding patientDilution

Fenger-Eriksen C et al. J Thromb Haemost 2009

N=20, *significant different from baseline, ** expected

Baseline 30% Haemodilution Relative decrease %

Haematocrit 0.43 ± 0.03 0.29 ± 0.02 - 32 ± 5

Platelet count (10*9L) 248 ± 65 181 ± 50* - 27± 5

P-fibrinogen (µmol/L) 9.5 ± 1.9 5.1 ± 0.8* - 44 ± 4.4**

Trombin Generation (nM*min) 1471 ± 309 1532 ± 247 + 3.8 ± 11

Postpartum hemorrhageFibrinogen and bleeding

• Fibrinogen level significantly associated with the worsening of bleeding

• Women requiring uterotonic prostaglandin-infusion– Fibrinogen levels <2 g/l – Positive predictive value for PPH at 100%

– Fibrinogen levels >4 g/l – Negative predictive value at 79%

B Charbit et al. J Thromb Haemost 2007;5:266-273

Fibrinogen substitution during massive bleeding 43 patients recieving fibrinogen concentrate

(Haemocomplettan) at Skejby Hospital, Hypofibrinogenaemia and massive bleeding

Increases fibrinogen Improves PT, APTT Reduces bleeding

Un

its

0

2

4

6

8

10

12

14

16

PRBC FFP Pooled platelets

p<0,0001

p<0,0001

p<0,001

Fenger-Eriksen C et al. Br J Anaesth 2008 Dec;101(6):769-73

Dilutional coagulopathy

• Are crystalloids better?

• Probably yes regarding coagulation

• Large volumina are required– Hyperchloremic acidosis

• Renal impairment• Secondary impairment of coagulation

Thrombin generationAcidose and hypothermia

Martini el al J Trauma 2005(58-5) 1002-1010

Sepsis and coagulationConclusion• Close relation between inflammtory response and

coagulation activationo Activationo Imbalance of regulatory mechanism and fibrinlolysis

o Dysfunctional fibrinogen from colloidso Acidosiso Hypothermiao Hyperfibrinolysiso Anaemiao Electrolyte disturbances

Blood transfusion

Circulation 2007;116:2544–52

Murphy GJ et al. Circulation 2007;116:2544–52

Blood transfusion

Am J Cardiol 2008;102:115–119

Aronson D et al. Am J Cardiol 2008;102:115–119

N Engl J Med 2008;358:1229–39

Koch CG et al. N Engl J Med 2008;358:1229–39