holley on coagulation management

Bedside Critical Care 2012

Reconsidering Coagulopathy and it’s Management ?

Anthony HolleyIntensivist

Royal Brisbane & Women’s Hospital


http://www.nba.gov.au/guidelines/order/index.htmlhttp://www.nba.gov.au/guidelines/review.html

Exsanguination


Haemorrhage remains a major and potentially reversible cause of all trauma deaths.

More pronounced in the setting of penetrating trauma.

Current literature from the Afghanistan and Iraq conflicts report that as many as 15% of casualties require massive transfusions

Mortality in this group is 20-50%


Coagulopathy

Acidosis Hypothermia

Bleeding

Kashuk JL, Moore EE, Millikan JS, Moore JB. Major abdominal vasculartrauma—a unified approach. J Trauma 1982; 22:672-679.

Classically Trauma-induced Coagulopathy

TOWARDS A DEFINITION, CLINICAL AND LABORATORY CRITERIA, AND A SCORING SYSTEM FOR DISSEMINATED INTRAVASCULAR COAGULATION

The consensual definition of DIC as proposed by the ISTH

“DIC is an acquired syndrome characterized by the intravascular activation of coagulation with loss of localization arising from different causes. It can originate from and cause damage to the microvasculature, which if sufficiently severe, can produce organ dysfunction”

Fletcher B. Taylor et al on behalf of the Scientific Subcommittee on Disseminated Intravascular Coagulation (DIC) of the International Society on Thrombosis and Haemostasis (ISTH) 2001


Diagnostic algorithm for the diagnosis of overt DIC

1.Risk assessment: Does the patient have a underlying disorder known to be associated with overt DIC? If yes: proceed; If no: do not use this algorithm;

2. Order global coagulation tests (platelet count, prothrombin time (PT), fibrinogen, soluble fibrin monomers or fibrin degradation products)

3. Score global coagulation test resultsplatelet count (>100 = 0; <100 = 1; <50= 2)elevated fibrin-related marker (e.g. soluble fibrin monomers/fibrin degradation products) (no increase: 0; moderate increase: 2; strong increase: 3)prolonged prothrombin time (< 3 sec.= 0; > 3 sec. but < 6 sec.= 1; > 6 sec. = 2)fibrinogen level (> 1.0 gram/l = 0; < 1.0 gram/l = 1)

4. Calculate score

5. If > 5: compatible with overt DIC; repeat scoring dailyIf < 5: suggestive (not affirmative) for non-overt DIC; repeat next 1-2 days


Clinical conditions that may be associated with overt DIC

1.sepsis/severe infection (any micro-organism)2.trauma (e.g. polytrauma, neurotrauma, fat embolism)3.organ destruction (e.g. severe pancreatitis)4.malignancy- solid tumors- myeloproliferative/lymphoproliferative malignancies5.obstetrical calamities- amniotic fluid embolism- abruptio placentae6.vascular abnormalities- Kasabach-Merrit Syndrome- large vascular aneurysms 7.severe hepatic failure8.severe toxic or immunologic reactions- snake bites- recreational drugs- transfusion reactions- transplant rejection


Diagnostic algorithm for the diagnosis of overt DIC

2. Order global coagulation tests (platelet count, prothrombin time (PT), fibrinogen, soluble fibrin monomers or fibrin degradation products)

3. Score global coagulation test results

platelet count (>100 = 0; <100 = 1; <50= 2)

elevated fibrin-related marker (e.g. soluble fibrin monomers/fibrin degradation products) (no increase: 0; moderate increase: 2; strong increase: 3)

prolonged prothrombin time (< 3 sec.= 0; > 3 sec. but < 6 sec.= 1; > 6 sec. = 2)fibrinogen level (> 1.0 gram/l = 0; < 1.0 gram/l = 1)

4. Calculate score

5. If > 5: compatible with overt DIC; repeat scoring dailyIf < 5: suggestive (not affirmative) for non-overt DIC; repeat next 1-2 days

A Time to Consider

1.Mechanism of coagulopathy2.Tranexamic acid3.Product ratios 4.Activated factor VII5.Best modality to assess coagulopathy


Dilution?


Little or no dilutional effect of crystalloid therapy on the standard tests of coagulation either in vitro or in healthy volunteers

Colloid vs CrystalloidCoagulopathy was present in 10% of

patients who received less than 500 ml of fluid

? Alternative mechanism


Moderate/severe hypothermia present < 9% of trauma patients

Relationship between hypothermia, shock and injury severity is a weak independent predictor of mortality (OR 1.19)

Very little effect of moderate hypothermia on coagulation proteases.

Significant effects on function and clinical bleeding only at temperatures < 33°C.

Hypothermia?


Effects of IV HCL acid on human volunteers.

Definite dose–response of acidaemia on clotting function by thromboelastometry.

Little clinically significant effect on protease function down to a pH of 7.2 in in-vitro studies

Animal studies: pH of 7.1 produces only a 20% prolongation of the PT & APTT.

Acidaemia?


Consumption regarded as a primary cause of traumatic coagulopathy

Little evidence for consumption of clotting factors as a relevant mechanism

In patients without shock coagulation times are never prolonged, regardless of the amount of thrombin generated

Consumption?

Time to Challenge the Dogma?


“None of these appears to be responsible for acute coagulopathy, and it appears that shock is the prime initiator of the process!"


Coagulopathy

Acidosis Hypothermia

Bleeding

Inju

ry

Hyperfibrinolysis

Classically Trauma-induced Coagulopathy

APC


Shock and systemic hypoperfusion?Dose-dependent prolongation of clotting

times with increasing systemic hypoperfusion.

Base deficit (BD) as a surrogate for perfusion

2% of patients with a BD < 6 mEq/l had prolonged clotting times

20% of patients with a BD > 6 mEq/l.

Drivers of Traumatic Coagulopathy?


Acute coagulopathy in massive transfusion appears to be due to activation of anticoagulant and fibrinolytic pathways.

Thrombomodulin–protein C pathway is implicated.

Mechanism of Acute Traumatic Coagulopathy


Normal

Haemostasis

Procoagulant

Activity

Antifibrinolytic activity

AnticoagulantActivity

fibrinolytic activity

Thrombus

Bleeding


With tissue hypoperfusion the endothelium expresses thrombomodulin which complexes with thrombin.

Less thrombin is available to cleave fibrinogen

Thrombin complexed to thrombomodulin activates protein C, which inhibits cofactors V and VIII

Protein C Activation

Protein C Anticoagulant Pathway


Biological Response Pathological in Shock


Tissues subjected to low-flow states generate an anticoagulant milieu

Avoids thrombosis of vascular beds.


Trauma is associated with increased fibrinolytic activity.

Tissue plasminogen activator (tPA) is released from the endothelium following injury and ischaemia.

Local control mechanism to reduce propagation of clot to normal vasculature

Hyperfibrinolysis

Hyperfibrinolysis

Reduction in plasminogen activator inhibitor-1 (PAI-1) levels in tissue hypoperfusion

APC

A new understanding of coagulopathy in trauma: potential therapeutic implications. 2012 Yearbook of Intensive Care and Emergency Medicine. Edited J.-L. Vincent. Springer. Read M, Holley A


CRASH-2 trial collaborators. The Lancet. 2010;376:23-32

Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with

significant haemorrhage (CRASH-2): a randomised, placebo-controlled trial

Tranexamic acid


ACEM ASM 2010

Plasminogen activator

PlasminPlasminogen

Blockade Blockade

Tranexamic AcidTranexamic AcidTranexamic AcidTranexamic AcidF

ibrin

olysis


The Study

Prospective double blind274 hospitals40 countriesn=20211Tranexamic (n=10 060) acid vs

placebo (10115)1 g over 10 minutes then 1 g over 8

hoursPrimary outcome: in hospital four week

mortality


Tranexamic AcidTranexamic Acid


But............

Entrance criteria soft (HR>110 bpm, SBP<90 mmHg)

70% of patients SBP > 90 mmHgOnly 16% of patients SBP <75 mmHgNo reduction in blood transfusion observedMedian no. of RBC units transfused = 3 in

both groupsNeeds to be given within three hours of

injury


Tranexamic acid safely reduces the risk of death in bleeding trauma patients!


Ratios


Holcomb JB, Wade CE, Michalek JE, Chisholm GB, Zarzabal LA, Schreiber MA, Gonzalez EA, Pomper GJ, Perkins JG, Spinella PC, Williams KL, Park MS. Increased plasma and platelet to red blood cell ratios improves outcome in 466massively transfused civilian trauma patients. Ann Surg 2008; 248:447-458.

Product Ratios


Massive data base ~ 25 00016% transfused 11.4% received massive transfusionsLogistic regression identified the ratio

of FFP to PRBC use as an independent predictor of survival.

Higher the ratio of FFP:PRBC the greater probability of survival.

The optimal ratio in this analysis was an FFP:PRBC ratio of 1:3 or less.

Teixeira PG, Inaba K, Shulman I, Salim A, Demetriades D, Brown C,Browder T, Green D, Rhee P. Impact of plasma transfusion in massively transfused trauma patients. J Trauma 2009; 66:693-697.

Practice Point

In patients with critical bleeding requiring massive transfusion, insufficient evidence was identified to support or refute the use of specific ratios of RBCs to blood components.



Activated Factor VIIActivated Factor VII

301 trauma patients were enrolled. 143 blunt, 137 penetrating.

Hauser et al. J Trauma. 2010

Sep;69(3):489-500 Bedside Critical Care 2012

Randomized prospective trial573 patients No effect on mortalityNo effect on thrombotic eventsTrial stopped early for lack of efficacy!


Levi M, Levy JH, Andersen HF, Truloff D. Safety of recombinant activated factor VII in randomized clinical trials. N Engl J Med 2010;363:1791-1800.


Recommendation 2

The routine use of rFVIIa in trauma patients with critical bleeding requiring massive transfusion is not recommended because of its lack of effect on mortality (Grade B) and variable effect on morbidity (Grade C).

Practice Point1. An MTP should include advice on the

administration of rFVIIa when conventional measures – including surgical haemostasis and component therapy – have failed to control critical bleeding.

2. NB: rFVIIa is not licensed for this use. Its use should only be considered in exceptional circumstances where survival is considered a credible outcome

3. When rFVIIa is administered to patients with critical bleeding requiring massive transfusion, an initial dose of 90 μg/kg is reasonable.


SummaryMore to coagulopathy than acidosis, hypothermia

and dilution.Almost certainly hypoperfusion is the principle

driver.Acidosis, hypothermia and dilution certainly

contribute.Despite advances in our understanding we haven’t

yet found the magic bullet.We will have to wait for the definitive word on

product ratios.Tranexamic acid given early seems to be safe and

effective and we are unlikely to get better evidence than CRASH2



Thank YouThank You

holley on coagulation management

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