Heme (Bleeding and Coagulopathies) in the ICU

General Topics To Discuss

• Transfusions

• DIC

• Thrombocytopenia

• Liver and renal disease related bleeding

• Lack of evidence in managing critical illness related bleeding is high – will discuss where evidence is good and bad!

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Overview

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Common ICU Disorders

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First Principal in Management

• Simple but hard to do:

– AVOID correction of LAB abnormalities with blood products unless there is a CLINICAL bleeding problem, a surgery is required, or both

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Major Bleeding and Transfusions

Major Bleeding and Transfusions

• Transfusions used liberally in critical care until transfusion-related infections known (e.g. HIV, hepatitis) and blood supply more limited

• Initial transfusion practice based on military and civilian casualties, not RCTs– Improved survival with FFP per unit of RBC but these data

flawed

• Now widespread use of FFP but not w/o risk– TRALI, ARDS

• This issue being investigated with current trials ongoing– North American Pragmatic, Randomized Optimal Platelets

and Plasma Ratios (multicenter RCT - trauma pts requiring massive transfusion, effect of products or transfusion ratios of plasma, plts, or RBCs on rates of death at 24h and 30d) –ended 12/2013

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Major Bleeding and Transfusions

• Using FFP in North America but in Europe, many abandoned use and use concentrates instead

• Others using tranexamic acid (derivative of lysine, acts as antifibrinolytic and competitively inhibits plasminogen)– New trial at Pitt called STAAMP (Study of Tranexamic Acid during

Air Medical Prehospital Transport, 1 gm to pts at risk of hemorrhage, 30d mortality)

• Tranexamic acid already recommended for major bleeding after trauma– RCT called CRASH-2 (Clinical Randomization of an

Antifibrinolytic in Significant Hemorrhage Study)– Those getting TA had 1/3 reduction in bleeding (within 3 hrs)

and did not have higher rates thrombosis although needs more study

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Hemostatic Support for Procedures

• No evidence for using FFP to correct abnormal results on coag screening prior to procedure

• No consensus for what results should trigger use of FFP so people have different practices– Author suggest PT ratio<1.5 is safe for CVC insertion

as thrombin generation is normal at that level

• In general, vitamin K needed for formation of factors 2,7,9, and 10, may be low in critical care settings– Author suggests supplementation with vitamin K

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Transfusion Strategy & Critical Care

• TRICC Trial• 1999 RCT, 838 critically ill pts enrolled with

euvolemia after initial tx by MDs• 418 patients to restrictive strategy (Hgb>7) and

maintained betw 7-9• 420 patients to liberal strategy (Hgb>10) and

maintained betw 10-12• Examined 30d mortality• 30d mortality similar between groups but much

less among pts who were less acutely ill

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Transfusion Strategy & Critical Care

• No difference in 30d mortality from all causes (p=0.11)

• Mortality rates during hospitalization were lower in restrictive strategy group (p=0.05)

• Mortality in ICU and 60d mortality lower in restrictive strategy group (p=0.29, p=0.23) but not significantly so

• Those with cardiac disease did not have more adverse outcomes in restrictive strategy group

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Restrictive strategy was at least as effective and possibly superior to liberal strategy in critically ill

• One landmark RCT examining transfusion requirements in critical care in 1999

• 838 critically ill patients, Hgb<9 within 72h of admission– 418 pts to restrictive strategy (Hgb<7)– 420 pts to liberal strategy (Hgb<10)

• Primary outcome – rate of death at 30d• Secondary outcomes – rate of death at 60d,

survival time in first 30d• Overall, 30d mortality similar betw groups

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Acute UGIB & Transfusions

• Prior RCTs of transfusion strategies excluded GI bleeders

• Observational and animal studies suggested transfusion may be harmful, especially in those with portal HTN

• This trial was an RCT to determine whether restrictive strategy was better than liberal transfusion strategy in pts with UGIB based on current guidelines at time of study in 2013

• 921 patients (461 to restrictive, 460 to liberal) enrolled

• Randomized according to presence/absence of liver cirrhosis

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Acute UGIB & Transfusions

• Restrictive strategy – Hgb threshold 7• Liberal strategy – Hgb threshold 9• Started with 1U transfusion• Primary outcome: rate of death within 45 d• Secondary outcomes: rate of further bleeding and

in-hospital complications• Followed other standards of care for UGIB• Rate of death from any cause lower in restrictive

group (p=0.02)• Adverse events lower in restrictive group (p=0.02)

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• Restrictive strategy resulted in shorter hospital stay, less need for rescue therapy, and further bleeding

• Transfusion may counteract splanchnic vasoconstriction caused by hypovolemia and induce increase splanchnic blood flow/pressure impair clot formation

• May induce abns in coag properties

• In those with cirrhosis and portal HTN, transfusion may cause rebound in portal pressure that precipitates rebleeding

Transfusions & Sepsis

• TRISS trial, Oct 2014 in NEJM

• 998 pts admitted to ICU with septic shock and Hgb of 9 or less

• Randomized to Hgb<7 or Hgb<9, received 1U of leukoreduced RBCs at a time

• Those with MI’s excluded

• Primary outcome = death at 90d

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90-day mortality the same between groups and adverse events similar. Half as much blood needed in restrictive group (~1500 fewer units).

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DIC

DIC• Clinicopathological diagnosis

• Characterized by intravascular activation of coagulation with loss of localization arising from a variety of causes

• Can be scored on ISTH scoring system

• Usu presents as hemorrhage and 5-10% of cases also have microthrombi alone

• Consumption of plts and coagulation factors as well as consumption of physiologic anticoagulants to inhibit them LOTS of bleeding!

• Sepsis is most common cause in ICU setting (infections caused by S. aureus and E. coli known offenders)

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DIC• Major RCTs in supplementation of physiologic

anticoagulants (activated protein C, antithrombin, and tissue factor pathway inhibitor) in sepsis

• NO reduction in death rates and increased bleeding episodes seen in these RCTs

• Manage DIC by managing underlying cause• Transfusion guidelines based on ‘expert opinion’ • Suggests replacement of coagulation proteins and plts in

those who are bleeding– Plts>50K and FFP for PT and PTT < 1.5x normal– Fibrinogen maintained at level >1.5g/L (150g/dL)

• Some advocate UFH in thrombotic phenotype but controversial due to difficulty in monitoring and bleeding provocation

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Thrombocytopenia

• Pathophysiological Mechanisms

• Immunologic Causes

• Thrombotic Microangiopathies

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Thrombocytopenia in the ICU

• Decreased production or increased destruction (immune or nonimmune) of plts or splenic sequestration

• 20% of medical ICU patients, tend to be sicker• Long differential so important to rule out etiology with

urgent action needed– HIT, TTP

• 10K is reasonable plt threshold in stable pts• Those with sustained failure of plts (myelodysplasia or

aplastic anemia) may be stable in 5-10K range• If bleeding, plts > 50K• If risk of CNS bleeding or undergoing neurosrgy, plts >

100K (although data is lacking)

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Immunologic Causes

• HIT is uncommon, drug-induced, autoimmune, prothrombotic disorder

– Formation of IgG antibodies causing plt activation (Ab to complexes of plt factor 4 + heparin)

– Need Thrombocytopenia >50% fall, Timing w/i 5-10d or less than day 1 if recent exposure (30d), new Thromobosis/skin necrosis, no oTher causes of plt fall

Thrombotic Microangiopathies

• Consists of profound thrombocytopenia + microangiopathic hemolytic anemia– Thrombotic thrombocytopenia purpura (TTP)

• Deficiency of a disintegrin and metalloproteinase with thrombospondin type 1 motif 12 (ADAMTS13)

• Results in plt aggregation• Untreated cases have death rate > 90%• Treat with early plasmapheresis and can use rituximab (with

autoimmune form) to reduce recurrence• Death usu by MI due to plt thrombi in coronaries

– Hemolytic-uremic syndrome (HUS)– HELLP syndrome

Liver & Renal Disease

Liver Disease

• Combined reduction in coagulation factors + reduction in physiologic anticoagulants

• So…coagulation is rebalanced• If bleeding does occur, then base transfusion on plt

count, PT, PTT, fibrinogen (although based on ‘expert opinion’ only)

• Remember the UGIB restrictive approach (only transfuse for Hgb<7)

• Tranexamic acid trial for GIB ongoing (HALT-IT) – 2016 expect data on primary outcome

• Vitamin K can be routinely administered to aid in coag factor synthesis

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Renal Disease

• Platelet dysfunction– dysfunctional von Willebrand factor

– production of thromboxane (increases plt aggregation)

– cAMP, cGMP

– uremic toxins (plt dysfxn), anemia, and altered plt granules

– Decreased production of erythropoietin anemia loss of laminar flow in arterioles so red cells don’t push plts and plasma along endothelium prolongation of bleeding time

• Dialysis improves plt function

• Erythropoietin, cryoprecipitate, conjugated estrogens, desmopressin, and tranexamic acid all shown to reduce bleeding time

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Bleeding Associated with Antithrombotic Therapy

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Summary• Not an abundance of evidence to guide transfusion in

critical care• No need for transfusions based on abnormal labs alone

BUT if patient is bleeding, need to react• For major UGIB bleeding, threshold for transfusion is Hgb<7• Look for DIC in the ICU, you will find it and most likely, you

will already be treating underlying disorder– AND if bleeding, then need to react although it may not improve

outcomes

• You will see thrombocytopenia all the time and the differential is big but HIT and TTP require urgent treatment– Although remember these are RARE compared to other

etiologies

• Consider renal and liver disease (chronic or acute!) when bleeding occurs in a critically ill patient

• Tranexamic acid trials will be one to watch!