approach to coagulopathy in the icu...coagulation u coagulation is the process in which blood clots...
TRANSCRIPT
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APPROACH TO COAGULOPATHY IN THE ICUDIC AND THROMBOTIC EMERGENCIES
NEIL KUMAR, MDUNIVERSITY OF ROCHESTER MEDICAL CENTER
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Disclosures
u I have no financial disclosures
u I am NOT A HEMATOLOGIST
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Outline
u Review of hemostasis and coagulopathyu Discuss laboratory markers for coagulopathyu Discuss an approach to a few specific coagulopathies and thrombotic
emergencies
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Outline
u Review of hemostasis and coagulopathyu Discuss laboratory markers for coagulopathyu Discuss an approach to a few specific coagulopathies and thrombotic
emergencies
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Coagulation
u Coagulation is the process in which blood clots
u Fibrinolysis is the process in which clot dissolves
u Hemostasis is the stopping of bleeding or hemorrhage.
u Ideally, hemostasis is a balance between coagulation and fibrinolysis
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Coagulation (classic pathways)
Michael G. CrooksSimon P. HartEur Respir Rev2015;24:392-399
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Coagulation (another view)
Gando, S. et al. (2016) Disseminated intravascular coagulationNat. Rev. Dis. Primers doi:10.1038/nrdp.2016.37
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Coagulation (yet another view)
Gando, S. et al. (2016) Disseminated intravascular coagulationNat. Rev. Dis. Primers doi:10.1038/nrdp.2016.37
u Inflammation and coagulation intersect with platelets in the middle
u An example of this is Disseminated Intravascular Coagulation.
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Outline
u Review of hemostasis and coagulopathyu Discuss laboratory markers for coagulopathyu Discuss an approach to a few specific coagulopathies and thrombotic
emergencies
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PT / INR
u Prothrombin Timeu Test of Extrinsic Pathwayu Take plasma (blood without cells) and re-add calcium
u Calcium was removed with citrate in tube
u Add tissue factor
u See how long it takes to clot and normalize PT to get INR
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Coagulation (classic pathways)
Michael G. CrooksSimon P. HartEur Respir Rev2015;24:392-399
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PT / INR
u Causes for elevated INRu Warfarin or other vitamin K antagonist
u Liver diseaseu Hepatocellular disease
u Cholestatic disease
u DIC
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aPTT
u Activated Partial Thromboplastin Timeu Test of Intrinsic Pathwayu Take plasma (blood without cells) and re-add calcium
u Calcium was removed with citrate in tube
u Add “partial thromboplastin”u Thromboplastin is a lab surrogate for tissue factor. It Is actually phospholipid
and tissue factor. Partial thromboplastin is just the phospholipid
u Add negative charged particle (usually kaolin or silica)u Negative charged particle in the vessel is collagen exposed by vessel injury
u See how long it takes to clot
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Coagulation (classic pathways)
Michael G. CrooksSimon P. HartEur Respir Rev2015;24:392-399
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aPTT
u Causes for elevated INRu Anticoagulant use such as heparin, bivalirudin
u Mildly elevated in warfarin use
u Liver disease
u DIC
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ACT
u Activated Clotting Timeu Test of entire coagulation cascade, except fibrinolysisu Take whole blood and mix with glass beads or kaolinu See how long clot will take to form
u Most commonly used in cardiac bypass due to extreme amounts of heparin used
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ACT
u ACT will thus be elevated in a wide range of circumstances;a short list could resemble the following:u Thrombocytopenia, or platelet dysfunction
u Clotting factor deficiency, or factor inhibitors
u Low fibrinogen
u Hypothermia
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TT
u Thrombin Timeu Measures conversion of fibrinogen to fibrin.u Take plasma and add thrombin
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TT
u Causes of an unusually prolonged thrombin time:u Heparin therapy
u Low fibrinogen levels
u Dysfunctional fibrinogen (eg. foetal fibrinogen)
u Direct thrombin inhibitors (eg. hirudin, argatroban, dabigatran)
u High levels of abnormal proteins, eg. paraproteins and fibrin degradation byproducts can lead to abnormal TT by interfering with the cleavage of fibrinogen by thrombin.
u Very high fibrinogen levels can paradoxically interfere with TT.
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Reptilase Time
u Reptilase is secreted by vipers and catalyzes fibrinogen to fibrinu Related to Thrombin Time
u Except, since it not mammalian, it doesn’t adhere to normal human homeostatic feedback mechanisms
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Reptilase Time
u Thus, reptilase time will not be affected by antithrombin III (and thus, by heparin)
u It will not be affected by direct thrombin inhibitors such as argatrobanor hirudin
u It will only react to abnormalities of fibrinogen.
u Thus, reptilase time will be abnormally increased in the following circumstances:u Low fibrinogen levelsu Dysfunctional fibrinogen (eg. foetal fibrinogen)u High levels of abnormal proteins, eg. paraproteins and fibrin degradation
byproductsu Very high fibrinogen levels
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Ecarin Clotting Time
u Ecarin is from venom and activates prothrombinu Bypasses extrinsic and intrinsic pathways
u ECT will be abnormal in the presence of any direct thrombin inhibitors.
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TEG / ROTEM
u Both are commercial types of viscoelastic tests.u TEG, the cup moves. ROTEM, the pin movesu It shows interaction of platelets with the coagulation cascade
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TEG / ROTEM
Gregory Semon, Michael Cheatham. TEG in Traumahttp://www.surgicalcriticalcare.net/Guidelines/TEG%202014.pdf
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TEG / ROTEM
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TEG / ROTEM
The Lancet Neurology 2017 16, 630-647DOI: (10.1016/S1474-4422(17)30197-7)
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u No one test can adequately give a good overview of coagulopathyu Even a battery of tests cannot always give a good overview of coagulopathy
u Why?
Tests of Coagulation
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Outline
u Review of hemostasis and coagulopathyu Discuss laboratory markers for coagulopathyu Discuss an approach to a few specific coagulopathies and thrombotic
emergencies
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u Extremely common in ICU patients – especially in the setting of surgery.u Commonly used transfusion triggers
u 10,000 / cubic millimeter for non-bleeding patientsu If known myelodysplasia or aplastic anemia, can consider a lower trigger
u 50,000 / cubic millimeter for bleeding patients
u 100,000 / cubic millimeter for central nervous system bleeding
Thrombocytopenia
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u Evaluationu Pseudothrombocytopenia?
u Blood sample clotted? EDTA-dependent platelet antibodies
u Large platelets that are missed by cell counters
u Drug related?u Heparin
u IIb/IIIa inhibitors
u ADP receptor antagonists
u Acute alcohol toxicity
u Hematinic deficiency, such as folic acid?
Thrombocytopenia
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u Other causesu Sepsis
u Major blood loss and hemodilution
u Mechanical fragmentationu Cardiopulmonary bypass
u ECMO
u IABP
u Renal dialysis?
u Immune mediated disorder
u Hyperspenism
u DIC
u Microangiopathic hemolytic anemia
Thrombocytopenia
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u Acquired syndromeu Intravascular activation of coagulationu Loss of localization arising from different causes.
DIC
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u Usually presents as hemorrhage, only about 10% of cases presenting as microthrombi alone.
u Sepsis is most common underlying cause in critical care
DIC
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u Early animal studies showed promise in the use of activated protein c, antithrombin, tissue factor pathway inhibitor.
u Studies in humans showed no survival benefit, but increased bleeding.
DIC
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u Consumption of coagulation proteins and platelets produces bleeding tendencies.u Prolonged prothrombin time
u Prolonged activated partial-thromboplastin time
u hypofibrinogenemia
u Elevated levels of fibrinogen degradation products
u Thrombocytopenia
DIC
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DIC
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u Management is based upon treating underlying causeu Expert opinion suggests replacing coagulation proteins and platelets in setting of
bleeding.
u Commonly used targets includeu Platelet level of 50,000 / cubic millimeter
u Prothrombin time less than 1.5 times normal control
u Fibrinogen level of 1.5 gram / liter
u Antifibrinolytics avoided due to widespread fibrin deposition (fibrinolytic system necessary in recovery)
u Heparin in thrombotic phenotype is controversial.
DIC
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u Characterized by profound thrombocytopenia and microangiopathichemolytic anemia (red-cell fragmentation)u Examples include
u Thrombotic thrombocytopenia purpura
u Hemolytic uremia syndrome
u HELLP syndrome
Thrombotic Microangiopathies
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u Acquired or hereditaryu ADAMTS13 cleaves vWF. In its absence, large multimers of vWF are present,
increasing risk for platelet thrombi in small vessels.u Acquired TTP diagnosis is supported by ADMTS13 level less than 10% of normal
activity.u Test not sufficiently sensitive nor specific to use in isolation.
Thrombotic thrombocytopenia purpuraADAMTS13 deficiency-mediated TMA
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u Initial presentation is varied. weakness, gastrointestinal symptoms, purpura, and transient focal neurologic abnormalities are common.
u Most patients have normal or only slightly elevated creatinine levels.u Treatment for hereditary is ADAMTS13 replacementu Survival for acquired is increased by plasma exchange. Initiaol management
is ADAMTS13 replacement with plasma infusion.u Glucocorticoids are standard treatment.
Thrombotic thrombocytopenia purpuraADAMTS13 deficiency-mediated TMA
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u Results from uncontrolled activation of alternative pathway of complement activation.
u Acute Kidney Injury in the setting of hypertension is common presentation.u Diagnostic criteria include
u Serum creatinine at or above upper limit of normal
u Microangiopathic hemolytic anemia
u Thrombocytopenia
u ADAMTS13 activity of 5% or more.
u Negative stool sample for Shiga-toxin producing infection.
u Treatment is with anti-complement agents. Eculizumab
Complement mediatedThrombotic Microangiopathy
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Conclusion
u Hemostasis is the interplay between coagulation and fibrinolysisu Laboratory evaluation is not perfectu Management of coagulopathy and thrombotic emergencies requires a
high degree of suspicion and vigilance.
u Referencesu Amish N. Raval et al. Circulation. 2017;135:e604-e633u Rachel Rosovsky et al. Techniques in Vascular and Interventional Radiology.
2017; 20,3:141-151u James N. George et al. New England Journal of Medicine. 2014;371:654-666u Beverly J. Hunt et al. New England Journal of Medicine. 2014;370:847-859