APPROACH TO COAGULOPATHY IN THE ICU DIC AND THROMBOTIC EMERGENCIES NEIL KUMAR, MD UNIVERSITY OF ROCHESTER MEDICAL CENTER Disclosures u I have no financial disclosures u I am NOT A HEMATOLOGIST Outline u Review of hemostasis and coagulopathy u Discuss laboratory markers for coagulopathy u Discuss an approach to a few specific coagulopathies and thrombotic emergencies Outline u Review of hemostasis and coagulopathy u Discuss laboratory markers for coagulopathy u Discuss an approach to a few specific coagulopathies and thrombotic emergencies 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 Coagulation (classic pathways) Michael G. Crooks Simon P. Hart Eur Respir Rev 2015;24:392-399 Coagulation (another view) Gando, S. et al. (2016) Disseminated intravascular coagulation Nat. Rev. Dis. Primers doi:10.1038/nrdp.2016.37 Coagulation (yet another view) u Inflammation and coagulation intersect with platelets in the middle u An example of this is Disseminated Intravascular Coagulation. Gando, S. et al. (2016) Disseminated intravascular coagulation Nat. Rev. Dis. Primers doi:10.1038/nrdp.2016.37 Outline u Review of hemostasis and coagulopathy u Discuss laboratory markers for coagulopathy u Discuss an approach to a few specific coagulopathies and thrombotic emergencies PT / INR u Prothrombin Time u Test of Extrinsic Pathway u 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 Coagulation (classic pathways) Michael G. Crooks Simon P. Hart Eur Respir Rev 2015;24:392-399 PT / INR u Causes for elevated INR u Warfarin or other vitamin K antagonist u Liver disease u Hepatocellular disease u Cholestatic disease u DIC aPTT u Activated Partial Thromboplastin Time u Test of Intrinsic Pathway u 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 Coagulation (classic pathways) Michael G. Crooks Simon P. Hart Eur Respir Rev 2015;24:392-399 aPTT u Causes for elevated INR u Anticoagulant use such as heparin, bivalirudin u Mildly elevated in warfarin use u Liver disease u DIC ACT u Activated Clotting Time u Test of entire coagulation cascade, except fibrinolysis u Take whole blood and mix with glass beads or kaolin u See how long clot will take to form u Most commonly used in cardiac bypass due to extreme amounts of heparin used 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 TT u Thrombin Time u Measures conversion of fibrinogen to fibrin. u Take plasma and add thrombin 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. Reptilase Time u Reptilase is secreted by vipers and catalyzes fibrinogen to fibrin u Related to Thrombin Time u Except, since it not mammalian, it doesn’t adhere to normal human homeostatic feedback mechanisms 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 argatroban or 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 levels u Dysfunctional fibrinogen (eg. foetal fibrinogen) u High levels of abnormal proteins, eg. paraproteins and fibrin degradation byproducts u Very high fibrinogen levels Ecarin Clotting Time u Ecarin is from venom and activates prothrombin u Bypasses extrinsic and intrinsic pathways u ECT will be abnormal in the presence of any direct thrombin inhibitors. TEG / ROTEM u Both are commercial types of viscoelastic tests. u TEG, the cup moves. ROTEM, the pin moves u It shows interaction of platelets with the coagulation cascade TEG / ROTEM Gregory Semon, Michael Cheatham. TEG in Trauma http://www.surgicalcriticalcare.net/Guidelines/TEG%202014.pdf TEG / ROTEM TEG / ROTEM The Lancet Neurology 2017 16, 630-647DOI: (10.1016/S1474-4422(17)30197-7) Tests of Coagulation u No one test can adequately give a good overview of coagulopathy u Even a battery of tests cannot always give a good overview of coagulopathy u Why? Outline u Review of hemostasis and coagulopathy u Discuss laboratory markers for coagulopathy u Discuss an approach to a few specific coagulopathies and thrombotic emergencies Thrombocytopenia 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 patients u 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 u Evaluation u 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 u Other causes u Sepsis u Major blood loss and hemodilution u Mechanical fragmentation u Cardiopulmonary bypass u ECMO u IABP u Renal dialysis? u Immune mediated disorder u Hyperspenism u DIC u Microangiopathic hemolytic anemia DIC u Acquired syndrome u Intravascular activation of coagulation u Loss of localization arising from different causes. DIC 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 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 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 DIC u Management is based upon treating underlying cause u Expert opinion suggests replacing coagulation proteins and platelets in setting of bleeding. u Commonly used targets include u 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. Thrombotic Microangiopathies u Characterized by profound thrombocytopenia and microangiopathic hemolytic anemia (red-cell fragmentation) u Examples include u Thrombotic thrombocytopenia purpura u Hemolytic uremia syndrome u HELLP syndrome Thrombotic thrombocytopenia purpura ADAMTS13 deficiency-mediated TMA u Acquired or hereditary u 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 purpura ADAMTS13 deficiency-mediated TMA 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 replacement u Survival for acquired is increased by plasma exchange. Initiaol management is ADAMTS13 replacement with plasma infusion. u Glucocorticoids are standard treatment. Complement mediated Thrombotic Microangiopathy 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 Conclusion u Hemostasis is the interplay between coagulation and fibrinolysis u Laboratory evaluation is not perfect u Management of coagulopathy and thrombotic emergencies requires a high degree of suspicion and vigilance. u References u Amish N. Raval et al. Circulation. 2017;135:e604-e633 u Rachel Rosovsky et al. Techniques in Vascular and Interventional Radiology. 2017; 20,3:141-151 u James N. George et al. New England Journal of Medicine. 2014;371:654-666 u Beverly J. Hunt et al. New England Journal of Medicine. 2014;370:847-859.