10/24/2013. Heparin-Induced Thrombocytopenia (HIT) Anticoagulation Management in ECMO Therapy:

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1 Anticoagulation Management in ECMO Therapy: Heparin-Induced (HIT) Michael H. Creer, MD Professor of Pathology Director, Clinical Laboratories, Medical Co- Director, Hematopathology and Chief, Division of Laboratory Medicine Learning Objectives 1. Understand the pathogenesis of HIT and the relative roles of immune complex formation, platelet activation and endothelial cell injury in HIT-associated thrombosis. Recognize the clinical features of HIT and learn to effectively utilize the clinical laboratory for diagnostic confirmation 3. Discuss the treatment strategy for appropriate anticoagulation of ECMO patients with active HIT The Many Paradoxical Features of Heparin- Induced Feature Heparin and (high bleeding risk) Mechanism of Drug-Induced T-Cell Dependent Primary Immune Response (CD4 + T H cells, conventional APC) Pattern of Pathologic Thrombosis Treatment Strategy Paradox Thrombosis (arterial and venous, skin necrosis, limb loss) Platelet Activation Dependent (minor role for mononuclear phagocytes (RES)) IgG and IgM antibodies appear simultaneously during primary immune response, NO Long-Term Immunologic Memory Venous Thrombosis much more frequent than Arterial Thrombosis (4:1) Anti-Platelet Agents Ineffective Alone, Focus on Inhibition of Thrombin Generation (anti-xa) or Activity (DTI) 1

2 Heparin-Induced Pathogenesis : Mechanism and Timing classic immune-mediated (minor) platelet activation dependant (major) Immune Response altered PF4 Ag processing neoepitope formation T-cell dependant Ab formation rapid onset with early IgM-IgG conversion or simultaneous IgM & IgG production lack of immunologic memory 3 Heparin-PF4 Immune Complex Structure and Immunogenicity type of heparin (UFH > LMWH >> heparinoids) heparin concentration duration of therapy amount of PF4 heparin/pf4 stoichiometry 1 Platelet Activation and Thrombin Generation FcγRII-dependant very strong activation stimulus NOT inhibited by: dec. TxA synthesis (ASA, NSAID) PY1 inhibition (Plavix, Prasugrel) 4 Influence of Heparin Anticoagulant Molecular Weight and Heparin-PF4 Immune Complex Stoichiometry on Platelet Activation HIT incidence = high HIT incidence = low no HIT Heparin-PF4 complex stoiciometry at therapeutic heparin conc. ( U/mL) Heparin-PF4 complex stoiciometry at high heparin conc. (100 U/mL) 5.4 kda = minimum MW for sulfated polysaccharide to bind more than 1 PF4 tetramer

3 in HIT Magnitude NOTE: platelet count decrease > 50,000/uL (only change) NOT DIAGNOSTIC FOR HIT HIT diagnostic criteria based on nadir and % decrease in platelet count Heparin-Induced Clinical Presentation and Laboratory Diagnosis of HIT Clinical signs of HIT Erythematous plaques 1 Deep venous thrombosis 1 Skin necrosis 1 Venous gangrene 1 Reproduced with permission Blackwell Publishing (Warkentin TE. Br J Haematol 1996 Warkentin TE et al. Ann Intern Med

4 Thrombotic Complications of HIT Venous thrombosis (30-70%) Deep vein thrombosis (DVT) Pulmonary embolism (PE) Adrenal necrosis (adrenal vein thrombosis) Cerebral venous (sinus) thrombosis Venous limb gangrene (VKA associated) Arterial thrombosis ( white clots ) (15-30%) Limb artery thrombosis Stroke Myocardial infarction Skin lesions at heparin injection sites (<10%) Skin necrosis Erythematous plaques Acute reactions after i.v. heparin bolus (<10%) Disseminated intravascular coagulation (DIC) (<10%) Diagnosis of HIT Clinical Assessment 8 Warkentin TE: Sem Thromb Haemost 30(4):73, 004 in HIT Timing in Patients with Transient (eg Surgery, ECMO, etc.) 4

5 Diagnosis of HIT Laboratory Assessment and US for VTE Warkentin TE: Sem Thromb Haemost 30(4):73, 004 in HIT: Timing in Relation to Onset of Antibody Production, Drop in Platelet Count and Onset of Thrombosis > Polyspecific EIA (IgG, IgM, IgA) mean + SEM Warkentin TE, Sheppard JI, Moore JC, et al: Studies of the immune response in heparin-induced thrombocytopenia. Blood 113:4693, 009.) Monospecific EIA (IgG or IgM or IgA) 5

6 Comparison of HIT ELISA and Serotonin Release Assay (SRA) data from St. Louis University Coagulation Consultants SRA ELISA Total (IgM, IgG, IgA, OD > 1.0) (TP) (FP) (FN) 9 0 (TN) 0 SRA + - ELISA IgG Only (OD > 0.4) + - (TP) (FP) 4 4 (FN) (TN) 5 38 (N = 71, prevalence SRA + = 41%) Sensitivity = 100% Specificity = 48% Agreement = 69% Sensitivity = 83% Specificity = 90% Agreement = 87% 1% 3% 5% 0.5% % 10% 1% 3% 0% 15% 50% 8% Orthopedic-UFH Orthopedic-LMWH Cardiac-UFH HIT-induced thrombosis: 50% of patients with thrombocytopenia Activation assay Antigen assay Schematic Iceberg Lee and Warkentin. Heparin-Induced. New York: Marcel Dekker; 000: Heparin-Induced Treatment of HIT 6

7 Natural History of HIT: Frequency of Thrombosis with Heparin Cessation Alone Cumulative Frequency of Thrombosis (%) % Days After Isolated HIT Recognized Warkentin and Kelton. Am J Med 1996;101. Management of HIT treatment DO s When HIT is strongly-suspected: Stop all heparin (both unfractionated and lowmolecular-weight heparin) Initiate alternative non-heparin anticoagulant because of high risk of symptomatic thrombosis Test for HIT antibodies Duplex ultrasonography to exclude DVT Not available in US BAYER discontinued production on May 31, 01 Prolongs PT (difficulty with warfarin Tx) Limited experience vs other DTI adapted in part from the: American College of Chest Physicians (ACCP) Evidence-Based Clinical Practice Guideline on Antithrombotic and Thrombolytic Therapy (8th Edition) 7

8 Warfarin in HIT Warfarin is considered contraindicated in patients with acute HIT until the platelet count has recovered (>150,000) Initiate VKA therapy with 5 mg Warfarin qd. DO NOT use a loading dose. Use during acute HIT only with an agent that reduces thrombin generation or inhibits thrombin Associated with progression of deep venous thrombosis to venous limb gangrene Caution if INR >4 Warkentin et al. Thromb Haemost 1998;79:1 7. Warkentin et al. Ann Intern Med 1997;17: Management of HIT treatment DON Ts When HIT is strongly-suspected: Do not start a vitamin K antagonist (VKA) - if started prior to diagnosis it should be reversed by vitamin K Do not use low-molecular-weight heparin (LMWH) Do not give platelet transfusions unless needed to manage serious hemorrhage Recommendation to give vitamin K applies particularly to direct thrombin inhibitors (DTIs), because prolongation of the aptt by warfarin can lead to underdosing of DTI therapy (in contrast, danaparoid is not monitored by aptt) 8th. ACCP Guidelines, Chest, 133, 008. Off-Label Use of Fondaparinux for Treatment of HIT 7.5 mg daily median dose (sq) (range.5-10 mg/day) (I prefer) the use of an antithrombin (AT) dependent factor Xa inhibitor (danaparoid or fondaparinux), a treatment approach that avoids certain pitfalls of DTI therapy but, more importantly, offers the known safety and benefit of these agents for the large majority of patients who turn out not to have HIT (note: fondaparinux is an off-label therapy for HIT) From: Warkentin TE: Heparin-Induced. In Hoffman,R. et al (editors) Hematology: Basic Principles and Practice, 6 th edition, Elsevier Saunders, 013, pages

9 Anticoagulation Efficacy Differs by Clotting Stimulus for Antithrombin Dependent Anticoagulants (BLOOD, 118: , 011) UFH LMWH Fondaparinux Contact-Induced Clotting (Catheter) Tissue Factor-Induced Clotting (no catheter) SUMMARY 6 Treatment Principles of HIT Two DO s Do stop all heparin (including heparin flushes, LMWH, etc) Do start an alternative non-heparin anticoagulant (usually in therapeutic doses) Two Don t s Don t administer Warfarin during acute thrombocytopenic phase Don t give prophylactic platelet transfusions (use for life-threatening bleeding only) Two Diagnostics Test for HIT antibodies Investigate for lower-limb DVT (eg duplex ultrasound) 9