Heparin-Induced Thrombocytopenia

1. Heparin-Induced Thrombocytopenia

2. Heparin--Required for inhibition of thrombin Thrombin Heparin (>18 monosaccharide units) Antithrombin Petitou and van Boeckel, Angew Chem Int Ed 2004; 43: 3118

3. Mechanism of Action of UFH, Fondaparinux, LMWH

4. Heparin and Clotting • 1958 at Dartmouth Medical Center • Roger Weismann (asst. professor of surgery) and Richard Tobin (surgical resident) described 20 patients who developed unexpected arterial emboli while receiving heparin

5. Heparin, Clotting, and Low Platelets • 1973—Silver, Rhodes, and Dixon • 8 patients receiving heparin noted to have low platelets, but clotting noted rather than bleeding • Their platelets clumped after exposure to heparin

6. What is HIT? • Serious complication of • Unfractionated Heparin (up to 5%) • Low molecular weight Heparin (<1%) • Both venous and arterial events • DVT most common • PE up to 25% • Acute limb occlusion (prior procedure or catheter site) • MI or CVA

7. When does it occur? • Any route or exposure to Heparin • SQ prophylaxis, IV, flushes, coated catheters • Amount required can be as small as 250u from heparin flushes or heparin coated catheters • ANY patient with 50% drop in platelet count while receiving heparin • Does not have to be abnormal plt count • E.G. 400,000200,000/ml • Does not have to present with thrombosis (“isolated HIT”)

8. HIT incidence Heparin administered to ~12 million pts/year in U.S. ~ 2.6 % Incidence overall ~120,000 pts/year will develop HIT (~60,000 w/ thrombosis) ~ 15% of patients treated with heparin >4 days showed >50% decreased in platelet counts Factors Most strongly associated with HIT Use of UFH (bovine > porcine) > LMWH (10 fold) Surgical > Medical > pregnant patients Females > Males Binds to the plasma protein antithrombin Antithrombin-heparin complex rapidly inhibits thrombin and factor Xa Only ~1/3 of heparin polymers bind and activate antithrombin

9. Definition of Heparin-Induced Thrombocytopenia • 1. A fall in platelet count to <100-150K or by 30-50% of baseline 5 or more days after starting Heparin • 2. +/- thrombotic complications • 3. Excluding other causes of thrombocytopenia • 4. Plus a + serologic test for HIT

10. Two types of HIT • Type I—non immune mediated • Platelet drop D1-4, then return to normal • Seldom less than 100,000/ml • Resolves without stopping heparin • No associated thrombosis • Also referred to as Nonimmune HAT (Heparin-associated thrombocytopenia) • Associated with nonspecific platelet activating mechanisms

11. Two types of HIT • Type II—immune mediated • Any patient with Plt < 150,000/ml or 30-50% of baseline platelet count • Platelet drop D5-14 of heparin exposure • Retreatment after prior HIT (within 3 months) may cause rapid plt drop (hours) • Significant thrombosis risk, even death • Also known as “white clot syndrome” • Median plt counts 59,000 but <15,000 seen • Also consider in patients with extension of thrombosis on Heparin or difficulty with maintaining therapeutic aPTT • Remainder of issues discussed refer to Type II

12. Pathogenesis of Immune HIT • Heparin-dependent IgG antibodies activate platelets (FcgIIa receptors) • Alpha granules of platelets release Platelet factor 4 (PF4) • Antibodies (IgG) recognize immune complexes of Heparin bound to PF4 • Immune complexes IgG+Heparin+PF4 bind to Fc receptors on platelet surface

13. Pathogenesis of Immune HIT Caiola E. Heparin-induced thrombocytopenia: how to manage it, how to avoid it. Cleve Clin J Med 2000; 67:621–624.

14. Activation of platelets by binding of immune complexes to Fc receptors Induction of tissue factor on endothelial cells Pathogenesis of Immune HIT Formation of IgG to neoepitopes on PF4 bound to heparin Generation of thrombin Warkentin, Annu Rev Med 1999; 50: 129

15. At risk populations • Cardiac surgery patients • Most likely to form HIT antibodies (50% risk) • Less than 5% of Ab + patients develop HIT • Dilutional thrombocytopenia from multiple transfusions tends to decrease by D6—persistent low platelets suggests HIT • Overall 1-2% frequency of HIT • Orthopedic patients • Only 15% form IgG antibodies • As many as 1/3 develop HIT • Overall 3-5% frequency of HIT • Explanation for population-dependent susceptibility is unknown

16. Multiple Iceberg Model of HIT thrombosis thrombocytopenia Ab formation

17. Clinical Presentations of HIT • Typical onset HIT • Heparin naïve, within 5-14 days after exposure (65% of cases) • Rapid onset HIT • Hours to days of heparin exposure in patients with prior heparin tx in last 100d (30% of cases) • Prior heparin dependent antibodies still present, amnestic response

18. Clinical Presentations of HIT

19. Clinical Presentations of HIT • Delayed onset HIT • 9-40 days after heparin withdrawal • 2-3% of HIT patients • Sent home off anticoagulants—return with new thrombotic event • High antibody titers and low/borderline platelet counts

20. Usual: DVT & PE Arterial thromboses Platelet rich thrombi “white clots” Lower limb artery occlusion > CVA > MI Unusual complications Heparin/warfarin skin necrosis Injection sites Fatty areas (breasts, buttocks and thighs) Limb ischemia syndromes Occlusion of large limb arteries (distal aorta, ileofemoral) Microemboli of small arteries/arterioles (distal limb ischemia with palpable pulse) Severe DVT  phlegmasia cerulea dolens Warfarin induced venous limb gangrene Thrombotic Complications

21. Heparin-Induced Skin Necrosis • Figure 1. A 36-year-old woman received prophylactic subcutaneous heparin injections after an elective cesarean section. On the fifth postoperative day, subcutaneous edema, redness, and pain developed at the injection site, and heparin was discontinued. The next day, central necrosis of the lesion developed, with a clear line of demarcation between the affected area and surrounding tissue (the diameter of the lesion was 20 cm). The patient did not have thrombocytopenia or thrombotic complications. She also had normal plasma concentrations of protein C and protein S. The lesion later became bullous, with subsequent necrosis of the entire lesion, and skin. Sept 5, 1996; Vol 335 (10):715

22. Other unusual complications • Acute systemic reaction • 5-30 min after IV bolus UFH • Abrupt fall plt count • Fever, chills, increased HR, HTN, flushing, N/V, CP • Sudden cardiorespiratory collapse • DIC • Low fibrinogen due to acquired ATIII and Pr C deficiency

23. Diagnosis: Clinical + Lab • Clinical: the four T’s

24. Diagnosis: Clinical + Lab Therapeutic decisions should not be delayed for the results of laboratory testing if the clinical suspicion of HIT is strong. Serum should be sent for HIT-Ig testing using a sensitive and specific functional assay (e.g., the platelet serotonin release assay), or antigen assay (e.g., PF4/heparin ELISA).

25. Management of HIT • Immediately stop all heparin (including IV flushes), including LMWH • Immediately begin treatment with a direct thrombin inhibitor (not warfarin) • Lepirudin or Argatroban (Grade 1C) • highest risk for thrombosis occurs after stopping heparin) • Continue until thrombocytopenia resolved, then begin warfarin • Overlap DTI & Warfarin for minimum of 5 days AND until INR is in target range Complete ACCP recommendations are published in Chest 2008 Jun;133(6 suppl):67S-968S

26. Management of HIT • If receiving VKA when HIT diagnosed, administer Vitamin K (Grade 1C) • Warfarin for at least 2-3 months, 3-6 mos if a thrombosis occurred. Start at low doses. • LMW heparin contraindicated; • Although fondaparinux does not appear to cross-react with HIT-Ig in vitro, its safety and efficacy in patients with HIT has not yet been established • ACCP recommends treatment of “isolated HIT” without thrombosis Complete ACCP recommendations are published in Chest 2008 Jun;133(6 suppl):67S-968S

27. Management of HIT • Obtain LE Ultrasound to evaluate for DVT • Heparin “allergy” noted in patient’s record, and sign posted at bedside • Obtain patient’s blood for confirmatory tests • ELISA for antibodies that bind to heparin/PF4 (strength of reaction (OD) important) • Platelet serotonin release assay (SRA) Complete ACCP recommendations are published in Chest 2008 Jun;133(6 suppl):67S-968S

28. Therapy of HIT • Use of heparin in patients w/ history of HIT • Probably safe if antibodies are absent by ELISA and SRA (usually disappear in ≤100 days,) • “Rapid Onset HIT” in pts with circulating antibodies, <24 hrs ( no evidence for anamnestic response) • Limit duration of exposure • Induction of HIT antibodies de novo may occur after 5-10 days, and should not be thrombogenic in the absence of heparin • Use of a GP IIb/IIIa inhibitor with DTI when DTI alone fails to relieve acute thrombosis? Complete ACCP recommendations are published in Chest 2008 Jun;133(6 suppl):67S-968S

29. Therapy of HIT • Warfarin should be avoided in acute HIT unless it is used in combination with therapeutic-dose danaparoid, lepirudin, or argatroban • Warfarin assoc w/ worsening venous thrombosis, venous limb gangrene, &/or skin necrosis when used alone or in combination with ancrod in acute HIT • Warfarin appropriate for longer term anticoagulation in pts w/ HIT and thrombosis • Warfarin should be delayed until therapeutic anticoagulation achieved, ideally until resolution of thrombocytopenia • Warfarin-associated thrombotic complications described in pts when alternative anticoagulant stopped prior to resolution of thrombocytopenia

30. Therapy of HIT • Surgical thromboembolectomy, or systemic/local thrombolysis may be appropriate for selected patients with large vessel arterial thrombo-embolism or severe pulmonary embolism, respectively. • Low-molecular-weight heparin (LMWH) should not be used in patients with HIT • LMWH is associated with treatment failure in several reports, and on occasion, has been associated with disastrous complications in patients with HIT

31. Therapy of HIT • Prophylactic platelet transfusions are not recommended in HIT • Petechiae and other clinical evidence for thrombocytopenic bleeding is uncommon in HIT • In addition, thrombotic events occurring soon after the transfusion of platelets have been reported • Platelet transfusion can be justified in thrombocytopenic patients who develop serious hemorrhagic complications

32. Therapy of HIT • Unfractionated and LMWH should be avoided in patients with a previous history of HIT • Under special circumstances, exceptions to this recommendation may be considered • For example, use of unfractionated heparin for cardiac surgery is a reasonable option for a patient with previous HIT in whom HIT antibodies are no longer detectable by sensitive and specific laboratory assay(s).

33. Parenteral Direct Thrombin Inhibitors • Lepirudin (Refludan) • Recombinant 65 amino acid polypeptide based on hirudin • Given IV to achieve aPTT 1.5-2.5* times the patient’s baseline • Half-life ~80 min, RENAL elimination • Anticoagulation effect not easily reversed • May develop antibodies that prolong the half-life and increase the aPTT (check aPTT daily) • Reports of anaphylaxis with re-exposure as high as 1/625 • Minimal prolongation of the PT (target INR 2-3 during overlap with warfarin) • Argatroban (Novastan) • Synthetic arginine analog • Interacts with active site of thrombin • Given IV to achieve aPTT 1.5-3.0 times the patient’s baseline • Half-life 40-50 min (unchanged in renal failure; increased in LIVER failure) • Prolongs PT (target INR ~4 during overlap with warfarin) *Greinacher and Warkentin recommend (Thromb. Res. 2006; 118: 165): (1) omitting bolus, decreasing initial infusion rate, and adjusting lepirudin dose to aPTT 1.5-2.0; (2) administering IV vitamin K to patients on warfarin.

34. Alternative Anticoagulants

35. Summary • Any exposure to UFH or LMW Heparin may result in HIT • Typical 50% drop in plts 5-14 days after HIT exposure • Thrombotic events associated • D/C Heparin and use alternative anticoagulant while awaiting labs • Continue DTI until normal plt count

36. References • JOHN R. BARTHOLOMEW, MD; SUSAN M. BEGELMAN, MD; AND AMJAD ALMAHAMEED, MD. Heparin-induced thrombocytopenia: Principles for early recognition and management CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 72 • SUPPLEMENT 1 APRIL 2005 • Clinical Guidelines of Thrombosis Interest Group of Canada; Principal Developers: D. Lee, T. Warkentin http://www.tigc.org/eguidelines/hit04.htm • Theodore E. Warkentin, MD. New Approaches to the Diagnosis of Heparin-Induced Thrombocytopenia. Chest. 2005;127:35S-45S. • John Kelton, MD. Heparin-Induced Thrombocytopenia, Update for 2006. Clinical Hematology and Oncology Conference 17 Feb 2006.