Heparin Induced Thrombocytopenia

Heparin Induced Thrombocytopenia Ann-Marie Liberman B.Sc.Phm., ACPR Clinical Pharmacist, Cardiac Surgery Clinical Trials Pharmacist Royal Columbian Hospital Fraser Health Disclosure Participated in research sponsored by Sanofi-Aventis Learning Objectives Describe the signs and symptoms of HIT Assess the likelihood of a patient having HIT Review the therapies for the treatment of HIT Describe the role of the pharmacist in the management of HIT 1

HIT and HITTS Antibody-mediated adverse effect Diagnosis based on clinical presentation and serology Clotting disorder, not bleeding disorder High risk for thrombosis (venous >arterial) HIT Type 2: Immune Thrombocytopenia Severe immunologic reaction Up to 5% of patients exposed to heparin Usually 5-14 days after heparin initiated or within 12 hours of reexposure platelet count decrease 50% from baseline (even if PLT > 150) Thrombosis while on or with recent exposure to UFH or LMWH exposure 2

HIT Type 1: Non-Immune Thrombocytopenia early, mild HIT, most often self-resolving with NO THROMBOSIS due to proaggregation of platelets but still functional Heparin antibodies NOT PRODUCED occurs on day 1-4 heparin therapy platelets usually > 100 x 10 9 /L heparin products can be continued HIT Mechanism Patients at Risk of HIT Risk for developing HIT High (>1%) Intermediate (0.1-1%) Low (<0.1%) Risk Factor Post op or trauma pt, especially cardiac, vascular or orthopedic surgery receiving UFH Post op pts receiving UFH flushes Post op pts receiving LMWH Medical or obstetric pts treated with therapeutic or prophylactic doses of UFH Medical or obstetrical pts treated with LMWH Crit Care Med 2006;34:2898 3

Clinical Assessment Pretest Probability Serology HIT: Diagnosis Clinical Assessment Clinical: Consider in any patient with drop in platelet count, new thrombosis or extension of thrombosis Thrombosis Venous (i.e. DVT, PE, venous limb gangrene, adrenal hemorrhage, necrosis and cerebral vein thrombosis) Arterial thrombosis (limb artery> stroke> MI>other sites) Heparin induced skin lesions (10-20%) Acute systemic reaction (25%) Decompensated disseminated intravascular coagulation (DIC) Pretest Probability 4

Potential Etiologies of Thrombocytopenia Sepsis and health-care associated infections Perioperative and postresuscitation hemodilution Drug-induced thrombocytopenia, including HIT Liver disease/hypersplenism Platelet consumption or destruction Massive transfusion Primary marrow disorder Antiphospholipid antibody syndrome/lupus anticoagulant Immune thrombocytopenia (ITP, TTP,PTP) Intravascular devices (IABP, LVAD, ECMO, pulmonary artery catheter) Crit Care Med 2006;34:2898 Pretest Probability Serology Pathologic: Platelet Activation Assays Serotonin Release Assay Gold Std 90% sensitivity, 100% specificity Immunologic Assays (Detection of HIT antibodies) Anti-PF4 assay (ELISA) - 10% false negative Particle Gel Immunoassay Heparin-Induced Thrombocytopenia. 3 rd Ed. Warkentin, ed. 5

Complications of HIT Heparin Induced Thrombocytopenic Thrombotic Syndrome (HITTS) Risk of limb amputation, organ failure Death Goal of Therapy Prevent thrombotic complications of HITTS Prompt recognition and initiation of alternative anticoagulation can reduce 30 day mortality due to thrombotic events from 25% to 12% Chest 2008; 133; 340-380 Interventions Discontinue all Heparin products and Low Molecular Weight Heparin including flushes/locks HIT assay Daily CBC LFTs U/S lower limb veins Document heparin as an allergy Chest 2008; 133; 340-380 6

Interventions Hold Warfarin until platelet count >150 If patient is already receiving warfarin, give Vitamin K 10 mg po or 5-10 mg IV Reduce risk of warfarin induced microvascular thrombosis Warfarin effect on aptt can lead to underdosing of alternative anticoagulant Chest 2008; 133; 340-380 HIT Treatment Options Argatroban Grade 1C Danaparoid Grade 1B Lepirudin Grade 1C Bivalirudin Grade 2C Fondaparinux Grade 2C Chest 2008; 133; 340-380 Danaparoid Bivalirudin Argatroban 7

Argatroban Reversible direct thrombin inhibitor Indicated for treatment of HIT and PCI with HIT Preferred in pts with renal impairment T 1/2 39-51 min Hepatic elimination adjust dose based on Child-Pugh score Argatroban Multicenter, nonrandomized, open-label, historical controlled trial HIT arm and HITTS arm Plt < 100 or 50% decrease Historical d/c heparin +/- po anticoagulants Study argatroban 2 mcg/kg/min to aptt 1.5-3 x baseline Lewis et at. Circulation 2001; 103; 1838-1843. Argatroban 1 - death, death by thrombosis, amputation, new thrombosis, bleeding 2 - Thrombocytopenia resolved with plt > 100 or maintained > 100 Lewis et at. Circulation 2001; 103; 1838-1843. 8

Argatroban Results N endpoint bleeding Argatroban 304 25.6 % (HIT) 43.8 % (HITTS) 3.1 % (HIT) 11.1 % (HITTS) Control 193 38.8 % (HIT) 56.5 % (HITTS) 8.2 % (HIT) 2.2 % (HITTS) Lewis et at. Circulation 2001; 103; 1838-1843. Danaparoid Heparinoid that inhibits factor Xa and factor IIa through antithrombin III Treatment and prophylaxis of HIT Require IV bolus T 1/2 25 hr, longer in renal failure No antidote Danaparoid Clinically probable HIT Thrombotic condition req. anticoagulation Danaparoid + warf vs dextran 70 + warf Chong, BH et al. Thromb Haemost 2001; 86: 1170-5. 9

Chong et al 2001 Danaparoid 2400 u iv bolus, 400 u/hr x 2h, 300u/hr x2 hr, 200u/hr x 5 days Dextran 70 IV infusion 1000 ml/24 hr then 500 ml/24 hr x 4 days Warfarin 10 mg x 2, 5mg x 1, then adjusted to INR 2-4 Chong, BH et al. Thromb Haemost 2001; 86: 1170-5. n Thrombotic events Chong et al. 2001 Danaparoid Dextran 70 25 17 43 36 HIT assay + Thrombocytopen ia resolution Complete res. Of thrombosis 19 23 24/43 15 15 5/36 Chong, BH et al. Thromb Haemost 2001; 86: 1170-5. Danaparoid IV 2500 units bolus, then 400 u/hr x4h, then 300 u/hr x4h, then 150-200 u/hr 750 units sc bid for prophylaxis Renally eliminated No effect on INR, PTT Anti-Xa levels can be monitored but are not recommended SAP currently Not available in US 10

Lepirudin Irreversible direct thrombin inhibitor Indicated for treatment and prevention of HIT No cross reactivity with HIT antibodies Renally eliminated T 1/2 80 min (IV), 2-3 hr (sc) T 1/2 48 hr if GFR < 15 ml/min Heparin-Induced Thrombocytopenia, 3rd ed. 2004. Lepirudin HIT 0.1 mg/kg/h IV infusion HITTS 0.4 mg/kg slow IV bolus then 0.15 mg/kg/h Reduce by 50% if renal impairment Target aptt 1.5-2.5 times baseline Monitor aptt, repeat in 4h, check twice daily Heparin-Induced Thrombocytopenia, 3rd ed. 2004. Lepirudin Prospective, multicenter study Diagnosis of HIT, excluded with renal insufficiency 0.4 mg/kg IV bolus the 0.15 mg/kg/hr Treatment 2-10 days, conversion to phenprocoumon Comparison with historical group Circulation 1999; 99: 73-80. 11

Lepirudin Circulation 1999; 99: 73-80. Lepirudin Antibodies to drug develop, causes prolonged t 1/2 Can only be used once in patient Fatal anaphylaxis can occur with initial or readministration Health Canada warning Heparin-Induced Thrombocytopenia, 3rd ed. 2004. Bivalirudin Reversible direct thrombin inhibitor Not indicated for HIT treatment Indicated for PCI, CABG T 1/2 25 min, 57 min in renal failure Metabolized by proteolysis (80%) 20% renally eliminated Chest 2008; 133; 340-380 12

0.1-0.4 mg/kg/h Bivalirudin Target aptt 1.5-2.5 times baseline Case series, no historical controls Place in therapy renal and hepatic insufficiency cardiac surgery PCI Chest 2008; 133; 340-380 Fondaparinux Selective factor Xa through antithrombin III potentiation Not indicated for HIT Indicated for ACS and STEMI, VTE prophylaxis Renally eliminated T 1/2 17-21 h, use caution in GFR < 30mL/min Chest 2008; 133; 340-380 Fondaparinux Fondaparinux vs Historical controls (DTI) 5 mg < 50, 7.5 mg 50-100 kg, 10 mg > 100 kg 2.5 mg daily if no thrombosis N=7 (F), N=6 (L), N=4 (A) Plt recovery in all fondaparinux pt, 8/10 for DTI No new thrombotic complications, major bleeds or death in any pt Ann Pharmacother 2009; 43: 1636-46 13

Fondaparinux Several case reports of fondaparinux causing HIT N Engl J Med. 2007; 356: 2653-2655. Rivaroxaban Oral Direct Thrombin Inhibitor In vitro testing of rivaroxaban with HIT antibodies Walenga et al. British J Hematol 2008; 143; 92-99. Rivaroxaban Walenga et al. British J Hematol 2008; 143; 92-99. 14

Rivaroxaban Further study required Shows potential based on biologic data Walenga et al. British J Hematol 2008; 143; 92-99. When is HIT resolved? Platelets > 150 and stable Reassess original indication for anticoagulation Initiating warfarin Plt > 150 and stable Overlap at least 5 days with anticoagulation INR target range x 2 days Begin with low doses max 5 mg daily 15

Argatroban/Warfarin switch over Warfarin therapy initiated Daily INR INR > 4 Stop argatroban and draw INR in 4 hours Immediately restart Argatroban Use INR for warfarin dosing If INR therapeutic for second day, D/C argatroban Argatroban/Warfarin switch over Typical orders: Hold argatroban daily at 0400 INR with daily bloodwork Restart argatroban as soon as bloodwork drawn DVT Prophylaxis in HIT Danaparoid 750 units sc bid Fondaparinux 2.5 mg sc daily 16

When can Heparin be reintroduced? HIT antibodies clear after ~100 days Can repeat HIT assay after 100 days Try to use other anticoagulants Cardiac surgery rechallenge with heparin or use bivalirudin Thrombocytopenia NYD Heparin in last 2 weeks Platelet count drop 50% And/or thrombotic event Exclude HIT as diagnosis, even if patient no longer receiving heparin References Chong, BH et al. Thromb Haemost 2001; 86: 1170-5. Lewis et at. Circulation 2001; 103; 1838-1843. Walenga et al. British J Hematol 2008; 143; 92-99. Crit Care Med 2006;34:2898 Warkentin ed. Heparin-Induced Thrombocytopenia, 3 rd ed. 2004. Chest 2008; 133: 340-380 Greinacher, A et al. Circulation 1999; 99: 73-80. Blackmer et al. Ann Pharmacother 2009; 43: 1636-46 Warkentin et al. N Engl J Med. 2007; 356: 2653-2655 17