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Management of Heparin Induced Thrombocytopenia

Management of Heparin Induced Thrombocytopenia. I-Wen Chang, MD March 30, 2004 Resident Grand Rounds. “Isolated” HIT. 74 year-old man with exertional chest pain Diagnosed with 3 vessel CAD and aortic aneurysm Baseline platelet count: 210,000 Day 1:CABG x 3 and aortic graft

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Management of Heparin Induced Thrombocytopenia

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  1. Management of Heparin Induced Thrombocytopenia I-Wen Chang, MD March 30, 2004 Resident Grand Rounds

  2. “Isolated” HIT • 74 year-old man with exertional chest pain • Diagnosed with 3 vessel CAD and aortic aneurysm • Baseline platelet count: 210,000 • Day 1:CABG x 3 and aortic graft • Post-Op: Atelectasis, slow to wean from ventilator • Arterial line maintained with heparin flushes

  3. “Isolated” HIT (cont’d) • Day 6: Platelet count: 65K • All heparin stopped • ELISA positive for HIT • Dopplers, arterial and venous 4 extremities all negative • Day 7: Platelet count: 80K • Day 8: Clinically improved • Patient extubated • Platelet count:105K

  4. “Isolated” HIT (cont’d) • Day 9 – Platelets 119K • Hematologist sign off case • Transfer to floor ordered • Later that day: fatal cardiac arrest due to acute graft occlusion

  5. HIT: How to treat??

  6. Heparin • Naturally occurring mucopolysaccharide • Binds and inactivates antithrombin-III • Recall that AT-III acts to neutralize serine protease, especially Factor Xa, thus inhibiting the generation of thrombin

  7. The Coagulation Cascade

  8. Type I HIT • 10 – 20 % frequency • Timing of onset 1-4 days • Nadir platelet count 100,000/uL • Not immune mediated • No thromboembolic sequelae • No hemorrhagic sequale • Observant management with continuation of heparin

  9. Heparin induced thrombocytopenia (HIT or HITT) Definition HIT is a serious immune-mediated syndrome in which the administration of heparin is associated with: - Thrombocytopenia - The generation of heparin dependent antibodies (typically IgG) - A high risk for thrombosis causing significant morbidity and mortality

  10. Heparin induced thrombocytopenia Clinical Presentation • Following the initiation of heparin: • Thrombocytopenia observed 5-14 days later; or may occur sooner with previous heparin exposure • Platelet count < 100,000/uL or • Platelet count 50% of baseline (preheparin)

  11. Heparin induced thrombocytopenia • 30% to 50% of patients with untreated HIT will have a thrombotic complication within 30 days Warkentin TE, Kelton JG. Am J Med. 1996;101:502-507.

  12. Pathophysiology of HIT • Presence of IgG antibodies that recognize PF4/heparin complexes on platelet surfaces and vascular walls • Binding of PF4/heparin complexes on platelets • Antibodies activate platelets via Fc receptor • Activated platelets release microparticles with prothrombotic activity

  13. Pathogenesis of HIT

  14. Laboratory testing for HIT

  15. Laboratory testing • There is no Gold Standard in diagnostic testing; HIT requires a clinical diagnosis

  16. HIT:Diagnostic Overview • Strongly consider HIT when: • Platelet count falls within correct temporal aspects: • 30% - 50% from baseline and/or • <150,000 • New thrombotic or thromboembolic event occurs • Absolute platelet count is not sole criterion for diagnosis: platelet nadir can remain in normal range in patients with HIT • Do not delay treatment: laboratory assays are only confirmatory

  17. HIT has occurred with all types of heparin

  18. HIT: Tip of the Iceberg • Thrombosis can occur in 30% to 80% of patients who develop asymptomatic thrombocytopenia • Asymptomatic thrombocytopenia can occur in 30%-50% of patients who develop HIT antibodies • HIT antibody is detectable in up to 10% of all patients receiving heparin and approx 50% of CABG patients

  19. Frequency of Clinical Sequelae in HIT Warkentin TE, Kelton JG. Am J Med

  20. Summary • HIT is a relatively common, often under-recognized, potentially devastating complication of heparin therapy • Diagnosis is based upon clinical suspicion • Treatment of HIT should not rely on laboratory confirmation • Untreated patients are at a high risk for having a thromboembolic complication

  21. HIT: Treatment Paradoxes • Clotting disorder, not bleeding disorder • Platelet transfusion can increase thrombosis risk • Simply stopping heparin may not prevent thrombosis • Warfarin contraindicated as acute monotherapy

  22. Alternative anticoagulants for treatment of HIT Agents approved for treatment of HIT • Danaparoid sodium (Orgaran) • Lepirudin (Refludan) • Argatroban (Argatroban or Novastan)

  23. Danaparoid sodium(Orgaran) • Inhibits Xa activity. Renal metabolism • Potential for cross reactivity (10-20%) with heparin antibodies • Withdrawn from US market in April 2002 • Approved for treatment and prevention of HIT-associated thrombosis in EU, Canada, New Zealand, Australia

  24. Lepirudin (Refludan) • Approved in USA for treatment of HIT-associated thrombosis • Dosing: bolus 0.4 mg/kg; infusion 0.15mg/kg/h (target aPTT 1.5-2.5 x baseline) • Renal excretion • T1/2 rises considerably higher in renal failure • Anti-hirudin antibodies (40-60%) that are usually not clinically significant • Rare cases of anaphylaxis reported post lepirudin bolus

  25. The Coagulation Cascade

  26. Lepirudin: Clinical Trials Greinacher A. et al. Recombinant hirudin (lepirudin) provides safe and effective anticoagulation in patients with heparin induced thrombocytopenia. Circulation. 1999;99(1):73-80. (HAT-1) Greinacher A. et al. Lepirudin for parenteral anticoagulation in patients with heparin induced thrombocytopenia. Circulation. 1999;100(6):587-593. (HAT-2) Greinacher A. et al. Heparin induced thrombocytopenia with thromboembolic complications. Blood. 2000;96:846-851. (Meta-analysis)

  27. LepirudinDesign of clinical trials • Prospective, intent-to-treat analysis with a historical control group • Inclusion criteria: • Clinical diagnosis of HIT based on platelet count with or w/o new TECs during heparin treatment AND • Laboratory confirmation of the presence of HIT antibodies (caused a treatment delay of 1.5 to 1.9 days) • Patients with severe renal dysfunction were enrolled in HAT-2, but were excluded from HAT-1

  28. Lepirudin: Patient Population

  29. Lepirudin Trial Results: Laboratory Outcomes in Patients with Baseline TECs HAT-1 HAT-2 Number of evaluable patients n=55 n=60 Effective anticoagulation 81.8% 75% Platelet recovery 90.9% 95%

  30. Lepirudin Clinical Efficacy:Results of HAT-1 and HAT-2 Cumulative Combined Incidence of Death, Limb Amputation, and New TECs

  31. Lepirudin Clinical Efficacy: Results of a Meta-analysis (HIT with TECs)

  32. Lepirudin:Clinical Events by Study Interval Period Relative to Onset of Lepirudin Adapted from Greinacher A et al. Blood

  33. Lepirudin:Hemorrhagic Adverse Events • In HAT-1 and HAT-2, the most common adverse event was bleeding, mostly minor • Bleeding events requiring transfusion were similar to control • No intracranial bleeds occurred in either study

  34. Lepirudin Therapy:Transition of Oral Anticoagulation • Do not rely on warfarin alone until HIT is adequately controlled • Allow several days for warfarin to attain its therapeutic effect • Do not discontinue lepirudin until • INR is consistently >2.0 • Absence of new TECs • Platelet recovery • Minimal effect on INR

  35. Summary of Lepirudin Studies • Lepirudin is effective in decreasing the combined risk of death, limb amputation and new TECs in all HIT (HIT and HITT) patients based on HAT-1 • Patients treated with lepirudin were effectively anticoagulated and achieved rapid platelet count recovery • An adverse HIT-associated clinical event is most likely to occur in first 2 days between the time of clinical diagnosis of HIT and the initiation treatment

  36. Argatroban • Approved in the USA for both prophylaxis and treatment of HIT-associated thrombosis • Dosing: 2ug/kg/min, w/o initial bolus (target aPTT 1.5-3 x baseline) • Hepato-biliary excretion • Argatroban increases INR; higher therapeutic range required during overlap argatroban/warfarin

  37. Mechanism of Argatroban

  38. Clinical Studies of Argatroban Lewis BE et al. Argatroban Anticoagulant Therapy in Patients with Heparin-Induced Thrombocytopenia. Circulation. 2001;103:1838-1843. (ARG-911 study) Lewis BE et al. Argatroban Anticoagulation in Patients with Heparin-Induced Thrombocytopenia. Arch Intern Med. 2003;163:1849-1856. (ARG-915 study)

  39. Clinical Trials of ArgatrobanStudy Design • Prospective, historically controlled • Inclusion criteria – acute HIT not required • Thrombocytopenia (<100,000) on heparin OR • A 50% reduction from preheparin platelet counts with no explanation besides HIT OR • Prior hx of positive HIT antibody even in the absence of thrombocytopenia or heparin challenge • Laboratory confirmation not required

  40. Argatroban-911:Patient Population HIT HITT

  41. Clinical Trials of ArgatrobanStudy Design • Primary composite endpoint: • Death (all-cause), amputation (all-cause), or new thrombosis within 37 day study period • Secondary endpoints: • Individual components of the composite endpoint • Resolution of thrombocytopenia • Achievement of adequate anticoagulation

  42. Clinical Trials of ArgatrobanStudy Design • Safety endpoint: • Major bleeding: Overt with a hemoglobin decrease > 2 g/dL, leads to a transfusion of > 2 units, intracranial, retroperitoneal, or into a major prosthetic joint • Minor bleeding: overt but fails criteria for major bleeding

  43. Argatroban-911:Clinical Trial Results (HIT Arm)

  44. Efficacy results for Argatroban Secondary endpoints (ARG-911 HIT Arm) Both secondary endpoints achieved statistical significance between control vs argatroban treated HIT patients

  45. Argatroban-911:Clinical Trial Results (HITT Arm)

  46. Efficacy results for Argatroban Secondary endpoints (ARG-911 HITT Arm) Both secondary endpoints achieved statistical significance between control vs argatroban treated HIT patients

  47. Efficacy results of argatroban Secondary endpoint(ARG-911) • Anticoagulation effect • The mean dose of argatroban administered was 2 ug/kg/min • 76% of HIT patients and 86% of HITT patients achieved a target aPTT by first assessment (within 3-5 hours of argatroban initiation) • Resolution of thrombocytopenia • 53% of HIT patients and 58% of HITT patients had a recovery of platelet count by day 3 (>100,000 uL or >1.5 times baseline) • Bleeding • No difference in bleeding rates

  48. Argatroban Therapy:Transition to Oral Anticoagulation • Do not rely on warfarin alone until HIT is adequately controlled • Argatroban increases INR • Do not discontinue argatroban until • INR>4.0 • Absence of new TECs • Platelet recovery • Obtain INR 4-6 hours after argatroban discontinuation • Reinitiate argatroban if INR falls below therapeutic range

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