1. Heparin-Induced Thrombocytopenia Farzaneh Dastan Assistant Professor of Pharmacotherapy, Pharm D, BCPS SBMU

2. Case  A 64-year-old woman  Hospitalized with endocarditis  Condition is clinically stable while she is receiving intravenous antibiotic agents  Decrease in platelet count from 161,000 per cubic millimeter on day 7 of hospitalization to 60,000 per cubic millimeter on day  Receiving low-molecular weight heparin at a dose of 40 mg per day since admission.  How should her case be further evaluated and treated?

3. Epidemiology  1 in 5000 hospitalized patients  Incidence rates of 1 to 3%: reported after cardiac surgery.  Thromboembolic complications: 50% of patients with confirmed HIT.  Most frequent complications: Venous thrombosis of the large vessels of the lower limbs and pulmonary embolism followed by peripheral arterial thrombosis and then stroke;  Myocardial infarction: uncommon  Thrombotic complications may also affect other vessels, including the cerebral sinus or splanchnic veins.

4. Heparin-associated Thrombocytopenia (HAT)  Nonimmune heparin-associated thrombocytopenia  Traditionally called type I HIT  Mediated by direct interaction between heparin and circulating platelets, causing platelet clumping or sequestration.  Self-limiting thrombocytopenia  Affects 10% of patients receiving heparin  Within the first 72 hours after heparin administration,  Platelet counts do not drop below 100,000/mm  Normalizes once the heparin is ceased

5. Heparin Induced Thrombocytopenia

6. Immediate Onset  who received within the previous 90 days (especially, ≤30 days), persistent circulating (PF4)– heparin antibodies  start abruptly on reexposure to heparin (rapid- onset HIT)  anaphylactoid reaction within 30 minutes after a heparin bolus

7. Delayed onset  Develops or worsens after heparin has been discontinued.  These patients can present with thrombosis up to 3 weeks after heparin exposure

8. Spontaneous or autoimmune HIT  Rare but often catastrophic form of HIT  Develops in the absence of heparin exposure  Most often after major surgery (especially knee replacement) or recent infection.  In contrast to typical HIT, in which the platelet count increases within 2 to 5 days after the start of an alternative anticoagulant  Autoimmune HIT may persist for weeks.

9. HIT  Occurs 5–10 days after receiving heparin  Median platelet count between 50 and 80*10 9 L  Dropped by 50%  Platelet count starts to rise 2–3 days after discontinuing heparin  Returns to normal within 4–10 days  Antibody disappears within 2–3 months after cessation of heparin therapy

10. HIT Criteria  (a) thrombocytopenia (ie, a drop of the platelet count to 50% from the patient’s baseline  (b) exclusion of other causes of thrombocytopenia (such as cancer, sepsis or chemotherapy)  (c) resolution of thrombocytopenia after cessation of heparin

12. Strategies & Evidence

18. Risk of HIT:

19. Diagnosis

21. Treatment  Key interventions:  Prompt cessation of heparin (if still being administered)  Initiation of an alternative anticoagulant at a therapeutic dose

23. Argatroban  After discontinuation: aPTT returns to normal within 2 hours  Standard starting dose is 2 microg/kg per minute by continuous intravenous infusion Aadjusted to maintain the aPTT at 1.5–3 times baseline and not to exceed 100 seconds  Metabolized by the liver  Reduced dose and adjustment in; impaired liver function, critically ill patients, or cardiac surgery.  aPTT at 4-hour intervals after drug initiation or dose change  Dose adjustment is not required in the presence of isolated renal impairment

25. Bivalirudin  0.15–0.2 mg/kg per hour  Adjusted to achieve an aPTT 1.5–2.5 times  Doses of 0.14 mg/kg per hour in patients with hepatic dysfunction  0.03–0.05 mg/kg per hour in patients with renal or combined hepatic and renal dysfunction  doses of 0.04–0.03 mg/kg per hour in those receiving continuous renal replacement therapy

26. Lepirudin and desirudin  Lepirudin: approved for use in HIT  Desirudin: Data limited  dose of either 15 or 30 mg subcutaneously every 12 hours suggested

27. Danaparoid  Analysis of outcomes:  Rate of treatment success (platelet count recovery without new thrombosis and absence of major adverse events requiring drug cessation): higher than 90%.  Renally metabolized  Approved for treatment of HIT  No longer marketed in the United  Drug shortages have limited its availability  Subcutaneously or intravenously  Does not cross the placenta.

28. Fondaparinux  Long half-life allows once-daily dosing  Monitored by the use of anti-factor Xa assay  In pregnant women with HIT  It is worth noting that HIT developed in a few cases with the use of fondaparinux  Easier than argatroban to use outside the intensive care unit.

29.  Exacerbations of HIT reported infrequently  small percentage have true in vivo and in vitro crossreactivity  If manifestations of HIT worsen despite sufficient levels of anti–factor Xa activity, treatment should be switched (e.g., to argatroban)

30. Non-vitamin K Antagonist Oral Anticoagulants (NOACs)  Recommended by the European Society of Cardiology  Orally using fixed dosing  Need little attention regarding monitoring and drug– drug interactions  Well proven in the management of venous and arterial thromboembolism  Can be continued long term without conversion to warfarin, which needs platelet count recovery  Short course of parenteral argatroban followed by NOACs for the treatment of patients with HIT is safe and effective

31. NOACs

34. RENAL REPLACEMENT THERAPY  Argatroban and danaparoid recommended for patients with HIT who need renal replacement therapy  Use of regional citrate is suggested for patients with a past history of HIT

35. PREGNANCY  For pregnant women with acute or subacute HIT:  Danaparoid has been suggested  lepirudin or fondaparinux may be considered if danaparoid not available

36. Warfarin  Vitamin K antagonists (e.g., warfarin and phenprocoumon) should not be given until HIT has abated  Platelet count has increased to >150,000 per cubic millimeter at a stable plateau for 2 consecutive days  Increase the risk of venous limb gangrene and limb loss by decreasing the level of protein C  Overlap with an alternative anticoagulant is needed  Warfarin should be slowly introduced at a dose of not more than 5 mg to avoid large loading doses.

37. SWITCHING TO AN ORAL ANTICOAGULANT  Avoidance of vitamin K antagonists (VKA) such as warfarin  Can induce skin necrosis owing to rapid depletion of protein C  Once HIT is confirmed, patient receiving VKA should be held and (INR) should be reversed by vitamin K.  Platelet recovery to normal level is a required to initiate VKA  Warfarin should be slowly introduced at a dose of not more than 5 mg to avoid large loading doses.

38. DURATION OF ANTICOAGULATION FOR HIT  Continued for 4–6 weeks in patients with confirmed isolated HIT  For a minimum of 12 weeks in patients associated with thromboembolic events.

39. IVIg  High-dose intravenous immune globulin G  Dose of 2 g per kilogram of body weight over a 2-day period  By blocking platelet Fcγ receptors  Limited data: may be an option (along with anticoagulation) in patients at high risk for thrombosis and bleeding (e.g., those who are pregnant or have sinus-vein thrombosis complicating HIT) or in patients who have autoimmune HIT

40. In patients with a history of HIT who require cardiac surgery:  Postponing surgery until platelet-activating anti– PF4–heparin antibodies disappear  Using heparin intraoperatively  Removal of platelet-activating anti–PF4–heparin antibodies by plasmapheresis,  Bivalirudin is a compatible anticoagulant for cardiac surgery if platelet-activating anti–PF4– heparin antibodies are present

41.  Prophylactic platelet transfusions avoided  Risk of bleeding is very low  Increase the risk of thrombosis

42. Guidelines  ACCP and national European guidelines recommend the use of a scoring system  Need for therapeutic-dose anticoagulation in cases of acute HIT  ACCP: assessing patients at high risk (>1%) for HIT every 2 to 3 days between day 4 and day 14

43. THANKS FOR YOUR ATTENTION