1. The HITS Keep Coming Marc J. Kahn, MD, MBA, FACP Peterman-Prosser Professor Tulane University School of Medicine New Orleans, LA

2. Clinical Case You are asked to see a 43 year old women following bilateral elbow fractures with new onset thrombocytopenia. The patient suffered a fall in a dog park and sustained bilateral radial and ulnar fractures requiring open reduction. She has a history of antiphospholipid antibody syndrome and is maintained on warfarin. Her platelet count fell from 290K to 50 K over five days. She is asymptomatic.

3. Definitions Lupus anticoagulant: prolongation of a clotting time (aPTT, DRVVT) Antiphospholipid Antibody: antibodies to cardiolipin, phospholipid, or  2GP1 APLA Syndrome: thrombosis with APLA

4. Lupus AnticoagAnti cardiolipin AB Anti  2GP1 Anti phospholipid AB

5. Antiphospholipid Antibody Syndrome High rate of arterial and venous thrombosis – 32% DVT – 9% PE – 13% CVA – 8% fetal loss 5-15% warfarin failure in preventing recurrence Ann Rheum Dis. 2011

6. Management of APLAS INR 2.0 to 3.0 INR 3.0 to 4.0 is NOT better* Indefinite anticoagulation *J Thromb Haemost. 2005;3:848-53.

7. Thrombocytopenia and APLAb Estimated that up to 25% patients with thrombocytopenia may have APLAb Nearly 25% patients with APLAb have thrombocytopenia

8. Our Patient’s Platelets

9. DDx of Thrombocytopenia Drug induced Heparin Induced Sepsis/DIC TTP Catastrophic APLA syndrome Not routine APLA due to sudden drop

10. Copyright © 2011 American Society of Hematology. Copyright restrictions may apply. John Lazarchick, ASH Image Bank 2011; 2011-1376 Peripheral smear

11. Ruled out diagnosis TTP DIC/Sepsis Catastrophic APLAS

12. Heparin Induced Thrombocytopenia Occurs 5 or more days after heparin therapy Can occur faster in patients with prior exposure (Warkentin NEJM 2001;344:1286) estimated to occur in up to 3% patients treated with unfractionated heparin 24-fold increased relative risk of thrombosis

13. Representative Case of Typical-Onset Heparin-Induced Thrombocytopenia, Followed by a Rapid-Onset Episode. Warkentin TE, Kelton JG. N Engl J Med 2001;344:1286-1292.

14. HITT pathophysiology P PF4 + heparin IgG Platelet activation, aggregation and clearance

15. Aster RH. N Engl J Med 1995;332:1374-1376.

16. Platelet factor 4 (PF4) Expressed in megakaryocytes stored in platelet  -granules highest heparin affinity of any platelet basic protein derived compound physiologic function remains unknown – ? Role in thrombosis – ? Role in platelet recovery after radiation chemokine class of molecule

17. 4 T’s Thrombocytopenia (>50% fall) Timing (5 to 10 days after heparin) Thrombosis (new) Thrombocytopenia from other causes Very HIGH negative predictive value J Thromb Haemost 2006;4:759

18. HIT workup ELISA for heparin/platelet factor 4 antibodies – Sensitivity = >90% – Specificity = 24-90% Functional serotonin release assay – Sensitivity > 90% – Specificity>90%

19. 14 C-serotonin release assay + 14 C-serotonin+ pt. serum + heparin DPM [heparin] 0.10.2

20. Management of HIT Need for anticoagulation AVOID WARFARIN as initial therapy Argatroban Lepirudin Bivalirudin (off-label) Fondaparinux (off-label)

21. Warfarin and HITT Associated with venous limb gangrene – Warkentin, et al. Ann Int Med 1997;127:804. FactorHalf-life (hrs) II72 VII8 IX24 X39 Protein C14 Protein S42

22. Argatroban Small molecule direct thrombin inhibitor Licensed by FDA for HIT in 2000 IV infusion Follow aPTT Also increases PT Metabolized by the liver

23. Lepirudin (Refludan®) Direct thrombin inhibitor Recombinant hirudin from medicinal leech IV infusion Follow aPTT Cleared by the kidney

24. Bivalirudin (Angiomax®) Direct thrombin inhibitor Synthetic congener of naturally occurring leech anticoagulant IV infusion Cleared by kidney Follow aPTT Not FDA approved for treatment of HIT

25. Fondaparinux (Arixtra®) Synthetic pentasaccharide Xa inhibitor subQ daily injection Renal excretion If monitoring necessary, anti Xa assay Not FDA approved for treatment of HIT

26. Low molecular weight heparin antithrombin Factor Xa Thrombin Unfractionated heparin Low mol wt heparin

27. Low molecular weight heparins Less likely to cause HIT than UFH But, in one study, 62% of HIT cases caused by dalteparin (Semin Thromb Hemost. 2011;37:653) Best avoided in setting of HIT

28. Thrombosis in hospitalized patients HIT APLA Syndrome Trauma Brain injury Pelvic surgery Orthopedic surgery Pregnancy Cancer

29. VT Prevention in Medical Patients Importance of risk stratification No difference in outcomes between LMWH and UFH Mechanical prophylaxis provided no benefit with harm in stroke patients Ann Int Med. 2011;155:602.

30. Platelet transfusion Bleeding very uncommon in HIT Transfused platelets can cause aggregation and thrombosis Platelet transfusions are to be avoided in HIT unless significant bleeding

31. Back to the Patient Heparin-PF4 ELISA NEGATIVE Serotonin Release Assay POSITIVE Clinically consistent with HIT Treated with Fondaparinux When to start warfarin?

32. Platelet counts

33. Patient Warfarin started when platelet count normalized Fondaprinux stopped when INR >3.0 Patient D/C from hospital without thrombosis or bleeding Returned to work on warfarin

34. How often do we need to monitor INR?

35. Warfarin monitoring every 12 weeks is not inferior to monitoring every 4 weeks in patients on stable warfarin doses. Schulman S, Parpia S, Stewart C, et al. Warfarin dose assessment every 4 weeks versus every 12 weeks in patients with stable international normalized ratios: a randomized trial. Ann Intern Med. 2011;155(10):653-9,

36. 12 week monitoring Patients stable for 6 months Otherwise uncomplicated patients

37. Pearls Antiphospholipid antibodies increase risk for arterial and venous thrombosis Typical patient with APLAS requires INR 2.0 to 3.0 Clinical suspicion important in diagnosis HIT AVOID WARFARIN with acute HIT HIT requires anticoagulation

38. Questions