HIT: A Real Threat or Artificial Epidemic?

1. HIT: A Real Threat or Artificial Epidemic? Nicholas Sadovnikoff, MD, FCCM Assistant Professor, Harvard Medical School Co-Director, Surgical Intensive Care Units Brigham and Women’s Hospital Boston, MA Kuwait City, Kuwait November 24, 2011

2. HIT: A Real Threat or Artificial Epidemic? • The answer is:

3. HIT: A Real Threat or Artificial Epidemic? • The answer is: • The former!

4. HIT: A Real Threat or Artificial Epidemic? • The answer is: • The former! • HIT represents a real threat

5. HIT: A Real Threat or Artificial Epidemic? • The answer is: • The former! • HIT represents a real threat • The dangers lie in • Failure to suspect

6. HIT: A Real Threat or Artificial Epidemic? • The answer is: • The former! • HIT represents a real threat • The dangers lie in • Failure to suspect • Failure to diagnose

7. HIT: A Real Threat or Artificial Epidemic? • The answer is: • The former! • HIT represents a real threat • The dangers lie in • Failure to suspect • Failure to diagnose • Failure to manage correctly

8. HIT: What are the facts? • Epidemiology • Pathophysiology • Diagnosis • Treatment/management • Prognosis

9. HIT: What are the facts? • Epidemiology • Incidence difficult to measure with precision due to difficulties in diagnosis • Estimates vary from 0.5% to 5% (mostly < 2%) • Higher with unfractionated heparin • Higher with patients exposed to CPB • Higher with bovine (lung) vs. porcine (intestine) source

10. HIT: What are the facts? • Pathophysiology • Heparin administration results in the formation of heparin-PF4 complexes • Antibodies (IgG) develop that bind these complexes • The resulting bound complexes • Activate platelets causing release of more PF4 and other prothrombotic substances • Cause clearance of platelets by the reticuloendothelial system

11. HIT: What are the facts?

12. HIT: What are the facts? • Diagnosis – two distinct clinical syndromes • “Type 1” – Rapid drop in platelet count upon exposure to heparin (24 – 48 hours) • Not associated with thrombotic complications • Anti-PF4/heparin antibody testing is negative • Resolves spontaneously without discontinuation of heparin

13. HIT: What are the facts? • Diagnosis – two distinct clinical syndromes • “Type 2” – Platelet count decline occurs > 4 days after heparin exposure • Anti-PF4/heparin antibody testing is positive • High risk of thrombotic complications (venous > arterial)

14. HIT: How to NOT diagnose it? • Other causes of thrombocytopenia • Bacterial infection • Bone marrow disease (leukemia, myelodysplastic disorders etc.) • Critical illness (typically parallels anemia of critical illness) • Immune thrombocytopenia purpura (ITP) • Thrombotic thrombocytopenia purpura (TTP) • Disseminated intravascular coagulation (DIC) (may coexist with HIT) • Post surgical/dilutional (nadir at 2 days postoperatively) • Drug-induced (the list is EXTENSIVE, but remember vancomycin)

15. HIT: How to NOT diagnose it? • Quinine/Quinidine group • Quinine • Quinidine • Heparin • Regular unfractionated heparin • Low molecular weight heparin • Gold salts • Antimicrobials • Antimony containing drugs • Stibophen • Sodium stibogluconate • Cephalosporins • Cephamandazole • Cefotetan • Ceftazidime • Cephalothin • Ciprofloxacin • Clarithromycin • Fluconazole • Fusidicacid • Gentamicin • Nilidixic acid • Penicillins • Ampicillin • Apalcillin • Methicillin • Meziocillin • Penicillin • Piperacillin • Pentamidine • Rifampin • Sulpha group • Sulfamethoxazole • Sulfamethoxypyridazine • Sulfisoxazole • Suramin • Vancomycin • Anti-inflammatory drugs • Acetaminophen • Salicylates • Aspiring • Diflunisal • Sodium amiosalicylate • Sulfasalazine • Diclofenac • Fenoprofen • Ibuprofen • Indomethacin • Meclofenamate • Mefanamic acid • Naproxen • Oxyphebutazone • Phenylbutazone • Piroxicam • Sulindac • Tolmetin • Cardiac medications and diuretics • Digoxin • Digitoxin • Amiodarone • Procainamide • Alprenolol • Oxprenolol • Captopril • Diazoxide • Alpha-methyldopa • Acetazolamide • Chlorothiazide • Chlorthalidone • Furosemide • Hydrochlorothiazide • Sprinolactone • Benzodiazepines • Diazepam • Anti-epileptic drugs • Carbamazepine • Phenytoin • Valproic acid • H2-antagonists • Cimetidine • Ranitidine • Sulfonylurea drugs • Chlorpropamid • Glibenclamide • Iodinated contrast agents • Retinoids • Isotretinoin • Etretinate • Anti-histamines • Antazoline • Chlorpheniramine • Illicite drugs • Cocaine • Heroin • Qunine containment • Antidepressants • Amitriptyline • Desipramine • Doxepin • Imipramine • Mianserine • Miscellaneous drugs • Tamoxifen • Actinomycin-D • Aminoglutethimide • Danazole • Desferrioxamine • Levamizole • Lidocaine • Morphine • Papaverine • Ticlopidine

16. HIT: How TO diagnose it? • Risk factors • Heparin for > 4 days • Recent heparin exposure (< 100 days) • Unfractionated heparin (> LMWH) • Post-surgical (> medical > OB) • Dose • Immunizing: prophylactic > therapeutic • Manifesting: therapeutic > prophylactic > flushes • Gender • Female > male

17. HIT: How TO diagnose it? • Clinical features – the “4 T’s” • Thrombocytopenia • Timing • Thrombosis • AlTernate cause possible

18. HIT: How TO diagnose it?

19. HIT: How TO diagnose it? • “4 T’s” clinical scoring • 0-2 points - very low likelihood • 3-5 points - moderate risk • 6+ points - high risk

20. HIT: How TO diagnose it? • Laboratory testing • Platelet count monitoring • Clinical risk • “4 T’s” • Clinical setting • ICU vs. floor vs. outpatient

21. HIT: How TO diagnose it? • Laboratory testing • ELISA testing for antibodies to PF4/heparin complexes • Serotonin release assay

22. HIT: How TO diagnose it? • Laboratory testing • ELISA testing for antibodies to PF4/heparin complexes • Sensitivity is good (83 - 97%) BUT • Specificity is only fair • Hence a negative test is reassuring, but a positive test is not definitively diagnostic • ELISAs that measure IgG only are superior to those that measure IgM and IgA class antibodies

23. HIT: How TO diagnose it? • Laboratory testing • Serotonin release assay – gold standard • Measures platelet activation in response to PF4/heparin complexes • Sensitivity and specificity are both high • Requires radioisotope reagents • Expensive and cumbersome • Not widely clinically available

24. HIT: How to treat it? • It is NOT SUFFICIENT to stop the heparin • But (for pity’s sake) DO stop the heparin

25. HIT: How to treat it? • It is NOT SUFFICIENT to stop the heparin • But (for pity’s sake) DO stop the heparin • Alternate anticoagulant/antithrombotic therapy is mandatory, BUT

26. HIT: How to treat it? • It is NOT SUFFICIENT to stop the heparin • But (for pity’s sake) DO stop the heparin • Alternate anticoagulant/antithrombotic therapy is mandatory, BUT • Low molecular weight heparin is not safe

27. HIT: How to treat it? • It is NOT SUFFICIENT to stop the heparin • But (for pity’s sake) DO stop the heparin • Alternate anticoagulant/antithrombotic therapy is mandatory, BUT • Low molecular weight heparin is not safe • Avoid early initiation of warfarin therapy

28. HIT: How to treat it? • Direct thrombin inhibitors: • Lepirudin • Bivalirudin • Argatroban • And several more about to be approved • Factor Xa inhibitors • Fondaparinux

29. HIT: How to treat it? • Warfarin therapy • Is warranted long-term (3-6 months) BUT

30. HIT: How to treat it? • Warfarin therapy • Is warranted long-term (3-6 months) BUT • May promote thrombosis acutely

31. HIT: How to treat it? • Warfarin therapy • Is warranted long-term (3-6 months) BUT • May promote thrombosis acutely • Therefore should not be initiated until platelet count has recovered to normal (>150K)

32. HIT: What about recurrence? • No apparent amnestic response

33. HIT: What about recurrence? • No apparent amnestic response • Patients with a history of HIT who are at least 100 days past heparin exposure AND

34. HIT: What about recurrence? • No apparent amnestic response • Patients with a history of HIT who are at least 100 days past heparin exposure AND who have negative anti-PF4/heparin assays may receive heparin in a routine manner

35. HIT: Take Home Messages • High index of suspicion when clinically likely (think of the “4 T’s”)

36. HIT: Take Home Messages • High index of suspicion when clinically likely (think of the “4 T’s”) • Not sufficient to discontinue heparin (risk of thrombotic events)

37. HIT: Take Home Messages • High index of suspicion when clinically likely (think of the “4 T’s”) • Not sufficient to discontinue heparin (risk of thrombotic events) • Do not start warfarin therapy until the platelet count has recovered

38. HIT: Take Home Messages • High index of suspicion when clinically likely (think of the “4 T’s”) • Not sufficient to discontinue heparin (risk of thrombotic events) • Do not start warfarin therapy until the platelet count has recovered • A previous diagnosis of HIT does not preclude heparin therapy if last exposure is >100 days and anti PF4/heparin test is (-)

39. Thank you for your attention