Heparin Induced Thrombocytopenia.ppt

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Heparin Induced Thrombocytopenia.ppt

  1. 1. Heparin-Induced Thrombocytopenia
  2. 2. Learning Objectives <ul><li>Understand the etiology and pathogenesis of Heparin-Induced Thrombocytopenia </li></ul><ul><li>Be able to differentiate the two types of HIT; Type I and Type II. </li></ul><ul><li>Recognize the signs and symptoms of Heparin-Induced Thrombocytopenia and institute appropriate treatment </li></ul><ul><li>Gain the knowledge necessary to minimize the occurence heparin-induced thrombocytopenia. </li></ul>
  3. 3. Case Question <ul><li>55 yo Female patient with history of HTN, Osteoarthritis is s/p Right knee replacement POD #6. The primary service noticed a platelet count of 50,000 today (on admission it was 200,000). You suspect HIT, and start Argatroban. You also send serological work-up for HIT. What is the next important step? </li></ul>
  4. 4. Case Question <ul><li>A) Immediately start Coumadin with Argatroban </li></ul><ul><li>B) Lower extremity Doppler </li></ul><ul><li>C) V/Q scan </li></ul><ul><li>D) Nothing currently indicated </li></ul>
  5. 5. Case Answer <ul><li>A) Immediately start Coumadin with Argatroban </li></ul><ul><li>B) Lower extremity Doppler </li></ul><ul><li>C) V/Q scan </li></ul><ul><li>D) Nothing currently indicated </li></ul>
  6. 6. Definition of HIT <ul><li>Heparin-induced thrombocytopenia is an antibody mediated pro-thrombotic disorder. </li></ul><ul><li>Diagnosis can be difficult. </li></ul>
  7. 7. Heparin-Induced Thrombocytopenia HIT Type I HIT Type II
  8. 8. Classificaiton of Type I and Type II HIT <ul><li>Type I HIT </li></ul><ul><li>Non-immune </li></ul><ul><li>Decrease in platelets is b/w 10-30,000/ml </li></ul><ul><li>Do not discontinue heparin </li></ul><ul><li>Type II HIT </li></ul><ul><li>Focus of this talk </li></ul><ul><li>Immune </li></ul><ul><li>Decrease in platelets by 50% or less than 150,000 </li></ul><ul><li>Heparin needs to be stopped </li></ul><ul><li>Alternative anticoagulation needs to be started </li></ul>
  9. 9. Type I HIT <ul><li>Non-immune </li></ul><ul><li>Platelet drop due to direct effect of heparin on platelet activation </li></ul><ul><li>Of no clinical consequence </li></ul><ul><li>Chong BH and Castaldi Pa. Platelet proaggregating effect of heparin: Possible mechanism for non-immune heparin associated thrombocytopenia . Aust N Z J Med 1986. </li></ul>
  10. 10. Arepally G and Ortel T. Heparin-Induced Thrombocytopenia. The New England Journal of Medicine.
  11. 11. Schematic of HIT ( TYPE II ) immune activation
  12. 12. A Theory for Thrombosis <ul><li>Formation of platelet plug </li></ul><ul><li>HIT antibodies also bind to endothelial cells  endothelial cell injury </li></ul><ul><li>Blank M, Shoenfeld Y, Tavor S, et al. Anti-platelet factor 4/heparin antibodies from patients with heparin-induced thrombocytopenia provoke direct activation of microvascular endothelial cells. Int Immunol 2002. </li></ul>
  13. 13. <ul><li>Occurs in 3% of those treated with unfractionated heparin </li></ul><ul><li>Type of Heparin used </li></ul><ul><li>bovine > porcine > low-molecular weight </li></ul><ul><li>Frequency of HIT </li></ul><ul><li>Surgical > Medical > Obstetric patients </li></ul>Epidemiology of HIT
  14. 14. Complications of HIT <ul><li>- Th rombocytopenia (bleeding rarely occurs) by spleen </li></ul><ul><li>-Platelet activation  binding to endothelial cells  </li></ul><ul><li>Leading to thrombosis </li></ul><ul><li>-DIC </li></ul><ul><li>-Anaphylactic type reactions </li></ul><ul><li>Thrombotic risk is 30x control. </li></ul><ul><li>Arepally G and Ortel T. Heparin-Induced Thrombocytopenia. The New England Journal of Medicine. </li></ul>
  15. 15. Thrombosis Location <ul><li>Venous or Arterial </li></ul><ul><li>Retrospective review of 127 patients with confirmed HIT: venous thrombosis occurred in 78 patients, vs 18 patients with arterial thrombosis (61% and 14%) </li></ul><ul><li>Warkentin TE and Kelton JG. A 14-year study of heparin-induced thrombocytopenia. Am J Medicine 1992; Vol (101): Pg 502. </li></ul>
  16. 16. Risk of Thrombosis <ul><li>Same study; those with only thrombocytopenia, had a 30-day thrombotic event was 53%. </li></ul><ul><li>Warkentin TE and Kelton JG. A 14-year study of heparin-induced thrombocytopenia. Am J Medicine 1992; Vol (101): Pg 502 . </li></ul>
  17. 17. Thrombosis from HIT <ul><li>Venous thrombosis and pulmonary embolism </li></ul><ul><li>Less frequently arterial thrombosis </li></ul><ul><li>Other: skin, coronary, CNS, adrenal </li></ul><ul><li>DVT </li></ul>
  18. 18. Onset of HIT <ul><li>HIT usually occurs within 5-10 days </li></ul><ul><li>Delayed-onset HIT occurs up to 2 weeks after treatment with heparin </li></ul><ul><li>Rapid onset HIT occurs less than 5 days </li></ul><ul><li>Due to pre-existing antibodies. </li></ul>
  19. 19. Recognizing HIT <ul><li>In any patient receiving heparin/LMWH </li></ul><ul><li>Unexplained thrombocytopenia </li></ul><ul><li>Thrombosis with thrombocytopenia </li></ul><ul><li>Necrotic skin lesions at site of heparin skin injection </li></ul>
  20. 20. Pre-test probability <ul><li>Multiple causes of thrombocytopenia in medical/surgical patients </li></ul><ul><li>Potential for false-positives with ELISA </li></ul><ul><li>The use of the “4 T’s” </li></ul>
  21. 21. Pre-test probability
  22. 22. Validation of the 4 T’s <ul><li>Among 111 patients with low pre-test probability; one had HIT (0.9%) </li></ul><ul><li>Intermediate scores: 11.4% with HIT </li></ul><ul><li>High scores: 34% with HIT </li></ul><ul><li>Lo GK, Julh D, Warkentin TE, et al. Evaluation of pretest clinical score (4 T’s) for the diagnosis of heparin-induced thrombocytopenia in two clinical settings. J Thromb Haemost 2006. </li></ul>
  23. 23. Diagnosis of HIT <ul><li>A decrease in platelet count by 50%, or platelet level less than 150,000. </li></ul><ul><li>Absence of other causes of thrombocytopenia </li></ul><ul><li>May be with or without thrombosis </li></ul><ul><li>Platelet do not drop below 30,000/ml </li></ul>
  24. 24. Arepally G and Ortel T. Heparin-Induced Thrombocytopenia. The New England Journal of Medicine.
  25. 25. Differential Diagnosis of Thrombocytopenia <ul><li>Drug Induced </li></ul><ul><ul><li>heparin </li></ul></ul><ul><ul><li>procainamide </li></ul></ul><ul><ul><li>diuretics (furosemide) </li></ul></ul><ul><ul><li>H 2 blockers (cimetidine) </li></ul></ul><ul><ul><li>thrombolytic therapy </li></ul></ul><ul><ul><li>GP IIb/IIIa antagonists </li></ul></ul><ul><li>Mechinical </li></ul><ul><ul><li>membrane oxygenator </li></ul></ul><ul><ul><li>intra-aortic balloon pump </li></ul></ul><ul><li>Pseudothrombocytopenia </li></ul><ul><ul><li>platelet clumping </li></ul></ul><ul><ul><li>hemodilution </li></ul></ul><ul><li>Associated disorders </li></ul><ul><ul><li>hypersplenism </li></ul></ul><ul><ul><li>infections/sepsis </li></ul></ul><ul><ul><li>hypotension and subsequent disseminated intravascular coagulation </li></ul></ul><ul><li>Other causes </li></ul><ul><ul><li>chronic idiopathic thrombocytopenia purpura with exacerbation </li></ul></ul><ul><ul><li>antiphospholipid antibody syndrome </li></ul></ul>
  26. 26. HIT without clinical symptoms of thrombosis <ul><li>Silent DVT’s </li></ul>
  27. 27. Serologic Studies <ul><li>Immunoassay </li></ul><ul><li>-ELISA </li></ul><ul><li>Functional Assays </li></ul><ul><li>-Serotonin release assay </li></ul><ul><li>-Heparin-Induced platelet aggregation </li></ul>
  28. 28. First Lab Test is Immunoassay <ul><li>ELISA </li></ul><ul><li>- measures binding of HIT antibodies from patient serum to PF4-heparin complex coated on the wells of the plate. </li></ul><ul><li>-Sensitivity >97% </li></ul><ul><li>-Specificity 74-86% </li></ul><ul><li>-High NPV </li></ul><ul><li>If high suspicion and with a positive test result; no further diagnositic work-up needed </li></ul>
  29. 29. Arepally G and Ortel T. Heparin-Induced Thrombocytopenia. The New England Journal of Medicine.
  30. 30. Need for functional assay <ul><li>If positive immunoassay, but intermediate suspicion of HIT </li></ul><ul><li>Up to 50% of patients after open heart surgery; 10% of medical patients have reactive anti-bodies against heparin-PF4 without HIT </li></ul><ul><li>Aster RH and Davoren A. Heparin-Induced Thrombocytopenia and Thrombosis. American Journal of Hematology. </li></ul>
  31. 31. Functional Assays <ul><li>Heparin-Induced Platelet aggregation </li></ul><ul><li>-donor platelets mixed with patient serum; measure aggregation with and without heparin </li></ul><ul><li>-Sensitivity >90% </li></ul><ul><li>-Specificity 77-100% </li></ul>
  32. 32. Functional Assays <ul><li>14-C Serotonin Release Assay </li></ul><ul><li>Gold Standard </li></ul><ul><li>-Donor platelets radio-labaled with 14-C radiocarbon, patient serum added, serotonin quantified </li></ul><ul><li>-mixed with low and high concentration of heparin </li></ul><ul><li>-Sensitivity and Specificity >95% </li></ul><ul><li>-cost, technical demands, not widely available </li></ul><ul><li>Sheridan D, Carter C, Kelton JG et al. A diagnositic test for heparin-induced thrombocytopenia. Blood 1986. </li></ul>
  33. 33. Treatment <ul><li>When clinical criteria are met, start treatment while awaiting laboratory results </li></ul><ul><li>Increase in platelet count after stopping heparin in the absence of other causes, may be diagnostic in the absence of confirmatory labs </li></ul>
  34. 34. Treatment of HIT <ul><li>Stop any heparin treatment, including heparin line flushes or use of heparin coated catheters </li></ul><ul><li>Platelet transfusions contraindicated </li></ul><ul><li>LMWH contraindicated due to cross-reactivity </li></ul><ul><li>Warfarin contraindicated initially </li></ul><ul><li>Start alternative anti-coagulation, even without any signs of thrombosis </li></ul><ul><li>-Argatroban </li></ul><ul><li>-Lepirudin </li></ul><ul><li>-Fondaparinux  case report of HIT </li></ul>
  35. 35. Coumadin not used initially <ul><li>Report of 8 patients with HIT, at which point heparin stopped and Coumadin started </li></ul><ul><li>Developed venous limb gangrene and full-thickness skin necrosis </li></ul><ul><li>Warkentin TE, Elavathil LJ, Hayward CP, et al. The pathogenesis of venous limb gangrene associated with heparin-induced thrombocytopenia . Ann Intern Med 1997. </li></ul>
  36. 36. Thrombin Inhibitors
  37. 37. Thrombin Inhibitors <ul><li>Lepirudin: </li></ul><ul><li>-direct thrombin inhibitor </li></ul><ul><li>-goal aPTT of 1.5-2.5x </li></ul><ul><li>-use another agent if there is renal insufficiency as it is renally excreted </li></ul><ul><li>-side-effects: bleeding (18%) </li></ul><ul><li>-anti-dote </li></ul>
  38. 38. Thrombin Inhibitors <ul><li>Lepirudin </li></ul><ul><li>-Lepirudin in 403 patients and 120 controls. Rate outcome of death, amputation, and thrombosis (at 35 days) lower vs control (20.3%, 43%; P value of <0.001). </li></ul><ul><li>Lubenow N. Eichler P, Lietz T, et al. Lepirudin for prophylaxis of thrombosis in patients with acute isolated heparin - induced thrombocytopenia : an analysis of 3 prospective studies . Blood 2004. </li></ul>
  39. 39. <ul><li>Argatroban </li></ul><ul><li>-direct thrombin inhibitor, interefers at thrombin active site </li></ul><ul><li>-adjusted to aPTT of 1.5-3x </li></ul><ul><li>-hepatic clearance so avoid in hepatobiliary disease </li></ul><ul><li>-side-effect: bleeding (7%), anaphylaxis </li></ul><ul><li>-anti-dote </li></ul>Thrombin Inhibitors
  40. 40. Thrombin Inhibitors <ul><li>Argatroban </li></ul><ul><li>Multicenter study of 722 patients with HIT </li></ul><ul><li>- outcome of death, amputation, thrombosis at 37 days lower vs control (34-35% vs 43%) </li></ul><ul><li>- Reduction in new thromboembolic complications (10-14% vs 25%; P value <0.05) </li></ul><ul><li>Lewis BE, Wallis DE, Leya F, et al. Argatroban anticoagulation in patients with heparin-induced thrombocytopenia. Arch Intern Med 2003. </li></ul><ul><li>Lewis BE, Wallis DE, Berkowitz SD, et al. Argatroban anticoagulant therapy in patients with heparin-induced thrombocytopenia. Circulation 2001. </li></ul>
  41. 41. Thrombin Inhibitors <ul><li>Bivalirudin- not fully investigated for HIT in most settings </li></ul>
  42. 42. Synthetic Pentasaccharide <ul><li>Fondaparinux: inhibitor of Xa </li></ul><ul><li>Case study of Fondaparinux not preventing HIT </li></ul><ul><li>Alsaleh KA, Al-Nasser SM, Bates SM et al. Delayed-onset HIT caused by low-molecular-weight heparin manifesting during Fondaparinux prophylaxis . Am J Hematol. 2008; Epub ahead of print. </li></ul><ul><li>Case study associated with episode of HIT, when used as prophylaxis. </li></ul><ul><li>Warkentin T, Maurer B, Aster R, et al. Heparin-Induced Thrombocytopenia associated with Fondaparinux. The New England Journal of Medicine. Boston: June 2007. Vol 356. </li></ul>
  43. 43. Persistent and Worsening Thrombosis despite HIT treatment <ul><li>Can use IVIG, plasma exchange, and aspirin if life-threatening thrombosis are worsening/persistant despite alternative anticoagulation </li></ul><ul><li>Thrombolysis </li></ul><ul><li>Thromboembolectomy </li></ul>
  44. 44. Course of Treatment HIT without Thrombosis <ul><li>HIT without any thrombosis: continue alternative anticoagulation for at least until platelet count normal </li></ul><ul><li>Increased risk of thrombosis for 2-4 weeks </li></ul><ul><li>Coumadin for 1-3 month </li></ul><ul><li>Studies required </li></ul>
  45. 45. Course of Treatment HIT with THROMBOSIS <ul><li>HIT with thrombosis: initiate coumadin once platelet count normal (overlap for 5 days with thrombin inhibitor until INR therapeutic); Continue coumadin for 3-6 months at INR of </li></ul><ul><li>2-3. </li></ul>
  46. 46. Re-treatment with Heparin in those with prior HIT <ul><li>HIT antibodies (IgG to PF4/heparin) persist 100 days/3 months </li></ul><ul><li>Use alternative anticoagulation </li></ul><ul><li>Heparin should still be avoided if possible </li></ul><ul><li>If heparin is essential (cardio-pulmonary bypass); need to confirm absence of HIT antibodies; and its use should be limited to procedure only </li></ul>
  47. 47. As Prophylaxis: UFH vs LMWH <ul><li>In a randomized, double blind clinical trial of 665 patients receiving DVT prophylaxis after hip surgery: </li></ul><ul><li>9/332 patients with UHF  HIT </li></ul><ul><li>None of 333 patients with LMWH </li></ul><ul><li>2.7% vs 0%; P value 0.0018 </li></ul><ul><li>Warkentin T, Levine M, Hirsh J, et al. Heparin-Induced Thrombocytopenia in Patients Treated with Low-Molecular-Weight Heparin or Unfractionated Heparin . The New England Journal of Medicine. </li></ul>
  48. 48. Other prevention Strategies <ul><li>Limit heparin duration; start Coumadin early in transitioning </li></ul><ul><li>In someone with history of HIT, heparin should be listed as an allergy </li></ul>
  49. 49. Areas of Uncertainty <ul><li>Argatroban vs Lepirudin </li></ul><ul><li>HIT antibodies are also present in patients that do not have any clinical manifestations. Uncertain why complications occur in some. </li></ul><ul><li>Arepally G and Ortel T. Heparin-Induced Thrombocytopenia. The New England Journal of Medicine. </li></ul>
  50. 50. Arepally G and Ortel T. Heparin-Induced Thrombocytopenia. The New England Journal of Medicine.
  51. 51. References I <ul><li>1) Arepally G and Ortel T. Heparin-Induced Thrombocytopenia. The New England Journal of Medicine. Boston: Aug, 2006. Vol 344 (8); Pgs 809-819. </li></ul><ul><li>2) Warkentin T, Maurer B, Aster R, et al. Heparin-Induced Thrombocytopenia associated with Fondaparinux. The New England Journal of Medicine. Boston: June 2007. Vol 356 (25); Pg 2653. </li></ul><ul><li>3) Aster RH and Davoren A. Heparin-Induced Thrombocytopenia and Thrombosis. American Journal of Hematology. 2006. Vol 81; Ppgs 36-44. </li></ul><ul><li>4) Warkentin T, Levine M, Hirsh J, et al. Heparin-Induced Thrombocytopenia in Patients Treated with Low-Molecular-Weight Heparin or Unfractionated Heparin . The New England Journal of Medicine. Boston: May 1995. Vol 332 (20); Pgs 1330-1336. </li></ul><ul><li>5) Muslimani A, Basma R and Daw H. Immune Heparin-Induced Thrombocytopenia Resulting from Preceding Exposure to Heparin Catheter Flushes.  American Journal of Hematology. 2007. Vol 82; Pgs 652-655. </li></ul><ul><li>6) Selleng K, Warkentin T and Greinacher A. Heparin-induced thrombocytopenia in intensive care patients . Critical Care Med 2007. Vol 35 (4); Pgs 1165-1176. </li></ul><ul><li>7) Cines D, Rauova L, Arepally G, et al. Heparin-Induced Thrombocytopenia: An autoimmune Disorder Regulated Through Dynamic Autoantigen Assembly/Disassembly . Journal of Clinical Apheresis. 2007. Vol 22; Pgs 31-36. </li></ul>
  52. 52. References II <ul><li>8) Lubenow N. Eichler P, Lietz T, et al. Lepirudin for prophylaxis of thrombosis in patients with acute isolated heparin-induced thrombocytopenia: an analysis of 3 prospective studies . Blood 2004; Vol 104: Pgs 3072-7. </li></ul><ul><li>9) Lewis BE, Wallis DE, Leya F, et al. Argatroban anticoagulation in patients with heparin-induced thrombocytopenia. Arch Intern Med 2003; Vol 163: Pgs1849-56. </li></ul><ul><li>10) Lewis BE, Wallis DE, Berkowitz SD, et al. Argatroban anticoagulant therapy in patients with heparin-induced thrombocytopenia. Circulation 2001; Vol. 103: Pgs 1838-43. </li></ul><ul><li>11) Chong BH and Castaldi Pa. Platelet proaggregating effect of heparin: Possible mechanism for non-immune heparin associated thrombocytopenia . Aust N Z J Med 1986; Vol 16; Pgs 715. </li></ul><ul><li>12) Martel N, Lee J and Wells PS. Risk for heparin-induced thrombocytopenia with unfractionated heparin and low-molecular-weight heparin thromboprophylaxis: a metanalysis . Blood 2005; Vol (106); Pg 2710. </li></ul>
  53. 53. References III <ul><li>13) Blank M, Shoenfeld Y, Tavor S, et al. Anti-platelet factor 4/heparin antibodies from patients with heparin-induced thrombocytopenia provoke direct activation of microvascular endothelial cells. Int Immunol 2002; Vol 12: Pg 121. </li></ul><ul><li>14) Warkentin TE and Kelton JG. A 14-year study of heparin-induced thrombocytopenia . Am J Medicine 1992; Vol (101): Pg 502. </li></ul><ul><li>15) Warkentin TE, Elavathil LJ, Hayward CP, et al. The pathogenesis of venous limb gangrene associated with heparin-induced thrombocytopenia . Ann Intern Med 1997; Vol 127: Pg 804. </li></ul><ul><li>16) Sheridan D, Carter C, Kelton JG et al. A diagnositic test for heparin-induced thrombocytopenia. Blood 1986; Vol 67: Pg 27. </li></ul><ul><li>17) Lo GK, Julh D, Warkentin TE, et al. Evaluation of pretest clinical score (4 T’s) for the diagnosis of heparin-induced thrombocytopenia in two clinical settings . J Thromb Haemost 2006; Vol 4: 759. </li></ul><ul><li>18) Alsaleh KA, Al-Nasser SM, Bates SM et al. Delayed-onset HIT caused by low-molecular-weight heparin manifesting during Fondaparinux prophylaxis . Am J Hematol. 2008; Epub ahead of print. </li></ul>
  54. 54. Questions?

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