1. Heparin-Induced Thrombocytopenia

2. Learning Objectives Understand the etiology and pathogenesis of Heparin-Induced Thrombocytopenia Understand the etiology and pathogenesis of Heparin-Induced Thrombocytopenia Be able to differentiate the two types of HIT; Type I and Type II. Be able to differentiate the two types of HIT; Type I and Type II. Recognize the signs and symptoms of Heparin- Induced Thrombocytopenia and institute appropriate treatment Recognize the signs and symptoms of Heparin- Induced Thrombocytopenia and institute appropriate treatment Gain the knowledge necessary to minimize the occurence heparin-induced thrombocytopenia. Gain the knowledge necessary to minimize the occurence heparin-induced thrombocytopenia.

3. Case Question 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? 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?

4. Case Question A) Immediately start Coumadin with Argatroban A) Immediately start Coumadin with Argatroban B) Lower extremity Doppler B) Lower extremity Doppler C) V/Q scan C) V/Q scan D) Nothing currently indicated D) Nothing currently indicated

5. Case Answer A) Immediately start Coumadin with Argatroban A) Immediately start Coumadin with Argatroban B) Lower extremity Doppler B) Lower extremity Doppler C) V/Q scan C) V/Q scan D) Nothing currently indicated D) Nothing currently indicated

6. Definition of HIT Heparin-induced thrombocytopenia is an antibody mediated pro-thrombotic disorder. Heparin-induced thrombocytopenia is an antibody mediated pro-thrombotic disorder. Diagnosis can be difficult. Diagnosis can be difficult.

7. Heparin-Induced Thrombocytopenia HIT Type IHIT Type II

8. Classificaiton of Type I and Type II HIT Type I HIT Type I HIT Non-immune Non-immune Decrease in platelets is b/w 10-30,000/ml Decrease in platelets is b/w 10-30,000/ml Do not discontinue heparin Do not discontinue heparin Type II HIT Focus of this talk Immune Decrease in platelets by 50% or less than 150,000 Heparin needs to be stopped Alternative anticoagulation needs to be started

9. Type I HIT Non-immune Non-immune Platelet drop due to direct effect of heparin on platelet activation Platelet drop due to direct effect of heparin on platelet activation Of no clinical consequence Of no clinical consequence Chong BH and Castaldi Pa. Platelet proaggregating effect of heparin: Possible mechanism for non-immune heparin associated thrombocytopenia. Aust N Z J Med 1986. Chong BH and Castaldi Pa. Platelet proaggregating effect of heparin: Possible mechanism for non-immune heparin associated thrombocytopenia. Aust N Z J Med 1986.

10. Arepally G and Ortel T. Heparin-Induced Thrombocytopenia. The New England Journal of Medicine.

11. Schematic of HIT (TYPE II) immune activation

12. A Theory for Thrombosis Formation of platelet plug Formation of platelet plug HIT antibodies also bind to endothelial cells  endothelial cell injury HIT antibodies also bind to endothelial cells  endothelial cell injury 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. 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.

13. Occurs in 3% of those treated with unfractionated heparin Occurs in 3% of those treated with unfractionated heparin Type of Heparin used Type of Heparin used bovine > porcine > low-molecular weight bovine > porcine > low-molecular weight Frequency of HIT Frequency of HIT Surgical > Medical > Obstetric patients Surgical > Medical > Obstetric patients Epidemiology of HIT

14. Complications of HIT - Th rombocytopenia (bleeding rarely occurs) by spleen - Th rombocytopenia (bleeding rarely occurs) by spleen -Platelet activation  binding to endothelial cells  -Platelet activation  binding to endothelial cells  Leading to thrombosis Leading to thrombosis -DIC -DIC -Anaphylactic type reactions -Anaphylactic type reactions Thrombotic risk is 30x control. Arepally G and Ortel T. Heparin-Induced Thrombocytopenia. The New England Journal of Medicine. Arepally G and Ortel T. Heparin-Induced Thrombocytopenia. The New England Journal of Medicine.

15. Thrombosis Location Venous or Arterial Venous or Arterial Retrospective review of 127 patients with confirmed HIT: venous thrombosis occurred in 78 patients, vs 18 patients with arterial thrombosis (61% and 14%) Retrospective review of 127 patients with confirmed HIT: venous thrombosis occurred in 78 patients, vs 18 patients with arterial thrombosis (61% and 14%) Warkentin TE and Kelton JG. A 14-year study of heparin-induced thrombocytopenia. Am J Medicine 1992; Vol (101): Pg 502. Warkentin TE and Kelton JG. A 14-year study of heparin-induced thrombocytopenia. Am J Medicine 1992; Vol (101): Pg 502.

16. Risk of Thrombosis Same study; those with only thrombocytopenia, had a 30-day thrombotic event was 53%. Same study; those with only thrombocytopenia, had a 30-day thrombotic event was 53%. Warkentin TE and Kelton JG. A 14-year study of heparin-induced thrombocytopenia. Am J Medicine 1992; Vol (101): Pg 502. Warkentin TE and Kelton JG. A 14-year study of heparin-induced thrombocytopenia. Am J Medicine 1992; Vol (101): Pg 502.

17. Thrombosis from HIT Venous thrombosis and pulmonary embolism Venous thrombosis and pulmonary embolism Less frequently arterial thrombosis Less frequently arterial thrombosis Other: skin, coronary, CNS, adrenal Other: skin, coronary, CNS, adrenal DVT DVT

18. Onset of HIT HIT usually occurs within 5-10 days HIT usually occurs within 5-10 days Delayed-onset HIT occurs up to 2 weeks after treatment with heparin Delayed-onset HIT occurs up to 2 weeks after treatment with heparin Rapid onset HIT occurs less than 5 days Rapid onset HIT occurs less than 5 days Due to pre-existing antibodies. Due to pre-existing antibodies.

19. Recognizing HIT In any patient receiving heparin/LMWH In any patient receiving heparin/LMWH Unexplained thrombocytopenia Unexplained thrombocytopenia Thrombosis with thrombocytopenia Thrombosis with thrombocytopenia Necrotic skin lesions at site of heparin skin injection Necrotic skin lesions at site of heparin skin injection

20. Pre-test probability Multiple causes of thrombocytopenia in medical/surgical patients Multiple causes of thrombocytopenia in medical/surgical patients Potential for false-positives with ELISA Potential for false-positives with ELISA The use of the “4 T’s” The use of the “4 T’s”

21. Pre-test probability

22. Validation of the 4 T’s Among 111 patients with low pre-test probability; one had HIT (0.9%) Among 111 patients with low pre-test probability; one had HIT (0.9%) Intermediate scores: 11.4% with HIT Intermediate scores: 11.4% with HIT High scores: 34% with HIT High scores: 34% with HIT 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. 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.

23. Diagnosis of HIT A decrease in platelet count by 50%, or platelet level less than 150,000. A decrease in platelet count by 50%, or platelet level less than 150,000. Absence of other causes of thrombocytopenia Absence of other causes of thrombocytopenia May be with or without thrombosis May be with or without thrombosis Platelet do not drop below 30,000/ml Platelet do not drop below 30,000/ml

24. Arepally G and Ortel T. Heparin-Induced Thrombocytopenia. The New England Journal of Medicine.

25. Differential Diagnosis of Thrombocytopenia Drug Induced Drug Induced heparin heparin procainamide procainamide diuretics (furosemide) diuretics (furosemide) H 2 blockers (cimetidine) H 2 blockers (cimetidine) thrombolytic therapy thrombolytic therapy GP IIb/IIIa antagonists GP IIb/IIIa antagonists Mechinical Mechinical membrane oxygenator membrane oxygenator intra-aortic balloon pump intra-aortic balloon pump Pseudothrombocytopenia Pseudothrombocytopenia platelet clumping platelet clumping hemodilution hemodilution Associated disorders hypersplenism infections/sepsis hypotension and subsequent disseminated intravascular coagulation Other causes chronic idiopathic thrombocytopenia purpura with exacerbation antiphospholipid antibody syndrome

26. HIT without clinical symptoms of thrombosis Silent DVT’s Silent DVT’s

27. Serologic Studies Immunoassay Immunoassay -ELISA -ELISA Functional Assays Functional Assays -Serotonin release assay -Serotonin release assay -Heparin-Induced platelet aggregation -Heparin-Induced platelet aggregation

28. First Lab Test is Immunoassay ELISA ELISA - measures binding of HIT antibodies from patient serum to PF4-heparin complex coated on the wells of the plate. - measures binding of HIT antibodies from patient serum to PF4-heparin complex coated on the wells of the plate. -Sensitivity >97% -Sensitivity >97% -Specificity 74-86% -Specificity 74-86% -High NPV -High NPV If high suspicion and with a positive test result; no further diagnositic work-up needed If high suspicion and with a positive test result; no further diagnositic work-up needed

29. Arepally G and Ortel T. Heparin-Induced Thrombocytopenia. The New England Journal of Medicine.

30. Need for functional assay If positive immunoassay, but intermediate suspicion of HIT If positive immunoassay, but intermediate suspicion of HIT Up to 50% of patients after open heart surgery; 10% of medical patients have reactive anti-bodies against heparin-PF4 without HIT Up to 50% of patients after open heart surgery; 10% of medical patients have reactive anti-bodies against heparin-PF4 without HIT Aster RH and Davoren A. Heparin-Induced Thrombocytopenia and Thrombosis. American Journal of Hematology. Aster RH and Davoren A. Heparin-Induced Thrombocytopenia and Thrombosis. American Journal of Hematology.

31. Functional Assays Heparin-Induced Platelet aggregation Heparin-Induced Platelet aggregation -donor platelets mixed with patient serum; measure aggregation with and without heparin -donor platelets mixed with patient serum; measure aggregation with and without heparin -Sensitivity >90% -Sensitivity >90% -Specificity 77-100% -Specificity 77-100%

32. Functional Assays 14-C Serotonin Release Assay 14-C Serotonin Release Assay Gold Standard Gold Standard -Donor platelets radio-labaled with 14-C radiocarbon, patient serum added, serotonin quantified -Donor platelets radio-labaled with 14-C radiocarbon, patient serum added, serotonin quantified -mixed with low and high concentration of heparin -mixed with low and high concentration of heparin -Sensitivity and Specificity >95% -Sensitivity and Specificity >95% -cost, technical demands, not widely available -cost, technical demands, not widely available Sheridan D, Carter C, Kelton JG et al. A diagnositic test for heparin-induced thrombocytopenia. Blood 1986. Sheridan D, Carter C, Kelton JG et al. A diagnositic test for heparin-induced thrombocytopenia. Blood 1986.

33. Treatment When clinical criteria are met, start treatment while awaiting laboratory results When clinical criteria are met, start treatment while awaiting laboratory results Increase in platelet count after stopping heparin in the absence of other causes, may be diagnostic in the absence of confirmatory labs Increase in platelet count after stopping heparin in the absence of other causes, may be diagnostic in the absence of confirmatory labs

34. Treatment of HIT Stop any heparin treatment, including heparin line flushes or use of heparin coated catheters Stop any heparin treatment, including heparin line flushes or use of heparin coated catheters Platelet transfusions contraindicated Platelet transfusions contraindicated LMWH contraindicated due to cross-reactivity LMWH contraindicated due to cross-reactivity Warfarin contraindicated initially Warfarin contraindicated initially Start alternative anti-coagulation, even without any signs of thrombosis Start alternative anti-coagulation, even without any signs of thrombosis -Argatroban -Argatroban -Lepirudin -Lepirudin -Fondaparinux  case report of HIT -Fondaparinux  case report of HIT

35. Coumadin not used initially Report of 8 patients with HIT, at which point heparin stopped and Coumadin started Report of 8 patients with HIT, at which point heparin stopped and Coumadin started Developed venous limb gangrene and full- thickness skin necrosis Developed venous limb gangrene and full- thickness skin necrosis Warkentin TE, Elavathil LJ, Hayward CP, et al. The pathogenesis of venous limb gangrene associated with heparin-induced thrombocytopenia. Ann Intern Med 1997. Warkentin TE, Elavathil LJ, Hayward CP, et al. The pathogenesis of venous limb gangrene associated with heparin-induced thrombocytopenia. Ann Intern Med 1997.

36. Thrombin Inhibitors

37. Lepirudin: Lepirudin: -direct thrombin inhibitor -direct thrombin inhibitor -goal aPTT of 1.5-2.5x -goal aPTT of 1.5-2.5x -use another agent if there is renal insufficiency as it is renally excreted -use another agent if there is renal insufficiency as it is renally excreted -side-effects: bleeding (18%) -side-effects: bleeding (18%) -anti-dote -anti-dote

38. Thrombin Inhibitors Lepirudin Lepirudin -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). 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.

39. Argatroban Argatroban -direct thrombin inhibitor, interefers at thrombin active site -direct thrombin inhibitor, interefers at thrombin active site -adjusted to aPTT of 1.5-3x -adjusted to aPTT of 1.5-3x -hepatic clearance so avoid in hepatobiliary disease -hepatic clearance so avoid in hepatobiliary disease -side-effect: bleeding (7%), anaphylaxis -side-effect: bleeding (7%), anaphylaxis -anti-dote -anti-dote Thrombin Inhibitors

40. Argatroban Argatroban Multicenter study of 722 patients with HIT Multicenter study of 722 patients with HIT - outcome of death, amputation, thrombosis at 37 days lower vs control (34-35% vs 43%) - outcome of death, amputation, thrombosis at 37 days lower vs control (34-35% vs 43%) - Reduction in new thromboembolic complications (10-14% vs 25%; P value <0.05) - Reduction in new thromboembolic complications (10-14% vs 25%; P value <0.05) Lewis BE, Wallis DE, Leya F, et al. Argatroban anticoagulation in patients with heparin-induced thrombocytopenia. Arch Intern Med 2003. Lewis BE, Wallis DE, Leya F, et al. Argatroban anticoagulation in patients with heparin-induced thrombocytopenia. Arch Intern Med 2003. Lewis BE, Wallis DE, Berkowitz SD, et al. Argatroban anticoagulant therapy in patients with heparin-induced thrombocytopenia. Circulation 2001. Lewis BE, Wallis DE, Berkowitz SD, et al. Argatroban anticoagulant therapy in patients with heparin-induced thrombocytopenia. Circulation 2001.

41. Thrombin Inhibitors Bivalirudin- not fully investigated for HIT in most settings Bivalirudin- not fully investigated for HIT in most settings

42. Synthetic Pentasaccharide Fondaparinux: inhibitor of Xa Fondaparinux: inhibitor of Xa Case study of Fondaparinux not preventing HIT Case study of Fondaparinux not preventing HIT 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. 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. Case study associated with episode of HIT, when used as prophylaxis. Case study associated with episode of HIT, when used as prophylaxis. 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. 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.

43. Persistent and Worsening Thrombosis despite HIT treatment Can use IVIG, plasma exchange, and aspirin if life-threatening thrombosis are worsening/persistant despite alternative anticoagulation Can use IVIG, plasma exchange, and aspirin if life-threatening thrombosis are worsening/persistant despite alternative anticoagulation Thrombolysis Thrombolysis Thromboembolectomy Thromboembolectomy

44. Course of Treatment HIT without Thrombosis HIT without any thrombosis: continue alternative anticoagulation for at least until platelet count normal HIT without any thrombosis: continue alternative anticoagulation for at least until platelet count normal Increased risk of thrombosis for 2-4 weeks Increased risk of thrombosis for 2-4 weeks Coumadin for 1-3 month Coumadin for 1-3 month Studies required Studies required

45. Course of Treatment HIT with THROMBOSIS 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 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 2-3. 2-3.

46. Re-treatment with Heparin in those with prior HIT HIT antibodies (IgG to PF4/heparin) persist 100 days/3 months HIT antibodies (IgG to PF4/heparin) persist 100 days/3 months Use alternative anticoagulation Use alternative anticoagulation Heparin should still be avoided if possible Heparin should still be avoided if possible If heparin is essential (cardio-pulmonary bypass); need to confirm absence of HIT antibodies; and its use should be limited to procedure only If heparin is essential (cardio-pulmonary bypass); need to confirm absence of HIT antibodies; and its use should be limited to procedure only

47. As Prophylaxis: UFH vs LMWH In a randomized, double blind clinical trial of 665 patients receiving DVT prophylaxis after hip surgery: In a randomized, double blind clinical trial of 665 patients receiving DVT prophylaxis after hip surgery: 9/332 patients with UHF  HIT 9/332 patients with UHF  HIT None of 333 patients with LMWH None of 333 patients with LMWH 2.7% vs 0%; P value 0.0018 2.7% vs 0%; P value 0.0018 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. 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.

48. Other prevention Strategies Limit heparin duration; start Coumadin early in transitioning Limit heparin duration; start Coumadin early in transitioning In someone with history of HIT, heparin should be listed as an allergy In someone with history of HIT, heparin should be listed as an allergy

49. Areas of Uncertainty Argatroban vs Lepirudin Argatroban vs Lepirudin HIT antibodies are also present in patients that do not have any clinical manifestations. Uncertain why complications occur in some. HIT antibodies are also present in patients that do not have any clinical manifestations. Uncertain why complications occur in some. Arepally G and Ortel T. Heparin-Induced Thrombocytopenia. The New England Journal of Medicine. Arepally G and Ortel T. Heparin-Induced Thrombocytopenia. The New England Journal of Medicine.

50. Arepally G and Ortel T. Heparin-Induced Thrombocytopenia. The New England Journal of Medicine.

51. References I 1) Arepally G and Ortel T. Heparin-Induced Thrombocytopenia. The New England Journal of Medicine. Boston: Aug, 2006. Vol 344 (8); Pgs 809-819. 1) Arepally G and Ortel T. Heparin-Induced Thrombocytopenia. The New England Journal of Medicine. Boston: Aug, 2006. Vol 344 (8); Pgs 809-819. 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. 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. 3) Aster RH and Davoren A. Heparin-Induced Thrombocytopenia and Thrombosis. American Journal of Hematology. 2006. Vol 81; Ppgs 36-44. 3) Aster RH and Davoren A. Heparin-Induced Thrombocytopenia and Thrombosis. American Journal of Hematology. 2006. Vol 81; Ppgs 36-44. 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. 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. 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. 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. 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. 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. 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. 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.

52. References II 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. 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. 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. 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. 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. 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. 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. 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. 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. 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.

53. References III 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. 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. 14) Warkentin TE and Kelton JG. A 14-year study of heparin-induced thrombocytopenia. Am J Medicine 1992; Vol (101): Pg 502. 14) Warkentin TE and Kelton JG. A 14-year study of heparin-induced thrombocytopenia. Am J Medicine 1992; Vol (101): Pg 502. 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. 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. 16) Sheridan D, Carter C, Kelton JG et al. A diagnositic test for heparin-induced thrombocytopenia. Blood 1986; Vol 67: Pg 27. 16) Sheridan D, Carter C, Kelton JG et al. A diagnositic test for heparin-induced thrombocytopenia. Blood 1986; Vol 67: Pg 27. 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. 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. 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. 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.

54. Questions?