1. Andreas Greinacher Institut für Immunologie und Transfusionsmedizin Ernst-Moritz-Arndt-Universität Greifswald Brædstrup, April 2006 Heparin-induced Thrombocytopenia: Pathogenesis, Diagnosis, and Management

2. Heparin-Platelet Interactions (Non immune heparin-associated thrombocytopenia (HIT type I)) Immune-mediated heparin-induced thrombocytopenia (HIT type II) = HIT clinico-pathological syndrome (clinical symptoms + antibodies) Platelet count decrease > 50% and/or new thrombotic complications between day 5-14 of heparin

3. Lys + Arg Heparin-induced thrombocytopenia a link between immune system and hemostasis Fc  RIIa Heparansulfate PF4 Heparin B-L Warkentin TE & Greinacher A. Heparin induced thrombocytopenia, 3rd ed, Marcel Dekker, New York 2004

4. Lys + Arg Heparin-induced thrombocytopenia a link between immune system and hemostasis Fc  RIIa Heparansulfate PF4 Heparin B-L Warkentin TE & Greinacher A. Heparin induced thrombocytopenia, 3rd ed, Marcel Dekker, New York 2004

5. Lys + Arg Heparin-induced thrombocytopenia a link between immune system and hemostasis Fc  RIIa Heparansulfate PF4 Heparin B-L Warkentin TE & Greinacher A. Heparin induced thrombocytopenia, 3rd ed, Marcel Dekker, New York 2004 Thrombin Tissue factor EC Anticoagulation Thrombosis

6. N=320 Greinacher Thromb Haemost 2004 Greinacher et al. Blood. 2000;96:846-51.

7. HIT: Platelet Counts in Laboratory- Confirmed HIT May Be Normal Adapted with permission from Warkentin TE. Semin Hematol. 1998;35(suppl 5):9-16. No HIT-associated thrombosis HIT-associated thrombosis HIT-associated thrombosis occurred in patients with platelet counts >150,000/mm 3 Platelet Count Nadir (1000/mm 3 ) No. of Patients With HIT 510 20305070100200300150 5001000 0 10 20 30 40 ~15% of patients with HIT have normal platelet counts

9. HIT: Temporal Aspects 1. Warkentin TE, Greinacher A, eds. Heparin-Induced Thrombocytopenia. 2. Warkentin TE, Kelton JG. N Engl J Med. 3. Warkentin TE, Kelton JG. Ann Intern Med. 4. Rice L et al. Ann Int Med. 5. Lubenow et al. Chest. 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 21 40 Days Heparin exposure Rapid-onset HIT (previous heparin exposure typically within 4 – 6 weeks) Typical-onset HIT (within 4 to 14 days) Delayed-onset HIT (average of 9 days after heparin is stopped)

10. Differential Diagnosis of HIT Drug dependent TP/PTP Pseudothrombocytopenia GPIIb/IIIa Inhibitor induced TP HIT is unlikely if: Platelet counts decrease between day 1 and 5 of heparin Patient shows overt bleeding Patient receives GPIIb/IIIa inibitors Patient is septic HIT is unlikely if: Platelet counts decrease between day 1 and 5 of heparin Patient shows overt bleeding Patient receives GPIIb/IIIa inibitors Patient is septic

11. Clinical Features of HIT: 4 T’s Thrombocytopenia Timing (of onset of platelet fall or thrombosis) Thrombosis oTher (diagnoses not seen)

12. 210 Thrombocytopenia > 50% platelet count fall to nadir ≥ 20 30-50% platelet count fall to nadir 10-19 <30% platelet count fall to nadir ≤ 10 Timing of fall in platelet count or other sequelae Onset d 5-10 or < 1 d (if heparin exposure within 30 d) > d 10, or timing unclear, or < d 1 with recent heparin 31- 100 d Platelet count fall < d 4 (without recent heparin exposure) Thrombosis or other sequelae New thrombosis; skin necrosis; post- heparin bolus acute systemic reaction Progressive or recurrent thrombosis; erythematous skin lesions; suspected thrombosis – not confirmed None OTher cause for thrombocytopenia No other cause for platelet count fall is evident Possible other cause is evident Definite other cause is present Diagnosis - pretest probability: the 4 T’s A B C D Lo et al. J Thromb Haemost 2006

13. Diagnosis - pretest probability Interpretation of 4 T’s score Score 0 - 3: very unlikely to be HIT (<5%) Score 4 - 5: a minority have HIT (10-30%) Score 6 – 8 : 20 to >80% have HIT, depending on the clinical setting and scorer´s experience: these patients usually require an alternative, non-heparin anticoagulant Lo et al. J Thromb Haemost 2006

14. Tage HIT Übernahme aus anderem Krankenhaus Platelets [x10 9 /L] 74 year old male patient heart failure sepsis multiorgan failure ICU, renal replacement CVVH UFH 1 2 3 4 admittance in ICU Days UFH Thrombocytopenia > 50% decrease : 2 Onset day 2: 0 Thrombosis, no: 0 Other reason, definite: 0

15. non heparin anticoagulant Tage HIT Übernahme aus anderem Krankenhaus Platelets [x10 9 /L] HIPA and ELISA IgG pos Transfer from another hospital Days UFH Thrombocytopenia > 50% decrease : 2 Onset day 9: 2 Thrombosis, no: 0 Other reason, probably: 1

16. PF4/heparin ELISA Microcolumn IgG/A/M HIPA-test 14 C-SRA IgG/ other antigens TAT D-Dimer Antigen test Functional test EC B-L Heparansulfat Thrombin Tissue factor Thrombosis

17. Frequency of “HIT”: Platelet Fall >30% and/or Thrombosis (Pos HIPA test) Greinacher et al. Blood 2005;106:2921-2 * Enoxaparin HIT 12/231 (5.2%) 0/271 (0.0%) P=0.00008 HIPA 25/202 (12.4%) 13/238 (5.5%) P=0.0101 EIA 46/196 (23.5%) 19/228 (8.3%) P=0.00002 UFHLMWH* HIT-T 6/231 (2.6%) 0/271 (0.0%)P<0.0092 HIT-T HIT HIPA EIA

18. Association of Risk for New Thrombosis and Positive HIT Test Schenk S et al. J Thorc Vasc Surg 2006 in press.

19. Adapted from Warkentin TE, Kelton JG. Am J Med. 1996;101:502–507. Occurrence of symptomatic thrombosis after stopping heparin in patients confirmed to have isolated HIT Cumulative thrombotic event-rate (%) Days After Isolated HIT Recognized 100 90 80 70 60 50 40 30 20 10 0 52.8% 0 2 4 6 10121416 8 18222628302420 N = 62 14-year retrospective study

20. HIT = White Clot Syndrome Recurrent arterial white clots LMWH UFH danaparoid

21. Start treatment at high clinical suspicion of HIT Lab-test confirms the diagnosis retrospectively Lubenow et al. JTH 2005;3:2428-36 Risk of Thrombosis in Acute HIT

22. When HIT is strongly-suspected Stop heparin (UFH/LMWH) Duplex ultrasonography for lower- limb DVT Order test for HIT antibodies Initiate alternative non-heparin anticoagulant in therapeutic dose even in patients without thrombosis

23. ACCP: Treatment of HIT “For patients with strongly suspected (or confirmed) HIT whether or not complicated by thrombosis we recommend use of an alternative, non-heparin anticoagulant in therapeutic doses such as” –Danaparoid (Grade 1B) –Lepirudin (Grade 1C+)* –Argatroban (Grade 1C)* –Bivalirudin (Grade 2C) *Differences in level of recommendations based primarily on availability of prospective, randomized, controlled trial data in HIT and non-HIT patients. Warkentin TE, Greinacher A. Chest. 2004;126:311S-337S.

24. 1. steady state of haemostasis procoagulatory factors anticoagulatory factors 2. heparinized patient heparin 5. acute HIT-patient (heparin stopped, on compatible anticoagulant) lepirudin/danaparoid/ argatroban HIT-related clotting activation 4. HIT-patient (heparin stopped) HIT-related clotting activation 3. HIT-patient (still on heparin) heparin HIT-related clotting activation lepirudin/danaparoid/ argatroban HIT-related clotting activation 6. subacute HIT-patient (heparin stopped, on compatible anticoagulant)

25. approval/availability? experience? renal impairment? liver impairment? isolated thrombocytopenia? uncomplicated DVT? monitoring tools? costs? Which treatment is optimal? Danaparoid? Lepirudin? Argatroban?

26. P. Eichler N. Lubenow K. Selleng D. Juhl C. Blumentritt U. Strobel B. Fürll T. Lietz T.E. Warkentin B. Pötzsch University Hospital Greifswald

27. Decrease of plt count > 50%New thrombosis Onset > 5 days of heparin? Previous heparin within the last 30 days? NoYes NoYes HIT very unlikely maintain heparin Other cause likely? NoYes Perform antigen test to rule out HIT HIT possible stop heparin Perform antigen test for HIT Therapeutic dose AC necessary due to primary disease? NoYes High bleeding risk? NoYes Use prophylactic dose AC e.g. danaparoid 750 t.i.d. (option in European Union, Australia, Canada) Use therapeutic dose alternative AC HIT test positive? NoYes HIT unlikely restart heparin HIT possible Functional test for HIT positive? NoYes HIT unlikelyHIT and/or plt – platelet AC – anticoagulation t.i.d. – three times daily

28. Patient Population affected by HIT is changing 1994 - 19972003 - 2004 Medical143/408 (35.0%)101/207 (48.8%) General surgery53/408 (13.0%)17/207 (8.2%) Cardio-vascular surgery31/408 (7.6%)24/207 (11.6%) Orthopedic/trauma125/408 (30.6%)2/207 (0.9%) Urology 48/408 (11.8%) 2/207 (0.9%) Gynecology3/207 (1.4%) Surgical intensive care31/207 (14.9%) No information17/207 (8.2%) Greinacher et al. 2005 and unpublished data

29. Which drug for which patient? Renal impairment Liver impairment Multi organ dysfunction Prophylactic dose history of HIT 1.Argatroban# 2.Danaparoid* 3.Bivalirudin 4.(Lepirudin) 1.Danaparoid* 2.Lepirudin# 3.Bivalirudin 4.(Argatroban) 1.Danaparoid* 2.Bivalirudin# 3.(Argatroban) 4.(Lepirudin) 1.Danaparoid 2.Fondaparinux (history) *preferable use in stable patients not expecting surgery; # preferable use in patients requiring invasive procedures with major bleeding risk; () use drug with great caution to avoid overdose

30. Danaparoid in HIT Danaparoid is used to anticoagulate HIT patients >20 years One small prospective randomized trial: danaparoid+dextran superior to warfarin+dextran Large international compassionate use program ~1000 patients Danaparoid is effective, dosage schedules are defined, bleeding complications do occur but therapeutic range is wide Review: B.H.Chong in Heparin-induced thrombocytopenia 3rd ed 2004; Warkentin&Greinacher eds

31. Cross-reactivity and platelet count recovery No cross-reactivity (N=16) Cross-reactivity (N=13) 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 024681012141618 30 Frequency of platelet count recovery (≥ 150 x 10 9 /L) Days to platelet count recovery during danaparoid treatment Unpublished data by Warkentin TE - used with permission

32. Cross-reactivity and platelet count recovery

33. Lepirudin Warkentin. Best Pract Res Clin Haematol 2004; 17: 105-125. 1 2 COO - +H3N+H3N Thrombin

34. Hist. control n=120Lepirudin n=339 Endpoints of lepirudin in HIT (HAT-1,-2,-3) Lubenow et al. JTH 2005;3:2428-36

35. Lepirudin Renal Function and Bleeding Risk (HAT-1,-2,-3) Lubenow et al. JTH 2005;3:2428-36

36. Anaphylactic reactions due to Refludan (lepirudin?) 64 mcardiacbolus<5minrecoveredsevere? 62 fcardiacbolus<5minrecoveredmoderate? 57 fHIT/cardiacbolus<5minrecoveredsevere? 67 fcardiacbolus<5minrecoveredsevere? 72 macute HIT/cardiac infusion<5minrecoveredmoderateyes 81 mhist. HIT/cardiac bolus<5minfatal8days 67 fhist. HIT/cardiac bolus<5minfatal1month 63 mhist. HIT/cardiac bolus<5minfatal2 months 62 mhist HIT vasc-surg ??fatal3 months outcomepreexposurecondition 5 anaphylactic reactions reported in ~ 32,500 treatments (0.015%) 4 anaphylactic reactions during reexposure; reexposure rate ~7.5% (0.16%) Start treatment in a setting with access to treatment of anaphylaxis Greinacher et al. Circulation; 2003:108: 2060-5

37. Argatroban argatroban 1 2

38. APTT, sec INR (Simplastin) INR (Innovin) 1 2 3 4 5 6 8 7 5070809010011012013014060 1 2 3 4 5 6 8 7 5070809010011012013014060 Warkentin TE, Greinacher A, et al.Thromb Haemost 2005, 94:958-64 Argatroban Melagatran Lepirudin Bivalirudin Argatroban Bivalirudin Melagatran Lepirudin DTIs differ in their effects on the INR

39. P=0.91 danaparoid with TEC at baseline n = 86 lepirudin with TEC at baseline n = 124 Comparison of Danaparoid and Lepirudin in HIT with Thrombosis Farner B et al. Thromb Haemost 2001;85:950-957.

40. danaparoid lepirudin Major bleedings > 2RBCs Farner B et al. Thromb Haemost 2001;85:950-957.

41. Lubenow et al. JTH 2005 Duration of Anticoagulation after HIT HIT with thrombosis: 3 – 6 months Isolated HIT: ??? At least until platelet counts normalized to a stable plateau T.E. Warkentin, J.Kelton Am J Hematol 1996; 101: Farner et al Thromb Haemost 2001

43. Protein C Cumarine immer überlappend mit parenteralem Antikoagulans beginnen. Max. 6 mg/Tag

44. In 2006 HIT is a widely recognized syndrome Catastrophic patients are rare in the clinic but HIT is increasing in out-patients Lab-assays rule out HIT, but antigen assays have the risk to overdiagnose HIT by 100% Effective drugs for management of HIT are available: balance risk of thrombosis/bleeding Basic research Clinical studies Continous medical education New drugs HIT

45. Lepirudin Life threatening thrombosis? Omit bolus dose NoYes Renal impairment? NoYes or unclear Reduce maintenance dose Creatinine unknown or 100-200 µmol/L: 0.05mg/kg/h Severe renal impairment: 0.001mg/kg/h Monitor every 4h until steady state is reached Monitor by prothrombin independent assay, e.g. ECA test Maintenance dose 0.1mg/kg/h Low prothrombin?* No Yes Monitor by aPTT Give bolus dose 0.4mg/kg b.w. 1.5-2.5x baseline, but not >80s** NoYes No changeAdjust dose, decrease or increase dose by 20% 0.5-1.0 µg/mL b.w. – body weight * e.g. liver impairment, DIC; previous treatment with vitamin K antagonists ** depending on laboratory dose response curve

46. Argatroban Low cardiac output/ cardiac shock Risk of reduced liver perfusion YesNo Use ECA test Monitor after 2h Low prothrombin* NoYes use aPTT 1.5-3x baseline, but not >100s NoYes No changeAdjust dose, 0.2-0.5µg/kg/min liver impairment (Child-Pugh score >6) No/ unclear Yes Start with 0.5µg/kg/minStart with 1.0µg/kg/min *e.g. liver impairment, DIC; pretreatment with vitamin K antagonists

47. Tage HIT Übernahme aus anderem Krankenhaus Thrombozyten [x10 9 /L] 74jähriger Patient, männlich dekompensierte globale Herzinsuffizienz kardiogener Schock mit Multiorganversagen Intensivtherapie, CVVH unfraktioniertes Heparin zur Antikoagulation 1. Heparin weitergeben, da es andere Erklärungen für die Thrombozytopenie gibt? 2. Heparin absetzen und therapeutische Dosierung alternatives Antikoagulanz beginnen? 3. Weitere Information einholen und HIT Test anfordern, Heparin weitergeben? 1 2 3 4

48. Tage HIT Übernahme aus anderem Krankenhaus Thrombozyten [x10 9 /L] HIPA und ELISA IgG pos 1. Heparin weitergeben, da es andere Erklärungen für die Thrombozytopenie gibt? 2. Heparin absetzen und therapeutische Dosierung alternatives Antikoagulanz beginnen? 3. Heparin absetzen und sehen was klinisch passiert?

49. Tage HIT Übernahme aus anderem Krankenhaus Thrombozyten [x10 9 /L]

50. Primary disease: acute pancreatitis low grade malignant NHL (known for 2 years) discharge to another hospital Was machen Sie: 1.Heparin weiter? 2.Alternative Antikoagulation? 3.HIT Test durchführen? Tracheotomie

51. Primary disease: acute pancreatitis low grade malignant NHL (known for 2 years) discharge to another hospital 14 days 8 days Was machen Sie: 1.NMH weiter? 2.HIT Test anfordern? 3.Alternative AK beginnen, dann HIT Test anfordern? Tracheotomie

52. Primary disease: acute pancreatitis low grade malignant NHL (known for 2 years) discharge to another hospital 14 days 8 days Tracheotomie Score: Thrombozytenabfall > 50%: 2 Beginn zwischen Tag 5 und 10 (UFH): 2 andere Erklärung für TP: 01.11. ja; 06.11. nein: 2

53. N. Lubenow K. Selleng D. Juhl P. Eichler C. Blumentritt U. Strobel B. Fürll T. Lietz T.E. Warkentin G. Lo S. Schenk B. Pötzsch University Hospital Greifswald

54. Approach to diagnose HIT T hrombocytopenia (> 50% decrease) T iming 5-14 days after starting heparin Unusual thromboembolism; skín lesions; anaphylaxis O T her cause not apparent T est for HIT antibodies positive (usually strongly positive) + + + + + + Yes HIT Strongly Suspected Possible T hrombosis Confirmed when positive in context of strong clinical suspicion

55. Studies comparing UFH and LMWH in medical patients, plus a large review of LMWH treatment during pregnancy Type of study Patient population HITHIT Antibodies LMWHUFHPLMWHUFHP Prospective cohorts 1;2 General medical 14/1754 (0.80%) 5/598 (0.84%) 1.00NR --- RCT 3 DVT treatment 1/720* (0.1%)** 8/356 (2.2%)** 0.0008745/720* (6.2%)*** 75/356 (21.1%)*** <0.0001 Prospective cohort 4 Neurology0/111 (0.0%) 5/200 (2.5%) 0.172/111 (1.8%) 41/200 (20.5%) <0.0001 Review 5 Pregnancy0/2,777 (0.0%) --- * combines short- and long-treated LMWH groups ** endpoint shown is symptomatic thrombosis associated with antibody formation (as per Table II in reference 4); for true HIT endpoint (defined as thrombocytopenia plus positive antibody), values are LMWH = 0/762 vs UFH = 1/375 (0.3%); p = 0.33 *** as per Table II in reference 4. Warkentin TE and Greinacher A, Blood 2005;106: 2931 – 2932 1 Girolmi et al Blood 2003; 2 Prandoni et al Blood 2005; 3 Lindhoff-Last et al Brit J Haematol 2002; 4 Pohl et al. Neurology 2005; 5 Greer et al. Blood 2005

56. Patients with TEC/evaluable patients (%) Odds Ratio95% confidence interval p-value Gender (406 patients) Male 80/167 (47.9%)1.0 Female 146/239 (61.1%)1.080.63-1.870.77 Age (405 patients) 0-39 years 16/34 (47.1%)1.0 40-59 years 57/103 (55.3%)2.710.96-7.610.06 60-79 years 134/232 (57.8%)1.940.76-4.960.16  80 years 19/36 (52.8%)0.980.29-3.290.98 Underlying disease (400 patients) Internal medicine 62/143 (43.4%)1.0 General surgery 20/53 (37.7%)0.720.34-1.510.38 Cardio-vascular Surgery 12/31 (38.7%)0.620.23-1.680.35 Orthopedic/trauma surgery 98/125 (78.4%)5.342.67-10.68<0.001 Others 30/48 (62.5%)1.700.76-3.840.20 Platelet count decrease (319 patients)  30% 5/19 (26.3%)1.0 > 30-50% 9/29 (31.0%)1.720.40-7.470.47 > 50-70% 27/57 (47.4%)3.630.95-13.860.06 > 70-90% 101/158 (63.9%)8.112.29-28.660.001 > 90% 38/56 (67.9%)8.792.26-34.170.002 Greinacher et al. Thromb Haemost 2005; 94:1 132-135