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Andreas Greinacher Institut für Immunologie und Transfusionsmedizin Ernst-Moritz-Arndt-Universität Greifswald B r ædstru

Heparin-induced Thrombocytopenia: Pathogenesis, Diagnosis, and Management. Andreas Greinacher Institut für Immunologie und Transfusionsmedizin Ernst-Moritz-Arndt-Universität Greifswald B r ædstrup, April 2006. Heparin-Platelet Interactions.

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Andreas Greinacher Institut für Immunologie und Transfusionsmedizin Ernst-Moritz-Arndt-Universität Greifswald B r ædstru

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

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

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

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

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

  7. ~15% of patients with HIT have normal platelet counts 40 No HIT-associated thrombosis HIT-associated thrombosis HIT-associated thrombosis occurred in patients with platelet counts >150,000/mm3 30 No. of Patients With HIT 20 10 0 5 10 500 1000 20 30 50 70 100 150 200 300 Platelet Count Nadir (1000/mm3) HIT: Platelet Counts in Laboratory-Confirmed HIT May Be Normal Adapted with permission from Warkentin TE. Semin Hematol. 1998;35(suppl 5):9-16.

  8. Rapid-onset HIT (previous heparin exposure typically within 4 – 6 weeks) Delayed-onset HIT (average of 9 days after heparin is stopped) HIT: Temporal Aspects Typical-onset HIT (within 4 to 14 days) 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 21 40 Days Heparin exposure 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.

  9. Drug dependent TP/PTP Pseudothrombocytopenia GPIIb/IIIa Inhibitor induced TP Differential Diagnosis of HIT 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

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

  11. Diagnosis - pretest probability: the 4 T’s A B C D Lo et al. J Thromb Haemost 2006

  12. Diagnosis - pretest probabilityInterpretation 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

  13. Übernahme aus anderem Krankenhaus HIT Platelets [x109/L] Tage Thrombocytopenia > 50% decrease : 2 Onset day 2 : 0 Thrombosis, no : 0 Other reason, definite : 0 admittance in ICU • 74 year old male patient • heart failure • sepsis • multiorgan failure • ICU, renal replacement CVVH • UFH UFH 1 2 3 4 Days

  14. Übernahme aus anderem Krankenhaus HIT Platelets [x109/L] Tage Thrombocytopenia > 50% decrease : 2 Onset day 9 : 2 Thrombosis, no : 0 Other reason, probably : 1 Transfer from another hospital HIPA and ELISA IgG pos UFH UFH non heparin anticoagulant Days

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

  16. Frequency of “HIT”: Platelet Fall >30%and/or Thrombosis (Pos HIPA test) UFH LMWH* HIT-T 6/231 (2.6%) 0/271 (0.0%) P<0.0092 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 HIT-T * Enoxaparin HIT HIPA EIA Greinacher et al. Blood 2005;106:2921-2

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

  18. Cumulative thrombotic event-rate (%) 100 90 80 70 60 50 40 30 20 10 0 N = 62 52.8% 10 12 14 16 18 20 22 24 26 28 30 0 2 4 6 8 Days After Isolated HIT Recognized Occurrence of symptomatic thrombosis after stopping heparin in patients confirmed to have isolated HIT 14-year retrospective study Adapted from Warkentin TE, Kelton JG. Am J Med. 1996;101:502–507.

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

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

  21. 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

  22. 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.

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

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

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

  26. and/or Decrease of plt count > 50% New thrombosis HIT possible stop heparin Perform antigen test for HIT Onset > 5 days of heparin? No Yes HIT test positive? Therapeutic dose AC necessary due to primary disease? Previous heparin within the last 30 days? Other cause likely? No Yes No Yes No Yes Yes No HIT very unlikely maintain heparin HIT possible HIT unlikely restart heparin High bleeding risk? Perform antigen test to rule out HIT Functional test for HIT positive? Yes No Yes No Use prophylactic dose AC e.g. danaparoid 750 t.i.d. (option in European Union, Australia, Canada) Use therapeutic dose alternative AC HIT HIT unlikely plt – platelet AC – anticoagulation t.i.d. – three times daily

  27. Patient Population affected by HIT is changing Greinacher et al. 2005 and unpublished data

  28. Which drug for which patient? *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

  29. 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

  30. 1.0 0.9 0.8 0.7 0.6 0.5 No cross-reactivity (N=16) 0.4 Cross-reactivity (N=13) 0.3 0.2 0.1 0 0 2 4 6 8 10 12 14 16 18 30 Cross-reactivity and platelet count recovery Frequency of platelet count recovery (≥ 150 x 109/L) Days to platelet count recovery during danaparoid treatment Unpublished data by Warkentin TE - used with permission

  31. Cross-reactivity and platelet count recovery

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

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

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

  35. Anaphylactic reactions due to Refludan (lepirudin?) condition outcome preexposure 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

  36. 1 2 Argatroban argatroban

  37. 8 8 7 7 6 6 5 5 4 4 3 3 2 2 1 1 50 50 60 60 70 70 80 80 90 90 100 100 110 110 120 120 130 130 140 140 DTIs differ in their effects on the INR Bivalirudin Melagatran Argatroban Melagatran Argatroban INR (Innovin) Bivalirudin INR (Simplastin) Lepirudin Lepirudin APTT, sec Warkentin TE, Greinacher A, et al.Thromb Haemost 2005, 94:958-64

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

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

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

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

  42. 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 New drugs Clinical studies HIT Continous medical education

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

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

  45. Übernahme aus anderem Krankenhaus HIT Thrombozyten [x109/L] Tage 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? • 74jähriger Patient, männlich • dekompensierte globale Herzinsuffizienz • kardiogener Schock mit Multiorganversagen • Intensivtherapie, CVVH • unfraktioniertes Heparin zur Antikoagulation 1 2 3 4

  46. Übernahme aus anderem Krankenhaus HIT Thrombozyten [x109/L] Tage 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? HIPA und ELISA IgG pos

  47. Übernahme aus anderem Krankenhaus HIT Thrombozyten [x109/L] Tage

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

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