Heparin-Induced Thrombocytopenia Clinical Studies and the Efficacy of Argatroban in Japan

ABSTRACT

Immune-mediated heparin-induced thrombocytopenia (HIT) is a life-threatening side effect of heparin therapy. HIT has been better recognized in Japan since April 2006 when prescribing information on heparin was revised to include HIT. Diagnosis and treatment of HIT in Japan, however, are still problematic because Japanese regulators have not yet approved any laboratory tests or pharmacological intervention for HIT, especially in patients with acute HIT who require surgery with cardiopulmonary bypass (CPB). We report on three specific cases anticoagulated with argatroban for CPB showing the difficulty of anticoagulation management. We review several retrospective studies and a multicenter, prospective cohort study that suggest a lower incidence of HIT in Japan than what is diagnosed in Western countries. This may be due to ethnic factors and/or different clinical practices. We conducted a multicenter, nonrandomized, open-label trial showing the efficacy and safety of argatroban when carefully dosed. From this study we describe a Japanese strategy to diagnose and treat HIT that may be of value elsewhere.

Heparin-induced thrombocytopenia - Japanese population - direct thrombin inhibitor - argatroban

REFERENCES

• 1 Warkentin T E, Greinacher A. Heparin-induced thrombocytopenia: recognition, treatment, and prevention: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy.  Chest. 2004;  126 311S-337S
• 2 Arepally G M, Ortel T L. Clinical practice. Heparin-induced thrombocytopenia.  N Engl J Med. 2006;  355 809-817
• 3 Warkentin T E. Drug-induced immune-mediated thrombocytopenia–from purpura to thrombosis.  N Engl J Med. 2007;  356 891-893
• 4 Amiral J, Bridey F, Dreyfus M et al.. Platelet factor 4 complexed to heparin is the target for antibodies generated in heparin-induced thrombocytopenia.  Thromb Haemost. 1992;  68 95-96
• 5 Rauova L, Poncz M, McKenzie S E et al.. Ultralarge complexes of PF4 and heparin are central to the pathogenesis of heparin-induced thrombocytopenia.  Blood. 2005;  105 131-138
• 6 Rauova L, Zhai L, Kowalska M A, Arepally G M, Cines D B, Poncz M. Role of platelet surface PF4 antigenic complexes in heparin-induced thrombocytopenia pathogenesis: diagnostic and therapeutic implications.  Blood. 2006;  107 2346-2353
• 7 Suvarna S, Rauova L, McCracken E K et al.. PF4/heparin complexes are T cell-dependent antigens.  Blood. 2005;  106 929-931
• 8 Greinacher A, Farner B, Kroll H, Kohlmann T, Warkentin T E, Eichler P. Clinical features of heparin-induced thrombocytopenia including risk factors for thrombosis. A retrospective analysis of 408 patients.  Thromb Haemost. 2005;  94 132-135
• 9 Warkentin T E, Heddle N M. Laboratory diagnosis of immune heparin-induced thrombocytopenia.  Curr Hematol Rep. 2003;  2 148-157
• 10 Warkentin T E, Kelton J G. Temporal aspects of heparin-induced thrombocytopenia.  N Engl J Med. 2001;  344 1286-1292
• 11 Warkentin T E, Kelton J G. Delayed-onset heparin-induced thrombocytopenia and thrombosis.  Ann Intern Med. 2001;  135 502-506
• 12 Warkentin T E, Roberts R S, Hirsh J, Kelton J G. An improved definition of immune heparin-induced thrombocytopenia in postoperative orthopedic patients.  Arch Intern Med. 2003;  163 2518-2524
• 13 Lo G K, Juhl D, Warkentin T E, Sigouin C S, Eichler P, Greinacher A. Evaluation of pretest clinical score (4 T's) for the diagnosis of heparin-induced thrombocytopenia in two clinical settings.  J Thromb Haemost. 2006;  4 759-765
• 14 Warkentin T E, Sheppard J A, Horsewood P, Simpson P J, Moore J C, Kelton J G. Impact of the patient population on the risk for heparin-induced thrombocytopenia.  Blood. 2000;  96 1703-1708
• 15 Martel N, Lee J, Wells P S. Risk for heparin-induced thrombocytopenia with unfractionated and low-molecular-weight heparin thromboprophylaxis: a meta-analysis.  Blood. 2005;  106 2710-2715
• 16 Francis J L, Palmer III G J, Moroose R, Drexler A. Comparison of bovine and porcine heparin in heparin antibody formation after cardiac surgery.  Ann Thorac Surg. 2003;  75 17-22
• 17 Pouplard C, May M A, Regina S, Marchand M, Fusciardi J, Gruel Y. Changes in platelet count after cardiac surgery can effectively predict the development of pathogenic heparin-dependent antibodies.  Br J Haematol. 2005;  128 837-841
• 18 Warkentin T E, Elavathil L J, Hayward C P, Johnston M A, Russett J I, Kelton J G. The pathogenesis of venous limb gangrene associated with heparin-induced thrombocytopenia.  Ann Intern Med. 1997;  127 804-812
• 19 Magnani H N. Heparin-induced thrombocytopenia (HIT): an overview of 230 patients treated with Orgaran (Org 10172).  Thromb Haemost. 1993;  70 554-561
• 20 Warkentin T E, Kelton J G. A 14-year study of heparin-induced thrombocytopenia.  Am J Med. 1996;  101 502-507
• 21 http://Available at www.clinicaltrials.gov (ClinicalTrials.gov Identifier: NCT00198575)
• 22 http://Available at www.clinicaltrials.gov (ClinicalTrials.gov Identifier: NCT00198588)
• 23 Pouplard C, Gueret P, Fouassier M et al.. Prospective evaluation of the ‘4Ts’ score and particle gel immunoassay specific to heparin/PF4 for the diagnosis of heparin-induced thrombocytopenia.  J Thromb Haemost. 2007;  5 1373-1379
• 24 Greinacher A, Eichler P, Lubenow N, Kwasny H, Luz M. Heparin-induced thrombocytopenia with thromboembolic complications: meta-analysis of 2 prospective trials to assess the value of parenteral treatment with lepirudin and its therapeutic aPTT range.  Blood. 2000;  96 846-851
• 25 Chong B H, Berndt M C. Heparin-induced thrombocytopenia.  Blut. 1989;  58 53-57
• 26 Greinacher A, Volpel H, Janssens U et al.. Recombinant hirudin (lepirudin) provides safe and effective anticoagulation in patients with heparin-induced thrombocytopenia: a prospective study.  Circulation. 1999;  99 73-80
• 27 Christiansen S, Jahn U R, Meyer J et al.. Anticoagulative management of patients requiring left ventricular assist device implantation and suffering from heparin-induced thrombocytopenia type II.  Ann Thorac Surg. 2000;  69 774-777
• 28 Reichert M G, MacGregor D A, Kincaid E H, Dolinski S Y. Excessive argatroban anticoagulation for heparin-induced thrombocytopenia.  Ann Pharmacother. 2003;  37 652-654
• 29 Ichikawa M, Oue M, Okamoto A et al.. A case of heparin-induced thrombocytopenia associated with unexpected excessive argatroban anticoagulation after abdominal aortic aneurysm resection.  Masui. 2006;  55 188-192
• 30 Magnani H N, Gallus A. Heparin-induced thrombocytopenia (HIT). A report of 1,478 clinical outcomes of patients treated with danaparoid (Orgaran) from 1982 to mid-2004.  Thromb Haemost. 2006;  95 967-981
• 31 Eichler P, Friesen H J, Lubenow N, Jaeger B, Greinacher A. Antihirudin antibodies in patients with heparin-induced thrombocytopenia treated with lepirudin: incidence, effects on aPTT, and clinical relevance.  Blood. 2000;  96 2373-2378
• 32 Kawada T, Kitagawa H, Hoson M, Okada Y, Shiomura J. Clinical application of argatroban as an alternative anticoagulant for extracorporeal circulation.  Hematol Oncol Clin North Am. 2000;  14 445-457
• 33 Furukawa K, Ohteki H, Hirahara K, Narita Y, Koga S. The use of argatroban as an anticoagulant for cardiopulmonary bypass in cardiac operations.  J Thorac Cardiovasc Surg. 2001;  122 1255-1256
• 34 Edwards J T, Hamby J K, Worrall N K. Successful use of argatroban as a heparin substitute during cardiopulmonary bypass: heparin-induced thrombocytopenia in a high-risk cardiac surgical patient.  Ann Thorac Surg. 2003;  75 1622-1624
• 35 Gasparovic H, Nathan N S, Fitzgerald D, Aranki S F. Severe argatroban-induced coagulopathy in a patient with a history of heparin-induced thrombocytopenia.  Ann Thorac Surg. 2004;  78 e89-e91
• 36 Zwicker J I, Uhl L, Huang W Y, Shaz B H, Bauer K A. Thrombosis and ELISA optical density values in hospitalized patients with heparin-induced thrombocytopenia.  J Thromb Haemost. 2004;  2 2133-2137
• 37 Koster A, Spiess B, Chew D P et al.. Effectiveness of bivalirudin as a replacement for heparin during cardiopulmonary bypass in patients undergoing coronary artery bypass grafting.  Am J Cardiol. 2004;  93 356-359
• 38 Koster A, Dyke C M, Aldea G et al.. Bivalirudin during cardiopulmonary bypass in patients with previous or acute heparin-induced thrombocytopenia and heparin antibodies: results of the CHOOSE-ON trial.  Ann Thorac Surg. 2007;  83 572-577
• 39 Koster A, Yeter R, Buz S et al.. Assessment of hemostatic activation during cardiopulmonary bypass for coronary artery bypass grafting with bivalirudin: results of a pilot study.  J Thorac Cardiovasc Surg. 2005;  129 1391-1394
• 40 Veale J J, McCarthy H M, Palmer G, Dyke C M. Use of bivalirudin as an anticoagulant during cardiopulmonary bypass.  J Extra Corpor Technol. 2005;  37 296-302
• 41 Zucker M L, Koster A, Prats J, Laduca F M. Sensitivity of a modified ACT test to levels of bivalirudin used during cardiac surgery.  J Extra Corpor Technol. 2005;  37 364-368
• 42 Potzsch B, Klovekorn W P, Madlener K. Use of heparin during cardiopulmonary bypass in patients with a history of heparin-induced thrombocytopenia.  N Engl J Med. 2000;  343 515
• 43 Selleng S, Lubenow N, Wollert H G, Mullejans B, Greinacher A. Emergency cardiopulmonary bypass in a bilaterally nephrectomized patient with a history of heparin-induced thrombocytopenia: successful reexposure to heparin.  Ann Thorac Surg. 2001;  71 1041-1042
• 44 Verma A K, Levine M, Shalansky S J, Carter C J, Kelton J G. Frequency of heparin-induced thrombocytopenia in critical care patients.  Pharmacotherapy. 2003;  23 745-753
• 45 Warkentin T E, Greinacher A. Heparin-induced thrombocytopenia and cardiac surgery.  Ann Thorac Surg. 2003;  76 2121-2131
• 46 Pouplard C, May M A, Iochmann S et al.. Antibodies to platelet factor 4-heparin after cardiopulmonary bypass in patients anticoagulated with unfractionated heparin or a low-molecular-weight heparin: clinical implications for heparin-induced thrombocytopenia.  Circulation. 1999;  99 2530-2536
• 47 Lewis B E, Wallis D E, Berkowitz S D et al.. Argatroban anticoagulant therapy in patients with heparin-induced thrombocytopenia.  Circulation. 2001;  103 1838-1843
• 48 Koster A, Buz S, Hetzer R, Kuppe H, Breddin K, Harder S. Anticoagulation with argatroban in patients with heparin-induced thrombocytopenia antibodies after cardiovascular surgery with cardiopulmonary bypass: first results from the ARG-E03 trial.  J Thorac Cardiovasc Surg. 2006;  132 699-700
• 49 Beiderlinden M, Treschan T A, Gorlinger K, Peters J. Argatroban anticoagulation in critically ill patients.  Ann Pharmacother. 2007;  41 749-754