RSS-Feed abonnieren
DOI: 10.1055/s-0031-1300949
Current and Emerging Therapeutics for Heparin-Induced Thrombocytopenia
Publikationsverlauf
Publikationsdatum:
07. Februar 2012 (online)
![](https://www.thieme-connect.de/media/sth/201201/lookinside/thumbnails/10.1055-s-0031-1300949-1.jpg)
Abstract
Heparin-induced thrombocytopenia (HIT) is a prothrombotic complication of heparin therapy. Little more than a decade ago, no effective agents were available to treat this devastating and potentially fatal disease. Since that time, driven by an increased understanding of pathogenesis, the management of HIT has undergone a revolution. Several effective agents for the treatment and prevention of HIT-associated thrombosis are now available. These drugs have transformed the natural history of the disease, dramatically reducing the incidence of thrombosis. Nevertheless, available therapies remain far from ideal. Anticoagulants currently approved for the treatment of HIT are expensive, complex to manage, and carry a substantial bleeding risk. Fortunately, a pipeline of agents await that hold the promise of greater safety, convenience, and cost-effectiveness. The objectives of this review are to discuss currently available drugs for the treatment of HIT, highlight the limitations of these agents, and examine future therapies.
-
References
- 1 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 (1) 95-96
- 2 Rauova L, Poncz M, McKenzie SE , et al. Ultralarge complexes of PF4 and heparin are central to the pathogenesis of heparin-induced thrombocytopenia. Blood 2005; 105 (1) 131-138
- 3 Martel N, Lee J, Wells PS. Risk for heparin-induced thrombocytopenia with unfractionated and low-molecular-weight heparin thromboprophylaxis: a meta-analysis. Blood 2005; 106 (8) 2710-2715
- 4 Warkentin TE, Levine MN, Hirsh J , et al. Heparin-induced thrombocytopenia in patients treated with low-molecular-weight heparin or unfractionated heparin. N Engl J Med 1995; 332 (20) 1330-1335
- 5 Girolami B, Prandoni P, Stefani PM , et al. The incidence of heparin-induced thrombocytopenia in hospitalized medical patients treated with subcutaneous unfractionated heparin: a prospective cohort study. Blood 2003; 101 (8) 2955-2959
- 6 Warkentin TE, Sheppard JA, Horsewood P, Simpson PJ, Moore JC, Kelton JG. Impact of the patient population on the risk for heparin-induced thrombocytopenia. Blood 2000; 96 (5) 1703-1708
- 7 Smythe MA, Koerber JM, Mattson JC. The incidence of recognized heparin-induced thrombocytopenia in a large, tertiary care teaching hospital. Chest 2007; 131 (6) 1644-1649
- 8 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 (3) 846-851
- 9 Warkentin TE, Kelton JG. A 14-year study of heparin-induced thrombocytopenia. Am J Med 1996; 101 (5) 502-507
- 10 Lewis BE, Wallis DE, Hursting MJ, Levine RL, Leya F. Effects of argatroban therapy, demographic variables, and platelet count on thrombotic risks in heparin-induced thrombocytopenia. Chest 2006; 129 (6) 1407-1416
- 11 Lubenow N, Eichler P, Lietz T, Greinacher A ; Hit Investigators Group. Lepirudin in patients with heparin-induced thrombocytopenia - results of the third prospective study (HAT-3) and a combined analysis of HAT-1, HAT-2, and HAT-3. J Thromb Haemost 2005; 3 (11) 2428-2436
- 12 Cuker A. Recent advances in heparin-induced thrombocytopenia. Curr Opin Hematol 2011; 18 (5) 315-322
- 13 Wallis DE, Workman DL, Lewis BE, Steen L, Pifarre R, Moran JF. Failure of early heparin cessation as treatment for heparin-induced thrombocytopenia. Am J Med 1999; 106 (6) 629-635
- 14 Warkentin TE, Greinacher A, Koster A, Lincoff AM ; American College of Chest Physicians Treatment and prevention of heparin-induced thrombocytopenia: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. 8th edition. Chest 2008; 133: 340S-380S
- 15 Cuker A. Heparin-induced thrombocytopenia: present and future. J Thromb Thrombolysis 2011; 31 (3) 353-366
- 16 Lewis BE, Wallis DE, Leya F, Hursting MJ, Kelton JG . Argatroban-915 Investigators. Argatroban anticoagulation in patients with heparin-induced thrombocytopenia. Arch Intern Med 2003; 163 (15) 1849-1856
- 17 Lewis BE, Wallis DE, Berkowitz SD , et al; ARG-911 Study Investigators. Argatroban anticoagulant therapy in patients with heparin-induced thrombocytopenia. Circulation 2001; 103 (14) 1838-1843
- 18 Cuker A, Arepally G, Crowther MA , et al. The HIT Expert Probability (HEP) Score: a novel pre-test probability model for heparin-induced thrombocytopenia based on broad expert opinion. J Thromb Haemost 2010; 8 (12) 2642-2650
- 19 Beiderlinden M, Treschan TA, Görlinger K, Peters J. Argatroban anticoagulation in critically ill patients. Ann Pharmacother 2007; 41 (5) 749-754
- 20 Sheth SB, DiCicco RA, Hursting MJ, Montague T, Jorkasky DK. Interpreting the international normalized ratio (INR) in individuals receiving argatroban and warfarin. Thromb Haemost 2001; 85 (3) 435-440
- 21 Harder S, Graff J, Klinkhardt U , et al. Transition from argatroban to oral anticoagulation with phenprocoumon or acenocoumarol: effects on prothrombin time, activated partial thromboplastin time, and Ecarin clotting time. Thromb Haemost 2004; 91 (6) 1137-1145
- 22 Greinacher A, Janssens U, Berg G , et al. Lepirudin (recombinant hirudin) for parenteral anticoagulation in patients with heparin-induced thrombocytopenia. Heparin-Associated Thrombocytopenia Study (HAT) investigators. Circulation 1999; 100 (6) 587-593
- 23 Greinacher A, Völpel 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 (1) 73-80
- 24 Tardy B, Lecompte T, Boelhen F , et al; GEHT-HIT Study Group. Predictive factors for thrombosis and major bleeding in an observational study in 181 patients with heparin-induced thrombocytopenia treated with lepirudin. Blood 2006; 108 (5) 1492-1496
- 25 Eichler P, Friesen HJ, 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 (7) 2373-2378
- 26 Song X, Huhle G, Wang L, Hoffmann U, Harenberg J. Generation of anti-hirudin antibodies in heparin-induced thrombocytopenic patients treated with r-hirudin. Circulation 1999; 100 (14) 1528-1532
- 27 Cardenas GA, Deitcher SR. Risk of anaphylaxis after reexposure to intravenous lepirudin in patients with current or past heparin-induced thrombocytopenia. Mayo Clin Proc 2005; 80 (4) 491-493
- 28 Greinacher A, Lubenow N, Eichler P. Anaphylactic and anaphylactoid reactions associated with lepirudin in patients with heparin-induced thrombocytopenia (HIT). Circulation 2003; 108: 2062-2065
- 29 Bittl JA, Chaitman BR, Feit F, Kimball W, Topol EJ. Bivalirudin versus heparin during coronary angioplasty for unstable or postinfarction angina: Final report reanalysis of the Bivalirudin Angioplasty Study. Am Heart J 2001; 142 (6) 952-959
- 30 Lincoff AM, Bittl JA, Harrington RA , et al; REPLACE-2 Investigators. Bivalirudin and provisional glycoprotein IIb/IIIa blockade compared with heparin and planned glycoprotein IIb/IIIa blockade during percutaneous coronary intervention: REPLACE-2 randomized trial. JAMA 2003; 289 (7) 853-863
- 31 Dyke CM, Smedira NG, Koster A , et al. A comparison of bivalirudin to heparin with protamine reversal in patients undergoing cardiac surgery with cardiopulmonary bypass: the EVOLUTION-ON study. J Thorac Cardiovasc Surg 2006; 131 (3) 533-539
- 32 Koster A, Spiess B, Jurmann M , et al. Bivalirudin provides rapid, effective, and reliable anticoagulation during off-pump coronary revascularization: results of the “EVOLUTION OFF” trial. Anesth Analg 2006; 103 (3) 540-544
- 33 Kiser TH, Fish DN. Evaluation of bivalirudin treatment for heparin-induced thrombocytopenia in critically ill patients with hepatic and/or renal dysfunction. Pharmacotherapy 2006; 26 (4) 452-460
- 34 Skrupky LP, Smith JR, Deal EN , et al. Comparison of bivalirudin and argatroban for the management of heparin-induced thrombocytopenia. Pharmacotherapy 2010; 30 (12) 1229-1238
- 35 Kiser TH, Mann AM, Trujillo TC, Hassell KL. Evaluation of empiric versus nomogram-based direct thrombin inhibitor management in patients with suspected heparin-induced thrombocytopenia. Am J Hematol 2011; 86 (3) 267-272
- 36 Frame JN, Rice L, Bartholomew JR, Whelton A. Rationale and design of the PREVENT-HIT study: a randomized, open-label pilot study to compare desirudin and argatroban in patients with suspected heparin-induced thrombocytopenia with or without thrombosis. Clin Ther 2010; 32 (4) 626-636
- 37 Boyce SW, Bandyk DF, Bartholomew JR, Frame JN, Rice L. A Randomized, Open-Label Pilot Study Comparing Desirudin and Argatroban in Patients with Suspected Heparin-Induced Thrombocytopenia With or Without Thrombosis: PREVENT-HIT Study. Am J Ther 2010; 18: 14-22
- 38 Chong BH, Gallus AS, Cade JF , et al; Australian HIT Study Group. Prospective randomised open-label comparison of danaparoid with dextran 70 in the treatment of heparin-induced thrombocytopaenia with thrombosis: a clinical outcome study. Thromb Haemost 2001; 86 (5) 1170-1175
- 39 Farner B, Eichler P, Kroll H, Greinacher A. A comparison of danaparoid and lepirudin in heparin-induced thrombocytopenia. Thromb Haemost 2001; 85: 950-957
- 40 Magnani HN, 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 (6) 967-981
- 41 Kovacs MJ. Successful treatment of heparin induced thrombocytopenia (HIT) with fondaparinux. Thromb Haemost 2005; 93 (5) 999-1000
- 42 Lobo B, Finch C, Howard A, Minhas S. Fondaparinux for the treatment of patients with acute heparin-induced thrombocytopenia. Thromb Haemost 2008; 99 (1) 208-214
- 43 Grouzi E, Kyriakou E, Panagou I, Spiliotopoulou I. Fondaparinux for the treatment of acute heparin-induced thrombocytopenia: a single-center experience. Clin Appl Thromb Hemost 2010; 16 (6) 663-667
- 44 Pappalardo F, Scandroglio A, Maj G, Zangrillo A, D’Angelo A. Treatment of heparin-induced thrombocytopenia after cardiac surgery: preliminary experience with fondaparinux. J Thorac Cardiovasc Surg 2010; 139 (3) 790-792
- 45 Warkentin TE. Fondaparinux: does it cause HIT? Can it treat HIT?. Expert Rev Hematol 2010; 3 (5) 567-581
- 46 Motokawa S, Torigoshi T, Maeda Y , et al. IgG-class anti-PF4/heparin antibodies and symptomatic DVT in orthopedic surgery patients receiving different anti-thromboembolic prophylaxis therapeutics. BMC Musculoskelet Disord 2011; 12: 22
- 47 Warkentin TE, Davidson BL, Buller HR , et al. Prevalence and risk of pre-existing heparin-induced thrombocytopenia antibodies in patients with acute VTE. Chest 2011; 140 (2) 366-373
- 48 Warkentin TE, Maurer BT, Aster RH. Heparin-induced thrombocytopenia associated with fondaparinux. N Engl J Med 2007; 356 (25) 2653-2655, discussion 2653–2655
- 49 Rota E, Bazzan M, Fantino G. Fondaparinux-related thrombocytopenia in a previous low-molecular-weight heparin (LMWH)-induced heparin-induced thrombocytopenia (HIT). Thromb Haemost 2008; 99 (4) 779-781
- 50 Salem M, Elrefai S, Shrit MA, Warkentin TE. Fondaparinux thromboprophylaxis-associated heparin-induced thrombocytopenia syndrome complicated by arterial thrombotic stroke. Thromb Haemost 2010; 104 (5) 1071-1072
- 51 Pistulli R, Oberle V, Figulla HR, Yilmaz A, Pfeifer R. Fondaparinux cross-reacts with heparin antibodies in vitro in a patient with fondaparinux-related thrombocytopenia. Blood Coagul Fibrinolysis 2011; 22 (1) 76-78
- 52 Hursting MJ, Soffer J. Reducing harm associated with anticoagulation: practical considerations of argatroban therapy in heparin-induced thrombocytopenia. Drug Saf 2009; 32 (3) 203-218
- 53 To L, Schillig JM, Desmet BD, Kuriakose P, Szandzik EG, Kalus JS. Impact of a pharmacist-directed anticoagulation service on the quality and safety of heparin-induced thrombocytopenia management. Ann Pharmacother 2011; 45 (2) 195-200
- 54 Cooper T, Taber D, Mazur J. Implementation of a collaborative drug therapy management service for inpatients receiving direct thrombin inhibitors. Am J Health Syst Pharm 2009; 66 (14) 1297-1303
- 55 Garcia D, Libby E, Crowther MA. The new oral anticoagulants. Blood 2010; 115 (1) 15-20
- 56 Hursting MJ, Verme-Gibboney CN. Risk factors for major bleeding in patients with heparin-induced thrombocytopenia treated with argatroban: a retrospective study. J Cardiovasc Pharmacol 2008; 52 (6) 561-566
- 57 Sachais BS, Rux AH, Hinds JL, Rux JJ . Rational design and characterization of platelet factor 4 antagonists. Paper presented at: Annual Meeting of the American Society of Hematology; December 6, 2010 ; Orlando, FL
- 58 Reilly MP, Sinha U, André P , et al. PRT-060318, a novel Syk inhibitor, prevents heparin-induced thrombocytopenia and thrombosis in a transgenic mouse model. Blood 2011; 117 (7) 2241-2246
- 59 Stolla M, Stefanini L, Andre P , et al. CalDAG-GEFI deficiency protects mice in a novel model of FcγRIIA-mediated thrombosis and thrombocytopenia. Blood 2011; 118 (4) 1113-1120
- 60 Nanwa N, Mittmann N, Knowles S , et al. The direct medical costs associated with suspected heparin-induced thrombocytopenia. Pharmacoeconomics 2011; 29 (6) 511-520
- 61 Wilke T, Tesch S, Scholz A, Kohlmann T, Greinacher A. The costs of heparin-induced thrombocytopenia: a patient-based cost of illness analysis. J Thromb Haemost 2009; 7 (5) 766-773
- 62 Baroletti S, Piovella C, Fanikos J, Labreche M, Lin J, Goldhaber SZ. Heparin-induced thrombocytopenia (HIT): clinical and economic outcomes. Thromb Haemost 2008; 100 (6) 1130-1135
- 63 Elalamy I, Le Gal G, Nachit-Ouinekh F , et al. Heparin-induced thrombocytopenia: an estimate of the average cost in the hospital setting in France. Clin Appl Thromb Hemost 2009; 15 (4) 428-434
- 64 Smythe MA, Koerber JM, Fitzgerald M, Mattson JC. The financial impact of heparin-induced thrombocytopenia. Chest 2008; 134 (3) 568-573