Fondaparinux for the treatment of patients with acute heparininduced thrombocytopenia

Summary

Heparin-induced thrombocytopenia (HIT) is a life-threatening immune response to heparin that is associated with a high risk of thromboembolic complications. We prospectively treated seven subjects with acute HIT with fondaparinux and compared the results to a similar historical control population from the same hospital. Six of the seven fondaparinux-treated subjects were transitioned to warfarin, beginning after platelet count recovery occurred. Ten historical controls were treated with a direct thrombin inhibitor (DTI), eight of which were transitioned to warfarin. The primary study outcome was platelet count recovery which was defined as an increase from baseline by at least 30% of nadir to greater than 100,000/mm³ by day seven. Seven subjects were prospectively treated with fondaparinux for a median of eight days. Six of the seven had HIT with thrombosis at the time of enrollment. All fondaparinux treated subjects had a complete platelet count recovery, and none experienced a new thromboembolic complication, major bleeding or death by week four. One subject underwent limb amputation. Ten historical controls were treated with a DTI for a median duration of eleven days. Platelet count recovery occurred in eight of the ten historical controls. No new thromboembolic complications or major bleeds occurred but limb gangrene occurred in four controls. The development of limb gangrene in the historical controls may have been a result of delayed recognition of HIT and/ or inappropriately early institution of warfarin in the historical controls. This pilot study suggests that fondaparinux may be useful in patients with acute HIT.

Keywords

Coagulation inhibitors - deep vein thrombosis - heparins - thrombocytopenia - fondaparinux

• References

• 1 Warkentin TE, Greinacher A. Heparin-induced thrombocytopenia: Recognition, treatment, and prevention. Chest 2004; 126 (Suppl. 03) 311s-337s.
• 2 Arepally GM, Ortel TL. Heparin-induced thrombocytopenia. N Engl J Med 2006; 355: 809-817.
• 3 Warkentin TE, Levine MN, Hirsh J. et al. Heparininduced thrombocytopenia in patients treated with lowmolecular- weight heparin or unfractionated heparin. N Engl J Med 1995; 332: 1330-1335.
• 4 Greinacher A, Farner B, Kroll H. et al. Clinical features of heparin-induced thrombocytopenia including risk factors for thrombosis. A retrospective analysis of 408 patients. Thromb Haemost 2005; 94: 132-135.
• 5 Warkentin TE, Kelton JG. Delayed-onset heparininduced thrombocytopenia and thrombosis. Ann Intern Med 2001; 135: 502-506.
• 6 Warkentin TE, Kelton JG. A 14 year study of heparin- induced thrombocytopenia. Am J Med 1996; 101: 502-507.
• 7 Wallis De, Workman DL, Lewis BE. et al. Failure of early heparin cessation as treatment for heparin-induced thrombocytopenia. Am J Med 1999; 106: 629-635.
• 8 Elalamy I, Lecrubier C, Potevin F. et al. Absence of in vitro cross-reaction of pentasaccharide with the plasma heparin-dependent factor of twenty-five patients with heparin-induced thrombocytopenia. Thromb Haemost 1995; 74: 1384-1385.
• 9 Amiral J, Lormeau JC, Marfaing-Koka A. et al. Absence of cross-reactivity of SR90107A/ORG31540 pentasaccharide with antibodies to heparin-PF4 complexes developed in heparin-induced thrombocytopenia. Blood Coagul Fibrinolysis 1997; 8: 114-117.
• 10 Ahmad S, Jeske WP, Walenga JM. et al. Synthetic pentasaccharides do not cause platelet activation by antiheparin-platelet factor 4 antibodies. Clin Appl Thromb Hemost 1999; 5: 259-266.
• 11 Savi P, Chong BH, Greinacher A. et al. Effect of fondaprinux on platelet activation in the presence of heparin- dependent antibodies: a blinded comparative multicenter study with unfractionated heparin. Blood 2005; 105: 139-144.
• 12 Warkentin TE, Cook RJ, Marder VJ. et al. Anti-platelet factor 4/heparin antibodies in orthopedic surgery patients receiving antithrombotic prophylaxis with fondaparinux or enoxaparin. Blood 2005; 106: 3791-3796.
• 13 Berlex.. Refludan (lepirudin [rDNA] for injection) prescribing information.. Montvale; NJ, USA: October 2004
• 14 GlaxoSmithKline.. Argatroban prescribing information.. Research Triangle Park; NC, USA: April 2005
• 15 The Medicines Company.. Angiomax (bivalirudin for injection) prescribing information. Parsippany; NJ, USA: December 2005
• 16 Gosselin RC, Dager WE, King JH. et al. Effect of direct-thrombin inhibitors: bivalirudin, lepirudin, and argatroban, on prothrombin time and INR values. Am J Clin Path 2004; 124: 593-599.
• 17 Bartholomew JR, Hursting MJ. Transitioning from argatroban to warfarin in heparin-induced thrombocytopenia: An analysis of outcomes in patients with elevated international normalized ratio. J Thromb Thrombolysis 2005; l19: 183-188.
• 18 GlaxoSmithKline.. Arixtra (fondaparinux sodium [injection] prescribing information.. Research Triangle Park; NC, USA: October 2005
• 19 Yusuf S, Mehta SR, Chrolavicious S. et al. Comparison of fondaparinux and enoxaparin in acute coronary syndromes. N Engl J Med 2006; 354: 1464-1476.
• 20 Parody R, Oliver A, Souto JC. et al. Fondaparinux (Arixtra) as an alternative anti-thrombotic prophylaxis when there is hypersensitivity to low molecular weight and unfractionated heparins (abstract). Hematologica 2003; 88: ECR32.
• 21 Rubin N. Treatment of heparin-induced thrombocytopenia with thrombosis (HITTS) in pregnancy with fondaparinux (abstract). Blood 2003; 102: 4190.
• 22 D’amico EA, Villaca PR, Gualandro FM. et al. Successful use of Arixtra in a patient with paroxysmal nocturnal hemoglobinuria, Budd-Chiari syndrome and heparin- induced thrombocytopenia. J Thromb Haemost 2003; 1: 2452-2453.
• 23 Harenberg J, Jorg I, Genyvesi T. Treatment of heparin induced thrombocytopenia with fondaparinux (letter). Haematologica 2004; 89: 1017-1018.
• 24 Kuo HM, Kovacs MJ. Successful treatment of heparin induced thrombocytopenia (HIT) with fondaparinux. Thromb Haemost 2005; 93: 999-100.
• 25 Bradner J, Halliey RK, Duter DJ. Fondaparinux in the treatment of heparin-induced thrombocytopenia (abstract). Blood 2004; 104: 1775.
• 26 Selleng K, Warkentin TE, Greeinacher A. Heparininduced thrombocytopenia in intensive care patients. Crit Care Med 2007; 35: 1165-1176.
• 27 D’Angelo A, Della Valle P, Fattorini A. et al. Disappearance of anti-PF4/heparin antibodies under prolonged fondaparinux administration in a patient with DVT associated with LMWH-induced thrombocytopenia. Thromb Haemost 2006; 95: 573-575.
• 28 Greinacher A, Gopinadhan M, Gunther J-U. et al. Close approximation of two platelet factor 4 tetramers by charge neutralization forms the antigens recognized by HIT antibodies. Arterioscler Thromb Vasc Biol 2006; 26: 2386-2393.
• 29 Warkentin TE, Maurer BT, Aster RH. Heparin-induced thrombocytopenia associated with fondaparinux. N Engl J Med 356 25: 2653-55.
• 30 Zwicker JI, Uhl L, Huang W-Y. et al. Thrombosis and ELISA optical density values in hospitalized patients with heparin-induced thrombocytopenia. J Thromb Haemost 2004; 2: 2133-2137.
• 31 Smythe MA, Warkentin TE, Stephens JL. et al. Venous limb gangrene during overlapping therapy with warfarin and a direct thrombin inhibitor for immune heparin-induced thrombocytopenia. Am J Hematol 2002; 71: 50-52.
• 32 Srinivasan AF, Rice L, Bartholomew JR. et al. Warfarin- induced skin necrosis and venous limb gangrene in the setting of heparin-induced thrombocytopenia. Arch Intern Med 2004; 164: 66-70.
• 33 Warkentin TE, Elavathil LL, Hayward CPM. et al. The pathogenesis of venous limb gangrene associated with heparin induced thrombocytopenia. Ann Intern Med 1997; 127: 804-812.
• 34 Bartholomew JR. Transition to an oral anticoagulant in patients with heparin-induced thrombocytopenia. Chest 2005; 127: 27S-34S.
• 35 2006 Red Book.. Thomson PDR, Montvale NJ. USA: 2006
• 36 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: 967-981.
• 37 Weitz JI. Emerging anticoagulants for the treatment of venous thromboembolism. Thromb Haemost 2006; 96: 274-284.