Bijsterveld Nick R, Moons Arno H, Boekholdt S Matthijs, van Aken Benien E, Fennema Hein, Peters Ron J G, Meijers Joost C M, Büller Harry R, Levi Marcel
Department of Cardiology, Academic Medical Center, University of Amsterdam, The Netherlands.
Circulation. 2002 Nov 12;106(20):2550-4. doi: 10.1161/01.cir.0000038501.87442.02.
The novel anticoagulant fondaparinux proved to be effective and safe in the postoperative prevention of venous thrombosis. Current phase III trials with this synthetic selective factor Xa inhibitor focus on its use in the treatment of patients with venous and arterial thrombosis. As with any anticoagulant therapy, there is a risk of bleeding complications; hence, a strategy to reverse the effects of fondaparinux is desirable. The aim of this study was to investigate whether recombinant factor VIIa (rFVIIa) could neutralize the anticoagulant effects of subcutaneously administered fondaparinux.
In a randomized, placebo-controlled design, 16 healthy male subjects received either a single subcutaneous dose of fondaparinux (10 mg) and a single intravenous bolus of rFVIIa (90 microg/kg; n=8), fondaparinux and placebo (n=4), or placebo and rFVIIa (n=4). Fondaparinux (or placebo) was administered 2 hours before rFVIIa (or placebo). Injection of rFVIIa after fondaparinux normalized the prolonged activated partial thromboplastin and prothrombin times and reversed the decrease in prothrombin activation fragments 1+2 (F(1+2)), as observed with fondaparinux alone. Thrombin-generation time and endogenous thrombin potential, which were inhibited by fondaparinux, normalized up to 6 hours after rFVIIa injection.
rFVIIa is capable of normalizing coagulation times and thrombin generation during fondaparinux treatment. The duration of this effect ranged from 2 to 6 hours after rFVIIa injection. These results suggest that rFVIIa may be useful to reverse the anticoagulant effect of fondaparinux in case of serious bleeding complications or need for acute surgery during treatment with fondaparinux.
新型抗凝剂磺达肝癸钠在术后预防静脉血栓形成方面已被证明是有效且安全的。目前针对这种合成性选择性Xa因子抑制剂的III期试验聚焦于其在治疗静脉和动脉血栓形成患者中的应用。与任何抗凝治疗一样，存在出血并发症的风险；因此，需要一种逆转磺达肝癸钠作用的策略。本研究的目的是调查重组因子VIIa（rFVIIa）是否能够中和皮下注射磺达肝癸钠的抗凝作用。
在一项随机、安慰剂对照设计中，16名健康男性受试者分别接受单次皮下注射磺达肝癸钠（10毫克）和单次静脉推注rFVIIa（90微克/千克；n = 8）、磺达肝癸钠和安慰剂（n = 4）或安慰剂和rFVIIa（n = 4）。磺达肝癸钠（或安慰剂）在rFVIIa（或安慰剂）之前2小时给药。在注射磺达肝癸钠后注射rFVIIa可使延长的活化部分凝血活酶时间和凝血酶原时间恢复正常，并逆转了单独使用磺达肝癸钠时观察到的凝血酶原激活片段1 + 2（F(1+2)）的降低。磺达肝癸钠抑制的凝血酶生成时间和内源性凝血酶潜力在注射rFVIIa后长达6小时恢复正常。
rFVIIa能够在磺达肝癸钠治疗期间使凝血时间和凝血酶生成恢复正常。这种作用的持续时间在注射rFVIIa后为2至6小时。这些结果表明，在磺达肝癸钠治疗期间发生严重出血并发症或需要进行急诊手术的情况下，rFVIIa可能有助于逆转磺达肝癸钠的抗凝作用。
