Recombinant factor VIIa reverses the in vitro and ex vivo anticoagulant and profibrinolytic effects of fondaparinux
Recombinant factor VIIa reverses the in vitro and ex vivo anticoagulant and profibrinolytic effects of fondaparinux
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DOI：
10.1046/j.1538-7836.2003.00536.x
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发表时间：
2003-11-01
影响因子：
10.4
通讯作者：
De Groot, PG
中科院分区：
文献类型：
--
作者：
Lisman, T;Bijsterveld, NR;De Groot, PG
背景资料：磺达肝癸钠是一种合成五糖，可选择性抑制凝血因子（F）Xa，注册用于预防髋部骨折、髋关节置换术和膝关节置换术后的静脉血栓栓塞。最近，研究表明，重组FVIIa（rFVIIa）逆转磺达肝癸钠在健康志愿者中的抗凝作用。目的：在这项研究中，我们探讨了体外和离体的影响，rFVIIa对凝块形成和凝血酶激活的纤溶抑制剂（TAFI）介导的下调纤溶后磺达肝癸钠管理。研究方法：在加入磺达肝癸钠的健康志愿者的合并正常血浆中，以及接受磺达肝癸钠单次推注给药、rFVIIa单次推注给药或两者的健康志愿者的系列样本中，进行体外凝块溶解试验。结果与结论：磺达肝癸钠显著延迟凝块形成，并且由于TAFI的活化降低，凝块溶解显著增加。添加重组FVIIa纠正了磺达肝癸钠诱导的血块形成抑制，血块溶解加速部分逆转。健康志愿者体内给予磺达肝癸钠（10 mg）同样导致血浆凝块溶解加速。随后给予rFVIIa（90 μ g kg（-1））使给药后6小时内的血栓溶解时间正常化。rFVIIa可能是磺达肝癸钠治疗出血并发症患者的良好治疗选择，因为血凝块形成和纤溶抵抗均得到改善。
Background: Fondaparinux is a synthetic pentasaccharide, which selectively inhibits coagulation factor (F) Xa, and is registered for prevention of venous thromboembolism following hip fracture, hip replacement, and knee replacement surgery. Recently, it was shown that recombinant FVIIa (rFVIIa) reverses anticoagulant effects of fondaparinux in healthy volunteers. Objectives: In this study, we have explored the in vitro and ex vivo effects of rFVIIa on clot formation and thrombin-activatable fibrinolysis inhibitor (TAFI)-mediated down-regulation of fibrinolysis after fondaparinux administration. Methods: In vitro clot lysis assays were performed in pooled normal plasma from healthy volunteers to which fondaparinux was added, and in serial samples from healthy volunteers who received a single bolus dose of fondaparinux, a single bolus dose of rFVIIa, or both. Results and conclusions: Fondaparinux significantly delayed clot formation, and clot lysis was significantly increased due to decreased activation of TAFI. Addition of recombinant FVIIa corrected the inhibited clot formation induced by fondaparinux, and the acceleration of clot lysis was partially reversed. In vivo administration of fondaparinux (10 mg) to healthy volunteers similarly resulted in accelerated plasma clot lysis. Subsequent administration of rFVIIa (90 mug kg(-1)) normalized the clot lysis time up to 6 h postadministration. rFVIIa might be a good therapeutic option in patients treated with fondaparinux who develop bleeding complications, since both clot formation as well as fibrinolytic resistance are improved.