Impact of Deficiency of Intrinsic Coagulation Factors XI and XII on Ex Vivo Thrombus Formation and Clot Lysis

J. Govers-Riemslag, Joke Konings, J. Cosemans, Johanna P. van Geffen, B. de Laat, J. Heemskerk, Y. Dargaud, H. ten Cate
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引用次数: 7

Abstract

Abstract The contributions of coagulation factor XI (FXI) and FXII to human clot formation is not fully known. Patients with deficiency in FXI have a variable mild bleeding risk, whereas FXII deficiency is not associated with bleeding. These phenotypes make FXII and FXI attractive target proteins in anticoagulant therapy. Here, we studied the mechanisms of fibrin clot formation, stability, and fibrinolytic degradation in patients with severe FXI or FXII deficiency. Thrombin generation was triggered in platelet-poor (PPP) and platelet-rich plasma (PRP) with the biological FXII trigger sulfatides. Intrinsic and extrinsic thrombus formation and degradation in whole blood were determined with rotational thromboelastometry (ROTEM). Clot formation under flow was assessed by perfusion of whole blood over collagen microspots with(out) tissue factor (TF). Thrombin generation and clot formation were delayed in FXII- and FXI-deficient patients triggered with sulfatides. In FXI-deficient plasma, this delay was more pronounced in PRP compared to PPP. In whole blood of FXII-deficient patients, clots were smaller but resistance to fibrinolysis was normal. In whole blood of FXI-deficient patients, clot formation was normal but the time to complete fibrinolysis was prolonged. In flow chamber experiments triggered with collagen/TF, platelet coverage was reduced in severe compared with moderate FXI deficiency, and fibrin formation was impaired. We conclude that quantitative defects in FXII and FXI have a substantial impact on contact activation-triggered coagulation. Furthermore, FXI deficiency has a dose-dependent suppressing effect on flow-mediated and platelet/TF-dependent clot formation. These last data highlight the contribution of particularly FXI to hemostasis.
缺乏FXI的患者有可变的轻度出血风险,而缺乏FXII与出血无关。这些表型使得FXII和FXI在抗凝治疗中具有吸引力的靶蛋白。在这里,我们研究了严重FXI或FXII缺乏症患者纤维蛋白凝块形成、稳定性和纤维蛋白溶解降解的机制。凝血酶的生成在血小板贫(PPP)和血小板富(PRP)血浆中由FXII触发的生物硫脂触发。用旋转血栓弹性测量法(ROTEM)测定全血中内在和外在血栓形成和降解。用组织因子(TF)在胶原微斑上灌注全血来评估血流下凝块的形成。由硫脂脂引发的FXII和FXII缺陷患者凝血酶生成和凝块形成延迟。在缺乏fxi的血浆中,与PPP相比,这种延迟在PRP中更为明显。在fxii缺乏患者的全血中,血块较小,但对纤维蛋白溶解的抵抗正常。fxi缺乏症患者全血凝块形成正常,但纤维蛋白溶解完成时间延长。在胶原/TF触发的流动室实验中,与中度FXI缺乏相比,重度FXI缺乏的血小板覆盖率降低,纤维蛋白形成受损。我们得出结论,FXII和FXI的定量缺陷对接触活化触发的凝血有实质性的影响。此外,FXI缺乏对血流介导和血小板/ tf依赖的凝块形成具有剂量依赖性的抑制作用。这些数据强调了FXI对止血的作用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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