Tucker Erik I, Marzec Ulla M, White Tara C, Hurst Sawan, Rugonyi Sandra, McCarty Owen J T, Gailani David, Gruber András, Hanson Stephen R
Departments of Biomedical Engineering, Oregon Health & Science University School of Medicine, Portland, OR 97239, USA.
Blood. 2009 Jan 22;113(4):936-44. doi: 10.1182/blood-2008-06-163675. Epub 2008 Oct 22.
The protease thrombin is required for normal hemostasis and pathologic thrombogenesis. Since the mechanism of coagulation factor XI (FXI)-dependent thrombus growth remains unclear, we investigated the contribution of FXI to thrombus formation in a primate thrombosis model. Pretreatment of baboons with a novel anti-human FXI monoclonal antibody (aXIMab; 2 mg/kg) inhibited plasma FXI by at least 99% for 10 days, and suppressed thrombin-antithrombin (TAT) complex and beta-thromboglobulin (betaTG) formation measured immediately downstream from thrombi forming within collagen-coated vascular grafts. FXI inhibition with aXIMab limited platelet and fibrin deposition in 4-mm diameter grafts without an apparent increase in D-dimer release from thrombi, and prevented the occlusion of 2-mm diameter grafts without affecting template bleeding times. In comparison, pretreatment with aspirin (32 mg/kg) prolonged bleeding times but failed to prevent graft occlusion, supporting the concept that FXI blockade may offer therapeutic advantages over other antithrombotic agents in terms of bleeding complications. In whole blood, aXIMab prevented fibrin formation in a collagen-coated flow chamber, independent of factor XII and factor VII. These data suggest that endogenous FXI contributes to arterial thrombus propagation through a striking amplification of thrombin generation at the thrombus luminal surface.
蛋白酶凝血酶是正常止血和病理性血栓形成所必需的。由于凝血因子XI（FXI）依赖性血栓生长的机制尚不清楚，我们在灵长类动物血栓形成模型中研究了FXI对血栓形成的作用。用新型抗人FXI单克隆抗体（aXIMab；2mg/kg）预处理狒狒，可使血浆FXI在10天内至少抑制99%，并抑制在胶原包被的血管移植物内形成的血栓下游立即测得的凝血酶-抗凝血酶（TAT）复合物和β-血小板球蛋白（βTG）的形成。用aXIMab抑制FXI可限制4毫米直径移植物中的血小板和纤维蛋白沉积，而血栓的D-二聚体释放没有明显增加，并可防止2毫米直径移植物的闭塞，而不影响模板出血时间。相比之下，用阿司匹林（32mg/kg）预处理可延长出血时间，但未能防止移植物闭塞，这支持了在出血并发症方面，FXI阻断可能比其他抗血栓药物具有治疗优势的观点。在全血中，aXIMab可防止在胶原包被的流动腔室中形成纤维蛋白，这与因子 XII 和因子 VII 无关。这些数据表明，内源性FXI通过在血栓腔表面显著放大凝血酶生成，促进动脉血栓的传播。
