von Willebrand factor-mediated platelet adhesion is critical for deep vein thrombosis in mouse models
von Willebrand factor-mediated platelet adhesion is critical for deep vein thrombosis in mouse models
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DOI：
10.1182/blood-2010-05-287623
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发表时间：
2011-01-27
期刊：
影响因子：
20.3
通讯作者：
Wagner, Denisa D.
中科院分区：
文献类型：
--
作者：
Brill, Alexander;Fuchs, Tobias A.;Wagner, Denisa D.
深静脉血栓形成(DVT)及其并发症肺栓塞是致残和死亡的常见原因。虽然血流障碍被认为是一个重要的触发因素，但DVT的启动机制仍然不清楚。在这里，我们展示了下腔静脉(IVC)48小时的血流限制导致血栓的形成，在结构上类似于人类深静脉血栓。血管性血友病因子(VWF)缺陷小鼠可免受下腔静脉血流完全(停滞)或部分(狭窄)限制所导致的血栓形成。VWF水平一半正常的小鼠也在狭窄模型中受到保护。除了促进血小板黏附，VWF还携带第VIII因子。反复输注重组第VIII因子并没有挽救VWF-/-小鼠的血栓形成，这表明凝血功能受损不是VWF-/-小鼠缺乏DVT的主要原因。注射GPG-290，一种突变的糖蛋白Ibα-免疫球蛋白嵌合体，特异性地抑制VWF A1结构域与血小板的相互作用，防止了野生型小鼠的血栓形成。活体显微镜显示，在DVT的早期阶段，野生型DVT的血小板和白细胞募集显著高于VWF-/-IVC。我们的结果证实了VWF-血小板相互作用在血流紊乱诱导的静脉血栓形成中的致病作用。(血。2011；117(4)：1400-1407)
Deep vein thrombosis (DVT) and its complication, pulmonary embolism, are frequent causes of disability and mortality. Although blood flow disturbance is considered an important triggering factor, the mechanism of DVT initiation remains elusive. Here we show that 48-hour flow restriction in the inferior vena cava (IVC) results in the development of thrombi structurally similar to human deep vein thrombi. von Willebrand factor (VWF)-deficient mice were protected from thrombosis induced by complete (stasis) or partial (stenosis) flow restriction in the IVC. Mice with half normal VWF levels were also protected in the stenosis model. Besides promoting platelet adhesion, VWF carries Factor VIII. Repeated infusions of recombinant Factor VIII did not rescue thrombosis in VWF-/- mice, indicating that impaired coagulation was not the primary reason for the absence of DVT in VWF-/- mice. Infusion of GPG-290, a mutant glycoprotein Ib alpha-immunoglobulin chimera that specifically inhibits interaction of the VWF A1 domain with platelets, prevented thrombosis in wild-type mice. Intravital microscopy showed that platelet and leukocyte recruitment in the early stages of DVT was dramatically higher in wild-type than in VWF-/- IVC. Our results demonstrate a pathogenetic role for VWF-platelet interaction in flow disturbance-induced venous thrombosis. (Blood. 2011; 117(4): 1400-1407)