Selective factor VIII activation by the tissue factor-factor VIIa-factor Xa complex
Selective factor VIII activation by the tissue factor-factor VIIa-factor Xa complex
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DOI：
10.1182/blood-2017-02-767079
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发表时间：
2017-10-05
期刊：
影响因子：
20.3
通讯作者：
Ruggeri, Zaverio M.
中科院分区：
文献类型：
--
作者：
Kamikubo, Yuichi;Mendolicchio, G. Loredana;Ruggeri, Zaverio M.
安全有效的抗血栓治疗需要了解导致病理性血栓形成的机制，但对止血的影响较小。我们发现，外源性组织因子(TF)凝血起始复合体可以选择性地激活抗血友病辅助因子FVIII，触发不依赖于凝血酶反馈环的止血内在凝血途径。在具有相对轻微的血栓形成损害的小鼠模型中，依赖于TF的FVIII激活通过接触时相生成的FixA设置血栓形成的阈值。在体外，FXA与Tf-FVIIa稳定结合可激活FVIII，但不激活Fv。此外，Tf-FVIIa的新生FXA产物可以暂时逃避Tf途径抑制剂对Konitz型抑制的缓慢动力学，优先激活FVIII而不是Fv。因此，Tf协同启动依赖FixA的凝血酶生成，而不依赖于凝血酶激活辅因子。因此，FVIIa突变体缺乏直接依赖Tf的凝血酶生成，但通过新生FXA保留FVIIa生成，可以支持内在途径凝血。在体外流动的血液中，具有受损的游离FXA生成但同时激活FVIII和FIX的TF-FVIIa突变复合体支持有效的FVIII依赖的血栓形成。因此，在凝血酶依赖的反馈环进一步放大凝血之前，一个先前未知的由TF启动的直接产生FVIIIa-FixA内在张力酶复合体的途径可能是先止血的，从而增加了血栓形成的风险。
Safe and effective antithrombotic therapy requires understanding of mechanisms that contribute to pathological thrombosis but have a lesser impact on hemostasis. We found that the extrinsic tissue factor (TF) coagulation initiation complex can selectively activate the antihemophilic cofactor, FVIII, triggering the hemostatic intrinsic coagulation pathway independently of thrombin feedback loops. In a mouse model with a relatively mild thrombogenic lesion, TF-dependent FVIII activation sets the threshold for thrombus formation through contact phase-generated FIXa. In vitro, FXa stably associated with TF-FVIIa activates FVIII, but not FV. Moreover, nascent FXa product of TF-FVIIa can transiently escape the slow kinetics of Kunitz-type inhibition by TF pathway inhibitor and preferentially activates FVIII over FV. Thus, TF synergistically primes FIXa-dependent thrombin generation independently of cofactor activation by thrombin. Accordingly, FVIIa mutants deficient in direct TF-dependent thrombin generation, but preserving FVIIIa generation by nascent FXa, can support intrinsic pathway coagulation. In ex vivo flowing blood, a TF-FVIIa mutant complex with impaired free FXa generation but activating both FVIII and FIX supports efficient FVIII-dependent thrombus formation. Thus, a previously unrecognized TF-initiated pathway directly yielding FVIIIa-FIXa intrinsic tenase complex may be prohemostatic before further coagulation amplification by thrombin-dependent feedback loops enhances the risk of thrombosis.