Modeling of human factor Va inactivation by activated protein C.
Modeling of human factor Va inactivation by activated protein C.
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DOI：
10.1186/1752-0509-6-45
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发表时间：
2012-05-20
影响因子：
--
通讯作者：
Everse SJ
中科院分区：
文献类型：
--
作者：
Bravo MC;Orfeo T;Mann KG;Everse SJ
由于对表征混凝过程的组分的库存、连通性和动态的理解相对成熟，它已成为物理化学建模的一个有吸引力的目标。这样的模型可以潜在地改进治疗方法的设计。凝血酶原复合体（由蛋白酶因子(F)Xa及其辅助因子FVa组成）作为凝血酶的主要生产者在这个网络中起着核心作用，凝血酶催化血小板的活化和纤维蛋白原向纤维蛋白的转化，而纤维蛋白是凝块的主要物质。一个关键的负反馈回路，阻止血块在损伤部位以外的传播是凝血酶依赖的活化蛋白C （APC）的产生，APC是一种使FVa失活的酶，从而中和凝血酶原复合物。APC对FVa的失活是复杂的，涉及到部分活性中间体的产生和FXa和凝血酶原对FVa的“保护”。经验验证的这一过程的数学模型将有助于提高凝血综合模型的预测能力。通过分析经验反应体系中FVa失活的时间过程，逐步构建人APC凝血酶原失活模型，并生成各反应体系对应的模型构建。这些模型构建的反应机制、速率常数和平衡常数最初来自于不同的研究小组，他们报道了APC在分离FVa、FXa或凝血酶原存在下的失活。模型预测是根据测量多种FVa降解中间体的出现和消失以及凝血酶原活性变化的经验数据进行评估的，血浆蛋白来源于多种制剂。我们的工作整合了先前发表的研究结果，通过对体外实验和数学结构的合作分析，我们能够产生一个最终的验证模型，该模型包括24种化学反应和相互作用，具有14个独特的速率常数，这些速率常数描述了24种物质的浓度通量。这项研究强调了失活过程的复杂性，并提供了一个描述蛋白C途径的方程模块，可以整合到现有的描述组织因子引发凝血的综合数学模型中。
Because understanding of the inventory, connectivity and dynamics of the components characterizing the process of coagulation is relatively mature, it has become an attractive target for physiochemical modeling. Such models can potentially improve the design of therapeutics. The prothrombinase complex (composed of the protease factor (F)Xa and its cofactor FVa) plays a central role in this network as the main producer of thrombin, which catalyses both the activation of platelets and the conversion of fibrinogen to fibrin, the main substances of a clot. A key negative feedback loop that prevents clot propagation beyond the site of injury is the thrombin-dependent generation of activated protein C (APC), an enzyme that inactivates FVa, thus neutralizing the prothrombinase complex. APC inactivation of FVa is complex, involving the production of partially active intermediates and “protection” of FVa from APC by both FXa and prothrombin. An empirically validated mathematical model of this process would be useful in advancing the predictive capacity of comprehensive models of coagulation. A model of human APC inactivation of prothrombinase was constructed in a stepwise fashion by analyzing time courses of FVa inactivation in empirical reaction systems with increasing number of interacting components and generating corresponding model constructs of each reaction system. Reaction mechanisms, rate constants and equilibrium constants informing these model constructs were initially derived from various research groups reporting on APC inactivation of FVa in isolation, or in the presence of FXa or prothrombin. Model predictions were assessed against empirical data measuring the appearance and disappearance of multiple FVa degradation intermediates as well as prothrombinase activity changes, with plasma proteins derived from multiple preparations. Our work integrates previously published findings and through the cooperative analysis of in vitro experiments and mathematical constructs we are able to produce a final validated model that includes 24 chemical reactions and interactions with 14 unique rate constants which describe the flux in concentrations of 24 species. This study highlights the complexity of the inactivation process and provides a module of equations describing the Protein C pathway that can be integrated into existing comprehensive mathematical models describing tissue factor initiated coagulation.
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DOI：
10.1073/pnas.90.3.1004
发表时间：
1993-02-01
影响因子：
11.1
作者：
DAHLBACK, B;CARLSSON, M;SVENSSON, PJ
通讯作者：
SVENSSON, PJ
DOI：
10.1073/pnas.0403072101
发表时间：
2004-06-15
影响因子：
11.1
作者：
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通讯作者：
Everse, SJ
影响因子：
1.1
作者：
Barhoover, Melissa A.;Kalafatis, Michael
通讯作者：
Kalafatis, Michael
影响因子：
2.9
作者：
Hockin, MF;Cawthern, KM;Mann, KG
通讯作者：
Mann, KG
影响因子：
4.8
作者：
Hockin, MF;Jones, KC;Mann, KG
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