A model for the stoichiometric regulation of blood coagulation
A model for the stoichiometric regulation of blood coagulation
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DOI：
10.1074/jbc.m201173200
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发表时间：
2002-05-24
影响因子：
4.8
通讯作者：
Mann, KG
中科院分区：
文献类型：
--
作者：
Hockin, MF;Jones, KC;Mann, KG
我们已经开发了一个模型的外源性血液凝固系统，包括化学计量的抗凝剂。该模型解释了维生素K依赖性促凝血复合物的形成、表达和增殖，并扩展了我们以前的模型，包括：（a）组织因子途径抑制剂（TFPI）介导的组织因子（TF）-VIIa及其产物复合物的失活;（B）抗凝血酶-III（AT-III）介导的Ha、m-Ha、因子VIIa、因子IXa和因子Xa的失活;（e）由因子Xa-膜产生的凝血酶对因子V和因子VIII的初始活化;（d）因子VIIIa解离/活性丧失;（e）TF与因子VII和VIIa之间存在的结合竞争和动力学活化步骤;和（f）由Ha、因子Xa和因子IXa对因子VII的活化。这些添加到我们早期的模型生成一个模型，由34个微分方程与42个速率常数，共同描述了27个独立的平衡表达式，其中描述了34个物种的命运。通过将皮摩尔浓度的TF“暴露”于由因子II、IX X、VII、VIIa、V和VIII以及抗凝剂TFPI和AT-III组成的电子环境中来启动模拟，所述抗凝剂TFPI和AT-III的浓度在正常血浆中发现或与凝血病理学相关。在凝血酶生成方面，反应随后通过可操作地定义为起始、增殖和终止的阶段进行。凝血酶的产生显示对TF、AT-III和TFPI的非线性依赖性，并且这些后者抑制剂的组合显示动力学阈值。在阈下TF下，TFPI和AT-M的组合抑制凝血酶的产生/表达;对于高于TF阈值的浓度，产生的凝血酶推注在数量上相等。与经验实验室数据的模型的比较表明，大多数实验观察到的参数被捕获，并准确地描述了病理，结果在增强或缺乏凝血酶生成。
We have developed a model of the extrinsic blood coagulation system that includes the stoichiometric anticoagulants. The model accounts for the formation, expression, and propagation of the vitamin K-dependent procoagulant complexes and extends our previous model by including: (a) the tissue factor pathway inhibitor (TFPI)-mediated inactivation of tissue factor (TF)-VIIa and its product complexes; (b) the antithrombin-III (AT-III)-mediated inactivation of Ha, m-Ha, factor VIIa, factor IXa, and factor Xa; (e) the initial activation of factor V and factor VIII by thrombin generated by factor Xa-membrane; (d) factor VIIIa dissociation/activity loss; (e) the binding competition and kinetic activation steps that exist between TF and factors VII and VIIa; and (f) the activation of factor VII by Ha, factor Xa, and factor IXa. These additions to our earlier model generate a model consisting of 34 differential equations with 42 rate constants that together describe the 27 independent equilibrium expressions, which describe the fates of 34 species. Simulations are initiated by "exposing" picomolar concentrations of TF to an electronic milieu consisting of factors II, IX X, VII, VIIa, V, and VIIII, and the anticoagulants TFPI and AT-III at concentrations found in normal plasma or associated with coagulation pathology. The reaction followed in terms of thrombin generation, proceeds through phases that can be operationally defined as initiation, propagation, and termination. The generation of thrombin displays a nonlinear dependence upon TF, AT-III, and TFPI and the combination of these latter inhibitors displays kinetic thresholds. At subthreshold TF, thrombin production/ expression is suppressed by the combination of TFPI and AT-M; for concentrations above the TF threshold, the bolus of thrombin produced is quantitatively equivalent. A comparison of the model with empirical laboratory data illustrates that most experimentally observable parameters are captured, and the pathology that results in enhanced or deficient thrombin generation is accurately described.