Mann K G, van't Veer C, Cawthern K, Butenas S
Department of Biochemistry, University of Vermont, College of Medicine, Burlington 05405-0068, USA.
Blood Coagul Fibrinolysis. 1998 Mar;9 Suppl 1:S3-7.
Three model systems have been used to study the dynamics of the blood clotting process initiated by tissue factor (TF): synthetic plasma mixtures prepared with purified coagulation proteins and inhibitors; mathematical models based on the reaction constants, stoichiometries and thermodynamics of individual catalyst and inhibitor reactions; and contact suppressed whole blood induced to clot in vitro by the addition of exogenous TF. In the three models, the generation of thrombin can be described in terms of an initiation phase in which pmol/l concentrations of the coagulation serine proteases are generated and the cofactor proteins factor V (FV) and FVIII are activated. Subsequently, explosive thrombin generation occurs during a propagation phase. The complementary inhibitory pathways extinguish the generation of thrombin. Tissue factor pathway inhibitor (TFPI), present in low concentrations, primarily influences the duration of the initiation phase and has little influence on the propagation phase. Antithrombin III (ATIII), present in higher concentrations, has little influence during the initiation phase, but decreases the rate of thrombin generation during the propagation phase. The protein C pathway cannot act in the absence of thrombin and therefore only influences the duration of the propagation phase by inactivating activated FV. Thus combinations of TFPI plus ATIII and TFPI plus protein C pathway components contribute to the synergistic inhibitory processes. As a consequence of the roles of pro, and anti-coagulants, the generation of thrombin by the TF pathway becomes a threshold limited process.
已使用三种模型系统来研究由组织因子（TF）引发的血液凝固过程的动力学：用纯化的凝血蛋白和抑制剂制备的合成血浆混合物；基于单个催化剂和抑制剂反应的反应常数、化学计量学和热力学的数学模型；以及通过添加外源性TF在体外诱导接触抑制全血凝固。在这三种模型中，凝血酶的生成可以用一个起始阶段来描述，在此阶段会生成pmol/l浓度的凝血丝氨酸蛋白酶，辅因子蛋白因子V（FV）和FVIII被激活。随后，在一个传播阶段会发生爆发性的凝血酶生成。互补的抑制途径会终止凝血酶的生成。低浓度存在的组织因子途径抑制剂（TFPI）主要影响起始阶段的持续时间，而对传播阶段影响很小。高浓度存在的抗凝血酶III（ATIII）在起始阶段影响很小，但会降低传播阶段凝血酶生成的速率。蛋白C途径在没有凝血酶的情况下无法发挥作用，因此仅通过使活化的FV失活来影响传播阶段的持续时间。因此，TFPI加ATIII以及TFPI加蛋白C途径成分的组合有助于协同抑制过程。由于促凝血剂和抗凝血剂的作用，TF途径引发的凝血酶生成成为一个阈值受限的过程。
