A mathematical model of coagulation under flow identifies factor V as a modifier of thrombin generation in hemophilia A
A mathematical model of coagulation under flow identifies factor V as a modifier of thrombin generation in hemophilia A
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DOI：
10.1111/jth.14653
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发表时间：
2020-02-01
影响因子：
10.4
通讯作者：
Neeves, Keith B.
中科院分区：
文献类型：
--
作者：
Link, Kathryn G.;Stobb, Michael T.;Neeves, Keith B.
血友病A患者的凝血因子VIII（FVIII）水平相似，但其出血模式的变异性很大，原因尚不清楚。目的使用先前验证的流动介导的凝血的数学模型作为筛选工具，以确定最有可能在FVIII缺乏的情况下增强凝血酶生成的参数。方法我们对我们的数学模型进行了全局敏感性分析（GSA），以确定凝血酶生成的潜在调节剂。通过校准的自动血栓描记术（CAT）和胶原蛋白-组织因子（TF）表面上的流动试验（剪切速率为每秒100次）确认来自GSA的候选物。结果模拟确定低正常的因子V（FV）（50%）作为最强的修饰剂，与高正常的凝血酶原（150%）结合时，额外的凝血酶增强。低正常FV水平或部分FV抑制（60%的活动）增加凝血酶生成的FVIII抑制或FVIII缺乏的血浆中CAT。部分FV抑制（60%）增加纤维蛋白沉积的流动试验与全血从个人轻度和中度FVIII缺乏。在两种实验模型中，这些效应都被正常高水平的凝血酶原水平放大。结论低FV水平可促进血友病A患者凝血酶生成。数学模型的进一步探索表明了一个潜在的机制：降低FV减少了FV和FVIII之间对活化血小板表面（APS）上因子Xa（FXa）的竞争，这增强了FVIII活化并挽救了FVIII缺乏血液中的凝血酶生成。
Background The variability in bleeding patterns among individuals with hemophilia A, who have similar factor VIII (FVIII) levels, is significant and the origins are unknown. Objective To use a previously validated mathematical model of flow-mediated coagulation as a screening tool to identify parameters that are most likely to enhance thrombin generation in the context of FVIII deficiency. Methods We performed a global sensitivity analysis (GSA) on our mathematical model to identify potential modifiers of thrombin generation. Candidates from the GSA were confirmed by calibrated automated thrombography (CAT) and flow assays on collagen-tissue factor (TF) surfaces at a shear rate of 100 per second. Results Simulations identified low-normal factor V (FV) (50%) as the strongest modifier, with additional thrombin enhancement when combined with high-normal prothrombin (150%). Low-normal FV levels or partial FV inhibition (60% activity) augmented thrombin generation in FVIII-inhibited or FVIII-deficient plasma in CAT. Partial FV inhibition (60%) boosted fibrin deposition in flow assays performed with whole blood from individuals with mild and moderate FVIII deficiencies. These effects were amplified by high-normal prothrombin levels in both experimental models. Conclusions These results show that low-normal FV levels can enhance thrombin generation in hemophilia A. Further explorations with the mathematical model suggest a potential mechanism: lowering FV reduces competition between FV and FVIII for factor Xa (FXa) on activated platelet surfaces (APS), which enhances FVIII activation and rescues thrombin generation in FVIII-deficient blood.