A mathematical model of coagulation under flow identifies factor V as a modifier of thrombin generation in hemophilia A.

Kathryn G Link, Michael T Stobb, Matthew G Sorrells, Maria Bortot, Katherine Ruegg, Marilyn J Manco-Johnson, Jorge A Di Paola, Suzanne S Sindi, Aaron L Fogelson, Karin Leiderman, Keith B Neeves

Journal of thrombosis and haemostasis : JTH 2020 Feb

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The variability in bleeding patterns among individuals with hemophilia A, who have similar factor VIII (FVIII) levels, is significant and the origins are unknown. 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. 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. 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. 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. © 2019 International Society on Thrombosis and Haemostasis.

Citation

Kathryn G Link, Michael T Stobb, Matthew G Sorrells, Maria Bortot, Katherine Ruegg, Marilyn J Manco-Johnson, Jorge A Di Paola, Suzanne S Sindi, Aaron L Fogelson, Karin Leiderman, Keith B Neeves. A mathematical model of coagulation under flow identifies factor V as a modifier of thrombin generation in hemophilia A. Journal of thrombosis and haemostasis : JTH. 2020 Feb;18(2):306-317