Mathematical Modeling to Identify Clotting Factor Combinations That Modify Thrombin Generation in Hemophilia

Background: In previous work, we used our mathematical model to identify modifiers of thrombin generation in hemophilia A (Link, JTH, 18, 2020). We performed thousands of simulations that varied clotting factors and inhibitors between 50 and 150% of their baseline plasma levels. From those simulations, we identified the combinations of factors and inhibitors that led to enhanced thrombin generation. We found that factor V (FV), at low normal levels (50%-75%), was a major contributor of the thrombin enhancement. The model elucidated an underlying mechanism to be substrate competition between factors V and VIII for activated factor X (FXa), which occurred early in the thrombin generation process. That study was focused on hemophilia A.

Aims: To identify factor combinations that enhance or attenuate thrombin generation in mild, moderate, and severe hemophilia A, B, and C.

Methods: Plasma levels for factors II, V, VII, VIII, IX, X, XI, tissue factor pathway inhibitor (TFPI), and antithrombin (AT) were fixed at one of three values: 50%, 100%, or 150% of normal. We simulated all possible combinations of these three factor levels for normal blood, and mild, moderate, and severe hemophilia A, B, and C type blood, characterized by deficiencies of 10, 5, and 1% of normal plasma levels. For each combination of factor levels, tissue factor (TF) was varied, and combinations of factor levels were identified as thrombin enhancing (or attenuating) when they resulted in at least a 10-fold increase (or decrease) in detectable thrombin levels. We used an updated version of our mathematical model that includes interactions between TFPI and partially cleaved FV.

Results: For simulations of severe hemophilia A and B, combinations of low normal levels (50%) of FV and TFPI and high normal levels (150%) of FII and FX lead to an increase in total thrombin. Interestingly, the opposite combinations (high normal FV and TFPI, low normal FII and FX) led to a decrease in total thrombin for simulations of mild hemophilia A and B. In some of the severe deficiency cases, high normal FVIII levels in hemophilia B and low normal FIX levels in hemophilia A were found to enhance thrombin generation. In normal blood and hemophilia C, combinations of low normal levels (50%) of FV and TFPI and high normal levels (150%) of FVIII and FIX led to an increase in total thrombin, and again the opposite levels attenuated thrombin generation. In some cases, low normal levels of AT also enhanced thrombin generation.

Conclusion(s): Our mathematical model identified new and testable combinations of parameters that enhance thrombin generation in severe hemophilia and attenuated thrombin generation in mild hemophilia.

Monroe:Sanofi: Research Funding. Leiderman:Novo Nordisk: Research Funding.