OC 07.5 - Mathematical modeling to identify clotting factor combinations that enhance thrombin generation in hemophilia

Background: Our model previously identified that low normal levels (50%-75%) of factor V (FV) enhanced thrombin generation in hemophilia A (Link, JTH, 18, 2020). This enhancement was found through a computational exploration through normal level factor combinations.

Aims: To identify factor levels that enhance thrombin generation in hemophilia B, C, and normal type blood using the methods developed in our previous work.

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. Our mathematical model individually simulated all possible combinations of these three factor levels (19,683 combinations) for normal, hemophilia A, B, and C type blood. For each combination of factor levels, tissue factor (TF) was varied between 1 and 15 fmol/cm^2, resulting in well over one million independent simulations. Combinations of factor levels were identified as thrombin enhancing when they resulted in at least a 10 fold increase in detectable thrombin levels.

Results: For all four simulated cases (normal, hemophilia A, B, and C) low normal (50%) levels of FV and high normal (150%) levels of factor II led to an increase in total thrombin. For normal and hemophilia C, high normal levels of factors VIII and IX increased thrombin generation, while high normal levels of factor VIII increased thrombin generation in hemophilia B. There was moderate enhancement of thrombin in hemophilia A with low normal levels of factors IX and FXI, and also AT, but only when FVIII was severely deficient (1%). When FVIII levels were raised to 10%, high normal levels of FIX resulted in increased thrombin.

Conclusion(s): Our mathematical model identified new and testable combinations of parameters that enhance thrombin generation in normal, hemophilia A, B, and C blood.