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

Hemophilia A is a bleeding disorder categorized as severe, mild, and
moderate deficiencies in factor VIII (FVIII). Within these categories the
variance in bleeding severity is significant and the origins unknown. The
number of parameters that could modify bleeding are so numerous that
experimental approaches are not feasible for considering all possible
combinations. Consequently, we turn to a mathematical model of coagulation
under flow to act as a screening tool to identify parameters that are most
likely to enhance thrombin generation. We performed global sensitivity
analysis on 110,000 simulations that varied coagulation factor levels by
50-150% of their normal values in humans while holding FVIII levels at 1%.
These simulations identified low factor V (FV) levels as the strongest
candidate, with additional enhancement when combined with high prothrombin
levels. This prediction was confirmed in two experimental models: Partial
FV inhibition boosted fibrin deposition in flow assays performed at 100
s^-1 on collagen-tissue factor surfaces using whole blood from individuals
with mild and moderate FVIII deficiencies. Low FV (≥50%) or partial FV
inhibition also augmented thrombin generation in FVIII-inhibited or
FVIII-deficient plasma in calibrated automated thrombography. These
effects were amplified by high prothrombin levels in both experimental
models. Our mathematical model suggests a mechanism in which FV and FVIII
compete to bind to factor Xa to initiate thrombin generation in low FV,
FVIII-deficient blood. This unexpected result was made possible by a
mechanistic mathematical model, providing an example of the potential of
such models in making predictions in complex biological networks.