| Autor: |
Link KG; Department of Mathematics, University of California Davis (K.G.L.)., Stobb MT; Department of Mathematics and Computer Science, Coe College, Cedar Rapids, IA (M.T.S.)., Monroe DM; Department of Medicine, UNC Blood Research Center, University of North Carolina at Chapel Hill (D.M.M.)., Fogelson AL; Departments of Mathematics and Biomedical Engineering, University of Utah, Salt Lake City (A.L.F.)., Neeves KB; Departments of Bioengineering and Pediatrics, Section of Hematology, Oncology, and Bone Marrow Transplant, Hemophilia and Thrombosis Center, University of Colorado, Denver (K.B.N.)., Sindi SS; Department of Applied Mathematics, University of California, Merced (S.S.S.)., Leiderman K; Department of Applied Mathematics and Statistics, Colorado School of Mines, Golden (K.L.). |
| Abstrakt: |
Bleeding frequency and severity within clinical categories of hemophilia A are highly variable and the origin of this variation is unknown. Solving this mystery in coagulation requires the generation and analysis of large data sets comprised of experimental outputs or patient samples, both of which are subject to limited availability. In this review, we describe how a computationally driven approach bypasses such limitations by generating large synthetic patient data sets. These data sets were created with a mechanistic mathematical model, by varying the model inputs, clotting factor, and inhibitor concentrations, within normal physiological ranges. Specific mathematical metrics were chosen from the model output, used as a surrogate measure for bleeding severity, and statistically analyzed for further exploration and hypothesis generation. We highlight results from our recent study that employed this computationally driven approach to identify FV (factor V) as a key modifier of thrombin generation in mild to moderate hemophilia A, which was confirmed with complementary experimental assays. The mathematical model was used further to propose a potential mechanism for these observations whereby thrombin generation is rescued in FVIII-deficient plasma due to reduced substrate competition between FV and FVIII for FXa (activated factor X). |
