Karin Leiderman, Colorado School of Mines – Applied Math Colloquium

Details: The talk will be at 4:00 in Phillips Hall, Room 332, and tea will be served at 3:30 in Phillips Hall, Room 330.

Title: A computational approach to understanding bleeding variability in hemophilia

Abstract: Hemophilia is a genetic bleeding disorder defined as the deficiency in a plasma protein necessary to produce stable blood clots. Significant advances in understanding the molecular basis of the hemophilia have been made, but observed variability in bleeding severity remains unexplained. Blood clot formation is seriously impaired in individuals with hemophilia, because the protein deficiency causes a significant reduction in thrombin generation, the major enzyme of clotting. Because clotting is complex and involves a large biochemical network of reactions coupled to biophysical processes such as blood flow and platelet aggregation, it is well suited for study with computational approaches. Using uncertainty and sensitivity analysis on a mathematical model of blood clotting under flow, we have identified plasma components that modify thrombin generation under hemophilic conditions with low tissue factor, which mimics the vascular beds where individuals with hemophilia bleed. Such low tissue factor conditions would normally produce little to no thrombin with hemophilia, but the modifiers facilitate thrombin generation in amounts on par with non-hemophilia blood. With guidance from the sensitivity analysis and further investigation using the mathematical model, we uncovered the biochemical mechanism underlying the modified thrombin response. In this talk, I will share these results in addition to experimental ones with microfluidic models that confirmed the identity of the modifiers. If time permits, I will also discuss progress on companion studies that include modeling clot formation in extravascular geometries.