Systems biology of bleeding disorders

FVIIa
Predicting bleeding in genetic bleeding disorders using computational and microfluidic models. Here, we show hemophilia response to bypass therapy for an individual with hemophilia A. Fibrin (green) and platelet (blue) accumulation in a microfluidic hemostasis model before and after treatment with a bypass agent. Dynamic fibrin deposition in the experiment is in good agreement with thrombin generation predicted by a spatial-temporal computational model of clot formation.

In recent years, significant advances in understanding the molecular basis of bleeding disorders have been made, but a large portion of the variability in bleeding severity remains unexplained. In this project, the focus is on hemophilia and von Willebrand disease (VWD), where the observed variability in bleeding patterns cannot be assigned to a single measurable parameter. The objective of this project is to identify biochemical and biophysical modifiers of bleeding in hemophilia and VWD using a systems biology approach consisting of computational models, microfluidic devices, and clinical genotyping and phenotyping.

Microfluidic model of hemostasis. Upper panel shows the velocity field in the model as simulated by computational fluid dynamics. Lower panel shows the formation of blood clot within the horizontal ‘injury’ channel that is coated with collagen and tissue factor.

As part of this project we have developed a microfluidic model of hemostasis that is sensitive to perturbations in both platelet function and coagulation. Here, we control the pressure gradient across a small injury that represents a hole in a blood vessel. The model captures the kinetics of both primary and secondary hemostasis and can be used to measure the mechanical stability of clots.

Our team includes Aaron Fogelson at the University of Utah, Karin Leiderman at the Colorado School of Mines, and Jorge Di Paola at University of Colorado, Denver.

 

Related Publications

M. Schoeman, K. Rana, N. Danes, M. Lehmann, J.A. Di Paola, A.L. Fogelson, K. Leiderman, K.B. Neeves. A microfluidic model of hemostasis sensitive to platelet function and coagulation. Cellular and Molecular Bioengineering, 10 (2017): 3-15. PMID:28529666

M. Schoeman, M. Lehmann, K.G. Neeves. Flow chamber and microfluidic approaches for measuring thrombus formation in genetic bleeding disorders. Platelets, 28 (2017): 463-471. PMID:28532218

A.A. Onasoga-Jarvis, K. Leiderman, A.L. Fogelson, M. Wang, M.J. Manco-Johnson, J.A. Di Paola, K.B. Neeves. The effect of factor VIII deficiencies and replacement and bypass therapies on thrombus formation under venous flow conditions in microfluidic and computational models. PLoS One, 8 (2013): e78732. PMID: 24236042