Biophysics and Bleeding Disorders

March is Bleeding Disorders Awareness Month in the US. More than three million Americans who have hemophilia, von Willebrand disease, and other rare bleeding disorders. These conditions prevent blood from clotting the way it should, which can lead to prolonged bleeding after injury, surgery, or physical trauma. We spoke with Biophysical Society member Valerie Tutwiler, an American Heart Association graduate research fellow in the lab of John Weisel at the University of Pennsylvania, about her hemostasis and thrombosis research.

What is the connection between your research and bleeding disorders?

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This recent cover of Biophysical Journal shows Tutwiler, Wang, Litvinov, Weisel, and Shenoy’s image of a colorized scanning electron microscope image of a coronary artery thrombus extracted from a heart attack patient.

Blood clotting or hemostasis is the process that stems bleeding. On one hand if you have insufficient clotting this can result in prolonged bleeding, on the other hand a hypercoagulable state can result in thrombosis. Thrombi can result in the obstruction of blood flow, which can cause heart attacks and strokes. My thesis research pertains largely to studying one portion of the coagulation process blood clot contraction, or the volume shrinkage of the clot, which has been implicated to play a role in hemostasis and the restoration of blood flow past otherwise obstructive thrombi.

Why is your research important to those concerned about bleeding disorders?

While there is much known about the various aspects of blood clotting relatively little is known about the process of clot contraction despite the clinical implications of its importance in the formation of a strong hemostatic seal and the restoration of blood flow past otherwise obstructive thrombi. The study of clot contraction is a highly interdisciplinary problem and as a result can be of interest to researchers from many different fields. Platelets are active contractile cells, which interact with an extracellular matrix of fibrin, a naturally occurring polymer with unique mechanical properties. The fibrin matrix can be imbedded with other blood cells, such as red blood cells, as well. From a biophysical standpoint the mechanisms of clot contraction have not been well understood. To better elucidate this process, we performed a systematic study on how the molecular and cellular composition of the blood influences the rate and extent of clot contraction along with the mechanical properties of the contracting clot using a novel application of an optical tracking system.

Additionally, to further explore the mechanical nature of the clot contraction process we developed a mathematical model that couples active platelets with a passive viscoelastic matrix made up of fibrin and red blood cells. The model predicts the process of clot contraction and explains some of the experimental observations of clot size, structure and mechanical forces. Interestingly, we found that clot contraction is altered in thrombotic states such as ischemic stroke patients. Collectively, these findings show that the study of clot contraction has the potential to inform the development of diagnostics and therapeutics.

How did you get into this area of research?

Since beginning research I have been interested in applying engineering techniques to answer biological questions. I became interested in hemostasis and thrombosis research while completing my first co-op experience in undergrad.

How long have you been working on it?

I began doing hemotology research during my undergraduate career. However, I started studying clot contraction specifically when I started my PhD research.

Do you receive public funding for this work? If so, from what agency?

I am currently funded by the American Heart Association as a pre-doctoral fellow, although we also receive funding from the National Institute of Health and National Science Foundation.

Have you had any surprise findings thus far?

We were surprised to find such a striking decrease in the extent of clot contraction in ischemic stroke patients compared to healthy subjects. Correlations with stroke severity suggest that clot contraction may be a potential pathogenic factor in ischemic stroke. These findings have led us to expand our study to other pathological conditions as well.

What is particularly interesting about the work from the perspective of other researchers?

Due to the conservation of the basic principles of contractile proteins and motility, the information learned from the development of a mathematical model of active contractile cells interacting with a viscoelastic matrix can be applied to a variety of different processes.

What is particularly interesting about the work from the perspective of the public?

Bleeding and thrombotic conditions remain leading causes of death and disability worldwide. Gaining a more thorough understanding of the processes involved in hemostasis and thrombosis will lead to the development of more effective diagnostic tools and more targeted therapeutics.

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