Blood clots are necessary to prevent excess bleeding and to aid in wound healing. A clot is comprised of red blood cells and platelets encased by a fibrin mesh. When a blood clot is no longer needed, it must be enzymatically degraded through a physiological process known as fibrinolysis. Fibrin provides the structural and mechanical stability of a blood clot, and changes to the fibrin structure can make a clot more prone or resistant to fibrinolysis. When a clot cannot be degraded physiologically, such as in the case of heart attack or stroke, an exogenous dose of tissue plasminogen activator (tPA) is delivered, initiating a process termed “external” fibrinolysis, or “thrombolysis.” tPA activates plasminogen into plasmin, the enzyme responsible for fibrin degradation. During plasmin-mediated fibrinolysis, soluble pieces of fibrin, called “fibrin degradation products” (FDPs), are produced. Our research combines mathematical modeling and wet-lab experimental approaches to reveal how the interplay between tPA, plasmin, and FDPs affects the rate and pattern of fibrinolysis.
The cover of the March 5 issue of Biophysical Journal displays two abutting fibrin clots that have been fluorescently labeled and imaged with a confocal microscope. This was the basis for our experiments aimed at understanding how tPA and FDPs diffuse into the clot. Comparing model and experimental results suggests that tPA can be forced to unbind from fibrin by plasmin degradation, resulting in FDPs with bound tPA. This is important because small FDPs diffuse into the clot, increasing the lysis rate by allowing tPA to hitch a ride farther into the clot than it would have on its own. Furthermore, we explored tPA variants that could improve the efficacy of tPA treatment. Our models suggest that a fibrin clot will be lysed faster if initiated by a tPA variant with a 10-times-bigger-than-physiological dissociation constant. This newfound understanding of tPA kinetics and diffusion can aid in the development of improved therapeutic strategies. Moreover, our work emphasizes the value of combining mathematical modeling and wet-lab experimental methods to reveal the mechanisms of complex processes.
More information about our research can be found at https://tutwiler-lab.weebly.com/.
— Brittany E. Bannish, Bradley Paynter, Rebecca A. Risman, Mitali Shroff, and Valerie Tutwiler