Blood clots are critical for stopping bleeding after injury and aid in wound healing but are dangerous if not regulated and cleared efficiently, because they can block the flow of blood and cause heart attacks and strokes. Blood clots are composed of red blood cells (RBCs) and platelets together with a polymeric fibrin network, which provides the structural and mechanical stability of the clot. After injury or during disease, the coagulation cascade becomes activated, and a blood clot forms. After clotting, the platelets apply contractile forces that pull on the fibrin fibers, leading to volume shrinkage of the clot, which is termed “clot contraction.” Clot contraction, or retraction, results in a series of structural changes explored in this article, including the compression of RBCs and densification and redistribution of fibrin and platelets to the exterior of the blood clot. We have previously shown that clot contraction limits the enzymatic degradation (fibrinolysis) of blood clots when the lytic enzyme is delivered after the blood clot has formed. This mimics the clinical administration of thrombolytics (drugs that initiate fibrinolysis) after an ischemic stroke or heart attack, for example. Although thrombolytic drugs have been used to treat heart attack and stroke for many years, clinicians are hesitant to administer them beyond 4 hours after the onset of blockage of the vessel because of reduced efficacy of clot breakdown and increased risk of bleeding. Our research aims to identify what factors are most significant for their reduced efficacy, with the goal of designing safer, more-efficient thrombolytic treatments. The elucidation of how clot contraction and resultant changes in clot structure influence the rate and extent of fibrinolysis has the potential to inform the design of better thrombolytics.

The cover of the September 6 issue of Biophysical Journal displays an in vitro contracted blood clot formed from a human blood sample and imaged by using a scanning electron microscope. This microscope allows us to visualize a cross section of the clot. We then used Adobe Photoshop to colorize the different clot components; red blood cells are red, platelets are yellow, and fibrin is green. This image highlights the structural changes that result from clot contraction. In our study, we used our mathematical model to isolate three structural changes: clot compaction, redistribution of fibrin, and densification of the fibrin exterior. This image illustrates the structural complexity of blood clots, and our study points to the importance of accounting for clot structure when assessing their enzymatic degradation.

We identified that the dense fibrin network (green) on the periphery of contracted clots is the dominant structural change that limits lysis from the exterior (thrombolysis). This points to the need for the development of a thrombolytic variant with an optimal binding affinity because its binding limits its efficacy. Strokes are one of the most common causes of morbidity and mortality, so better treatments will have a wide benefit. The development of a thrombolytic variant with an optimal affinity for fibrin can overcome the obstacle of reduced efficacy of treatment at later times after stroke onset. Our mathematical model has the potential to allow us to figure out how to optimize the affinity, although other experimental techniques will be needed to design and test such variants.

- Rebecca A. Risman, Ahmed Abdelhamid, John W. Weisel, Brittany E. Bannish, and Valerie Tutwiler