SUMMARY

Arterial thrombosis is responsible for cardiovascular diseases, representing 25% of the underlying cause of deaths in the U.S. in 2021. Arteries should be recanalized within 6 hours post occlusion to prevent tissue necrosis by thrombolysis or thrombectomy. While clots break under tension in both treatments, the explanation of how platelet thrombi can be strong is unknown. Strengthening or weakening mechanisms of macroscopic clot by contraction and bonds breakage remain elusive.

Occlusive arterial thrombi stem from a process called shear-induced platelet aggregation (SIPA). The thrombus needs to be strong to form and occlude arterial flow under high shear stress and high pressure. Arterial thrombi are composed of platelet and elongated von Willebrand Factor as opposed to coagulation clots composed of red blood cells and fibrin. SIPA thrombi are 7 times stronger than coagulation clot. High platelet density and elevated local vWF concentration by activated platelets indicate that thrombus tensile strength may stem from the VWF network. Platelet-VWF and VWF-VWF bond strengths (~10 pN) are 100 times smaller than VWF fiber strength (~1000 pN).

The overall goal of this proposal is to test the hypothesis that thrombus strength stems from its VWF network with its architecture allowing high VWF-VWF bond density. A consequence of the VWF network is that the role of platelets is limited to providing a surface for VWF strands and are secondary to SIPA strength. I further hypothesize that thrombus architecture and strength highly depend on vWF length, strength may vary by a factor of 2 with the presence of ultralong VWF (~15 µm). After occlusion, I hypothesize that the thrombus will gain additional strength from platelet contraction as it condenses clot architecture to increase bond density. I will measure the thrombus before and after platelet contraction.