"What makes blood clots break off?" A Back-of-the-Envelope Computation Toward Explaining Clot Embolization.

PURPOSE: One in four deaths worldwide is due to thromboembolic disease; that is, one in four people die from blood clots first forming and then breaking off or embolizing. Once broken off, clots travel downstream, where they occlude vital blood vessels such as those of the brain, heart, or lungs, leading to strokes, heart attacks, or pulmonary embolisms, respectively. Despite clots' obvious importance, much remains to be understood about clotting and clot embolization. In our work, we take a first step toward untangling the mystery behind clot embolization and try to answer the simple question: "What makes blood clots break off?" METHODS: To this end, we conducted experimentally-informed, back-of-the-envelope computations combining fracture mechanics and phase-field modeling. We also focused on deep venous clots as our model problem. RESULTS: Here, we show that of the three general forces that act on venous blood clots-shear stress, blood pressure, and wall stretch-induced interfacial forces-the latter may be a critical embolization force in occlusive and non-occlusive clots, while blood pressure appears to play a determinant role only for occlusive clots. Contrary to intuition and prior reports, shear stress, even when severely elevated, appears unlikely to cause embolization. CONCLUSION: This first approach to understanding the source of blood clot bulk fracture may be a critical starting point for understanding blood clot embolization. We hope to inspire future work that will build on ours and overcome the limitations of these back-of-the-envelope computations.

Mechanical properties of clot made from human and bovine whole blood differ significantly.

Thromboembolism - that is, clot formation and the subsequent fragmentation of clot - is a leading cause of death worldwide. Clots' mechanical properties are critical determinants of both the embolization process and the pathophysiological consequences thereof. Thus, understanding and quantifying the mechanical properties of clots is important to our ability to treat and prevent thromboembolic disease. However, assessing these properties from in vivo clots is experimentally challenging. Therefore, we and others have turned to studying in vitro clot mimics instead. Unfortunately, there are significant discrepancies in the reported properties of these clot mimics, which have been hypothesized to arise from differences in experimental techniques and blood sources. The goal of our current work is therefore to compare the mechanical behavior of clots made from the two most common sources, human and bovine blood, using the same experimental techniques. To this end, we tested clots under pure shear with and without initial cracks, under cyclic loading, and under stress relaxation. Based on these data, we computed and compared stiffness, strength, work-to-rupture, fracture toughness, relaxation time constants, and prestrain. While clots from both sources behaved qualitatively similarly, they differed quantitatively in almost every metric. We also correlated each mechanical metric to measures of blood composition. Thereby, we traced this inter-species variability in clot mechanics back to significant differences in hematocrit, but not platelet count. Thus, our work suggests that the results of past studies that have used bovine blood to make in vitro mimics - without adjusting blood composition - should be interpreted carefully. Future studies about the mechanical properties of blood clots should focus on human blood alone.