Collaborative Research: Blood Clotting at the Extreme -- Mathematical and Experimental Investigation of Platelet Deposition in Stenotic Arteries

该项目将数学和计算科学家以及生物工程师聚集在一起，研究狭窄(狭窄)动脉内形成血栓的基本生物物理和生化机制。这些血栓是导致大多数心脏病发作和许多中风的原因，了解它们是如何在动脉狭窄的极端物理条件下形成的，可能会为如何预防它们带来新的想法。在严重狭窄的动脉中非常快的血流意味着，在更典型的生理情况下，许多经过充分研究的导致血液凝结的过程在这些动脉中最多只能起到很小的作用。最近的实验，包括一位现任研究人员的实验室的实验，表明血液中一种特定的流动敏感蛋白在允许血小板聚集在一起，在狭窄的动脉中形成凝块的重要性。该项目涉及将这种蛋白质的假设作用纳入由该项目的其他研究人员开发的一种新颖而复杂的动脉血栓形成计算模型中，并使用扩展的模型来表征该蛋白质的已知特性可以解释狭窄动脉中的血栓形成的条件。通过将新模型的预测与进一步的实验室实验进行比较，该模型将得到改进，其预测能力将得到提高，我们将增加对狭窄动脉在极端物理条件下如何形成血栓的理解。由于在动脉狭窄的情况下形成血栓的挑战类似于止血，了解这种血栓是如何形成的也可能有助于开发干预措施来限制创伤后的出血。大多数动脉血栓是由称为血小板的血细胞与受损的血管壁和血小板粘连形成的？彼此凝聚在一起。血小板粘附力和凝聚力都是通过形成分子键来完成的，分子键涉及到血小板上的特定蛋白质？与血管壁或血浆中的其他特定蛋白质结合的表面。为了将血小板结合在一起，这些结合必须共同能够承受血液流动施加在血小板上的力量。对于许多类型的血小板-血小板结合，只有当血小板在适当的化学或物理刺激下已经被激活时，血小板才能形成这种类型的结合。血小板的激活过程需要时间。对于通过高度狭窄的动脉的血小板来说，没有足够的时间对激活刺激做出反应，如果液体试图附着在血管壁上，对它施加的力是巨大的。目前对这种情况下血栓是如何形成的知之甚少，但最近的实验导致了一种假设，即血液中一种独特的流动敏感蛋白(von Willebrand因子)介导的键是至关重要的。这个项目将通过数学建模、计算机模拟和实验室实验相结合的方式来探索这一假设。将开发一种新的多相模型，用于描述代表血液的粘性流体和代表不断增长的血小板凝块的可渗透、粘弹性、可破裂材料之间的机械相互作用。稳健和高效的数值方法的发展将允许探索模型？S的行为。模型结果将与狭窄动脉的体外物理模型的结果进行比较。比较将导致模型的改进以及物理实验的设计和解释。建模和实验之间的这种相互作用为推动科学发现提供了强大的引擎。

This project brings together mathematical and computational scientists and bioengineers to study the fundamental biophysical and biochemical mechanisms underlying the formation of blood clots within stenosed (constricted) arteries. These are the blood clots responsible for most heart attacks and many strokes, and understanding how they can form under the extreme physical conditions in a stenotic artery may lead to new ideas for how to prevent them. The very fast blood flow in severely stenosed arteries means that many of the well-studied processes responsible for blood clotting in more physiologically typical situations can play at most a minor role in these arteries. Recent experiments, including ones from the laboratory of one of the current investigators, suggest the importance of a specific flow-sensitive protein in the blood in allowing blood platelets to clump together to form a clot in stenotic arteries. This project involves incorporating the hypothesized role of this protein into a novel and sophisticated computational model of arterial blood clot formation, developed by this project's other investigators, and to use the expanded model to characterize the conditions under which that protein's known properties could explain clot formation in stenotic arteries. Through comparisons of the new model's predictions with further laboratory experiments, the model will be refined and its predictive capabilities improved, and our understanding of how blood clots form under the extreme physical conditions in stenotic arteries will be increased. Because the challenges of forming a blood clot under the conditions in a stenotic artery are similar to those of stanching hemorrhage from a major artery, understanding of how such clots form may also aid in development of interventions to limit bleeding following trauma.Most arterial blood clots are formed by the adhesion of blood cells known as platelets to an injured blood vessel wall and by platelets? cohesion to one another. Platelet adhesion and cohesion are both accomplished through the formation of molecular bonds that involve specific proteins on the platelets? surfaces binding to other specific proteins on the vascular wall or in the blood plasma. To hold the platelets together, the bonds must collectively be able to withstand the forces imposed on the platelet clump by the blood flow. For many types of platelet-platelet bonds, a platelet can form that type of bond only if the platelet has already become activated in response to appropriate chemical or physical stimuli. The platelet activation process takes time. For a platelet moving through a highly constricted artery, there is not enough time to respond to activation stimuli and the forces that the fluid exerts on it if it tries to attach to the vessel wall are enormous. How clots form in this situation is poorly understood, but recent experiments lead to the hypothesis that bonds mediated by a uniquely flow-sensitive protein (von Willebrand factor) in the blood are critical. This project will explore that hypothesis through a combination of mathematical modeling, computer simulation, and laboratory experimentation. A novel multiphase model will be developed of the mechanical interactions between a viscous fluid representing the blood and a permeable, viscoelastic, fracturable material representing a growing platelet clot. Development of robust and efficient numerical methods will allow exploration of the model?s behavior. Model results will be compared with results from an in vitro physical model of a stenotic artery. The comparison will lead to model refinements and to the design and interpretation of the physical experiments. Such interplay between modeling and experiments provides a powerful engine for driving scientific discovery.