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

合作研究：极端血液凝固——狭窄动脉中血小板沉积的数学和实验研究

• 批准号: 1716898
• 负责人: Aaron Fogelson
• 金额: $ 19.32万
• 依托单位: University of Utah
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1716898&HistoricalAwards=false
• 关键词: Collaborative; Research; Blood; Clotting; Extreme

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.

该项目汇集了数学和计算科学家和生物工程师，研究狭窄（收缩）动脉内血栓形成的基本生物物理和生化机制。 这些是导致大多数心脏病发作和许多中风的血块，了解它们如何在狭窄动脉的极端物理条件下形成可能会导致如何预防它们的新想法。严重狭窄的动脉中非常快的血流意味着许多在生理学上更典型的情况下负责血液凝固的经过充分研究的过程在这些动脉中最多只能发挥次要作用。最近的实验，包括来自当前研究者之一的实验室的实验，表明血液中特定的流动敏感蛋白在允许血小板聚集在一起以在狭窄的动脉中形成凝块中的重要性。该项目涉及将这种蛋白质的假设作用纳入该项目的其他研究人员开发的动脉血凝块形成的新颖而复杂的计算模型中，并使用扩展模型来表征该蛋白质的已知特性可以解释狭窄动脉中凝块形成的条件。 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，我们对狭窄动脉在极端物理条件下如何形成血凝块的理解也将增加。 由于在狭窄动脉的条件下形成血凝块的挑战类似于从大动脉止血的挑战，了解这种凝块如何形成也可能有助于开发干预措施，以限制创伤后出血。大多数动脉血凝块是由称为血小板的血细胞粘附到受伤的血管壁和血小板形成的。彼此的凝聚力。血小板粘附和凝聚都是通过分子键的形成来完成的，这些分子键涉及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。为了将血小板固定在一起，这些键必须共同能够承受血流施加在血小板团块上的力。 对于许多类型的血小板-血小板键，只有当血小板已经响应于适当的化学或物理刺激而被激活时，血小板才能形成那种类型的键。血小板活化过程需要时间。 对于在高度收缩的动脉中移动的血小板，没有足够的时间对激活刺激做出反应，并且如果它试图附着在血管壁上，流体施加在其上的力是巨大的。 在这种情况下如何形成凝块知之甚少，但最近的实验导致的假设，键介导的独特的流动敏感蛋白（血管性血友病因子）在血液中是至关重要的。这个项目将通过数学建模，计算机模拟和实验室实验的结合来探索这一假设。一种新的多相模型将开发的粘性流体代表血液和一个可渗透的，粘弹性的，可断裂的材料代表一个不断增长的血小板凝块之间的机械相互作用。发展强大的和有效的数值方法将允许探索的模式？的行为。将模型结果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和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。

项目成果

Computational investigation of platelet thrombus mechanics and stability in stenotic channels

• DOI: 10.1016/j.jbiomech.2021.110398
• 发表时间: 2021-04-29
• 期刊: JOURNAL OF BIOMECHANICS
• 影响因子: 2.4
• 作者: Du, Jian;Aspray, Elise;Fogelson, Aaron
• 通讯作者: Fogelson, Aaron

Shear-induced platelet aggregation: 3D-grayscale microfluidics for repeatable and localized occlusive thrombosis

• DOI: 10.1063/1.5113508
• 发表时间: 2019-09-01
• 期刊: BIOMICROFLUIDICS
• 影响因子: 3.2
• 作者: Griffin, Michael T.;Kim, Dongjune;Ku, David N.
• 通讯作者: Ku, David N.

Platelet α-granules are required for occlusive high-shear-rate thrombosis

• DOI: 10.1182/bloodadvances.2020002117
• 发表时间: 2020-07-01
• 期刊: BLOOD ADVANCES
• 影响因子: 7.5
• 作者: Kim, Dongjune A.;Ashworth, Katrina J.;Ku, David N.
• 通讯作者: Ku, David N.

Clot Permeability, Agonist Transport, and Platelet Binding Kinetics in Arterial Thrombosis

• DOI: 10.1016/j.bpj.2020.08.041
• 发表时间: 2020-11-17
• 期刊: BIOPHYSICAL JOURNAL
• 影响因子: 3.4
• 作者: Du, Jian;Kim, Dongjune;Fogelson, Aaron L.
• 通讯作者: Fogelson, Aaron L.