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，以研究狭窄（狭窄）动脉中血凝块形成的基本生物物理和生化机制。 这些是负责大多数心脏病发作和许多中风的血块，并且了解它们如何在狭窄动脉的极端身体状况下形成可能会导致有关如何预防它们的新想法。严重狭窄的动脉中的非常快的血流意味着，在更典型的生理典型情况下，导致血液凝结的许多经过良好的过程在这些动脉中最多起作用。最近的实验，包括当前研究者之一的实验室的实验，这表明血液中特定的流动蛋白在使血小板结合在一起以在狭窄动脉中形成凝块的重要性。该项目涉及将该蛋白质的假设作用纳入由该项目的其他研究者开发的新型且复杂的计算模型，并使用扩展的模型来表征蛋白质已知特性可以解释狭窄动脉中的凝块形成的条件。 通过将新模型的预测与进一步的实验室实验的比较，该模型将得到完善，并提高了其预测能力，并且我们对狭窄动脉极端身体状况下血液凝块形成如何形成的理解将增加。 因为在狭窄动脉的条件下形成血块的挑战与从主要动脉出血的挑战相似，因此了解这种凝块形式的理解也可能有助于开发干预措施，以限制创伤后出血。彼此之间的凝聚力。血小板粘附和内聚力都是通过形成涉及血小板上特定蛋白的分子键来完成的吗？表面与血管壁或血浆中的其他特定蛋白质结合。为了将血小板固定在一起，键必须能够通过血流来承受在血小板上施加的力。 对于许多类型的血小板键，仅当血小板已经因适当的化学或物理刺激而被激活时，血小板才能形成该类型的键。血小板激活过程需要时间。 对于通过高度狭窄的动脉移动的血小板，没有足够的时间来响应激活刺激，如果试图连接到容器壁上的液体会施加的力会施加的力。 在这种情况下，在这种情况下形成凝块的形成方式很少，但是最近的实验导致了以下假设：键是由血液中独特的流动敏感蛋白（von willebrand因子）介导的，这是至关重要的。该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讨这一假设。将开发出一种新型的多相模型，以代表血液的粘性流体与代表不断增长的血小板凝块的可渗透，粘弹性，可骨折的材料之间的机械相互作用。稳健有效的数值方法的发展将允许探索模型的行为。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。

项目成果

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.

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

Occlusive thrombosis in arteries

• DOI: 10.1063/1.5115554
• 发表时间: 2019-12-01
• 期刊: APL BIOENGINEERING
• 影响因子: 6
• 作者: Kim, Dongjune;Bresette, Christopher;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.