Multiscale modeling and empirical study of a mechanism limiting blood clot growth

描述(申请人提供)：当血管破裂时，形成止血凝块，主要由血小板和纤维蛋白组成，以限制血液损失。生理性血液凝结受到高度调控，但病理性凝块(血栓)可能在血管内形成并限制流向器官的血液，或者凝块碎片(栓子)可以分离并携带到肺部，导致一种称为肺栓塞的危及生命的并发症。此外，血栓在冠状动脉中形成，导致心脏病发作，在脑血管中形成，导致缺血性中风。高发病率和高死亡率(每年仅静脉血栓栓塞性疾病就有大约90万例和30万例死亡)突显了研究限制血栓形成的过程的生物医学重要性。然而，阻止血栓生长的机制却知之甚少。特别是，目前的血栓形成模型并没有解决纤维蛋白网络(FNW)的结构如何影响凝血因子的时空演变，以及在限制血栓生长的流动条件下FNW与血小板之间的相互作用。该方案结合开发3D多尺度血液凝块建模环境(MBCME-3D)和耦合MBCME-3D模拟以及使用光钳和微流体室的专门设计的实验，来研究FNW在调节血液凝块生长中扮演的两个特定角色：1)阻止蛋白质运输；2)在生理或病理条件下介导血小板-FNW结合动力学。这将导致对常见的临床情景的详细检查，即由于部分阻塞和管腔狭窄而增加血液切变率，这被认为是一个关键的组成部分，影响纤维蛋白的产生和血小板的结合，这些机制限制了血液凝块的增长。更好地了解血栓的结构和性质以及血栓生长的机制及其在血流条件下的局限性，将有助于医生通过确定调节血栓形成的参数的临界值来估计单个患者的血栓性疾病的风险。此外，推广的MBCME-3D将能够详细模拟生物细胞和蛋白质在存在的流体环境中的运动 这将有助于开发用于生物医学研究的各种预测性多尺度计算模型。

DESCRIPTION (provided by applicant): When a blood vessel ruptures, a hemostatic clot, consisting mainly of platelets and fibrin, is formed to restrict the loss of blood. Physiological blood clotting is highly regulated, but a pathological clot (thrombus) may form within a vessel and restrict blood flow to organs or clot pieces (emboli) can detach and be carried to the lungs, causing a life-threatening complication called pulmonary embolism. Also, clots are formed in coronary arteries, causing heart attacks, and in brain vessels, causing ischemic strokes. The high morbidity and mortality rates (about 900,000 incidences and 300,000 deaths annually just from venous thromboembolic disease) underscore the biomedical importance of studying processes limiting clot formation. However, the mechanisms stopping clot growth are poorly understood. In particular, current models of thrombus development do not address how structure of fibrin network (FNW) affect spatial-temporal evolution of blood coagulation factors and the interplay between FNW and platelets under flow conditions limiting blood clot growth. This proposal combines development of 3D Multiscale Blood Clot Modeling Environment (MBCME-3D) and coupling MBCME-3D simulations and specifically designed experiments using optical tweezers and microfluidic chambers, to study two specific roles that a FNW plays in regulating blood clot growth: 1) impeding protein transport; and 2) mediating platelet-FNW binding kinetics under physiological or pathological conditions. This will result in detailed examination of the common clinical scenario of increasing blood shear in response to partial obstruction and narrowing of the vessel lumen, which is considered a critically important component, affecting both the generation of fibrin and binding of platelets, mechanisms limiting blood clot growth. Better understanding of the structure and properties as well as the mechanisms of clot growth and its limitations under blood flow will help physicians to estimate risk of thrombotic disease for an individual patient by identifying critical values of parameters o processes regulating thrombogenesis. Additionally, the generalized MBCME-3D will be able to simulate in detail motion of biological cells and proteins in the fluid environment in the presence of porous biogels at the micro- and mesoscale which will contribute to the development of a variety of predictive multiscale computational models for biomedical research.