An integrated computational and experimental approach to understanding the hemostatic response during treatment of bleeding

一种综合计算和实验方法来了解出血治疗期间的止血反应

• 批准号: 10405443
• 负责人: AARON L FOGELSON
• 金额: $ 63.28万
• 依托单位: COLORADO SCHOOL OF MINES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-10 至 2022-08-16
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10405443
• 关键词: Adhesions; Agreement; Anticoagulants; Biochemical; Biochemistry; Biological Assay; Biological Markers; Biophysical Process; Blood; Blood Coagulation Disorders; Blood Platelets; Blood Vessels; Blood flow; Characteristics; Clinical; Coagulation Process; Complex; Coupled; Data; Development; Event; Factor VIIa; Fibrin; Foundations; Gel; Goals; Hemophilia A; Hemorrhage; Hemostatic Agents; Hemostatic function; Individual; Intestines; Knowledge; Laboratories; Lead; Link; Mathematics; Measurement; Measures; Methods; Microfluidics; Mission; Modeling; Muscle; Outcome; Physiological Processes; Plasma; Platelet aggregation; Polymers; Process; Proteins; Public Health; Reaction; Recombinants; Research; Risk; Site; Surface; System; Testing; Thrombosis; Thrombus; United States National Institutes of Health; Update; Variant; Warfarin; base; improved; individual response; injured; innovation; insight; mathematical model; novel; platelet function; predictive modeling; prothrombin complex concentrates; recombinant FVIIa; response; soft tissue; synergism; thrombotic; treatment response; treatment strategy; vascular bed; vascular factor

Individuals with hemophilia or taking anticoagulants are at risk for bleeding, but where they bleed is different. Understanding how these two types of perturbations to the hemostatic system interact in distinct vascular beds (VBs) will inform decisions about bleeding treatment. Bleeding is treated using prohemostatic agents, but individual responses to these agents are highly variable and the mechanisms underlying the variability are unknown. Hemostasis is a nonlinear process involving complex coagulation biochemistry coupled to platelet function, VBs, and biophysical mechanisms including blood flow; it is well suited for study with an integrated computational and experimental approach. The long-term goal of this research is to develop mathematical models that improve the treatment of bleeding. The overall objective is to develop and validate mathematical models of bleeding that will identify mechanisms underlying variable responses to prohemostatics and in different VBs. The central hypothesis is that global sensitivity analysis (GSA) applied to mechanistic mathematical models of bleeding will elucidate synergies and/or cooperation among platelet, vascular, and plasma components and predict experimentally-verified hemostatic responses. This hypothesis is based on preliminary data produced using exactly this approach in the applicants’ laboratories. The rationale is that the proposed quantitative methods and the identification of modifiers of the hemostatic response will together provide a foundation for developing assays that test for specific and previously unidentified biomarkers. Guided by strong preliminary data, this hypothesis will be tested in three specific aims: 1) Develop and refine mathematical models of hemostasis, 2) Determine the mechanistic link between bleeding site and bleeding cause, and 3) Identify modifiers of hemostasis that regulate responses to prohemostatics in hemophilia A. In Aim 1, existing models will be extended to include essential features of platelet and fibrin dynamics and validated with microfluidic assays. In Aim 2, submodels of anticoagulants will be developed and incorporated into the hemostasis models. Experimental measurements of VB characteristics will be acquired. GSA will identify the causes of VB site-specific variability in the hemostatic response. In Aim 3, submodels of prohemostatics will be developed and incorporated into the hemostasis models. GSA will identify the causes of variability in responses to them during treatment of hemophilia A. The approach is innovative because (1) the mathematical models and experimental assays will be developed in tandem to iteratively and optimally inform one another, and (2) novel submodels of anticoagulants and prohemostatics will be added to a comprehensive model of the hemostatic system that includes platelet, fibrin, and VB dynamics coupled to coagulation and flow. The proposed research is significant because it is expected to (1) provide mechanistic explanations for site- specific bleeding in hemophilia A and anticoagulant use, and (2) provide mechanism-based knowledge to potentially guide clinical decisions in the treatment of bleeding.

患有血友病或服用抗凝剂的人有出血的风险，但出血的部位不同。 了解这两种类型的止血系统扰动如何在不同的血管床中相互作用 (VB) 将告知有关出血治疗的决定 使用止血剂治疗出血，但是。 个体对这些药物的反应差异很大，并且差异背后的机制是 止血是一个非线性过程，涉及与血小板耦合的复杂凝血生物化学。 功能、VB 和生物物理机制（包括血流）；它非常适合综合研究 这项研究的长期目标是发展数学和实验方法。 改善出血治疗的模型的总体目标是开发和验证数学。 出血模型将确定对止血剂的不同反应的潜在机制 不同的 VB 的中心假设是全局敏感性分析（GSA）应用于机械。 出血的数学模型将阐明血小板、血管和血液之间的协同作用和/或合作。 血浆成分并预测经实验验证的止血反应。 申请人实验室正是使用这种方法产生的初步数据。 提出的定量方法和止血反应调节剂的鉴定将一起 为开发测试特定的和先前未识别的引导生物标志物的测定奠定了基础。 通过强有力的初步数据，该假设将在三个具体目标上进行测试：1）开发和完善 止血的数学模型，2）确定出血部位与出血之间的机制联系 原因，以及 3) 确定调节血友病 A 中促止血反应的止血调节剂。 目标 1，现有模型将扩展到包括血小板和纤维蛋白动力学的基本特征以及 通过微流体测定进行验证 在目标 2 中，将开发并合并抗凝剂的子模型。 将获得 VB 特性的实验测量结果。 确定 VB 止血反应位点特异性变异的原因。在目标 3 中，子模型。 GSA 将开发促止血剂并将其纳入止血模型中，以确定止血的原因。 在治疗血友病 A 期间对它们的反应存在差异。该方法具有创新性，因为 (1) 数学模型和实验分析将同时开发，以迭代和最佳方式提供信息 彼此之间，以及（2）抗凝剂和止血剂的新子模型将被添加到一个综合的模型中。 止血系统模型，包括血小板、纤维蛋白和与凝血和流动耦合的 VB 动力学。 拟议的研究意义重大，因为它预计将（1）为位点提供机制解释 A 型血友病的特定出血和抗凝剂的使用，以及 (2) 提供基于机制的知识 可能指导出血治疗的临床决策。