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

基本信息

批准号：
10813290
负责人：
AARON L FOGELSON
金额：
$ 71.46万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-10 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10813290
关键词：
Adhesions Agreement Anticoagulants Biochemical Biochemistry Biological Assay Biological Markers Biophysical Process Blood Blood Coagulation Disorders Blood Platelets Blood Vessels Blood flow Brain Characteristics Clinical Coagulation Process Complex Coupled Data Development Event Factor VIIa Fibrin Foundations Gel Goals Hemophilia A Hemorrhage Hemostatic Agents Hemostatic function Individual Intestines Joints Knowledge Laboratories 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 biomarker identification improved individual response injured innovation insight mathematical model novel platelet function predictive modeling prothrombin complex concentrates response soft tissue synergism thrombotic treatment response treatment strategy vascular bed vascular factor

项目摘要

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.

血友病或服用抗凝剂的个体有出血的风险，但是出血的地方是不同的。了解这两种对止血系统的扰动如何在不同的血管床中相互作用（VBS）将为有关出血治疗的决定提供信息。出血是使用直角剂治疗的，但是对这些药物的个人反应是高度可变的，可变性的机制是未知。止血是一种非线性过程，涉及复杂的凝血生物化学与血小板结合功能，VBS和生物物理机制，包括血流；它非常适合学习计算和实验方法。这项研究的长期目标是发展数学改善出血治疗的模型。总体目标是开发和验证数学出血模型将识别出对肢体局限学的可变响应基础的机制和不同的VBS。中心假设是应用于机械的全球灵敏度分析（GSA）出血的数学模型将阐明血小板，血管和/或合作血浆成分并预测实验验证的止血反应。该假设基于初步数据在申请人的实验室中完全使用这种方法生成。理由是提出的定量方法和止血反应的修饰符的鉴定将共同为开发用于测试特定和以前未识别的生物标志物的阿萨斯的基础。指导通过强大的初步数据，该假设将以三个特定的目的进行检验：1）开发和完善止血的数学模型，2）确定出血部位和出血之间的机械联系原因和3）识别止血的修饰剂，这些修饰剂调节对血友病的血液骨化反应。 AIM 1，现有型号将扩展到包括血小板和纤维蛋白动力学的基本特征以及用微流体测定验证。在AIM 2中，将开发并纳入抗凝剂的子模型进入止血模型。将获得VB特性的实验测量。 GSA会确定止血反应中VB位点特异性变异性的原因。在AIM 3中止血模型将开发并纳入止血模型。 GSA将确定在血友病的治疗过程中对它们的反应变异性。该方法具有创新性，因为（1）数学模型和实验测定将与迭代和最佳信息一起开发彼此，（2）新颖的抗凝剂和直肠化的子模型将被添加到全面止血系统的模型，包括血小板，纤维蛋白和VB动力学，结合凝结和流动。拟议的研究很重要，因为它有望（1）为站点提供机械解释 - 血友病和抗凝剂的特定出血，（2）提供基于机制的知识潜在地指导出血治疗的临床决策。