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

患有血友病或服用抗凝剂的个体有出血的风险，但出血的部位不同。 了解止血系统的这两种扰动如何在不同的血管床中相互作用 (VBs)将为出血治疗的决策提供信息。使用促止血剂治疗出血，但 个体对这些药剂的反应是高度可变的，并且可变性的潜在机制是 未知止血是一个非线性过程，涉及复杂的凝血生化耦合血小板 功能，VBs和生物物理机制，包括血流;它非常适合与综合研究 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，将确定潜在的机制，变量的反应，促止血剂， 不同的VB中心假设是，全局敏感性分析（GSA）适用于机械 出血的数学模型将阐明血小板、血管和 血浆成分，并预测实验验证的止血反应。这个假设是基于 在申请人的实验室中完全使用这种方法产生的初步数据。理由是， 所提出的定量方法和止血反应修饰剂的鉴定将一起 为开发检测特异性和以前未识别的生物标志物的检测方法提供了基础。指导 通过强有力的初步数据，这一假设将在三个具体目标中得到检验：1）发展和完善 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）确定调节血友病A中促止血剂反应的止血调节剂。在 目的1，现有的模型将扩展到包括血小板和纤维蛋白动力学的基本特征， 用微流控分析验证。在目标2中，将开发并纳入抗凝剂的子模型 止血模型。将获得VB特性的实验测量。GSA将 确定止血反应中VB位点特异性变异性的原因。在目标3中， 将开发促止血剂并将其纳入止血模型中。GSA将确定 血友病A治疗期间对它们的反应的变异性。这种方法是创新的，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 （2）抗凝剂和促止血剂的新子模型将被添加到一个全面的 止血系统的模型，包括血小板、纤维蛋白和与凝血和流动耦合的VB动力学。 这项研究具有重要意义，因为它有望（1）为场地提供力学解释， 血友病A的特异性出血和抗凝剂使用，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。

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.