Shear-Induced Hemostatic Dysfunction and Bleeding in CF-VAD Patients

CF-VAD 患者中剪切引起的止血功能障碍和出血

基本信息

批准号：
8888742
负责人：
Bartley P GriffIth
金额：
$ 54.27万
依托单位：
UNIVERSITY OF LOUISVILLE
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-20 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8888742
关键词：
Adult Adverse event Affect Annual Reports Biocompatible Biological Biological Markers Biomedical Engineering Blood Blood Coagulation Factor Blood Platelets Blood flow Blood specimen Cells Characteristics Clinical Clinical Management Data Databases Destinations Device Designs Device or Instrument Development Devices Diagnosis Disease Elements Engineering Environment Event Failure Functional disorder Goals Heart Transplantation Heart failure Hematology Hemorrhage Hemostatic Agents Hemostatic function Implant Infection Injury Interagency Registry for Mechanically Assisted Circulatory Support Knowledge Laboratories Link Liquid substance Logistic Regressions Measures Mechanics Medical Modeling Molecular Molecular Profiling Myocardial Organ failure Outcome Patients Physiological Plasma Quality of life Recovery Research Risk Series Staging Stratification Structure Survival Rate Technology Testing Thrombosis Time Transplant Recipients Ventricular Weight base clinically significant design experience hemodynamics implantation improved indexing next generation novel public health relevance research study shear stress success ventricular assist device

项目摘要

DESCRIPTION (provided by applicant): Heart failure (HF) affects 5.1 million adult patients in the US. About 50% of people diagnosed with HF will die within 5 years. Ventricular assist device (VAD) therapy has evolved into a standard therapy for patients with advanced HF, not only as a bridge to myocardial recovery or cardiac transplantation but also as a destination therapy. The recent data suggest that approximately 85 and 75% of patients supported with continuous flow VADs (CF-VADs) will survive at 12 and 24 months, respectively. These survival rates are approaching those of heart transplant patients. However, bleeding has become a significant problem for the CF-VAD therapy. Thus it is critical to understand the bleeding risk of CF-VAD support and their underlying mechanistic origins. Given the potential of the CF-VAD therapy for end-stage HF patients and the need to reduce significant device associated complications, we propose to conduct a series of clinical, biological and bioengineering experiments to seek a better understanding of shear-induced hemostatic dysfunction (SIHD) and bleeding in HF patients supported with CF-VADs and their link to blood flow dynamics of CF-VADs and pre-existing hemostatic disorder of HF patients. Further we seek to uncover the underlying molecular mechanisms of SIHD for better medical management and to create a database of SIHD for VAD design refinements. Three specific aims of the proposed project are: (1) To determine temporal changes of biomarkers of SIHD in HF patients prior to and during CF-VAD support and to link these changes to post-implant bleeding events; (2) To model shear stress indices (SSI) of CF-VADs and link them to measured biomarkers of SIHD and Bleeding in CF- VAD patients with consideration of pre-existing hemostatic disorder and patient-specific SIHD sensitivity to SSI prior to receiving a CF-VAD; and (3) To elucidate underlying molecular mechanisms of SIHD associated with CF-VADs and to establish a database of biomarkers of SIHD for VAD design improvement. Altogether, a combination of clinical hematology, biological as well as bioengineering approaches will be used to derive the basic knowledge behind bleeding complications and to investigate the influence of device-specific non- physiological fluid dynamic characteristics like shear stress and exposure time on SIHD. The successful completion of this project will create a new knowledge of bleeding associated with CF-VADs. The new knowledge can be used by clinicians to refine bleeding risk stratification in patients for the improved quality of life and by engineers to develop less traumatic, next generation biocompatible VADs.

描述（由申请人提供）：心力衰竭 (HF) 影响着美国 510 万成年患者，大约 50% 的心力衰竭患者将在 5 年内死亡。对于晚期心力衰竭，不仅可以作为心肌恢复或心脏移植的桥梁，而且可以作为目标治疗。最近的数据表明，大约 85% 和 75% 的患者接受连续流量 VAD 的支持。 (CF-VAD) 的存活率分别接近心脏移植患者的存活率，然而，出血已成为 CF-VAD 治疗的一个重要问题，因此了解出血风险至关重要。鉴于 CF-VAD 治疗对终末期心力衰竭患者的潜力以及减少重大设备相关并发症的需要，我们建议进行一系列临床、生物学和生物工程实验寻找更好地了解 CF-VAD 支持的心力衰竭患者中剪切诱导的止血功能障碍 (SIHD) 和出血及其与 CF-VAD 的血流动力学和心力衰竭患者先前存在的止血障碍之间的联系。该项目的三个具体目标是：(1) 确定心力衰竭患者中 SIHD 生物标志物的时间变化。 CF-VAD 支持期间和期间，并将这些变化与植入后出血事件联系起来；(2) 对 CF-VAD 的剪切应力指数 (SSI) 进行建模，并将其与 CF-VAD 患者的 SIHD 和出血的测量生物标志物联系起来；在接受 CF-VAD 之前考虑先前存在的止血障碍和患者特异性 SIHD 对 SSI 的敏感性；以及 (3) 阐明与 SIHD 相关的潜在分子机制CF-VAD 并建立 SIHD 生物标志物数据库，以改进 VAD 设计。总而言之，将结合临床血液学、生物学和生物工程方法来获取并发症背后的出血基础知识，并研究设备的影响。特定的非生理液体 SIHD 上的剪切应力和暴露时间等动态特征将创建与 CF-VAD 相关的出血新知识。主教可以利用这些新知识来完善患者的出血风险分层，以提高治疗质量。生命和工程师开发创伤较小的下一代生物相容性 VAD。