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

 描述（由申请人提供）：心力衰竭（HF）影响美国510万成人患者。大约50%的HF患者会在5年内死亡。心室辅助装置（VAD）治疗已发展成为晚期HF患者的标准治疗，不仅是心肌恢复或心脏移植的桥梁，也是目的治疗。最近的数据表明，大约85%和75%的患者支持的连续流VAD（CF-VAD）将生存12个月和24个月，分别。这些存活率正在接近心脏移植患者。然而，出血已成为CF-VAD治疗的一个重要问题。因此，了解CF-VAD支持的出血风险及其潜在的机制起源至关重要。考虑到终末期HF患者CF-VAD治疗的潜力以及减少显著器械相关并发症的需要，我们建议进行一系列临床研究，生物学和生物工程学实验，以寻求更好地了解CF-VAD支持的HF患者中的剪切诱导止血功能障碍（SIHD）和出血及其与CF-VAD血流动力学和HF患者既存止血障碍的联系。此外，我们试图揭示SIHD的潜在分子机制，以更好地进行医疗管理，并创建一个数据库的SIHD VAD设计的改进。该项目的三个具体目标是：（1）确定HF患者在CF-VAD支持之前和期间SIHD生物标志物的时间变化，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患者中SIHD和出血的测量生物标志物联系起来，同时考虑预先存在的止血障碍和患者-在接受CF-VAD之前对SSI的特异性SIHD敏感性;以及（3）阐明与CF-VAD相关的SIHD的潜在分子机制，并建立SIHD生物标志物数据库，用于VAD设计改进。总之，将使用临床血液学、生物学和生物工程方法的组合来获得出血并发症背后的基本知识，并研究器械特异性非生理性液体的影响 动态特性，如剪切应力和暴露时间对SIHD的影响。该项目的成功完成将为CF-VAD相关出血提供新的知识。临床医生可以使用这些新知识来改善患者的出血风险分层，以提高生活质量，工程师可以开发创伤较小的下一代生物相容性VAD。

 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.