Hemolysis and Platelet Activation during Continuous Flow Mechanical Circulatory Support

项目摘要/摘要： 心力衰竭(HF)已经达到流行的程度，全世界有540多万人受到影响，其负担 预计在未来十年将呈指数级增长。连续机械循环支持(MCS) 用于终末期心力衰竭或急性心源性休克患者的流量(CF)泵导致严重 提高存活率。然而，设备操作仍然充满严重的不良事件(SAE) 导致过度的发病率。Cf泵血栓和中风的发生率很高，从而促使 需要揭示他们的血液学机制和治疗靶点。在慢性CF泵领域， 新设计的心脏伴侣(HM)3设备，具有更好的血液相容性，如更广泛的血液 血流通道，确实显示了原位泵血栓的减少；然而，存在致残缺血 卒中持续升高。严重血栓形成事件的这种持久性，尽管设备设计发生了变化， 因此，充分阐明血栓形成的潜在机制是至关重要的。 溶血与设备血栓形成和缺血性中风的关系最近被认识到，并正在 符合溶血导致的血栓前状态。因为明显的临床溶血可能是下游的 已经在装置中形成的血栓的影响，并且考虑到在较新的 对于耐用设备的产生，我们转而专注于评估亚临床低水平的体内影响 溶血对血小板活化和聚集的影响(PA/A)。在溶血性疾病中，如镰状细胞 贫血时，细胞外血红蛋白可能通过清除一氧化氮(NO)和与前列环素结合而诱导PA/A。 血管性血友病因子(VWF)的血栓性超大分子(UL)多聚体通过 金属蛋白酶(ADAMTS 13)。 我们的初步发现表明，在慢性和急性CFMCS中，LLH与7-TO有关 随后发生血栓事件的风险增加15倍，包括缺血性中风。此外，我们注意到， 平均血小板体积(MPV)，PA/A的替代标记物和血栓前vWF水平在 有促黄体生成素的患者与无促黄体生成素的患者比较。我们的研究结果还表明， 接受血小板的患者在耐用CF泵支持期间发生血栓事件和持续LLH的MPV 没有信号增强剂，西地那非。 这项建议将评估假设，即在CF泵支持期间LLH与增加 LLHPA/A和西地那非均可降低PA/A。在目标1中，我们将招募慢性(HM 2和HM 3)患者 和急性(VA、ECMO和Impella)CFMCS，以评估有和没有LLH者之间的PA/A。在……里面 二次分析，我们还将检查这种联系是否可能与血小板的变化有关 CGMP、vWF活性、vWF UL/HMW多聚体和ADAMTS13活性。在AIM 2中，门诊患者使用耐用CF 正在进行促黄体生成素的泵支持将随机(1：1)接受西地那非或安慰剂双盲试验 在分配给药后将测量15天内PA/A标志物的变化 并与基线进行比较。

Project Summary / Abstract: Heart failure (HF) has reached epidemic proportions effecting over 5.4 million people worldwide and its burden is expected to grow exponentially in the next decade. Mechanical circulatory support (MCS) with continuous flow (CF) pumps for patients with end stage heart failure or acute cardiogenic shock has led to drastic improvements in survival. However, device operation remains fraught with serious adverse events (SAEs) leading to excessive morbidity. CF pump thrombosis and stroke are occurring at high rates, thereby prompting a need to uncover their hematologic mechanisms and therapeutic targets. In the chronic CF pump field, the newly designed Heart Mate (HM) 3 device, with features of greater hemocompatability such as wider blood flow passages, did show a reduction of in-situ pump thrombosis; however, the presence of disabling ischemic stroke remained elevated. Such persistence of severe thrombotic events, despite alterations in device design, makes it critically important to fully elucidate mechanisms underlying thrombus formation. The association of hemolysis with device thrombosis and ischemic stroke has recently been recognized and is consistent with a hemolysis induced pro-thrombotic state. Since overt clinical hemolysis may be a downstream effect of thrombus already formed in the device and given that in-situ thrombosis may no longer occur in newer generation of durable devices, we instead focus on assessing the in-vivo impact of sub clinical low level hemolysis (LLH) on platelet activation and aggregation (PA/A). In hemolytic disorders such as sickle cell anemia, extracellular hemoglobin may induce PA/A by scavenging nitric oxide (NO) and binding to pro- thrombotic ultra large (UL) multimers of von Willebrand factor (vWF) to prevent their proteolysis by the metalloproteinase (ADAMTS 13). Our preliminary findings indicate that during both chronic and acute CF MCS, LLH was associated with a 7 to 15 fold increased risk of subsequent thrombotic events, including ischemic stroke. Moreover, we noted that mean platelet volume (MPV), a surrogate marker of PA/A, and pro-thrombotic vWF levels were higher in patients with LLH in comparison to those with no LLH. Our findings also indicate a substantial reduction in thrombotic events and MPV with ongoing LLH during durable CF pump support in patients receiving a platelet NO signaling potentiation agent, sildenafil. This proposal will evaluate the hypotheses that LLH during CF pump support is associated with an increase in PA/A and sildenafil can lower PA/A during LLH. In Aim 1, we will recruit patients on chronic (HM 2 and HM 3) and acute (VA ECMO and Impella) CF MCS, to assess PA/A between those with and without LLH. In secondary analyses, we will also examine whether this association may be related to changes in platelet cGMP, vWF activity, vWF UL/HMW multimers and ADAMTS13 activity. In Aim 2, outpatients on durable CF pump support with ongoing LLH will be randomized (1:1) to receive sildenafil or placebo in a double-blinded manner for a 15 day period and changes in PA/A markers will be measured after assigned drug administration and compared to baseline.