Hemolysis and Platelet Activation during Continuous Flow Mechanical Circulatory Support

连续流动机械循环支持期间的溶血和血小板活化

基本信息

批准号：
10548171
负责人：
Omar Saeed
金额：
$ 14.9万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-01-15 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10548171
关键词：
ADAMTS Acute Adverse event Antiplatelet Drugs Aspirin Award Binding Biological Markers Biology Blood Platelets Blood flow Cardiogenic Shock Chemosensitization Chronic Clinical Clinical Research Cyclic GMP Data Device Designs Devices Disease Dose Double-Blind Method Epidemic Erythrocytes Event Exposure to Extracorporeal Membrane Oxygenation Generations Heart Heart failure Hematological Disease Hematology Hemoglobin Hemolysis Hemolysis Induction Hemorrhage Hour In Situ In Vitro Investigation Ischemic Stroke Laboratories Measures Mediating Mediator Mentors Metalloproteases Morbidity - disease rate Nitric Oxide Oral Organ Outpatients P-Selectin Partner in relationship Patient Recruitments Patients Persons Pharmaceutical Preparations Placebos Platelet Activation Platelet Glycoprotein GPIIb-IIIa Complex Platelet aggregation Prevention Prevention strategy Primary Prevention Proteolysis Pump Randomized Regimen Risk Serious Adverse Event Sickle Cell Anemia Signal Transduction Stroke Surrogate Markers Techniques Testing Thrombosis Thrombus Training United States Food and Drug Administration career clinical epidemiology design extracellular improved improved outcome in vivo inhibitor mechanical circulatory support miniaturized device operation pharmacologic phosphodiesterase V placebo controlled study prevent primary endpoint randomized trial secondary analysis secondary endpoint sildenafil therapeutic target thromboembolic stroke thrombotic thrombotic complications translational scientist von Willebrand Factor

项目摘要

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.

项目摘要 /摘要：心力衰竭（HF）的流行比例在全球范围内影响超过540万人及其负担预计将在未来十年内成倍增长。机械循环支持（MCS）连续末期心力衰竭或急性心源性休克患者的流量（CF）泵已导致剧烈生存的改善。但是，设备操作仍然充满严重的不良事件（SAE）导致发病过度。 CF泵血栓形成和中风以高速率发生，从而促使需要发现其血液学机制和治疗靶标。在慢性CF泵字段中新设计的心伴侣（HM）3设备，具有更大的血液相容性，例如较宽的血液流通过，确实显示出原位泵血栓形成的减少；但是，残疾缺血的存在中风仍然升高。尽管设备设计发生了改变，但严重的血栓形成事件的这种持久性使完全阐明血栓形成的机制至关重要。溶血与装置血栓形成和缺血性中风的关联最近已被认识到，IS 与溶血诱导的促血栓形成状态一致。由于明显的临床溶血可能是下游设备中已经形成的血栓的影响，鉴于现场血栓形成可能不再发生相反，我们的生成耐用设备，专注于评估次临床低水平的体内影响血小板激活和聚集（PA/A）的溶血（LLH）。在溶血疾病（例如镰状细胞）中贫血，细胞外血红蛋白可以通过清除一氧化氮（NO）并结合促疾病来诱导PA/A von Willebrand因子（VWF）的血栓形成超大（UL）多聚体，以防止其蛋白水解金属蛋白酶（Adamts 13）。我们的初步发现表明，在慢性和急性CF MC中，LLH与7至7 15倍增加了随后发生的血小板事件的风险，包括缺血性中风。而且，我们注意到平均血小板体积（MPV），PA/A的替代标记和亲栓性VWF水平较高与没有LLH的患者相比，LLH患者。我们的发现还表明大幅减少在接受血小板的患者中，在耐用的CF泵支持期间，血栓性事件和MPV持续使用LLH 没有信号增强剂，西地那非。该提案将评估CF泵支持期间LLH的假设与增加有关 PA/A和西地那非可以在LLH期间降低PA/A。在AIM 1中，我们将招募慢性患者（HM 2和HM 3）和急性（va ecmo和impella）CF MC，以评估有和没有LLH的患者之间的PA/A。在次要分析，我们还将检查该关联是否可能与血小板的变化有关 CGMP，VWF活动，VWF UL/HMW多聚体和ADAMTS13活动。在AIM 2中，耐用CF的门诊病人持续使用LLH的泵支撑将被随机分配（1：1），以双眼接收西地那非或安慰剂分配药物给药后，将测量15天的时间，并测量PA/A标记的变化并与基线相比。

项目成果

期刊论文数量（11）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Preventing driveline infection during left ventricular assist device support by the HeartMate 3: A survey-based study.

在 HeartMate 3 的左心室辅助装置支持期间预防动力传动系统感染：一项基于调查的研究。

DOI：
10.1111/aor.14187
发表时间：
2022
期刊：
Artificial organs
影响因子：
2.4
作者：
Saeed,Omar;Moss,Noah;Barrus,Bryan;Vidula,Himabindu;Shah,Samit;Feitell,Scott;Masser,KristiS;Kilic,Arman;Moin,Danyaal;Atluri,Pavan;Barati,Edo
通讯作者：
Barati,Edo

Impact and Measurement of Blood Pressure During Continuous Flow Left Ventricular Assist Device Support: The Pressure Is On!

连续流动左心室辅助装置支持期间血压的影响和测量：压力已开启！

DOI：
10.1097/mat.0000000000000960
发表时间：
2019
期刊：
ASAIO journal (American Society for Artificial Internal Organs : 1992)
影响因子：
0
作者：
Saeed,Omar;Jorde,UlrichP
通讯作者：
Jorde,UlrichP

Outcomes of Non-ST-Segment Myocardial Infarction During Chronic Heart Failure and End-Stage Renal Disease.

慢性心力衰竭和终末期肾病期间非 ST 段心肌梗死的结果。

DOI：
10.1016/j.amjcard.2023.05.007
发表时间：
2023
期刊：
The American journal of cardiology
影响因子：
0
作者：
Alhuarrat,MajdAlDeen;Alhuarrat,MohammedRasoul;Varrias,Dimitrios;Patel,SnehalR;Sims,DanielB;Latib,Azeem;Jorde,UlrichP;Saeed,Omar
通讯作者：
Saeed,Omar

Characteristics and Outcomes of COVID-19 Patients Supported by Venoarterial or Veno-Arterial-Venous Extracorporeal Membrane Oxygenation.

DOI：
10.1053/j.jvca.2022.01.049
发表时间：
2022-08
期刊：
Journal of cardiothoracic and vascular anesthesia
影响因子：
2.8
作者：
Haroun MW;Patel SR;Sims DB;Jorde UP;Goldstein DJ;Saeed O
通讯作者：
Saeed O

PREVENTion of non-surgical bleeding by management of HeartMate II patients without anti-platelet therapy (PREVENT II) trial.

通过管理不接受抗血小板治疗的 HeartMate II 患者来预防非手术出血 (PREVENT II) 试验。

DOI：
10.1016/j.healun.2020.05.003
发表时间：
2020
期刊：
The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation
影响因子：
0
作者：
Jorde,UlrichP;Katz,JasonN;Colombo,PaoloC;Stulak,John;Saeed,Omar;Egnaczyk,Gregory;Haeusslein,Ernest;McCann,Patrick;Crandall,Daniel;Franke,Abi;Adamson,Robert;PREVENTIIstudyinvestigators
通讯作者：
PREVENTIIstudyinvestigators