DEVELOPMENT OF A NOVEL WHOLE BLOOD COAGULATION ASSAY

新型全血凝固测定法的开发

• 批准号: 7375159
• 负责人: Donald Fitzpatrick Brophy
• 金额: $ 2.37万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-12-01 至 2006-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7375159
• 关键词: DEVELOPMENT; NOVEL; WHOLE; BLOOD; COAGULATION

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Over the last 40 years, our understanding of blood coagulation has changed significantly. Newer, more potent antiplatelet and anticoagulant medications have been introduced. Despite the innovation of drug therapy, our standard laboratory assays of hemostasis do not reflect our new insights into the clotting mechanism, and do not serve as adequate laboratory monitors for these new drugs. Current clinical laboratory assays are performed on plasma samples that do not contain platelets. It is becoming increasingly apparent that whole blood is the most appropriate patient sample for analyzing coagulation. The Hemodyne Hemostasis Analysis System (H.A.S.) analyzes whole blood samples using quantitative physical techniques. Previous investigations have shown that the parameters measured by the H.A.S. reflect not only the structural qualities of the blood clot, but also platelet function during clot formation. The H.A.S. is the first ex vivo system to quantitatively assess platelet function during clot formation. Due to the recent introduction of very potent antiplatelet and anticoagulant medications, the ability to monitor their effects is increasingly important. These potent drugs have a very narrow therapeutic window between efficacy and toxicity. Although they effectively control thrombosis in hypercoagulable conditions, their relative potency increases the risk of major hemorrhage. Unfortunately conventional monitoring parameters (i.e., PT, aPTT, INR) cannot measure or predict efficacy or toxicity. Thus, clinicians cannot adequately (or safely) monitor these new drug therapies for safety or efficacy. While the routine monitoring of some anticoagulants (such as low molecular weight heparin (LMWH)) may not be necessary in normal patients, the importance of documenting adequate and safe clinical response is critical in complex patients with concurrent risk factors for hemorrhage (e.g., patients with hepatic or renal dysfunction). We have compelling preliminary data conducted in end-stage renal disease (ESRD) subjects that demonstrate an enhanced anticoagulant response following exposure to the LMWH enoxaparin. For these special populations, clinicians desperately need an inexpensive assay that can quickly measure efficacy and predict risk of toxicity. We believe the H.A.S. can serve this role, and improve the care to these special populations with coagulation disorders. By doing so, this would allow clinicians to tailor anticoagulant therapy to achieve successful outcomes while preventing adverse bleeding events. These outcomes should result in reduced healthcare costs. This study has two specific aims. The first involves using the Hemodyne Hemostasis Analysis System , to define the in vivo relationship of antifactor Xa activity to thrombin generation time (TGT) following increasing doses of enoxaparin (0.25, 0.50 and 1.0 mg/kg) in two groups of subjects: 1) normal, healthy subjects without renal dysfunction; and 2) subjects with end-stage renal disease (ESRD; creatinine clearance < 10 mL/min) on maintenance hemodialysis. The second goal is to determine the ability of the Hemodyne Hemostasis Analysis System to characterize intergroup (control versus ESRD) differences in thrombin generation time over 12 hours following single dose enoxaparin 1 mg/kg. All previous and current measures of platelet function must be performed with clotting by characterizing these important clotting parameters, the H.A.S. is a sensitive, novel, whole blood assay that monitors coagulation status in various disease states and in patients on anticoagulant therapy.

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子弹和调查员（PI）可能已经从其他NIH来源获得了主要资金，因此可以在其他清晰的条目中代表。列出的机构适用于该中心，这不一定是调查员的机构。在过去的40年中，我们对血液凝血的理解发生了很大变化。已经引入了更新，更有效的抗血小板和抗凝药物。尽管对药物疗法进行了创新，但我们止血的标准实验室测定并不能反映我们对凝血机制的新见解，也不是这些新药的适当实验室监测器。当前的临床实验室测定是对不含血小板的血浆样品进行的。越来越明显的是，全血是用于分析凝血的最合适的患者样本。血差止血分析系统（H.A.S.）使用定量物理技术分析全血样品。先前的研究表明，H.A.S.测量的参数不仅反映了血块的结构质量，还反映了凝块形成过程中血小板功能。 H.A.S.是第一个在凝块形成过程中定量评估血小板功能的离体系统。 由于最近引入了非常有效的抗血小板和抗凝药物，监测其作用的能力越来越重要。这些有效的药物在功效和毒性之间具有非常狭窄的治疗窗口。尽管它们有效地控制了在可触及的条件下的血栓形成，但它们的相对效力会增加重大出血的风险。不幸的是，常规监测参数（即PT，APTT，INR）无法测量或预测功效或毒性。因此，临床医生无法（或安全地）监测这些新药物的安全或功效。尽管在正常患者中可能不需要对某些抗凝剂的常规监测（例如低分子量肝素（LMWH）），但记录足够和安全的临床反应的重要性对于具有出血的同时风险因素（例如，患有肝或肾功能障碍的患者）至关重要。我们拥有在末期肾脏疾病（ESRD）受试者中进行的引人注目的初步数据，这些数据表明在暴露于LMWH依诺肝素后的抗凝反应增强。 对于这些特殊人群，临床医生迫切​​需要一个廉价的测定法，该测定法可以快速衡量功效并预测毒性的风险。我们相信H.A.S.可以发挥这种作用，并改善患有凝结障碍的特殊人群的护理。通过这样做，这将使临床医生能够量身定制抗凝治疗以取得成功的结果，同时防止不良出血事件。这些结果应导致医疗保健成本降低。 这项研究有两个具体的目标。首先涉及使用血近止血分析系统，以在增加剂量的Enoxaparin（0.25、0.50、0.50和1.0 mg/kg）的剂量增加两组中，抗乳酸Xa活性与凝血酶产生时间（TGT）的体内关系：1）正常的，健康的受试者，没有肾脏失调的正常受试者； 2）在维持血液透析上患有末期肾脏疾病的受试者（ESRD；肌酐清除率<10 mL/min）。第二个目标是确定单剂量Enoxaparin 1 mg/kg之后，在12小时内凝血酶生成时间的组间（控制与ESRD）差异的能力。 必须通过表征这些重要的凝血参数H.A.S.来执行所有先前和当前血小板功能的度量。是一种敏感，新颖的全血分析，可在各种疾病状态和抗凝治疗中监测凝血状态。