A rapid microfluidic diagnostic assay for the measurement of Direct Oral Anticoagulants from patient whole blood

翻译后摘要：直接口服抗凝剂（DOAC）正在成为首选的方法来管理 抗凝，特别是在血栓溶解性疾病中。DOAC的使用预计将达到300亿美元，在全球范围内， 五年，超过其他抗凝剂，如华法林。虽然非常有效，但DOAC可能会增加出血 风险和复杂的紧急护理，这可能包括使用昂贵的DOAC逆转剂。为流动 诊断无法充分识别由DOAC引起的问题，因此存在越来越多的安全问题 联合委员会呼吁进行实验室检测监测，这类药物得到了加强， 基于安全DOAC和逆转剂使用的方法。无论是治疗中风/VTE/PE患者， 例如，对于心律失常患者或创伤/紧急手术患者，实时确定患者的心律不齐状态是可能的。 抗凝治疗，包括DOAC类型（Xa因子抑制剂与直接凝血酶抑制剂）对于快速护理至关重要 避免不良出血的决定。核心实验室检测DOAC的一个重要限制是长度 这可能会超过典型的20分钟决策窗口。FloBio是 开发第一个DOAC体外诊断产品，为医生提供快速的知识， 在紧急护理环境中的抗凝状态。使用我们的分析仪/成像站和一次性DOAC检测 我们的新方法结合了血液动力学流动和离散凝块激活， 模拟生理性血液凝固。在不到10分钟的时间内，医疗保健提供者将知道患者的相对DOAC 浓度和DOAC分类。 FloBio的第一阶段工作已经证明了一种可扩展的、多路复用的、一次性的DOAC测定盒/微流体 促进体外自然凝血级联的装置，用于测量测定信号的仪器， 分析软件，为最终用户提供简单的结果评估和临床数据， 该测定法和装置检测人血液中DOAC类别和水平的可行性。FloBio的创新是 这是市场上第一个提供纤维蛋白和血小板聚集实时数据的诊断分析 基础血管和凝血蛋白，在流动下，重演体内凝血过程。 在第二阶段，FloBio将专注于验证DOAC检测在100名受试者的临床研究在大学 宾夕法尼亚本研究将验证该检测试剂盒在一年内检测类和DOAC水平的能力。 临床患者人群。使用DOAC掺入的健康成人血液的第二项临床研究将确定 器械、检测试剂盒和系统范围、灵敏度、特异性、方差和一致性。临床试验数据将 根据检测的金标准LCMS进行验证。关键检测功能的自动化也将 评估以减少测定中的变化，以及完全集成、可自动化、一次性DOAC的可行性 将在健康人血液样本中证明检测试剂盒。工作的结果将是一个全面的 经过审核的DOAC检测系统，已准备好在IIb期全面开发。

Abstract: Direct oral anticoagulants (DOACs) are becoming the preferred approach to managing anticoagulation, particularly in thrombolytic disorders. DOAC use is anticipated to reach $30B globally in the next five years, overtaking other anticoagulants such as warfarin. While highly effective, DOACs can elevate bleeding risks, and complicate emergency care, which may include the use of expensive DOAC reversal agents. As current diagnostics fail to adequately identify problems caused by DOACs, there exists growing safety concerns for this class of drugs that are reinforced by the Joint Commission’s call for laboratory test monitoring, and evidence- based approaches for safe DOAC, and reversal agent use. Whether treating a stroke/VTE/PE patient, heart arrhythmia patient, or trauma/urgent surgery patient, the real-time determination of a patient’s state of anticoagulation, including DOAC type (factor Xa inhibitor vs. direct thrombin inhibitor) is critical for rapid care decisions to avoid adverse bleeding. A significant limitation of core laboratory detection of DOACs is the length of time to results, which can exceed more than the typical 20-minute decision making window. FloBio is developing the first DOAC in vitro diagnostic product to provide physicians with rapid knowledge of anticoagulation state in emergency care settings. With our analyzer/imaging station, and disposable DOAC assay cartridge/microfluidic device, our novel approach combines hemodynamic flow, and discrete clot activation, to mimic physiological blood clotting. In less than 10 minutes, a healthcare provider will know a patient’s relative DOAC concentration, and the DOAC classification. FloBio’s Phase I work has demonstrated a scalable, multiplex, disposable DOAC assay cartridge/microfluidic device that facilitates the natural blood clotting cascade in vitro, an instrument for measuring assay signals, analytic software to provide the end user with a simple outcomes assessment, and clinical data that validates the feasibility of the assay and device to detect DOAC class and level in human blood. FloBio’s innovation is a diagnostic assay that will be the first in the market to provide real-time data on fibrin and platelet accumulation on basal vascular and coagulation proteins, under flow, that recapitulates in vivo coagulation processes. In Phase II, FloBio will focus on validating the DOAC assay in a 100 subject clinical study at the University of Pennsylvania. This study will validate the capability of the assay to detect both class and DOAC level, within a clinical patient population. A second clinical study with DOAC spiked healthy adult blood will determine the device, assay and system range, sensitivity, specificity, variance, and consistency. Clinical assay data will be validated against the gold standard of detection, LCMS. Automation of critical assay functions will also be evaluated to reduce variation in the assay, and the feasibility of a fully integrated, automatable, disposable DOAC assay cartridge will be demonstrated in healthy human blood samples. The outcome of the work will be a fully vetted DOAC assay system that is ready for full development in Phase IIb.