Combined Use of Polycarboxybetaine Coatings with a Selective FXIIa Inhibitor to Create Potent Biomaterial Anticoagulation Without Bleeding During Extracorporeal Life Support

聚羧基甜菜碱涂层与选择性 FXIIa 抑制剂的组合使用可在体外生命支持期间产生有效的生物材料抗凝作用而不会出血

• 批准号: 10743109
• 负责人: Keith E Cook
• 金额: $ 7.48万
• 依托单位: CARNEGIE-MELLON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10743109
• 关键词: Acute Respiratory Distress Syndrome; Adsorption; Affect; Anticoagulation; Binding; Biocompatible Materials; Bleeding time procedure; Blood; Blood Platelets; Bolus Infusion; Cessation of life; Chronic lung disease; Clinical; Coagulation Process; Cyclic Peptides; Dose; Effectiveness; Emergency department visit; Extracorporeal Membrane Oxygenation; Factor XIIa; Fibrinogen; Formulation; Goals; Hemorrhage; Heparin; Hour; In Vitro; Intensive Care Units; Intravenous; Life; Mechanical ventilation; Oryctolagus cuniculus; Patients; Persons; Plasma Proteins; Proteins; Recovery; Surface; Technology; Thromboplastin; Time; Tissues; Transplantation; biomaterial interface; clinical application; improved; in vivo; inhibitor; intravenous drip; mortality; nanomolar; respiratory; sheep extracorporeal membrane oxygenation; surface coating; thrombotic complications

Abstract Over 190,000 people suffer from acute respiratory distress syndrome in the US each year, with mortality rates from 30-40% with the best treatment. In addition, there are over 12 million patients with chronic lung disease, 6.9 million emergency room visits, and over 180,000 deaths. When mechanical ventilation is insufficient to support these patients, extra-corporeal membrane oxygenation (ECMO) is used as a bridge to recovery or bridge to transplantation. Unfortunately, ECMO is plagued by bleeding and thrombotic complications that reduce patient survival by approximately 40 and 33%, respectively. The cause of coagulation is primarily surface adsorption of plasma proteins, subsequent activation of the intrinsic branch of the coagulation cascade, and platelet binding to adsorbed fibrinogen. This is combated using systemic, intravenous heparin, but this inhibits both biomaterial- induced coagulation in the ECMO circuit and tissue-factor induced coagulation in the patient’s tissues, resulting in bleeding complications. To eliminate both of these problems simultaneously, we propose to combine two means of selectively inhibiting coagulation at the blood-biomaterial interface while leaving tissue-based coagulation intact. The first is biomaterial surface coating with zwitterionic polycarboxybetaine (PCB). Our initial results demonstrate that the PCB coating dramatically decreases protein adsorption and platelet binding in vitro and long-term clot formation during sheep ECMO. The second is FXII900, a potent, highly-selective bicyclic peptide FXIIa inhibitor. FXII900 inhibits surface-induced activation of coagulation at nanomolar concentrations without affecting the tissue-based extrinsic branch or common branch of the coagulation cascade. In our preliminary, short-term rabbit ECMO studies, we demonstrate a 94% reduction in clot formation vs. standard clinical heparin anticoagulation. At the same time, FXII900 plus PCB maintained a normal bleeding time, while the heparin increased the bleeding time to 2.9 times normal. The goals of this proposal are to extend this technology toward clinical applications by i) proving the effectiveness of combined PCB plus FXII900 anticoagulation during 5-day in vivo extracorporeal life support and ii) developing long-acting FXII900 formulations that enable bolus dosing every 8 or 12 hours rather than a continuous intravenous drip. If successful, these studies would lead to a clinical anticoagulation strategy that i) reduces bleeding and thrombotic complications during ECMO, ii) reduces ECMO mortality, and iii) simplifies clinical application of ECMO. These benefits, when combined, might also allow safe long-term ECMO outside the intensive care unit.

摘要 美国每年有超过19万人患有急性呼吸窘迫综合征，死亡率高 从30-40%到最好的治疗。此外，还有1200多万慢性肺病患者， 690万急诊室就诊，超过18万人死亡。当机械通风不足以 为了支持这些患者，体外膜氧合(ECMO)被用作康复的桥梁或桥梁 为了移植。不幸的是，ECMO受到出血和血栓并发症的困扰，这会减少患者的 存活率分别提高约40%和33%。混凝的原因主要是表面吸附 血浆蛋白、随后凝血级联固有分支的激活和血小板结合 到吸附的纤维蛋白原。这是使用全身静脉肝素来对抗的，但这抑制了生物材料- ECMO回路中的诱导凝血和患者组织中的组织因子诱导的凝血，结果 在出血并发症中。为了同时消除这两个问题，我们建议将两个问题结合起来 选择性地抑制血液-生物材料界面处的凝血，同时保留基于组织的 凝血完好无损。第一种是用两性离子聚羧酸甜菜碱(PCB)包覆生物材料表面。我们最初的 结果表明，在体外，印刷电路板涂层显著降低了蛋白质的吸附和血小板的结合 和绵羊体外反搏过程中的长期凝块形成。第二种是FXII900，一种强大的、高度选择性的双环 多肽FXIIa抑制剂。FXII900在纳摩尔浓度下抑制表面诱导的凝血激活 而不影响凝固级联的基于组织的外在分支或共同分支。在我们的 初步的短期兔ECMO研究表明，与标准相比，血栓形成减少了94% 临床肝素抗凝。同时，FXII900 plus印刷电路板保持了正常的出血时间，而 肝素使出血时间延长至正常的2.9倍。这项提案的目标是延长这一期限 技术走向临床应用：i)证明组合PCB+FXII900的有效性 体内5天体外生命支持中的抗凝作用和II)开发长效FXII900 能够每8或12小时推注一次的配方，而不是连续静脉滴注。如果成功， 这些研究将导致临床抗凝策略：i)减少出血和血栓形成 ECMO期间的并发症，ii)减少ECMO死亡率，iii)简化ECMO的临床应用。这些 当这些好处结合在一起时，也可能允许在重症监护病房外进行安全的长期ECMO。