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.

抽象的 美国每年有超过 190,000 人遭受急性呼吸综合征困扰，死亡率很高 30-40% 的人接受最佳治疗 此外，还有超过 1200 万慢性肺病患者， 当机械通气不足时，将有 690 万人次进入急诊室，并导致超过 18 万人死亡。 为了支持这些患者，体外膜肺氧合（ECMO）被用作康复的桥梁或桥梁 不幸的是，ECMO 受到出血和血栓并发症的困扰，导致患者病情减少。 存活率分别约为 40% 和 33% 凝结的原因主要是表面吸附。 血浆蛋白，随后激活凝血级联的内在分支，以及血小板结合 可以使用全身静脉注射肝素来对抗吸附的纤维蛋白原，但这会抑制生物材料- ECMO 回路中的诱导凝血和患者组织中的组织因子诱导凝血，导致 为了同时消除这两个问题，我们建议将两个问题结合起来。 选择性抑制血液-生物材料界面处的凝血同时留下组织基的方法 第一个是我们最初的两性离子聚羧基甜菜碱（PCB）生物材料表面涂层。 结果表明，PCB 涂层可显着降低体外蛋白质吸附和血小板结合 第二种是 FXII900，一种有效的、高选择性的双环药物。 肽 FXIIa 抑制剂在纳摩尔浓度下抑制表面诱导的凝血激活。 不影响我们的凝血级联的基于组织的外在分支或共同分支。 初步、短期兔 ECMO 研究表明，与标准相比，凝块形成减少了 94% 临床肝素抗凝的同时，FXII900加PCB维持了正常的出血时间。 肝素将出血时间增加到正常值的 2.9 倍，该提案的目标是延长这一时间。 通过 i) 证明 PCB 与 FXII900 组合的有效性，将技术推向临床应用 5 天体内体外生命支持期间的抗凝和 ii) 开发长效 FXII900 如果成功，可以每 8 或 12 小时一次推注给药，而不是连续静脉滴注。 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) 降低 ECMO 死亡率，iii) 简化 ECMO 的临床应用。 综合起来，ECMO 的好处还可能允许在重症监护病房外进行安全的长期 ECMO。