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

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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.