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.
