Abstract 714: Targeting Coagulation Factor XII to Protect from Cardiac Ischemia Reperfusion Injury
Formation of fibrin is critical for limiting blood loss at a site of blood vessel injury (hemostasis), but may also contribute to vascular thrombosis and thus exaggerate myocardial ischemia/reperfusion injury. Hereditary deficiency of factor XII (FXII), the protease that triggers the intrinsic pathway of coagulation in vitro, is not associated with spontaneous or excessive injury-related bleeding, but can reduce thrombus formation. Therefore, we studied the contribution of FXII for myocardial ischemia reperfusion injury. Following 30 minutes of ischemia and 24 hours of reperfusion infarct size in FXII deficient mice was significantly reduced as compared to wild type controls (infarct/area at risk, WT vs. FXII−/−, 73.5%±4.4% vs. 42.3±1.6%, p<0.001) despite similar area at risk (WT vs. FXII−/−, 28.3%±1.7% vs. 29.9±1.0%, p=n.s.). There was no difference in bleeding complications and bleeding time. Mice deficient in the FXII substrate factor XI were similarly protected from ischemia reperfusion injury (infarct/area at risk, FXI−/−, 16.9%±4.1%, vs. WT p<0.001). The phenotype of FXII−/−mice could be rescued by intravenous application of human FXII (infarct/area at risk, FXII−/−+FXII, 77.3%±8.4%, p<0.001 vs. FXIIKO). WT mice treated with the FXII inhibitor PCK (Pro-Phe-Arg-chloromethylketone) were similarly protected from myocardial ischemia/reperfusion injury (infarct/area at risk, 46.5% ±3.7%, vs. WT p<0.001). The data suggest that the intrinsic pathway is crucial for pathological clotting in myocardial ischemia reperfusion injury. FXII inhibition may offer a selective and safe strategy to reduce ischemic injury.