FIBRIN CONTRIBUTES TO MICROVASCULAR OBSTRUCTIONS AND PARENCHYMAL CHANGES DURING EARLY FOCAL CEREBRAL-ISCHEMIA AND REPERFUSION

Background and Purpose Ischemic cerebral injury is associated with activation of the blood coagulation cascade. To elucidate the contribution of fibrin formation to microvascular injury during focal cerebral ischemia and reperfusion, we have studied the time course and the localization of fibrin deposition in cerebral microvessels and the surrounding tissues during ischemia/reperfusion in a well-described nonhuman primate model. Methods Cerebral tissues from adolescent male baboons were examined after 2-hour middle cerebral artery occlusion (n=3) and after 3 hours of middle cerebral artery occlusion and 1-hour (n=6), 4-hour (n=3), and 24-hour (n=4) reperfusion; tissues from control primates (n=3) also were examined. Fibrin deposition was detected by immunohistochemical techniques using the fibrin-specific monoclonal antibody MH-1. The number and size distribution of microvessels associated with fibrin were quantified by video-imaging microscopy. Results Fibrin was associated with microvessels only in the ischemic zone where severe neuronal injury was documented, its frequency increasing with the reperfusion period (F-4,F-26=3.80, P<.05). Extravascular fibrin deposition was significantly increased by 24-hour reperfusion compared with the other subjects (P<.05). Preischemia infusion of the anti-tissue factor monoclonal antibody TF9-6B4 resulted in significant reduction of intramicrovascular fibrin (P<.038 versus no intervention) at 1-hour reperfusion but had no effect on extravascular fibrin deposition. Conclusions These results suggest that microvascular fibrin deposition accumulates in a time-dependent manner during focal cerebral ischemia/reperfusion and that exposure of plasma to perivascular tissue factor is partially responsible for occlusion formation. During ischemia the large plasma protein fibrinogen extravasates and interacts with parenchymal tissue factor, forming significant extravascular fibrin by 24 hours of reperfusion.