REGULATION OF ARTERIAL THROMBOLYSIS BY PLASMINOGEN-ACTIVATOR INHIBITOR-1 IN MICE

Background-Platelet-rich arterial thrombi are resistant to lysis by pl asminogen activators. However, the mechanisms underlying thrombolysis resistance are poorly defined. Plasminogen activator inhibitor-1 (PAI- 1), which is present in plasma, platelets, and vascular endothelium, m ay be an important determinant of the resistance of arterial thrombi t o lysis. However, in vitro studies examining the regulation of platele ts-rich clot lysis by PAI-1 have yielded inconsistent results. Methods and Results-We developed a murine arterial injury model and applied i t to wild-type (PAI-1 +/+) and PAI-1-deficient (PAI-1 -/-) animals. Fe Cl3 was used to induce carotid artery thrombosis. Thrombi consisted pr edominantly of dense platelet aggregates, consistent with the histolog y of thrombi in large-animal arterial injury models and human acute co ronary syndromes. To examine the role of PAI-1 in regulating endogenou s clearance of platelet-rich arterial thrombi, thrombi were induced in 22 PAI-1 +/+ mice 14 PAI-1 -/- mice. Twenty-four hours later, the amo unt of residual thrombus was determined by histological analysis of mu ltiple transverse sections of each artery. Residual thrombus was deter mined by histological analysis of multiple transverse sections of each artery. Residual thrombus was detected in 55 of 85 sections (64.7%) o btained from PAI-1 +/+ mice compared with 19 or 56 sections (33.9%) fr om PAI-1 -/- mice (P=.009). Computer-assisted planimetry analysis reve aled that mean thrombus cross-sectional area was 0.033+/-0.027 mm(2) i n PAI-1 +/+ mice versus 0.016+/-0.015 mm(2) in PAI-1 -/- mice (P=.048) . Conclusion-PAI-1 is an important determinant of thrombolysis at site s of arterial injury. Application of this model to other genetically a ltered mice should prove useful for studying the molecular determinant s of arterial thrombosis and thrombolysis.