Background—The origin and contribution of plasminogen activator inhibitor-1 (PAI-1) and its cofactor vitronectin (VN) to arterial thrombosis/thrombolysis in vivo is controversial.

Methods and Results—Ferric chloride was used to induce carotid artery injury in 97 wild-type (WT), 84 PAI-1−/−, and 84 VN−/− mice. Complete thrombotic occlusion was observed in 70% of PAI-1−/− mice versus 92% of WT (P<0.001) and 87% of VN−/− (P=0.015) mice. In vessels that occluded, mean times to occlusion were significantly longer in PAI-1−/− than in WT or VN−/− mice. The initial thrombotic response of VN−/− mice was similar to that of WT mice, but their thrombi were unstable and frequently embolized. As a result, the patency rate of carotid vessels 30 minutes after injury was as high in VN−/− mice (36%) as in PAI-1−/− mice (which demonstrate progressive thrombolysis) and significantly higher than that of WT mice (12%; P=0.013). Histochemical and reverse transcription–polymerase chain reaction studies revealed an early upregulation of PAI-1 mRNA and protein expression in the thrombus and the vessel wall, which persisted for ≥1 week. VN protein also accumulated after injury, but VN mRNA levels remained low at all times.

Conclusions—PAI-1 and VN participate in the thrombotic response to arterial injury by preventing premature thrombus dissolution and embolization. The accumulation of PAI-1 in the thrombus/vessel wall after injury may result, at least in part, from local synthesis, whereas the VN protein appears to be derived from plasma.