Mouse carotid artery ligation induces platelet-leukocyte-dependent luminalfibrin, required for neointima development

The relationship between platelet and leukocyte activation, coagulation, an d neointima development was investigated in noninjured murine blood vessels subjected to blood stasis. The left common carotid artery of C57BL/6J mice was ligated proximal to the bifurcation, Tissue-factor expression in lumin al leukocytes progressively increased over 2 weeks. On day 3 after ligation , in addition to infiltrated granulocytes, platelet microthrombi and platel et-covered leukocytes as well as tissue-factor-positive fibrin deposits lin ed the endothelium. Maximal neointima formation in carotid artery cross sec tions of control mice equaled 28+/-3.7% (n = 11) and 42+/-5.1% (n = 8) of t he internal elastic lamina cross-sectional area 1 and 2 weeks after ligatio n. In FVIII-/- mice, stenosis was significantly lower 1 (11+/-3.6%, n = 8) and 2 (21+/-4.7%, n = 7) weeks after ligation (both P<0.01 versus backgroun d-matched controls). In u-PA(-/-) mice, luminal stenosis was significantly higher 1 (38+/-7.0%, n = 7) and 2 (77+/-5.6%, n = 6) weeks after ligation ( P<0.05 and P<0.01, respectively, versus matched controls). In <alpha>(2)-AP (-/-) mice, stenosis was lower at 1 week (14+/-2.6%, n = 7, P<0.01) but not at 2 weeks. Responses in tissue-type plasminogen activator or plasminogen activator inhibitor-1 gene-deficient mice equaled that in controls. Reducin g plasma fibrinogen levels in controls with ancrod or inducing partial thro mbocytopenia with busulfan resulted in significantly less neointima, but in flammation was inhibited only in busulfan-treated mice. We conclude that st asis induces platelet activation, leading to microthrombosis and platelet-l eukocyte conjugate formation, triggering inflammation and tissue-factor acc umulation on the carotid artery endothelium. Delayed coagulation then resul ts in formation of a fibrin matrix, which is used by smooth muscle cells to migrate into the lumen.