Polymorphonuclear leucocytes mediate endogenous thrombus lysis via a u-PA-dependent mechanism

Many human thrombi lyse spontaneously without the administration of lytic d rugs and cause no clinical symptoms. The mechanisms by which this occurs ar e incompletely understood. We found that model thrombi prepared from whole human blood in a Chandler loop also exhibited significant spontaneous lysis . Lysis was inhibited by chemical protease inhibitors, consistent with prot eolysis resulting primarily from serine proteases, with a small contributio n from matrix metalloproteinases. Whole blood was fractionated into platele t-rich plasma and cell populations. Significant spontaneous lysis was obser ved in platelet-rich thrombi enriched with polymorphonuclear leucocytes (PM Ns), whereas mononuclear cells (MCs) and erythrocytes did not contribute to lysis. Incorporation of antibodies to urokinase (u-PA) and its receptor u- PAR neutralized a large proportion of the activity. Incubation of plasma wi th PMNs generated free u-PA activity, which was also detectable in model th rombi and in vivo human thrombi. Purified neutrophils, free of eosinophils, generated activity identical to PMNs. Smaller contributions to lysis by ti ssue-type plasminogen activator (t-PA). elastase and cathepsin G were also identified. These findings suggest a major role for circulating PMNs in end ogenous thrombus lysis.