Plasmin generation induces neutrophil aggregation: Dependence on the catalytic and lysine binding sites

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Abstract
We established that plasmin (10−10M to 10−6M) caused neutrophils (PMN) to aggregate using an in vitro assay. Plasminogen had no PMN aggregatory activity even at a concentration of 2 μM. However, plasminogen caused PMN to aggregate when incubated with plasminogen activators [tissue plasminogen activator (25–200 U/ml) or urokinase (5–500 U/ml)]. Tissue plasminogen activator and urokinase alone had no PMN aggregatory activity. Analysis of these incubation mixtures indicated that plasmin was generated in the process and that the time course of plasmin generation correlated with the aggregation response. Active-site-inhibited plasmin did not induce PMN aggregation, indicating that a functional catalytic site was required for the response. Pretreatment of PMN with either active-site-inhibited plasmin or tranexamic acid prevented PMN aggregation by plasmin, indicating that both binding of plasmin to the cell surface via the lysine binding sites and catalysis were required for the response. The generation of plasmin during activation of fibrinolysis may play a pro-inflammatory role by mediating aggregation of PMN.