Key Points

  • Platelets harbour a pool of plasminogen that is released and retained on the activated membrane via the novel platelet receptor Plg-RKT.

  • Platelet-derived plasminogen drives surface-mediated plasminogen activation and local fibrinolysis.

Plasminogen activation rates are enhanced by cell surface binding. We have previously demonstrated that exogenous plasminogen binds to phosphatidylserine-exposing and spread platelets. Platelets contain plasminogen in their α-granules but secretion of plasminogen from platelets has not been studied. Recently, a novel transmembrane lysine-dependent plasminogen receptor, Plg-RKT, has been described on macrophages. Here, we analyzed the pool of plasminogen in platelets and examined whether platelets express Plg-RKT. Plasminogen content of the supernatant of resting and collagen/thrombin-stimulated platelets was similar. Pre-treatment with the lysine analogue, εACA, significantly increased platelet-derived plasminogen (0.33 nmol/108 plts vs. 0.08 nmol/108 plts) in the stimulated supernatant, indicating a lysine-dependent mechanism of membrane retention. Lysine-dependent, platelet-derived plasminogen retention on thrombin and convulxin activated human platelets was confirmed by flow cytometry. Platelets initiated fibrinolytic activity in fluorescently labelled plasminogen-deficient clots and in turbidimetric clot lysis assays. A 17 kDa band, consistent with Plg-RKT, was detected in the platelet membrane fraction by Western blotting. Confocal microscopy of stimulated platelets revealed Plg-RKT co-localized with platelet-derived plasminogen on the activated platelet membrane. Plasminogen exposure was significantly attenuated in thrombin and convulxin stimulated platelets from Plg-RKT-/- mice compared to Plg-RKT+/+ littermates. Membrane exposure of Plg-RKT was not dependent on plasminogen, as similar levels of the receptor were detected in plasminogen-/- platelets. These data highlight Plg-RKT as a novel plasminogen receptor in human and murine platelets. We show for the first time that platelet-derived plasminogen is retained on the activated platelet membrane and drives local fibrinolysis, by enhancing cell-surface mediated plasminogen activation.

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