title: Platelets and soluble fibrin promote plasminogen activation causing downregulation of platelet glycoprotein Ib/IX complexes: protection by aprotinin.
abstract: Blood loss during and after open-heart surgery with cardiopulmonary bypass (CPB) is largely caused by platelet dysfunction. Previous studies indicate that plasmin can induce platelet dysfunction and affect primary hemostasis by proteolytic degradation and/or redistribution of essential platelet membrane glycoprotein complexes such as the glycoprotein Ib/IX complex. In this study, we present a model for plasmin generation localized on the platelet surface. Platelets treated with soluble fibrin or platelets in a mixture with soluble fibrin, t-PA, and plasminogen caused a significantly increased plasmin generation (p<0.01), dependent on t-PA, soluble fibrin, and platelet concentration. The plasmin generation resulted in a downregulation of platelet membrane glycoprotein Ib/IX glycoprotein complexes. Finally, we demonstrated that inhibitors of fibrinolysis, such as %2-antiplasmin, tranexamic acid, and aprotinin, can inhibit plasmin activity in the fluid phase. The downregulation of platelet glycoprotein Ib/IX complexes, however, was only prevented by aprotinin and not by alpha2-antiplasmin and tranexamic acid. These in vitro observations suggest a platelet localized activation of plasminogen, dependent on t-PA, enhanced by the presence of soluble fibrin. Since high concentrations of soluble fibrin and elevated levels of t-PA during CPB are observed, plasmin activity on the platelet surface during this period is anticipated. This plasmin activity reduces platelet metabolic functions and can be directed towards membrane glycoproteins such as glycoprotein Ib/IX complexes, thereby affecting hemostasis during and after CPB.
authors.affiliation: Blood Interaction Research, Cardiopulmonary Surgery, University of Groningen, The Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: de Haan
authors.forename: W
authors.initials: W
authors.lastname: van Oeveren
mesh_terms: D000911:Antibodies, Monoclonal; D000933:Antifibrinolytic Agents / Q000494:pharmacology*; D007611:Aprotinin / Q000494:pharmacology*; D001792:Blood Platelets / Q000502:physiology*; D015536:Down-Regulation / Q000187:drug effects; D005337:Fibrin / Q000494:pharmacology / Q000502:physiology*; D005341:Fibrinolysin / Q000187:drug effects / Q000494:pharmacology; D005343:Fibrinolytic Agents / Q000494:pharmacology; D006801:Humans; D010958:Plasminogen / Q000494:pharmacology / Q000502:physiology*; D010974:Platelet Aggregation / Q000187:drug effects*; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000378:metabolism*; D010959:Tissue Plasminogen Activator / Q000502:physiology*; D014148:Tranexamic Acid / Q000494:pharmacology; D000979:alpha-2-Antiplasmin / Q000494:pharmacology
chemical_list: D000911:Antibodies, Monoclonal; D000933:Antifibrinolytic Agents; D005343:Fibrinolytic Agents; D019038:Platelet Glycoprotein GPIb-IX Complex; D000979:alpha-2-Antiplasmin; D014148:Tranexamic Acid; D005337:Fibrin; D010958:Plasminogen; D007611:Aprotinin; D010959:Tissue Plasminogen Activator; D005341:Fibrinolysin