Prothrombinase components can accelerate tissue plasminogen activator-catalyzed plasminogen activation.
The enzymatic and cofactor subunits of human prothrombinase, factor Xa (FXa) and factor Va (FVa), respectively, were evaluated as modulators of Glu- and Lys-plasminogen (Pg) activation by tissue plasminogen activator (tPA). The data revealed that both FXa and FVa could accelerate tPA activity by as much as 60-fold for Lys-Pg and > 150-fold for Glu-Pg. This function of FVa depended on pretreatment with plasmin (Pn), whereas the FXa fibrinolytic cofactor activity was endogenous. In the native state, FVa was observed to inhibit the acceleration of Pn generation by FXa. These effects were dependent on Ca2+ and procoagulant phospholipid. Interactions between plasminogen and prothrombinase components were quantified. The apparent Kd for binding to FXa was 35 nM. Strikingly, the affinity between FVa and Pg was increased by approximately 2 orders of magnitude when the FVa was Pn-pretreated (Kd = 0.1 microM). These data cumulatively suggest a mechanism by which Pn production is coordinated with coagulation and localized to sites where procoagulant phospholipid is exposed on a cell surface.
Pryzdial
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Research Department, Canadian Red Cross Society, Ottawa, Ontario.
Bajzár
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Nesheim
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D000595:Amino Acid Sequence; D002384:Catalysis; D004591:Electrophoresis, Polyacrylamide Gel; D015943:Factor Va / Q000378:metabolism / Q000494:pharmacology; D015951:Factor Xa / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D007457:Iodine Radioisotopes; D008239:Lysine / Q000378:metabolism; D008969:Molecular Sequence Data; D010958:Plasminogen / Q000378:metabolism; D010960:Plasminogen Activators / Q000737:chemistry / Q000494:pharmacology*; D011485:Protein Binding; D013925:Thromboplastin / Q000737:chemistry / Q000494:pharmacology*; D010959:Tissue Plasminogen Activator / Q000494:pharmacology*
D007457:Iodine Radioisotopes; D015943:Factor Va; D010958:Plasminogen; D013925:Thromboplastin; D010960:Plasminogen Activators; D015951:Factor Xa; D010959:Tissue Plasminogen Activator; D008239:Lysine