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 act ivator (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-P g. This function of FVa depended on pretreatment with plasmin (Pn), wh ereas the FXa fibrinolytic cofactor activity was endogenous. In the na tive state, FVa was observed to inhibit the acceleration of Pn generat ion by FXa. These effects were dependent on Ca2+ and procoagulant phos pholipid. Interactions between plasminogen and prothrombinase componen ts were quantified. The apparent K-d for binding to FXa was 35 nM. Str ikingly, the affinity between FVa and Pg was increased by approximatel y 2 orders of magnitude when the FVa was Pn-pretreated (K-d = 0.1 mu M ). These data cumulatively suggest a mechanism by which Pn production is coordinated with coagulation and localized to sites where procoagul ant phospholipid is exposed on a cell surface.