FAMILIAL ASSOCIATION OF HIGH-LEVELS OF HISTIDINE-RICH GLYCOPROTEIN AND PLASMINOGEN-ACTIVATOR INHIBITOR-1 WITH VENOUS THROMBOEMBOLISM

High levels of histidine-rich glycoprotein (HRGP) and plasminogen acti vator inhibitor-1 (PAI-1) have been claimed to contribute to the hypof ibrinolytic state observed in patients with venous thrombosis. These a bnormalities were detected, respectively, in eight and 10 members of a family from which four of seven members with both abnormalities had v enous thromboembolism. Binding of tissue plasminogen activator (t-PA) by PAI-1 may induce hypofibrinolysis. To determine whether plasminogen binding by HRGP may influence plasminogen activation, we studied the fibrinolytic activity of members of this family cohort with a system t hat detects modifications in plasmin generation by proteins interferin g with the binding of plasminogen to fibrin. Plasminogen activation wa s performed by adding plasma to fibrin surfaces to which t-PA had been previously bound in the presence of 40 mg/ml bovine serum albumin and 20 mumol/L of the lysine analog trans-4-(aminomethyl)-cyclohexane car boxylic acid to prevent nonspecific binding and thereby the inhibitory effect of elevated PAI-1 levels. The generation of plasmin as a funct ion of time was detected (1) by photometric analysis with a chromogeni c substrate highly selective for plasmin and (2) by measuring the bind ing and activation of plasminogen at the fibrin surface with radiolabe led plasminogen. The amount of plasmin generated by plasma from patien ts having high levels of HRGP (160% to 280%) was similar to that of a control group having normal levels of HRGP (100% +/- 22%). Similar res ults were obtained with a plasma artificially depleted in HRGP and sup plemented with various amounts of this protein. No correlation between HRGP level and t-PA-mediated plasminogen activation was observed. The se results indicated that in a plasma milieu HRGP does not modify the binding and activation of plasminogen at the fibrin surface. It seems therefore unlikely that the excess HRGP found in the plasma of these p atients might be related to the thromboembolic events.