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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 activator inhibitor-1 (PAI-1) have been claimed to contribute to the hypofibrinolytic state observed in patients with venous thrombosis. These abnormalities were detected, respectively, in eight and 10 members of a family from which four of seven members with both abnormalities had venous 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 that detects modifications in plasmin generation by proteins interfering with the binding of plasminogen to fibrin. Plasminogen activation was 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 carboxylic acid to prevent nonspecific binding and thereby the inhibitory effect of elevated PAI-1 levels. The generation of plasmin as a function of time was detected (1) by photometric analysis with a chromogenic substrate highly selective for plasmin and (2) by measuring the binding and activation of plasminogen at the fibrin surface with radiolabeled plasminogen. The amount of plasmin generated by plasma from patients having high levels of HRGP (160% to 280%) was similar to that of a control group having normal levels of HRGP (100% +/- 22%). Similar results were obtained with a plasma artificially depleted in HRGP and supplemented with various amounts of this protein. No correlation between HRGP level and t-PA-mediated plasminogen activation was observed.(ABSTRACT TRUNCATED AT 250 WORDS)