Tumour cell u-PA as a cause of fibrinolytic bleeding in metastatic disease.

Tumour cells may express urokinase type plasminogen activator (u-PA). This may influence the invasive properties of the cells but has seldom been implicated in production of a systemic bleeding state. Two patients are described in whom severe bleeding occurred in association with disseminated malignancies. Thrombin generation was little disturbed and platelet numbers were insufficient to account for the bleeding. Florid plasmin generation was evident in the circulation and the fibrinolytic inhibitor tranexamic acid controlled the bleeding well. Free active u-PA was demonstrated in the circulation and u-PA antigen on the malignant cells which invaded the marrow of one of the patients. Tumour cell u-PA may occasionally be responsible for a bleeding state.

Proteins of the fibrinolytic system in human thrombi.

The proteins of fibrinolysis have been quantified in human thrombi, to assess the balance between plasminogen activators and their major inhibitor PAI-1. The relative roles of PAI-1 and alpha 2-AP were also examined since we have previously shown that both platelet PAI-1 and plasma alpha 2-AP are important determinants of clot lysis in vitro. Extracts and sections were prepared from human thrombi for quantitative immunoassay and immunohistochemical staining respectively. PAI-1 and alpha 2-AP were present at high concentrations. Levels of t-PA and t-PA-PAI-1 complex were relatively low. Staining confirmed the presence of abundant PAI-1, associated primarily with platelet material within the thrombus and also with fibrin. Staining for alpha 2-AP was also intense and demonstrated strong association with fibrin. The alpha 2-AP concentration was similar to its high plasma concentration, whereas PAI-1 levels were up to 30 times greater than that in circulating blood, suggesting that active recruitment of platelets contributes to the high PAI-1 concentration in thrombi.

The roles of alpha 2-antiplasmin and plasminogen activator inhibitor 1 (PAI-1) in the inhibition of clot lysis.

The relative importance of the two major inhibitors of fibrinolysis, alpha 2-antiplasmin (alpha 2-AP) and plasminogen activator inhibitor (PAI-1), were investigated using a simple microtitre plate system to study fibrin clot lysis in vitro. Cross-linked fibrin clots contained plasminogen and tissue plasminogen activator (t-PA) at concentrations close to physiological. Purified alpha 2-AP and PAI-1 caused dose-dependent inhibition. All the inhibition due to normal plasma, either platelet-rich or poor, was neutralised only by antibodies to alpha 2-AP. Isolated platelets, at a final concentration similar to that in blood, 2.5 x 10(8)/ml, markedly inhibited clot lysis. This inhibition was neutralised only by antibodies to PAI-1. At the normal circulating ratio of plasma to platelets, alpha 2-AP was the dominant inhibitor. When the platelet:plasma ratio was raised some 20-fold, platelet PAI-1 provided a significant contribution. High local concentrations of PAI-1 do occur in thrombi in vivo, indicating a role for PAI-1, complementary to that of alpha 2-AP, in such situations.