The International Standard for Plasminogen Activator Inhibitor-1 (PAI-1) Activity

Summary

Since the finding that plasminogen activator inhibitor-1 (PAI-1) may influence the initiation and progression of acute myocardial infarction, the assay of PAI-1 in plasma using a variety of commercial kits has become commonplace. The need for a standard to define the activity of PAI-1 prompted an international collaborative study (ICS) to calibrate the functional potency of a lyophilised plasma PAI-1 preparation (92/654). Since PAI-1 inhibits the 2 major plasminogen activators, tissue-type plasminogen activator (t-PA) and urinary-type plasminogen activator (u-PA) in an equimolar manner it was important to establish the potency of the PAI-1 inhibitor in terms of both t-PA and u-PA neutralisation. While the ICS indicated a wide spread of data between the laboratories the mean value of 27.5 t-PA neutralisation units and 7.0 u-PA neutralisation units was confirmed by numerous assays at NIBSC using a tedious but technically reliable titration assay procedure. The plasma PAI-1 proposed standard (92/654) was stable at 20° C for 20 months.

The Fibrinolysis Subcommittee of the Scientific and Standardization Committee (SSC) of the International Society on Thrombosis and Haemostasis (ISTH), (meeting in Leuven, Belgium in September 1994) has recommended that the plasma PAI-1 (92/654) should be accepted as the International Standard for PAI-1 and should define a unitage in terms of both t-PA and u-PA neutralisation. Subsequently the Expert Committee on Biological Standardization of the World Health Organization (ECBS-WHO) meeting in Geneva, Switzerland in October 1995 approved plasma PAI-1 (92/654) as the International Standard.

• References

• 1 Chmielewska J, Ranby M, Wiman B. Evidence for a rapid inhibitor to tissue plasminogen activator in plasma. Thromb Res 1983; 31: 427-436
• 2 Kruithof EKO, Tran-Thang C, Ransijn A, Bachmann F. Demonstration of a fast acting inhibitor of plasminogen activators in plasma. Blood 1984; 64: 907-913
• 3 Verheijen JH, Chang GTG, Kluft C. Evidence for the occurrence of a fast-acting inhibitor of tissue-type plasminogen activation in human plasma. Thromb Haemost 1984; 51: 392-395
• 4 Hamsten A, Wiman B, de Faire W, Blomback M. Increased plasma levels of a rapid inhibitor of tissue plasminogen activator in young survivors of myocardial infarction. N Engl J Med 1985; 313: 1557-1563
• 5 Paramo J, Gascoine PS, Pring JB, Gaffney PJ. The relative inhibitor by a2 antiplasmin and plasminogen activator inhibitor-1 of clot lysis in vitro. Fibrinolysis 1990; 4: 169-175
• 6 Wagner OF, Binder BR. Purification of an active plasminogen activator inhibitor immunologically related to the endothelial type plasminogen activator inhibitor from the conditioned media of a human melanoma cell line. J Biol Chem 1986; 261: 14474-14481
• 7 Gaffney PJ, Curtis AD. A collaborative study to establish the 2nd International Standard for tissue plasminogen activator (t-PA). Thromb Haemost 1987; 58: 1085-1087
• 8 Gaffney PJ, Heath AB. A collaborative study to establish a standard for high molecular weight urinary-type plasminogen activator (HMW/u-PA). Thromb Haemost 1990; 64: 398-401
• 9 Alesh DC, Declerck PJ, De Mol M, Welles K, Collen D. Purification and characterisation of natural and recombinant human plasminogen activator inhibitor-1 (PAM). Eur JBioch 1988; 175: 531540
• 10 Eriksson E, Ranby M, Gyzander E, Risberg E. Determination of plasminogen activator inhibitor in plasma using t-PA and a chromogenic single point poly-D-lysine stimulated assay. Thromb Res 1988; 50: 91-101
• 11 Declerck PJ, Verstreken M, Collen D. An immunofunctional assay for active plasminogen activator inhibitor-1 (PAI-1). Fibrinolysis 1988; 2 (Suppl. 02) Suppl 77-78