21 Urokinase-type plasminogen activator (u-PA) and the risk of coronary events in patients with angina pectoris (AP)

Abstract

Introduction. This study addresses the rote of circulatory u-PA in the prevention and precipitation of arterial thrombosis. u-PA occurs in three forms: the inactive zymogen scu-PA, the active enzyme tcu-PA and u-PA#, the inactive complex of tcu-PA with inhibitors. In apparently healthy individuals (n=50) scu-PA amounts 2.2±0.4 ng/ml, u-PA# 1.1 ±0.8 ng/ml and the concentration of tcu-PA is neglectable. Methods. 3043 AP patients from all over Europe (ECAT AP Study) were followed for two years for the occurrence of coronary events. Blood collection and angiographie assessment of the severity of the disease (VESS, the number of more than 50% occluded coronary vessels of the patient) were performed on admission. u-PA analysis was performed centrally, on 2410 patients. Total u-PA Ag was measured by ELISA. scu-PA by BIA. and u-PA# was calculated as the difference between the two. Statistics: ANOVA, multiple regression analysis; partial correlation coefficients p are provided. Results. AP patients have on average a lower scu-PA ( 1.9±0.5 ng/ml) and a higher u-PA# level ( 1.6±0.6 ng/ml) than healthy individuals (P<0.001 ). The scu-PA level varies significantly between medical centres in Europe (range of means 1.3 - 2.3 ng/ml, 14 centres, P<0.001), and is negatively correlated (p = -0.32, P<0.001) with the event rate of the centres, which ranges from 1.5 to 7.0 events per 100 patients. By comparison, LDL cholesterol is positively correlated with the event rate (p = 0.13, P<0.001 ) and u-PA# is not correlated. However, scu-PA, and also LDL chol, are not correlated with the risk of an event as such, but with VESS, the severity of coronary occlusion (scu-PA negatively: p = -0.08, P= 0.001 ; LDL chol positively: p = 0.16, P<0.001 ). The risk of an event is correlated with u-PA# and VESS, both positively, without any association between the two (u-PA#: p = 0.10, P= 0.004; VESS: p = 0.13, P<0.001 ). The effects of a scries of known risk factors are subordinate to those of u-PA# and VESS, and are annihilated in competition therewith. The risk of an event in the highest u-PA# quintile relative to the lowest is 2.6, and the standardized relative risk is 1.5. For VESS these figures amount 5.1 and 1.8, respectively. Discussion: scu-PA is negatively correlated with the severity of coronary occlusion of the patients and with the event rate of the centres. We propose that the subnormal blood scu-PA levels, which are indicative of an impaired fibrinolytic potency and a resulting intensified thrombotic tendency, are of causative importance in the long-term evolution of AP. u-PA# is a novel risk marker, which is not associated with the severity of coronary occlusion. We suggest that the supernormal blood u-PA# levels reflect another aspect of the severity of the patient's condition, such as vascular resistance.