Urokinase-mediated fibrinolysis in the synovial fluid of rheumatoid arthritis patients may be affected by the inactivation of single chain urokinase type plasminogen activator by thrombin

Background-Excessive fibrin deposition within the inflamed joints of rheuma toid arthritis (RA) patients suggests that local fibrinolysis is inefficien t, which seems to be in contrast with the observed increased levels of urok inase type plasminogen activator (u-PA). Thrombin-mediated inactivation of single chain u-PA (scu-PA) into an inactive form called thrombin-cleaved tw o chain u-PA (tcu-PA/T) may provide a possible explanation for this contrad iction. Aim-To assess the occurrence of tcu-PA/T in the synovial fluid of patients with RA and with osteoarthritis (OA), and in the synovial fluid of controls to find support for thrombin-mediated inactivation of scu-PA in RA. Methods-Levels of scu-PA and tcu-PA/T were measured in the synovial fluid o f 20 RA patients, nine OA patients and 14 controls using sensitive bioimmun oassays. Total urokinase antigen was quantified by a urokinase ELISA. Results-tcu-PA/T was found in the synovial fluid of all RA and OA patients. Only in seven of 14 control samples, levels of tcu-PA/T could be measured above the detection limit of the assay (0.2 ng/ml). The concentrations of t cu-PA/T, scu-PA and u-PA:Ag were significantly higher in the synovial fluid of the RA and OA patients as compared with the controls, while the RA pati ents had significantly higher levels of tcu-PA/T and u-PA:Ag than the OA pa tients. In RA, tcu-PA/T seemed to account for more than 40% of total urokin ase antigen, while the contribution of tcu-PA/T to total urokinase antigen was only minor in OA and the controls (9.0% and 6.6%, respectively). Conclusion-A significant part of the high total urokinase antigen in the sy novial fluid of RA patients can be attributed to tcu-PA/T, implying that a large amount of scu-PA is not available for fibrinolysis because of its ina ctivation by thrombin. Thus, thrombin may promote the inflammation process in RA by inhibiting the fibrinolytic system and preventing the removal of f ibrin.