Cerebrospinal fluid plasminogen, plasmin and protease inhibitors in multiple sclerosis

Objective: to study plasma and cerebrospinal fluid (CSF) concentrations of plasminogen, plasmin, plasmin-alpha(2)-antiplasmin (PAP) complex and the protease inhibitory capacity in multiple sclerosis (MS) patients. Design: patients diagnosed as having MS were involved in this study. The reference subjects had lumbar punctures for clinical reasons but were exclusive of having either MS or other types of neurological disease. The identities of MS and reference samples were unknown to the researcher until laboratory results were ready. Setting: department of Neurology, Helsinki University Central Hospital, Finland. Subjects and methods: plasminogen, plasmin, alpha(2)-antiplasmin, PAP complex, alpha(2)-macroglobulin and alpha(1)-antitrypsin levels were studied by microplate chromogenic assays, ELISA and zymography in 34 patients with MS and 24 reference subjects. Results. significantly lower mean levels of CSF plasminogen concentrations were observed in MS in comparison with reference subjects (MS: 0.40+/-0.003%, REF: 0.67+/-0.12%; P<0.01). Higher concentrations of PAP complex were detected in CSF of MS patients when compared with reference subjects (P<0.05). Zymography was employed for the qualitative screening of samples for plasmin activity. Plasmin activity could not be detected in either plasma or CSF samples in MS or reference samples. There was no significant differences between CSF alpha(2)-antiplasmin, alpha(2)-macroglobulin and alpha(1)-antitrypsin in MS when compared to reference subjects. There were no significant correlation amongst the CSF anti-proteolytic analytes either in MS or reference subjects. Finally, plasma plasminogen, PAP complex and inhibitor concentrations were within reference ranges in MS patients. Conclusions: Lower levels of CSF plasminogen and quantifiable amounts of PAP complex in MS CSF provide further evidence of plasminogen activation in the studied patients. We previously found highly raised tissue-type plasminogen activator activity in MS CSF.(4,5) Inability to detect plasmin activity in CSF with the highly sensitive zymography, suggests formation of inactive complexes with alpha(2)-antiplasmin. Furthermore, MS CSF has normal serine protease inhibitory capacity when compared to reference subjects.