Impaired fibrinolysis in multiple sclerosis: a role for tissue plasminogen activator inhibitors.
Tissue plasminogen activator (tPA), a neuronal as well as the key fibrinolytic enzyme, is found concentrated on demyelinated axons in multiple sclerosis lesions together with fibrin(ogen) deposits. The decreased tPA activity in normal-appearing white and grey matter and lesions of multiple sclerosis is reflected in diminished fibrinolysis as measured by a clot lysis assay. Nonetheless, peptide products of fibrin, including D-dimer, accumulate on demyelinated axons-the result of fibrinogen entry through a compromised blood-brain barrier (BBB). Analysis of tissue samples on reducing and non-reducing polyacrylamide gels demonstrates complexes of tPA with plasminogen activator inhibitor-1 (PAI-1) but not with neuroserpin, a tPA-specific inhibitor concentrated in grey matter. As total tPA protein remains unchanged in acute lesions and the concentration of PAI-1 rises several fold, complex formation is a probable cause of the impaired fibrinolysis. Although the tPA-plasmin cascade promotes neurodegeneration in excitotoxin-induced neuronal death, in inflammatory conditions with BBB disruption it has been demonstrated to have a protective role in removing fibrin, which exacerbates axonal injury. The impaired fibrinolytic capacity resulting from increased PAI-1 synthesis and complex formation with tPA, which is detectable prior to lesion formation, therefore has the potential to contribute to axonal damage in multiple sclerosis.
Gveric
Djordje
D
Department of Neuroinflammation, Institute of Neurology, 1 Wakefield Street, London WC1N 1PJ, UK. d.gueric@ion.ucl.ac.uk
Herrera
Blanca
B
Petzold
Axel
A
Lawrence
Daniel A
DA
Cuzner
M Louise
ML
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002460:Cell Line; D005260:Female; D005338:Fibrin Fibrinogen Degradation Products / Q000378:metabolism; D005342:Fibrinolysis; D006801:Humans; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000097:blood* / Q000378:metabolism; D009479:Neuropeptides / Q000378:metabolism; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D015849:Plasminogen Inactivators / Q000502:physiology*; D015843:Serpins / Q000378:metabolism; D010959:Tissue Plasminogen Activator / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000097522:Neuroserpin
D005338:Fibrin Fibrinogen Degradation Products; D009479:Neuropeptides; D017395:Plasminogen Activator Inhibitor 1; D015849:Plasminogen Inactivators; D015843:Serpins; D010959:Tissue Plasminogen Activator; D000097522:Neuroserpin; C036309:fibrin fragment D