Brain Advance Access originally published online on June 4, 2003
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Brain, Vol. 126, No. 7, 1590-1598,
July 2003
© 2003 Guarantors of Brain
doi: 10.1093/brain/awg167
Impaired fibrinolysis in multiple sclerosis: a role for tissue plasminogen activator inhibitors
11 Department of Neuroinflammation, Institute of Neurology, University College London, London, UK, and 2 Department of Vascular Biology, American Red Cross Holland Laboratory, Rockville, Maryland, USA
Correspondence to: Dr Djordje Gveri, Department of Neuroinflammation, Institute of Neurology, 1 Wakefield Street, London WC1N 1PJ, UK E-mail: d.gueric{at}ion.ucl.ac.uk
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.
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