Impaired fibrinolysis in multiple sclerosis: a role for tissue plasminogen activator inhibitors

Brain. 2003 Jul;126(Pt 7):1590-8. doi: 10.1093/brain/awg167. Epub 2003 Jun 4.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Cell Line
  • Female
  • Fibrin Fibrinogen Degradation Products / metabolism
  • Fibrinolysis*
  • Humans
  • Male
  • Middle Aged
  • Multiple Sclerosis / blood*
  • Multiple Sclerosis / metabolism
  • Neuropeptides / metabolism
  • Neuroserpin
  • Plasminogen Activator Inhibitor 1 / metabolism
  • Plasminogen Inactivators / physiology*
  • Serpins / metabolism
  • Tissue Plasminogen Activator / antagonists & inhibitors*
  • Tissue Plasminogen Activator / metabolism

Substances

  • Fibrin Fibrinogen Degradation Products
  • Neuropeptides
  • Plasminogen Activator Inhibitor 1
  • Plasminogen Inactivators
  • Serpins
  • fibrin fragment D
  • Tissue Plasminogen Activator