Brain Advance Access originally published online on June 4, 2003
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  L. Lovrecic, S. Ristic, N. Starcevic-Cizmarevic, B. Brajenovic-Milic, Sasa Sega Jazbec, J. Sepcic, M. Kapovic, and B. Peterlin PAI and TPA gene polymorphisms in multiple sclerosis Multiple Sclerosis, March 1, 2008; 14(2): 243 - 247. [Abstract] [PDF]
|
|
|
|
 |
|
 C. Marik, P. A. Felts, J. Bauer, H. Lassmann, and K. J. Smith Lesion genesis in a subset of patients with multiple sclerosis: a role for innate immunity? Brain, November 1, 2007; 130(11): 2800 - 2815. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. E. Benarroch Tissue plasminogen activator: Beyond thrombolysis Neurology, August 21, 2007; 69(8): 799 - 802. [Full Text] [PDF]
|
|
|
|
|
|
V. Lehmensiek, S. Sussmuth, G. Tauscher, J. Brettschneider, S. Felk, F. Gillardon, and H. Tumani Cerebrospinal fluid proteome profile in multiple sclerosis Multiple Sclerosis, August 1, 2007; 13(7): 840 - 849. [Abstract] [PDF]
|
|
|
|
 |
|
 I. B. Kovacs and J. Yamamoto Spontaneous Thrombolysis: A Forgotten Determinant of Life or Death Clinical and Applied Thrombosis/Hemostasis, July 1, 2006; 12(3): 358 - 363. [Abstract] [PDF]
|
|
|
|
 |
|
 E. East, D. Baker, G. Pryce, H. R. Lijnen, M. L. Cuzner, and D. Gveric A Role for the Plasminogen Activator System in Inflammation and Neurodegeneration in the Central Nervous System during Experimental Allergic Encephalomyelitis Am. J. Pathol., August 1, 2005; 167(2): 545 - 554. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Gveric, B. M. Herrera, and M. L. Cuzner tPA Receptors and the Fibrinolytic Response in Multiple Sclerosis Lesions Am. J. Pathol., April 1, 2005; 166(4): 1143 - 1151. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A Petzold, M J Eikelenboom, G Keir, D Grant, R H C Lazeron, C H Polman, B M J Uitdehaag, E J Thompson, and G Giovannoni Axonal damage accumulates in the progressive phase of multiple sclerosis: three year follow up study J. Neurol. Neurosurg. Psychiatry, February 1, 2005; 76(2): 206 - 211. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Yepes and D. A. Lawrence New Functions for an Old Enzyme: Nonhemostatic Roles for Tissue-Type Plasminogen Activator in the Central Nervous System Experimental Biology and Medicine, December 1, 2004; 229(11): 1097 - 1104. [Abstract] [Full Text] [PDF]
|
|