I would like to propose a model for MS and CCSVI that implicates fibrin/fibrinogen as a mediator of the inflammary reaction. The first 8 points describe the hypothesis and the following text provides some supporting evidence for it. It gets quite technical.
Microvascular Hypercoagulability Model for MS:
1) MS is a result of the stenosis or obstruction of the larger veins (internal jugulars, vertebrals, azygous) that drain the central nervous system.
2) This obstruction of the larger veins in turn results in reduced rate and velocity of flow in the microvasculature (capillaries and post capillary venules) upstream from the stenosis or obstruction. This deduction is supported by simple hemodynamic principals.
3) Reduced blood flow and stasis results in ischemia and activation of the coagulation cascade at the micro-vascular level.
4) This activation of the coagulation cascade is of a continuous low grade nature that results in the production of fibrin strands in the microvasculature and increases blood viscosity, reducing blood flow further. It does not result in the formation of clot.
5) In this setting of stasis and ischemia, there is breakdown of the blood brain barrier with entry of fibrin strands into the central nervous system. The stasis of blood, as well, results in capillary and venular dilatation that facilitates breaching of the blood brain barrier.
6) Fibrin strands deposit on the axon myelin sheath, impair its functioning and therefore the transmission of neuronal impulses. If fibrin could be removed before death of the nerve cell, nerve function could be restored. If myelin damage progresses to cell death, nerve function cannot be restored. The entry of fibrin into the tissues stimulates the production of cytokines by the cells, stimulating the immune response.
7) An inflammatory reaction ensues and results in the infiltration of T lymphocytes into the CNS that proceed to remove myelin debris, dead tissue and fibrin degradation products. Demyelinating plaques then result.
8) With the breakdown of the blood brain barrier, erythrocytes enter the CNS tissue as well, and their breakdown results in the deposition of iron, as is seenin histologic specimens of MS demyelinating lesions and MRI images of the brains of MS patients.
If this theory is true, then following four points can be deduced and their validation would provide very strong evidence to this theory’s validity. Below each point is some scientific evidence for it.
1) Fibrin and fibrin degradation products such as D-dimer should be visible around the nerve axon prior to the arrival of T and B lymphocytes and d-dimer levels should be increased in the multiple sclerosis population:
“The detection of an apparent increase in tPA-PAI-1 complex formation and fibrin degradation peptides in both normal appearing white matter and normal appearing grey matter (in EAE mice brains) is the most striking observation of the study. With increasing evidence of axonal damage at the earliest stages of the inflammatory demyelinating reaction in multiple sclerosis, deposition of fibrin and an imbalance in the tPA-PAI1 ratio in apparently normal tissue would produce a situation in which axonal integrity is compromised.”
“ There is MRI evidence of fibrin deposition prior to clinical signs of multiple sclerosis (Kermode et al., 1990) and immunochemically, it precedes the cerebral parenchymal reactions and demyelination (Wakefield et al 1994)”
“Persistent blood-brain barrier damage and fibrin exudation are prominent features of demyelinating lesions (Claudio et al., 1995) and similarly precede the clinical manifestations of experimental allergic encephalomyelitis (EAE) an animal model for multiple sclerosis (Inoue et al., 1996)”
“In the white matter tissue sections from control and multiple sclerosis cases, D-dimer was confined to the lumen and walls of blood vessels whilst in acute multiple sclerosis lesions, it was immunocolonized on foamy macrophages and large diameter axons. Immunostaining of serial sections with antibody directed against neuromonofilament protein confirmed axonal localization of fibrin D-dimer.”
Homocysteine and D-dimer levels were significantly higher in both male and female MS patients when compared to the control group. Plasma D-dimer levels, in males, were approximately twice as high (p = 0.001) while in female subjects they were approximately three times higher (p = 0.001) (Aksungar et al., 2007)
2) Fibrin deposition around axons may be responsible for impaired neuronal transmission and if fibrin could be removed before cell death occurs, then nerve conductivity should be improved or restored. Removal of fibrin strands can be accomplished by mechanisms that optimize fibrinolytic activity:
“Studies in peripheral nerve injury have shown that fibrin deposition is a factor impeding axonal regeneration whilst removal of fibrin is associated with restoration of axonal function (Akassoglou et al., 2000). Plasminogen activators are central to degrading fibrin and extracellular matrix proteins in the CNS, dissolving adhesive contacts to promote synaptic contact and axonal outgrowth (Lo et al 2002)”
“Downstream damaged axons (covered with fibrin) would be restricted in their ability to penetrate the altered extracellular matrix environment and adherent inflammatory cells to attain synaptic contact.
“In experimental models of peripheral nerve damage, mice deficient for tPA or plasminogen display aggravated axonal degeneration and delayed functional regeneration, which can be rescued by fibrinogen deficiency (Akassoglou and Strickland, 2002). Fibrin is co-localized on the denuded multiple sclerosis axon with tPA and there is accumulation of high molecular weight fibrin peptides, products of tPA proteolysis. In the chronic inflammatory state, this could be seen as an attempt to reduce fibrin accumulating on the demyelinated axon and interfering with axonal function. However, the decrease in fibrinolytic potential in multiple sclerosis tissue is not due to a descrease in tPA, but to formation of complexes with inhibitors, most likely PAI1, as observed in samples and in preformed complexes of tPA and PAI-1 standards electrophoresed without reduction”
“In the chronic inflammation characteristic of multiple sclerosis, co-localization of tPA to demyelinated axons with non-phosphoylated neurofilament and fibrin(ogen) suggest an association with axonal damage (Gveric et al., et al). Alternatively, it may represent a protective mechanism to remove fibrin deposits, which exacerbate axonal injury as reported in the model of sciatic nerve damage (Akassouglou et al., 2000) and promote regeneration by activation of growth factors (Siconolfi and Seeds, 2001).”
“Tissue plasminogen activator(tPA) is the key fibrinolytic enzyme, the activation rate of which is greatly enhanced in the presence of fibrin (chandler et al., 2000). tPA is also present at a high concentration in neurons, where upon activation, it has been found to have a role in neuronal development and synaptic remodeling (Calabresi et al., 2000). In neurodegenerative diseases, disruption of neuronal cell links with the extracellular matrix by tPA-generated plasmin is a mechanism of cell death (Strickland 2001). “
“The evident dependence of peripheral nerve regeneration on the plasminogen activator system has important implications for neuroprotection in the CNS and specifically for therapeutic approaches in multiple sclerosis to minimize fibrin deposition in the earliest stages of lesion formation.”
3) Tissue samples of active demyelinating lesions should demonstrate decreased fibrinolytic activity. As fibrin is being produced at a rapid rate in the microvasculature, so is the action of to breaking it down with TPA. As TPA is being used up rapidly, fibrinolytic activity (fibrinolysis) will therefore be decreased locally at the tissue level:
“The data reported in this study demonstrate the fibrinolytic potential in demyelinating multiple sclerosis lesions to be markedly diminished- the result of a documented reduction in tPA enzyme activity and increase in PA-1inhibitor levels (Gveric et al 2001). “
4) This reduction in fibrinolytic activity should be even greater in active lesions as stasis as well as fibrin production would be greater:
“In contrast, all multiple sclerosis tissue samples were characterized by markedly decreased fibrinolytic activity. The lowest fibrinolytic activity was observed in acute multiple sclerosis lesions with t1/2 of 255.8 +/- 79.54 min and only 13 +/- 17% of the clot degraded.”
Please note that all the material above in quotation marks was taken from the following paper:
Impaired Fibrinolysis in Multiple Sclerosis: a role for tissue plasminogen activator inhibitors. Gveric et al. Brain(2003), 126, 1590-1598
All the references mentioned above can be found in the reference section of this paper.
Coagulation status and biochemical and inflammatory markers in multiple sclerosis. Aksungar et al., 2007. Journal of Clinical Neuroscience Volume 15, issue 4, April 2008.
Last edited by North52
on Sat Nov 06, 2010 5:29 pm, edited 2 times in total.