fibrinogen may be the trigger

A forum to discuss Chronic Cerebrospinal Venous Insufficiency and its relationship to Multiple Sclerosis.

Re: fibrinogen may be the trigger

Postby PointsNorth » Fri Nov 30, 2012 4:42 pm

For my edification . . .

I thought that in 2006 Dr. Z speculated that reflux led to a breach of the BBB and consequently the deposition of iron, not fibrinogen. Since Charcot we have noted the peri-venular iron deposition in the brain. As I understand it, both fibrin and iron can can trigger an autoimmune response. Is there some relationship between iron and fibrin?
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Re: fibrinogen may be the trigger

Postby 1eye » Fri Nov 30, 2012 5:17 pm

You can't just release fibrinogen, you have to release fibrinogen in the specific environment created by CCSVI hemodynamics.

Let's say the fibrinogen is a trigger leading to inflammation and white matter lesions and that the fibrinogen is a result of the weakened blood-brain barrier as a result of CCSVI hemodynamics/focal hypertension/lack of shear stress. Those same dynamics are also causing a reduction in the transfer of solutes across the blood-brain barrier, and slowed cerebrospinal fluid flow, and maybe some CSF pressure on the brain stem, and reduced oxygen, nutrients and waste removal, and the totality of all these effects is what makes MS be like MS. Theoretically. A complex outcome with a simple solution: venoplasty.


What is needed to prove all this is a human or group of humans willing to undergo a specific experiment designed to breach the blood brain barrier (maybe there are tons of ways to do that) and see if the resulting fibrinogen does anything "MS"-like to them. Any volunteers? No?

...

Are the lesions of "MS" any more prevalent around venules than arterioles? Is it peri-venular, or just peri-vascular? If it's veins only, that means lesions don't happen so much when there is enough oxygen, or sugar, or some other component of raw blood that the brain uses, or there are a lot less oxygen reduction byproducts, like free radicals, or carbon dioxide.
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Re: fibrinogen may be the trigger

Postby cheerleader » Fri Nov 30, 2012 6:11 pm

PointsNorth wrote:For my edification . . .

I thought that in 2006 Dr. Z speculated that reflux led to a breach of the BBB and consequently the deposition of iron, not fibrinogen. Since Charcot we have noted the peri-venular iron deposition in the brain. As I understand it, both fibrin and iron can can trigger an autoimmune response. Is there some relationship between iron and fibrin?


Zamboni's thesis, The Big Idea, looked at similarities between chronic venous disease (CVD) and MS. It was not exclusively about iron.
He noted that fibrin cuffs, formed by deposition of fibrin, were found in both CVD and MS, as well as dilated veins, venous hypertension, over-expession of MMPs, oxidative stress---a virtual cascade of pathological events which created venous ulcers in the legs, and were similar in MS lesions.

Fibrin cuffs are not an exclusive finding of CVD, but are commonly visible around cerebral veins in the course of MS and today they are interpreted as ongoing reparative processes20,21 (Figure 1B). MRI venography confirms in vivo the close relationship between the main cerebral veins and the inflammatory plaques. In 94/95 MS lesions, a central vein was visible.22 When cortical lesions occur, they arise within the territory of the principal cortical veins.23,24 In another study, contrast MRI allowed documentation of the break-down of the blood-brain barrier (BBB). Such an injury preceded other MRI abnormalities and the clinical evidence of a new lesion. This supports the view that a defect in the BBB, and therefore inflammation, is an early and possibly crucial event in the pathogenesis of a new lesion in MS.2

Here's the paper:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1633548/
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Re: fibrinogen may be the trigger

Postby 1eye » Fri Nov 30, 2012 6:55 pm

PointsNorth wrote:For my edification . . .

I thought that in 2006 Dr. Z speculated that reflux led to a breach of the BBB and consequently the deposition of iron, not fibrinogen. Since Charcot we have noted the peri-venular iron deposition in the brain. As I understand it, both fibrin and iron can can trigger an autoimmune response. Is there some relationship between iron and fibrin?


Good question. I don't know. If we are talking about more or mainly, or only perivenular, not just perivascular, another thing blood uses in capillaries (which eventually start to disappear), besides the chemical energy of rust to iron, and as it burns sugar to carbon dioxide producing free radicals, etc, is kinetic energy, given to it by pressure from heart muscles. I don't think it ever completely stops moving, but when it arrives at bends and junctions (like the ones lesions are found around) it loses momentum and speed. Changing from laminar to turbulent, slower flow, is I think, one result, along with the chemical changes. Perhaps others are conditions necessary for lesion formation?

Is there a necessity, for this damage to occur, that blood be moving sufficiently slowly? Do veins have ti be below or above a certain size? Maybe below that size and/or speed the vessels die off?
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Re: fibrinogen may be the trigger

Postby cheerleader » Wed Dec 05, 2012 6:19 pm

Cece wrote:A question was raised elsewhere that seems relevant: if fibrinogen is the trigger, then why wouldn't any insult that released fibrinogen result in the same lesion? So stroke, etc, would look like MS.


Agree, Cece. And there are white matter lesions in stroke, ischemic disease, TIAs migraine and LA. But the disease process in MS is chronic and progressive. Fibrinogen is induced as part of the coagulation cascade that happens after an ischemic event, or a break in the blood brain barrier. This is studied in ischemic stroke---although the break in the blood brain barrier is a given, so they are not making animal models of stroke to see whether fibrinogen crosses over the BBB. But researchers are noting elevated levels of circulating fibrinogen in stroke patients' plasma. Like the hypercoagulation I saw in Jeff at his first flare, when I asked his neuro why his SED rate was so high, why his Crp was so high...

Ischemic stroke triggers an acute phase response resulting in a rise of circulating inflammatory markers.19 The induction of tissue injury in the vasculature triggers inflammatory response which activates upregulation of hepatic fibrinogen and initiates coagulation cascade. Because fibrinogen is an acute phase protein, the high concentrations associated with stroke and with its risk factors could at least in part be a response to brain damage and the underlying vessel wall disease. It is, however, a mistake to assume that this detracts from the value of measuring fibrinogen for clinical purposes or from the pathogenetic importance of raised concentrations. Levels of fibrinogen are strongly associated with stroke severity in almost all studied populations.6 Because stroke severity is also strongly associated with mortality and functional outcome after stroke, it is not surprising that fibrinogen is also associated with mortality and outcome. Fibrinogen remains independently associated with mortality and outcome even after adjusting for stroke severity; it seems that this marker may provide additional general prognostic information.


In particular, the effects on stroke prognosis of lowering raised fibrinogen concentrations have not yet been established. There is currently no definitive evidence that lowering fibrinogen will necessarily improve prognosis. However, many secondary prevention interventions have been linked to lower fibrinogen levels. In particular, diet, exercise, and smoking cessation all lead to both reduced fibrinogen levels and reduced vascular risk. Several pharmacological agents proven to reduce vascular risk influence fibrinogen levels. Apart from ancrod,41 which is given intravenously and only in acute situations, there are at present no selective fibrinogen-lowering agents. If and when these do become available, their long-term safety as well as their effectiveness will have to be established to identify the best therapeutic regimen based on fibrinogen concentrations integrated with clinical findings and objective imaging.

http://stroke.ahajournals.org/content/40/5/1549.full

which is why I created the endothelial health program for Jeff, and looked at MS as a vascular disease...because his serum numbers indicated an activation of the coagulation cascade.
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Re: fibrinogen may be the trigger

Postby 1eye » Wed Dec 05, 2012 6:46 pm

Can levels of proteins like fibrinogen and ET1 be used as reliable markers of "MS"? CCSVI?
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Re: fibrinogen may be the trigger

Postby thisisalex » Tue Jan 01, 2013 6:56 am

Hi guys
I went through this topic and read the Nature study and one thing is not clear to me.
1. a healthy mouse is given
2. the mouse has been infected with EAE
3. there was a BBB disruption
4. there was fibrinogen leaking into brain tissue
5. cell death
6. inflammation

It looks like BBB disruption was CAUSED by EAE which means we do not need CCSVI here on any other factor.

What do you think?

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Re: fibrinogen may be the trigger

Postby Cece » Tue Jan 01, 2013 12:59 pm

http://www.ncbi.nlm.nih.gov/pubmed/20832870
J Neuroimmunol. 2010 Dec 15;229(1-2):180-91. doi: 10.1016/j.jneuroim.2010.08.011. Epub 2010 Sep 15.

Blood-brain barrier disruption and enhanced vascular permeability in the multiple sclerosis model EAE.

Bennett J, Basivireddy J, Kollar A, Biron KE, Reickmann P, Jefferies WA, McQuaid S.

Source
University of British Columbia, Biomedical Research Centre, Vancouver, British Columbia, Canada.
Abstract
Multiple sclerosis (MS) is a demyelinating disease characterized by the breakdown of the blood-brain barrier (BBB), and accumulation of inflammatory infiltrates in the central nervous system. Tight junctions are specialized cell-cell adhesion structures and critical components of the BBB that have previously been shown to be abnormally distributed in MS tissue. To evaluate whether experimental autoimmune encephalomyelitis (EAE) provides a suitable model for this aspect of MS disease, we examined the expression and distribution of ZO-1 over the course of disease in EAE. We observed a dramatic relocalization of ZO-1 which precedes overt clinical disease and correlates with the sites of inflammatory cell accumulation. Treatment of in vitro cultures of murine brain endothelial cells with components of EAE induction provided similar findings, with relocalization of ZO-1 and increased permeability of endothelial monolayers. BBB disruption in the EAE model appears to parallel disease progression in MS, with direct effects on the cerebrovascular endothelium, making it an ideal tool for future evaluation of tight junction breakdown and repair in MS-like pathology.

EAE is an induced disease, and as such can only be an analogue for MS which occurs naturally. EAE does not occur naturally. It's clear that once MS or EAE is established, the inflammation involved with either disease can impact blood-brain barrier breakdown.
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Re: fibrinogen may be the trigger

Postby Bethr » Thu Jan 03, 2013 12:20 am

PointsNorth wrote:For my edification . . .

I thought that in 2006 Dr. Z speculated that reflux led to a breach of the BBB and consequently the deposition of iron, not fibrinogen. Since Charcot we have noted the peri-venular iron deposition in the brain. As I understand it, both fibrin and iron can can trigger an autoimmune response. Is there some relationship between iron and fibrin?


Could the common denominator be the peptide Hepcidin?
Hepcidin (the master controller of iron metabolism) is reduced by hypoxia, reduced hepcidin increases iron absorption and also increases fibrin? Under hypoxia both serum iron and fibrin (agregating platelets) are increased.

Hepcidin is also reduced in common HFE genetic hemochromatosis type I (without the hypoxia of course, so fibrin would be unaffected). In hypoxia both fibrin and iron are increased.

cheers......
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Re: fibrinogen may be the trigger

Postby MSBOB » Fri Jan 04, 2013 12:14 am

I imagine that all sorts of things can cause leakage oc the BBB. Alergies, blood flow, viruses, drugs, vitamin deficiencies, fatty food, posture, trama, and things maybe other things. Any theory of MS could be strengthened from this article. The great thing about it is that there's a downstream link that can be targeted that is common regardless of the cause. I believe the article was approaching a novel treatment to stop microglial cells from grouping up and cleaning up the damage and creating harmful byproducts. It is interesting.
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Re: fibrinogen may be the trigger

Postby PointsNorth » Wed Jan 09, 2013 11:16 pm

Fibrinogen Level Tied to Poorer PCI Outcomes

http://www.medpagetoday.com/Cardiology/PCI/36734

Thought that Clopidogrel (plavix) is still used by some docs . . in CCSVI venoplasty - but only after the procedure? Perhaps some prescribe for pre-procedure use? Pradaxa would have a similar effect re: fibrinogen I think. This must be standard procedure? I was on Pradaxa for a month post procedure.
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Re: fibrinogen may be the trigger

Postby MSBOB » Thu Jan 10, 2013 12:39 am

PointsNorth wrote:Fibrinogen Level Tied to Poorer PCI Outcomes

http://www.medpagetoday.com/Cardiology/PCI/36734

Thought that Clopidogrel (plavix) is still used by some docs . . in CCSVI venoplasty - but only after the procedure? Perhaps some prescribe for pre-procedure use? Pradaxa would have a similar effect re: fibrinogen I think. This must be standard procedure? I was on Pradaxa for a month post procedure.


That is absolutely fascinating! Thanks for sharing. It raises a lot of thoughts.
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