fibrinogen may be the trigger

[Cece]

http://www.sciencedaily.com/releases/20 ... 154215.htm

High-resolution real-time images show in mice how nerves may be damaged during the earliest stages of multiple sclerosis. The results suggest that the critical step happens when fibrinogen, a blood-clotting protein, leaks into the central nervous system and activates immune cells called microglia.

This new research fits well with CCSVI. Reduced shear stress leads to a leaky blood-brain barrier leads to diapedesis and the deposition of red blood cells, iron, and fibrinogen in the brain. Then the immune system responds, leading to inflammation and white matter lesions.

In addition to offering an explanation for why the blood-brain barrier is leaky in the first place, CCSVI also offers an explanation for the ongoing progressive neurodegeneration even in the absence of inflammation. The brain is being continually stressed by the effects of the outflow obstructions.

CCSVI is not proven and it's not perfect but it's the most cogent explanation for what is actually seen in MS patients, including the intraluminal abnormalities seen in the extracranial veins of autopsied MS patients according to Dr. Fox's own research.

some thoughts on fibrinogen http://healthyprotocols.com/2_fibrinogen.htm

[MrSuccess]

yes indeed .... another common sense suggestion that the brain needs to have a complete circuit of blood flow in order to function properly.

Having given great thought to the process of MS ...... MrSuccess has come to conclude that MS is OFTEN triggered by TRAUMA. There is numerous statistical proof to back up this claim.

As is sadly acknowledged ..... there is MS in children. As MrSuccess has previously pointed out ..... forcep delivery would inflict head/neck trauma. As would the positioning of the child while still in the womb. And HORROR of all HORRORS .... the Shaken Baby Syndrome ....

And now for the GOOD News . The medical profession can now diagnose a faulty head-neck-heart blood flow system. And even better GOOD news .... it can be treated .

This was unthinkable 5 years ago.

Imagine where this will all be in 5 years from now !


MrSuccess

[cheerleader]

Here is the full paper, online for free---
http://www.nature.com/ncomms/journal/v3 ... s2230.html
Fibrinogen-induced perivascular microglial clustering is REQUIRED for the development of axonal damage in neuroinflammation.
Not "might be" or maybe. Read the paper. Wow.

This is what Dr. Zamboni proposed in his "Big Idea" paper in 2006.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1633548/
Huge. Am forwarding to the researchers....
cheer

[Anonymoose]

Possibly relevant??

VEGF
The original functional discovery of VEGF, which was initially called vascular permeability factor (VPF). Increased vascular permeability can facilitate leakage of plasma proteins such as fibrinogen, which can then form an extracellular fibrin gel-effectively, a provisional extracellular matrix that promotes development of new blood vessels. Also, the first paper to suggest a mechanism for ascites fluid accumulation caused by tumors such as ovarian cancer.
Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid
Senger, D.R. et al.
Science 219, 983-985 (1983)

http://www.nature.com/focus/angiogenesi ... /vegf.html

[cheerleader]

Hey Anonymous--
VEGF is certainly implicated in endothelial dysfunction and breakdown of the BBB in MS
http://www.ncbi.nlm.nih.gov/pubmed/12387457
http://www.direct-ms.org/sites/default/ ... n%2003.pdf
Here's an earlier thread where we discussed this:
http://www.thisisms.com/forum/chronic-c ... 15579.html

This new paper is not looking at what opens up the BBB (which could very well be VEGF and endothelial dysfunction due to venous insufficiency)---but what is happening after the breach has been made.

A prominent consequence of BBB leakage in MS is the local extravasation of plasma fibrinogen and other circulating hemostatic factors that results in the local deposition of perivascular fibrin matrices21. Fibrin deposition in active demyelinating MS lesions correlates with increased inflammatory activity23 and microglial activation24. In early pre-demyelinating MS lesions, fibrin deposition and microglial activation are the first histopathological alterations, which precede the infiltration of T lymphocytes and demyelination2.

and that's pretty big news.
cheer

[Anonymoose]

Hey Anonymous--
VEGF is certainly implicated in endothelial dysfunction and breakdown of the BBB in MS
http://www.ncbi.nlm.nih.gov/pubmed/12387457
http://www.direct-ms.org/sites/default/ ... n%2003.pdf
Here's an earlier thread where we discussed this:
http://www.thisisms.com/forum/chronic-c ... 15579.html

This new paper is not looking at what opens up the BBB (which could very well be VEGF and endothelial dysfunction due to venous insufficiency)---but what is happening after the breach has been made.

A prominent consequence of BBB leakage in MS is the local extravasation of plasma fibrinogen and other circulating hemostatic factors that results in the local deposition of perivascular fibrin matrices21. Fibrin deposition in active demyelinating MS lesions correlates with increased inflammatory activity23 and microglial activation24. In early pre-demyelinating MS lesions, fibrin deposition and microglial activation are the first histopathological alterations, which precede the infiltration of T lymphocytes and demyelination2.

and that's pretty big news.
cheer

But if you keep the BBB intact by suppressing VEGF, wouldn't that prevent the damaging fibrinogen-microglia interaction? Has anyone tried Avastin to suppress VEGF? Off to search

[Daisy3]

Might explain RRMS. Does not do anything for people with progressive forms of the disease.

[1eye]

I've had more bonks on the head since "SPMS" than I did before that, from falling. I'm not sure that's universally true. I also have not had a lot (some, though) that were contemporaneous with an MS attack, as far as I know. However, if that fact were combined with knowledge that I was having age-related increasing vein problems anyway, that might explain a few things. Right now, although I am not diabetic, I am fighting an ulcerated cut on a foot which is also infected. These last quite a bit longer than they should, because with my aging I suffer more vein problems. I have never had exceptionally good circulation.

If fibrinogen were in the blood stream for any reason (a stent maybe? any operation?) would that be capable of crossing an already-breached BBB? If so, progression might just be a steady accumulation from, ah, "many cuts". Does an internally formed blood clot get a lot of fibrinogen in it? Will pre-thinned blood more easily cross the BBB? I knew I had a family history of stroke, so is it related to my "MS"?

My neurologist, back in 1982 when I had my first event, said it was probably just a "bruise on the brain".

[cheerleader]

Just some more info, to clear up what fibrinogen is and isn't---

Fibrinogen is always present in the blood.The normal range is 200 - 400 milligrams per deciliter (mg/dL).
Fibrinogen is a protein which is made in our livers. It's the sigaling protein for fibrin, which allows our blood to clot. When people develop venous ulcers on their legs, due to chronic venous insufficiency, it's fibrinogen that leaks from the veins and creates a build up of fibrin, depleting the tissue of oxygen and allowing those hallmark ulcers to form. This is called a "fibrin cuff." It's fibrinogen which initiates the coagulation cascade and causes our blood to thicken, as a response to low oxygen levels.

Dr. Zamboni was the first to suggest that MS lesions looked a lot like venous ulcers because of the fibrin cuffs found in both sites of injury. And researchers have noted that fibin deposition comes FIRST, before demylination.

Compromised vasculature in the nervous tissue is a pathogenic manifestation apparent in traumatic injuries, such as spinal cord, optic nerve, and sciatic nerve injury, as well as in central nervous system (CNS) diseases with autoimmune characteristics, such as multiple sclerosis (MS) (7). Blood-brain barrier (BBB) disruption precedes clinical symptoms in MS patients (8), and fibrin is deposited in the lesions (9, 10), apparently before cerebral tissue injury and demyelination (11). Fibrin deposition also coincides with areas of demyelination (12), as well as with areas of axonal damage.
http://www.pnas.org/content/101/17/6698.full

This finding, in accord with the earlier literature [2], suggests the presence of a procoagulant state in MS, and elements of the coagulation system such as fibrin and tissue factor (TF) are found in MS lesions
http://www.jneuroinflammation.com/content/5/1/27

In particular, a proinflammatory role for fibrinogen has been reported in vascular wall disease, stroke, spinal cord injury, brain trauma, multiple sclerosis, Alzheimer's disease, rheumatoid arthritis, bacterial infection, colitis, lung and kidney fibrosis, Duchenne muscular dystrophy, and several types of cancer.
http://www.ncbi.nlm.nih.gov/pubmed/22037947

A fibrous protein called fibrinogen, found in circulating blood and important in blood clotting, can promote multiple sclerosis when it leaks from the blood into the brain, triggering inflammation that leads to MS-related nerve damage. Researchers at the University of California, San Diego (UCSD) School of Medicine have identified a fibrin-derived peptide that inhibits this specific inflammation process in mouse models of MS, reducing MS symptoms.
http://www.sciencedaily.com/releases/20 ... 105436.htm

The most important take away from all of this is that according to this brand new research, the first thing that happens after the BBB is breached is the crossing over of fibrinogen, which is toxic to neurons. Neuronal death precedes demyelination and inflammation.
And neuronal death is found in progressive MS (as measured by gray matter loss)---even though there is no inflammation present.
cheer

[Cece]

http://www.ncbi.nlm.nih.gov/pubmed/22037947

Semin Immunopathol. 2012 Jan;34(1):43-62. Epub 2011 Oct 31.

Fibrinogen as a key regulator of inflammation in disease.

Davalos D, Akassoglou K.

Gladstone Institute of Neurological Disease, University of California, San Francisco, San Francisco, CA 94158, USA.

Abstract
The interaction of coagulation factors with the perivascular environment affects the development of disease in ways that extend beyond their traditional roles in the acute hemostatic cascade. Key molecular players of the coagulation cascade like tissue factor, thrombin, and fibrinogen are epidemiologically and mechanistically linked with diseases with an inflammatory component. Moreover, the identification of novel molecular mechanisms linking coagulation and inflammation has highlighted factors of the coagulation cascade as new targets for therapeutic intervention in a wide range of inflammatory human diseases. In particular, a proinflammatory role for fibrinogen has been reported in vascular wall disease, stroke, spinal cord injury, brain trauma, multiple sclerosis, Alzheimer's disease, rheumatoid arthritis, bacterial infection, colitis, lung and kidney fibrosis, Duchenne muscular dystrophy, and several types of cancer. Genetic and pharmacologic studies have unraveled pivotal roles for fibrinogen in determining the extent of local or systemic inflammation. As cellular and molecular mechanisms for fibrinogen functions in tissues are identified, the role of fibrinogen is evolving from a marker of vascular rapture to a multi-faceted signaling molecule with a wide spectrum of functions that can tip the balance between hemostasis and thrombosis, coagulation and fibrosis, protection from infection and extensive inflammation, and eventually life and death. This review will discuss some of the main molecular links between coagulation and inflammation and will focus on the role of fibrinogen in inflammatory disease highlighting its unique structural properties, cellular targets, and signal transduction pathways that make it a potent proinflammatory mediator and a potential therapeutic target.

Caveat about the research that started this thread: it's EAE mouse research, and should be looked at in humans to see if it is true for us as well.
oh my goodness, Cheer's link actually talks about the leakage of blood into the brain being the source of the fibrinogen (in EAE mice again), and Dr. Zamboni's concept of CCSVI had from the beginning a role for the leakage of blood into the brain to be causing damage. He had postulated that it was the iron in the blood, and maybe instead it's the fibrinogen. Cheer's link also shows that there is a peptide that could be tested that counters this very specific fibrinogen-related inflammation. But that research is from five years ago, has there been any follow-up?

[1eye]

A fundamental question in the development of inflammatory demyelination has been the identity of the early triggers and the amplifiers of disease pathogenesis. It is considered axiomatic that large-scale transmigration across the BBB is associated with loss of barrier function. Studies from neuropathology in early MS lesions that showed fibrin deposition and microglial activation in the absence of parenchymal T cells or demyelination suggested that there are other mechanisms in play that might open the BBB and activate microglia2, 3, 4, 5. However, standard histopathology techniques cannot decipher which comes first (that is, microglial activation or BBB disruption). Our study shows that fibrinogen that enters into the CNS after BBB leakage is sufficient and specific among blood proteins to trigger rapid microglial responses even in the healthy CNS in the absence of a pre-existing lesion. Thus, it is possible that in genetically susceptible individuals, early events at the gliovascular interface, such as fibrinogen leakage in the CNS, might function as triggers that are sufficient to promote autoimmune responses resulting in further BBB disruption, demyelination and plaque formation. Indeed, CD11b-positive monocytes modulate autoimmune responses48 and perivascular microglia and pial macrophages have properties of antigen-presenting cells49, 50, 51. Therefore, early cluster formation mediated by fibrin/CD11b signaling may contribute to the development of autoimmunity. These mechanisms might also be in play in active MS plaques, where release of proinflammatory cytokines by infiltrating macrophages and T cells may further open the BBB and enhance fibrin deposition in the CNS. Similar to microglia, astrocyte activation also occurs early in EAE before significant T-cell entry, and is associated with axonal damage in the optic nerve52. As fibrinogen induces astrocyte activation53, it is possible that it might also contribute to the early activation of astrocytes in neuroinflammation. Identifying fibrinogen as a trigger for perivascular microglial activation in early disease stages is crucial for the understanding of microglial functions and their contribution to CNS autoimmune disease as well as for the development of therapies targeting early stages in MS pathogenesis.

Sounds pretty definite to me. BBB leaks, fibrinogen activates microglia, they and macrophages home in on the damage, and only then do you get the signal (antigen-presentation?) for the autoimmune reaction. No?

Probably the BBB leaks for all kinds of reasons. CCSVI being one.

[MrSuccess]

yes ... this is labrat-labmouse research. I would expect anyone interested in this study will have picked up on that.

that said .... these researchers have produced some profound information using animals as their test subjects. In this case .... mice.

the researchers have certainly done their work . It is extensive. Well done.

I'll be interested to listen to what the medical experts say about this fibrinogen discovery.

I say .... " complete the circuit " ....... " solve the problem."



MrSuccess

[1eye]

If mammals didn't share a need for clotting, red blood, etc., you would not be able to use large coumadin doses to cause fatal bleeding in rats. I think they may share these fundamental cell types and chemistry with us. I am sure the proof will come.

Concentrate on stopping and preventing the BBB breach event. Since that can be caused multiple ways, prevention is very hard, especially in the genetically susceptible. That might be good news to drug manufacturers, but solutions downstream of that leave the person with the problem if they stop taking the drug. Not getting hit on the head is a step in the right direction.

It might be preventable if you are young and/or don't have much accumulated damage. If the CCSVI syndrome has caused it, and DNA caused that, maybe somebody else's bone marrow, or stem cells, is the only fix. It's still good to know the hows and whys of damage, even when it is too late to fix it. Finding the cause of a problem is at least half of the solution.

Repairing damage is best achieved by oligodendrocytes making new myelin and/or by stem cells becoming brain cells, once the original equipment is gone.

Diet does seem to be a powerful weapon, promoting a healthy endothelium and preventing breaches.

[Cece]

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.

Hmmmm.

Thoughts:
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 brainstem, 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.

[MrSuccess]

... this research was partially funded by the National MS Society. A good use of their funding.

to simplify : these researchers discovered that blood leaks out of brain blood vessels ... in areas they are NOT supposed to leak ..... when this happens .... the autoimmune system activates and it try's to REPAIR the spot that is bleeding.

MrSuccess asks the simple question .... were these test subjects subjected to any trauma to their neck ? Did the test subjects have REDUCED or COMPLETE OUTFLOW BLOCKAGE of blood flow between their brain and heart ?

As I have propositioned before ....... a healthy organ has unimpeded blood flow INTO it and OUT of it . A perfect circuit.

In the case of CCSVI - MS ..... the great discovery is the REDUCED or STOPPED flow of blood returned back into the heart. This situation places a burden on the vascular system leading into the brain - and I suspect WITHIN the brain. I offer "Dawson's Fingers" as an example.

MrSuccess suggests .... what happens as a result ..... the brains blood vessels weakest points ..... will leak blood in microscopic amounts. The body's protective system moves to stop this from happening. A lession is leftover proof of the battle. A scar. An INTERNAL scar. Your Autoimmune -obviously- system works as it is supposed to.

MrSuccess asks : Why in Hell would you want to interfer with that with DMD's ?

Complete the Circuit ....... that's the answer.


MrSuccess