Blood-Clotting Protein May Offer Early Detection of MS

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

Blood-Clotting Protein May Offer Early Detection of MS

Postby Cece » Thu Nov 14, 2013 5:40 pm

http://www.bioquicknews.com/node/1420
A protein involved in blood clotting may be a new indicator to help detect multiple sclerosis (MS) lesions before symptoms arise. The presence of the clotting protein, thrombin, signals an early stage of the disease when the blood-brain barrier is breached and the brain’s immune response is set into motion. The research was presented at Neuroscience 2013, the annual meeting of the Society for Neuroscience and the world’s largest source of emerging news about brain science and health. 30,000 scientists are attending this meeting. “Our research shows this indicator is a promising approach for detecting MS-like lesions early, even before major symptoms appear,” said senior author Katerina Akassoglou, Ph.D., of the Gladstone Institutes and the University of California, San Francisco. “Such sensitive indicators could act as red flags that signal neuroinflammatory changes in the brain not only in MS, but also in other diseases such as Alzheimer’s.” MS is a debilitating disorder that can be intermittent or progressive, and causes numbness, fatigue, difficulty walking, paralysis, and loss of vision in 2 million people worldwide. MS arises when the body’s immune system attacks its own myelin sheaths, the protective coverings that surround neurons and allow signals to move from one cell to the next. The researchers found that thrombin, usually a beneficial protein involved in blood clotting, builds up in the central nervous system as MS progresses. Thrombin enters in the brain together with fibrinogen, another clotting protein when the protective barrier between the blood and brain becomes leaky. Thrombin converts the fibrinogen to fibrin which activates brain’s immune cells that break down the protective myelin sheath that surrounds neurons in the central nervous system. Because thrombin levels increase as the disease progresses, the researchers conclude that it could be used as an early detector of the disease. In their studies, the researchers used a mouse model and demonstrated that MS symptoms increased as thrombin levels rose. Early detection of MS could result in more successful treatment of the disease. Research was supported with funds from the National Multiple Sclerosis Society, the Nancy Davis Foundation for Multiple Sclerosis, and the National Institutes of Health. Dr. Akassoglou outlined her findings in a press conference held on Sunday, November 10, and this summary was distributed with the press release. The scientific presentation of Dr. Akassoglou’s work will be delivered on Monday, Novermber 11. Neuroscience 2013 continues through Wednesday, November 13.

If thrombin has an adverse effect on MS (by converting fibrinogen to fibrin which activates the brain's immune cells), then is this a potential pharmaceutical target?
This also ties in nicely with CCSVI. Deranged hemodynamics resulting from CCSVI may weaken the blood-brain barrier, resulting in diapedesis leakage of thrombin and fibrinogen.
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Re: Blood-Clotting Protein May Offer Early Detection of MS

Postby 1eye » Sat Nov 16, 2013 10:18 am

The involvement of the clotting cascade seems to be a fruitful avenue of inquiry. I think the evidence against autoimmunity (whatever that is) is inescapable. It seems it is becoming widely recognized that these clotting chemicals are more important than T or B cells which are only involved much later on. There is no mistaken recognition of self as an invader, rather some normally benign clotting agents cross a breach in the BBB, resulting in inflammation and the involvement of the immune system.

The researchers found that thrombin, usually a beneficial protein involved in blood clotting, builds up in the central nervous system as MS progresses. Thrombin enters in the brain together with fibrinogen, another clotting protein when the protective barrier between the blood and brain becomes leaky. Thrombin converts the fibrinogen to fibrin which activates brain’s immune cells that break down the protective myelin sheath that surrounds neurons in the central nervous system.


Iron in the form of blood cells follows the same leaky path. The leaks can happen for many reasons. Outflow problems are a major one. These problems themselves can have several causes: infection, congenital malformations, misaligned atlas, probably more. If there are outflow problems, the BBB is breached as a result. T cells and B cells come later. Macrophages digest the blood cells and iron is deposited. See also this reference, courtesy of cheerleader: http://www.nature.com/ncomms/journal/v3/n11/full/ncomms2230.html:
Here we show that the blood protein fibrinogen induces rapid microglial responses toward the vasculature and is required for axonal damage in neuroinflammation. Using in vivo two-photon microscopy, we demonstrate that microglia form perivascular clusters before myelin loss or paralysis onset and that, of the plasma proteins, fibrinogen specifically induces rapid and sustained microglial responses in vivo. Fibrinogen leakage correlates with areas of axonal damage and induces reactive oxygen species release in microglia. Blocking fibrin formation with anticoagulant treatment or genetically eliminating the fibrinogen binding motif recognized by the microglial integrin receptor CD11b/CD18 inhibits perivascular microglial clustering and axonal damage. Thus, early and progressive perivascular microglial clustering triggered by fibrinogen leakage upon blood-brain barrier disruption contributes to axonal damage in neuroinflammatory disease.

Seems like thrombin and fibrinogen must cross first, causing damage and immune involvement. Now they're even proposing a method of early detection!
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Re: Blood-Clotting Protein May Offer Early Detection of MS

Postby cheerleader » Sat Nov 16, 2013 1:18 pm

Saw this was in the news again, Cece. You're right, 1eye, it kind of makes the vascular connection even more clear.
But this happens in all diseases of neurodegeneration and hypoperfusion---not just MS.
It's from the break down of the BBB.
Gladstone Labs is looking at it in MS to try and find a way to block fibrin, or use it to diagnose MS early-- to monetize their "discovery"---instead of asking WHY fibrin and the coagulation cascade are activated in the first place. But this thrombin/fibrin activation happens in Alzheimer's, Parkinson's, dementia, ischemia, hypoperfusion.

I wrote about this last year, when they first came out with their research. All of the peer-reviewed research is at the link below:
http://ccsviinms.blogspot.com/2012/11/w ... t-nov.html

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Re: Blood-Clotting Protein May Offer Early Detection of MS

Postby Cece » Sat Nov 16, 2013 1:25 pm

The involvement of the clotting cascade seems to be a fruitful avenue of inquiry. I think the evidence against autoimmunity (whatever that is) is inescapable. It seems it is becoming widely recognized that these clotting chemicals are more important than T or B cells which are only involved much later on. There is no mistaken recognition of self as an invader, rather some normally benign clotting agents cross a breach in the BBB, resulting in inflammation and the involvement of the immune system.

What I fear is that what has been set into motion is not as easily stopped as it was started. Even if a breached brain-blood barrier and the thrombin and fibrinogen is the initial problem, the immune system could still respond in an abnormal or excessive way that then leads to the development of autoimmunity. And once autoimmunity is developed, it may continue even if the initial conditions such as the CCSVI have been treated. You don't want CCSVI, and you don't want a genetic predisposition to autoimmunity, and you especially don't want both, in this scenario.
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Re: Blood-Clotting Protein May Offer Early Detection of MS

Postby cheerleader » Sat Nov 16, 2013 1:39 pm

Cece--I'm going to try to allay that fear by saying that progressive MS is proof that "autoimmunity" is only a temporary phase, part of the response for young adults. This is what Dr. Peter Stys proposes in his new research---that this reaction is due to younger individuals having a more severe t cell response, which is why it is not a factor in the progressive phase of MS.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3673225/
(but I add the caveat that Jeff has remained on Copaxone before, during and after his CCSVI venoplasty)

I'd also like to point us back to Dr. Zamboni's original Big Idea--where he looked at the fibrin cuffs he found in venous disease and ulcers of the legs, and compared them to MS.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1633548/
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Re: Blood-Clotting Protein May Offer Early Detection of MS

Postby 1eye » Sun Nov 17, 2013 7:42 am

See the thread mentioned below. Clotting time explains maybe gender difference in "MS" incidence!
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