Blood Matters

Seven years ago, when Jeff was diagnosed with MS, I asked his neurologist why his blood was hypercoagulated.  Why were his fibrinogen, c reactive protein, pro-thrombin and SED rates so high?  Why did he have all those tiny blood spots on his legs?  She replied that she didn't know, since it "had nothing to do with his MS."

But seven year later, we know that wasn't true for him, and it's apparently not true for other people with MS.

Blood matters.

After Jeff's diagnosis I went to the library and read medical journals online. I read Dr. Roy Swank's research, and saw he noted this blood vessel breakdown, as evidenced by what he called, "capillary fragility" on the limbs of his MS patients during their relapses, manifesting as blood spots called petechiae.  (see pic below.)   He saw hypercoagulation in their serum, too.    Dr. Swank knew it mattered.  In 1958, he saw what I was seeing on Jeff's legs in 2007.

Additional evidence that blood vessel fragility may be an important aspect of MS derives from Swank's study in which he concluded that MS is not confined primarily in or localized to the CNS: He observed small cutaneous hemorrhages in 77.4% of female patients observed repeatedly over a 5-9 year period. In 66.7% of these patients, the hemorrhages were spontaneous. `Biopsies of 5 spontaneous hemorrhages, where trauma could be confidently ruled out, revealed extravasated red blood cells infiltrating the deeper layers of the derma and the subcutaneous fat.' Swank goes on to state that `a number of patients have described petechial hemorrhages in large numbers after having their blood pressure taken both under and distal to the cuff.' He notes that the petechial hemorrhages are similar to sub- cutaneous hemorrhages seen in capillary resistance studies.   
Swank RL. Subcutaneous hemorrhages in multiple sclerosis. Neurology. 1958; 8: 497-498.

Jeff's hypercoagulation and petechiae were related to his MS.  Dr. Swank did not have the science of nitric oxide as EDRF in his time, but modern researchers have since connected hypercoagulation and clotting proteins as evidence of endothelial dysfunction and a break down of the blood brain barrier, and activation of the coagulation cascade.  This research comes decades after Dr. Swank's discoveries, but confirms what he saw as "blood vessel fragility."  We now know that endothelial dysfunction and a break in the BBB will affect the blood through out the body.  Once the coagulation cascade is activated, it is systemic.  And these extravasated red blood cells will leak and appear throughout the body.  Just like Jeff's petechiae--and the break in his blood brain barrier.

The disruption of integrity of the walls of brain blood microvessels rapidly activates the coagulation cascade. 
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3268209/

The coagulation cascade plays a major role in the development of an inflammatory response in MS.
http://circres.ahajournals.org/content/110/9/1157.extract#

Other researchers have noted hypercoagulation and high fibrin levels in the blood of pwMS for decades.  But these markers have been largely ignored.  Until recently.
Here's more on this research from the Gladstone Institute.

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. 

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. 
http://www.bioquicknews.com/node/1420

More researchers are noting this break in the endothelium, and detecting these microscopic bleeds in the MS brain.  At the ISNVD conference, Dr. Yulin Ge recently discussed how 7T MRI technology is allowing us to see tiny hemorrhages in the MS brain which occur before demyelination.  This further elucidates the microvascular connection to MS.
From his abstract at the ISNVD:

Being the most common demyelinating disease of the central nervous system, multiple sclerosis (MS) MS has a significant microvascular pathological component as a consequence of the perivascular inflammation. The role of vascular pathology in MS was suggested long ago. Now there is accumulating evidence of a primary vascular pathogenesis in MS. In vivo studies of vascular and hemodynamic impairment in MS may provide insights into the etiology and pathophysiology of MS and offer the potential metrics for assessment of outcome of the disease. 

Canadian microbiologists have recently published a paper on the iron around MS lesions, and link it to the vasculature and "chronic extravasation of hemoglobin", or microbleeds causing oxidative stress in the brain. 
http://www.ncbi.nlm.nih.gov/pubmed/24504127

Dr. Zamboni saw the parallels of venous disease of the legs and MS, and wrote about iron deposition and the inflammatory response in his 2006 publication,
The Big Idea: Iron-dependent inflammation in venous disease and proposed parallels in multiple sclerosis  http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1633548/

These researchers would tell you that blood matters.  When red blood cells enter brain tissue, there are serious repercussions--including oxidative stress, inflammation, iron deposition and an upregulation of clotting proteins.   Why does the blood brain barrier become leaky, and allow plasmic particles access into brain tissue? The exact mechnism is not known, but it appears to be related to endothelial dysfunction.  It may be venous hypertension, lack of shear stress, and hypoxic injury created by CCSVI which is compounded by environmental factors like diet, exercise, stress, UV rays, viral and bacterial infections and smoking.  We need more research.

MS researchers ignore this connection at the peril of their patients' brains---and lives.
I'll keep writing about it, until the day when neurologists understand the connection of the red blood spots I saw on Jeff's legs, the lesions in his brain and spine, and his MS diagnosis.
Joan

What has Changed?

In the five years since Dr. Zamboni's first publication on the connection of MS to extracranial hemodynamics, there have been many changes in mainstream MS treatment and new discoveries made by researchers around the world.

The relationship of the vascular system in MS is being explored, and dealt with in a sideways manner by neurologists.  I do not expect we will ever hear that CCSVI is valid science from neurologists--they will attempt to rename it, requantify slowed venous return and hypoperfusion, and make it their own.  They will call Dr. Zamboni's discovery of CCSVI junk science- while they are working on patenting drugs to address blood flow in pwMS.  This is because neurologists work with pharma and write prescriptions.  They do not deal with the mechanistics of the brain's circulation or with the venous malformations Dr. Zamboni has discovered.  They are not phlebologists or vascular surgeons. For MS specialists, this discovery of hemodynamic alterations goes beyond their practical expertise.

However, one neurologist recently published a paper on the vascular connection to MS, and said this:

"...vascular contributions in MS do appear to support the notion of the vasculature being an initiating target in MS etiology and not simply a bystander presentation of other disease processes. Perhaps the strongest support for this is the number of MS therapies that have been developed, which target leukocyte binding to activated endothelial cells, a central component of the blood-brain barrier (BBB)."
http://www.biomedcentral.com/1741-7015/11/219

Here are drugs being developed by neurologists to address blood flow:
http://ccsviinms.blogspot.com/2013/08/medications-for-ms-addressing-blood.html

What have we learned since Dr. Zamboni first began publishing his research on CCSVI?  

1. People with MS (pwMS) have slower cerebral hemodynamics than normal people.  Their blood flow exits the brain at a slower rate. There are hemodynamic differences between normal people and those with MS. Hypoperfusion is real, it opens the blood brain barrier and it damages the brain.  Whether it is a cause or effect of MS will be debated for decades, however vascular researchers have shown better perfusion and cerebral blood flow (CBF) and cerebral spinal fluid (CSF) flow after venoplasty for CCSVI.

http://www.hindawi.com/journals/msi/2013/598093

http://www.ncbi.nlm.nih.gov/pubmed/23523158

2. People with MS do better with exposure to UV rays, which may explain the long-established link of MS rates and northern latitudes. UV ray exposure relieves symptoms in many.  This may be due to increased vitamin D levels, but it might also be due to the way in which UV rays release nitric oxide, change the endothelium and increase blood flow. 

http://ccsviinms.blogspot.com/2013/06/photorelaxation-uv-rays-and-ccsvi-june.html

3. People with MS are being advised to consider their nutrition and to eat more fruits, vegetables and whole foods and less saturated fats and processed foods.   When Dr. Swank suggested this 60 years ago, it was called "junk science" and people with MS were told it wouldn't do them an ounce of good.  It is now given as helpful advice by the NMSS and the AAN.   

Same thing with exercise.  Only a few years ago, pwMS were advised not exert themselves, but to rest and conserve their energy.  Now we know that physical exercise and activity delays progression, and reverses gray matter atrophy.  Same thing with smoking cessation, stress reduction, and better sleep.  All of these cardiovascular lifestyle changes can make a difference.

http://www.nationalmssociety.org/living-with-multiple-sclerosis/healthy-living/index.aspx

4. Oxidative stress and inflammation are recognized as driving forces in MS progression.  This has lead to exploratons of new modalities of treatment, like the Nrf2 pathway. 

http://ccsviinms.blogspot.com/2012/09/oxidative-stress-multiple-sclerosis-and.html

5. Gray matter health has been recognized as a more accurate biomarker of MS progression than white matter lesions.  Gray matter atrophy will become the new target for MS therapies.

http://ccsviinms.blogspot.com/2012/01/iron-and-gray-matter-what-do-we-know.html

6. PwMS have much higher levels of the clotting proteins- fibrin and endothelin-1 in their serum than normals. These are markers of endothelial dysfunction.

http://ccsviinms.blogspot.com/2012/11/whats-blood-got-to-do-with-it-nov.html

7. Upright MRI has allowed us to see how cerebrospinal fluid and blood return to the heart is slowed and impeded in pwMS.

http://www.fonar.com/news/100511.htm

8.  The venous endothelium is being studied, and researchers are noting that there are changes happening to the lining of the veins in people with neurodegenerative disease.

http://www.biomedcentral.com/1741-7015/11/219

9.  CCSVI is being explored around the globe.  There are literally hundreds of papers published in vascular and neurological journals.  New papers come to press every day.  The connection of blood flow and diseases of neurodegeneration continues, as doctors admit that lifestyle interventions and prevention are staving off Alzheimer's and dementia, while none of the drugs have helped one bit.

http://www.ccsvi.org/index.php/component/search/index.php?option=com_search&task=search

10.  The ISNVD has been established.  There is now an international society of researchers working on understanding the venous connection to neurovascular disease.  Their fourth conference will be held in San Francisco in February, 2014.  The International Society for Neurovascular Disease is convening, publishing, and moving this research forward.
http://isnvdconference.org

All of these connections between MS and the cardiovascular system are new.  And this has happened in just the past five years.  

For those waiting for venoplasty to be accepted as an MS treatment, we have to step back and view the other changes that have happened in MS care.  

The American Academy of Neurologists has several papers featured on their page which connect slowed blood flow and neurodegenerative disease.  They have a patient outreach branch--The American Brain Foundation-- and they have a yearly Brain Fair to discuss diet and lifestyle changes people with neurodegenerative diseases, including MS, should consider.  So much for Dr. Swank's junk science.

Here's a wonderful video Christopher Alkenbrack found on Dr. Roy Swank's work.  It was made in 1989 as part of a Canadian news investigation into the success of Dr. Swank's diet in pwMS as compared to a vastly more expensive and failed chemotherapy trial.  If you haven't seen it, it's a must watch.  

Because today, 25 years later, the NMSS is making these very same dietary and lifestyle recommendations to pwMS.  Yet when asked about dietary changes for pwMS, the neurologist in this video from 1989 says there is "little to no benefit."

https://www.youtube.com/watch?feature=player_embedded&v=lEnn_AZT-SU 

When reporters, scientists, neurologists, MS specialists and others say, "Oh, the connection of CCSVI to MS, that's junk science."  We've investigated it, and there's nothing there"---remind them about Dr. Roy Swank.  Remind them how long it took his observations of "capillary fragility", slowed blood flow, increased fibrin and hypercoagulation to be accepted as part of MS.    

He was noting endothelial dysfunction decades before scientists knew about nitric oxide and how environmental factors contributed to blood flow.  And he has never once been credited by mainstream neurology.  You won't see his name or read his research in their journals.  But he was right.

Dr. Zamboni's discovery has revolutionized how we look at cerebral blood flow, by studying the under-researched extracranial venous system, and utilizing doppler ultrasound to understand venous malformations which alter cerebral hemodynamics.  Like Dr. Swank, Dr. T.J.Putnam and others, he is decades ahead of his time.  His discovery of CCSVI may very well be the rest of the equation in understanding the slowed venous return and endothelial dysfunction found in pwMS.   To say that it is junk science, and that there is no connection of venous return in MS, is to negate scientific fact.  

Joan

Fibrinogen---found In ALL neurodegenerative diseases, not just MS

December 4, 2012 at 9:29am

The "news" this week was that fibrinogen, an essential clotting protein, crosses over the blood brain barrier in the mouse model of MS and initiates the disease process by destroying nerve cells.  

Fibrinogen-induced perivascular microglial clustering is required for the development of axonal damage in neuroinflammation

http://www.nature.com/ncomms/journal/v3/n11/full/ncomms2230.html

But this isn't news.  Researchers have been studying this process in neurodegenerative disease for a decade.  Because this process happens when the blood brain barrier breaks down.

The overall findings from study of Alzheimer's Disease brain tissue and in vivo in Abeta(1-42) and Abeta(1-42) plus fibrinogen stimulated rat hippocampus suggest microglial responses to promote increased extravasation of blood protein as a critical component in amplifying inflammatory reactivity and causing neuronal damage in inflamed AD brain.

http://www.ncbi.nlm.nih.gov/pubmed/18657226

Fibrinogen is a pleiotropic blood protein that regulates coagulation, inflammation and tissue repair. Fibrinogen extravasates in the nervous system after injury or disease associated with vascular damage or blood-brain barrier (BBB) disruption. Fibrinogen is not merely a marker of BBB disruption, but plays a causative role in neurologic disease as a potent inducer of inflammation and an inhibitor of neurite outgrowth. Fibrinogen mediates functions in the nervous system as a ligand for cell-specific receptors. In microglia, fibrinogen mediates activation of Akt and Rho via the CD11b/CD18 integrin receptor, while in neurons fibrinogen induces phosphorylation of epidermal growth factor (EGF) receptor via the alphavbeta3 integrin. Pharmacologic targeting of the interactions of fibrinogen with its nervous system receptors could provide novel strategies for therapeutic intervention in neuroinflammatory and neurodegenerative diseases.

http://www.ncbi.nlm.nih.gov/pubmed/19630789

Why the race for researchers to understand fibrinogen?

Because pharma wants to monetize a way to block it.

That's right....researchers are not studying WHY fibrinogen is breaking through the blood brain barrier.  No one is looking at causation.

Everyone is studying this to find a pharmacological means of stopping fibrinogen.

But, what if there is an underlying mechanism which begins fibrinogen activation in all neurodegenerative disease?

Wouldn't that be something to study?  Wouldn't that be causation, and lead to potential answers in disease aetiology?

Here's a paper I researched and wrote up for CCSVI Alliance on the discovery of CCSVI in other neurological disease.  It proposes the mechanism found in common with CCSVI in neurodegenerative disease.  Slowed cerebral bloodflow.

http://www.ccsvi.org/index.php/the-basics/ccsvi-in-other-neurological-diseases

HYPOPERFUSION.   A mechanism found in all neurodegenerative disease, which starts fibrin deposition in the brain. This is being studied by stroke researchers.  A decline in cerebral bloodflow initiates fibrin deposition in the brain immediately.

One of the most surprising findings of the present study is that the decline of cerebral blood flow (CBF) in conjunction with hypoxia is sufficient to induce rapid microvascular thrombosis and fibrin deposition within the brain (Figure 9). By analyzing challenged fibrinogen-null mice we have established that fibrin(ogen) plays an important role the reperfusion deficits and brain infarction (Figure 10). These results suggest that if cerebral ischemia is accompanied with hypoxia, this combination can precipitate local coagulation and impede reperfusion after ischemia, similar to the previously described no-reflow phenomenon after cerebral ischemia5 and cardiac arrest.56 It seems likely that fibrin stabilization of platelet thrombi is a major determinant of brain tissue damage. If so, we would predict that a similar, if not more impressive, protection from tissue damage could be realized in mice with a profound defect in platelet function. It is also conceivable that fibrin-mediated inflammatory processes drive secondary tissue damage in the brain. Thus, the modified Levine/Vannucci model described here may be useful for testing new therapies to restore postischemic reperfusion in the face of thrombolytic agents and other approaches to reopened large vessels.

Regarding the mechanism of ischemia/hypoxia-induced thrombosis, it seems likely that hypoxia alters the balance between anti- and procoagulation properties of the endothelial cells in cerebral blood vessels. Although focal ischemia can trigger platelet accumulation and fibrin deposition, these events typically show a late-onset after a transient hyperemia phase.49,53 In contrast, the present study shows that the combination of ischemia and hypoxia precipitates these events almost immediately. 

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1780162/

Please encourage and support the researchers of the International Society for Neurovascular Disease.  

http://www.isnvd.org

There are only a few groups looking at disease aetiology, or what is causing the disease process.

Blocking fibrinogen won't cure MS.  

Understanding why there is fibrinogen in brain tissue may.

Joan

What's blood got to do with it?

Nov. 27, 2012  10:17 AM

NIH researchers find that fibrinogen appears to be "the trigger" which begins neurodegeneration in MS.

http://www.nih.gov/news/health/nov2012/ninds-27.htm

Researchers are honing in on fibrinogen as a mediator in vascular disease, and they are also finding a link in MS.

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 signaling 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.  

 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1633548/

And researchers have noted that fibin deposition comes FIRST, before demyelination.

Here is some recent research on this connection:

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