Microvascular Hypercoagulability Model for MS

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

Postby North52 » Mon Nov 08, 2010 10:36 am

Dear Mladen,

In reference to your comment:

"This is not the only way. To keep flow on 25 cars/second in one line, you can speed up trafic in that one line five times! The trafic in the town remain the same."

But how do you increase the the speed of the traffic 5 times? This will not happen by itself. You will need to increase the pressure of the flow going into the stenosis. The way to do this would be to increase cardiac output and or increase blood pressure, which will increase inflow pressure. I doubt this happens in the setting of ccsvi. In the setting of ccsvi, I suspect venous pressure upstream of the obstruction will be slightly increased but not enough to bring flow back to where it was prior to the stenosis. In reality, I suspect pressure is increased minimally and the blood will choose an alternative route, one with reduced resistance in order to get back to the heart. This is why collaterals form and why you can have reflux. These collateral routes and refux scenarios will attempt to maintain normal blood flow, but I suspect they will never be as efficient as a non-stenosed vein so flow in the capillaries will remain reduced.

North
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Postby malden » Mon Nov 08, 2010 1:56 pm

...But how do you increase the the speed of the traffic 5 times? This will not happen by itself....

Sry, no more Matchbox analogy... just pure hemodynamic basic cardiovascular physiology concept:

http://www.cvphysiology.com/Hemodynamics/H012.htm

Image
" ...
Kinetic energy and pressure energy can be interconverted so that total energy remains unchanged. This is the basis of Bernoulli's Principle. This principle can be illustrated by a blood vessel that is suddenly narrowed then returned to its normal diameter. In the narrowed region, the velocity increases as the diameter decreases (V ∝ 1/D2). If the diameter is reduced by one-half in the region of the stenosis, the velocity increases 4-fold. Because KE ∝ V2, the KE increases 16-fold. If the total energy is conserved, then the 16-fold increase in KE must result in a proportionate decrease in PE. Once past the narrowed segment, the KE and PE will revert back to their original values because the diameter is the same as before the narrowed segment. This simplistic model assumes that there is no loss of total energy along the length of the vessel. In fact, there will be some loss of total energy and pressure (as indicated in the figure) because of the high resistance in the narrowed region and because of turbulence that occurs distal to the narrowed region. To summarize this concept, blood flowing at higher velocities has a higher ratio of kinetic energy to potential (pressure) energy.
... "

Best regards, M.
Last edited by malden on Mon Nov 08, 2010 2:05 pm, edited 1 time in total.
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Postby MS_HOPE » Mon Nov 08, 2010 1:58 pm

Due to my MS-fogged brain, I can't say that I'm following much of the technical discussion here. But I'm VERY much appreciating the respectful, civil tone, and the spirit of explaining and educating. Thank you, guys (and gals?).
CCSVI:  Making Sense of MS
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Postby malden » Mon Nov 08, 2010 2:08 pm

MS_HOPE wrote:Due to my MS-fogged brain, I can't say that I'm following much of the technical discussion here. But I'm VERY much appreciating the respectful, civil tone, and the spirit of explaining and educating. Thank you, guys (and gals?).

You are not alone in this fogg... this is just ours "lucida intervala" ;)
Last edited by malden on Mon Nov 08, 2010 2:10 pm, edited 2 times in total.
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Postby Cece » Mon Nov 08, 2010 2:09 pm

What I notice about Malden's diagram is that the arrows all go one way. But in CCSVI, there is reflux. There should be arrows on the diagram also going the other way. The blood volume within the stenosed area will not equal the total blood volume in the area just before the stenosed area. This will affect the equations.
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Postby Cece » Mon Nov 08, 2010 2:14 pm

Malden wrote:
MS_HOPE wrote:Due to my MS-fogged brain, I can't say that I'm following much of the technical discussion here. But I'm VERY much appreciating the respectful, civil tone, and the spirit of explaining and educating. Thank you, guys (and gals?).

You are not alone in this fogg... this is just ours "lucida intervala" ;)

Malden, you spelled this correctly initially and then edited in a second 'g' on fog and an 's' on our.
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Postby malden » Mon Nov 08, 2010 2:18 pm

Cece wrote:What I notice about Malden's diagram is that the arrows all go one way. But in CCSVI, there is reflux. There should be arrows on the diagram also going the other way. The blood volume within the stenosed area will not equal the total blood volume in the area just before the stenosed area. This will affect the equations.

Tell this to your hemodynamic professor and you fail exam. You can draw arrows and flowers all over the drawing.... but that's not the science: it's art. Reflux is past time, even Zamboni avoid to mention it in his last statement about CCSVI.
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Postby North52 » Mon Nov 08, 2010 4:03 pm

Dear Mladen,

I feel like I am back in highschool physics class. It's making my brain work. Thanks for you responses.

I am still, however, convinced that you are not correct in your analysis. What you explained with your pressure volume relationship makes sense in your closed system. At the point of narrowing, velocity will increase as you stated, and I understand that. What your example, however, does not illustrate is that the volume of flow will be the same compared to an example without stenosis. I will try to illustrate my point using a simple analogy:

Take two buckets of water that have short tubes of the same length underneath them that are draining their respective bucket. Now assume one tube is very large and one tube is tiny (ie the stenosis). Which bucket will will have its contents drained faster? It would obviously be the one with the larger tube draining it. The rate of flow (or voume of flow per second) of in the stenosed tube will be less. Like you stated, the velocity of flow will be much greater in the small tube but this velocity will not be fast enough for the rate of flow to catch up to the larger tube's flow. The only way you can have it catch up is to increase the pressure pushing down on the water in the bucket.

Regards,

North
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Postby cheerleader » Mon Nov 08, 2010 7:10 pm

Hi North--just checked out your thread. Good stuff! I believe the fibrin is most-likely a result of diffuse cerebral hypoxia. It was the hypoxia induced coagulation cascade that I looked into after Jeff's diagnosis in '07 with MS. He came home from a week at high altitude with 20 lesions, 6 enhancing, and the strangest blood numbers. High SED, hypercoagulation, high liver enzymes and jaundice and petechiae. His neuro said it wasn't related to MS, but that got me on the vascular trail...and researching endothelial dysfunction and how to over come it.

Here's the paper that cinched it for me--you'll see how fibrin fits into the picture--

Cerebral Ischemia-Hypoxia Induces Intravascular Coagulation and Autophagy.

F Adhami, G Liao, YM Morozov, A Schloemer, VJ Schmithorst, JN Lorenz, RS Dunn, CV Vorhees, M Wills-Karp, JL Degen, RJ Davis, N Mizushima, P Rakic, BJ Dardzinski, SK Holland, FR Sharp, CY Kuan

Hypoxia is a critical factor for cell death or survival in ischemic stroke, but the pathological consequences of combined ischemia-hypoxia are not fully understood. Here we examine this issue using a modified Levine/Vannucci procedure in adult mice that consists of unilateral common carotid artery occlusion and hypoxia with tightly regulated body temperature. At the cellular level, ischemia-hypoxia produced proinflammatory cytokines and simultaneously activated both prosurvival (eg, synthesis of heat shock 70 protein, phosphorylation of ERK and AKT) and proapoptosis signaling pathways (eg, release of cytochrome c and AIF from mitochondria, cleavage of caspase-9 and -8). However, caspase-3 was not activated, and very few cells completed the apoptosis process. Instead, many damaged neurons showed features of autophagic/lysosomal cell death. At the tissue level, ischemia-hypoxia caused persistent cerebral perfusion deficits even after release of the carotid artery occlusion. These changes were associated with both platelet deposition and fibrin accumulation within the cerebral circulation and would be expected to contribute to infarction. Complementary studies in fibrinogen-deficient mice revealed that the absence of fibrin and/or secondary fibrin-mediated inflammatory processes significantly attenuated brain damage. Together, these results suggest that ischemia-hypoxia is a powerful stimulus for spontaneous coagulation leading to reperfusion deficits and autophagic/lysosomal cell death in brain.


Here's more on fibrin---

One of the most surprising findings of the present study is that the decline of 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. Understanding the mechanism by which combined ischemia-hypoxia alters the homeostatic properties of endothelial cells in cerebral vessels may suggest novel prophylactic therapies in clinical situations when the imminent risk of cerebral ischemia and hypoxia is high, such as coronary bypass surgery.


Here's the whole paper...enjoy-

http://ajp.amjpathol.org/cgi/content/full/169/2/566
cheer
Husband dx RRMS 3/07
dx dual jugular vein stenosis (CCSVI) 4/09
http://ccsviinms.blogspot.com
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Postby North52 » Mon Nov 08, 2010 8:06 pm

Deer Cheerleader,

Thank you for sharing this very interesting article with me. Until now, I assumed that the coagulation cascade was actived because of reduced blood flow or stasis, but after reading this study, hypoxia seems to be a more likely culprit. I realized that stasis cannot happen without causing hypoxia.

I also want thank you for all the other articles that you referred me to. They have been very helpful in my efforts to better understand ms, and coagulation in the setting of ccsvi. I also want to say that I read all your stuff on endothelial health. I was very impressed and really think you have great insight into the ms disease process, more so in fact than most health care professionals (especially neurologists!).

If you haven't already, I would like strongly suggest that you read the following article that I came across recently. It summarizes how fibrinogen/fibin is implicated in the pathophysiology of MS. I learned a lot from it. The article is "Fibrinogen Signal Transduction as a Mediator and Therapeutic Target in Inflammation: lessons from multiple sclerosis" Here's the link:

http://www.ncbi.nlm.nih.gov/pubmed/18045138

If you do not have access to the full article, pm me and I can email it to you.

Thanks,

North
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Postby malden » Tue Nov 09, 2010 3:48 am

Dear North,

It's making my brain work too ;)

This brain/barrel analogy is not new in this forum, even bigger brains than your's and mine are using it to explain something that's not explainable.

So, what's wrong with this model? Let me try to explain.

...Take two buckets of water that have short tubes of the same length underneath them that are draining their respective bucket. Now assume one tube is very large and one tube is tiny (ie the stenosis)...

Bucket model for the explain stenosis you suggest to use is not the "one tube is very large and one tube is tiny", it is "tubes are the same size, but one tube is narrowed (tiny) somewhere in the tube".

And that is the crucial diference.

What bucket, from my model, will have its contents drained faster? Neither! The rate of flow (or voume of flow per second) in the both tubes will be the same (in case of ideal fluid). Both buckets will drain empty in the same time.

Why is this so?
Because the exit flow speed from tubes (v) is v=sqrt(2*9.81*dh);
where dh="diference in high between tube exit and bucket water level".
If both tube ends are on the same level and the buckets are also, then dh1=dh2 and then v1=v2.
Both tubes have the same cross section (A) at the exit end (A1=A2).
The rate of flow (or voume of flow per second, Q) at the end of both tubes is Q=A*v and is the same for both the tubes (Q1=Q2). It doesn't change during the whole tube - it is constant.
Only what is changing is velocity in the narrowed tube, but only at the location of narrowing (velocity increased to drive the same flow thru smaller crosssection).

Only difference can be, that in real fluid some turbulence in stenosis region leads to a decrease in flow. Turbulence depends of a flow speed and viscosity, high velocities and low blood viscosity are more likely to cause turbulence. It's more important in arteries (higher flow speed) then in veins (lower flow speeds)

Regards,

Mladen.
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Postby sbr487 » Tue Nov 09, 2010 6:14 am

Malden wrote:Reflux is past time, even Zamboni avoid to mention it in his last statement about CCSVI.


http://ang.sagepub.com/content/57/5/556.abstract

Contradictory reports on the significance of several hemodynamic phenomena, such as femoral vein incompetence and incompetent calf perforators, impede orientation in venous hemodynamics. Venous pressure difference arising between the popliteal and the posterior tibial vein during the activity of the calf muscle venous pump was reported for the first time about 50 years ago, but regrettably, this important discovery continues to be unrespected. The venous pressure difference has since been termed ambulatory pressure gradient and seems to be the key factor triggering the venous reflux in the lower limb as well as the process leading to varicose vein recurrence. On the other hand, simultaneous recordings of the mean venous pressure in the posterior tibial and long saphenous veins demonstrated that the pressure curves have been identical at rest, during ambulation, and in the recovery period, a finding typical of conjoined vessels. Bidirectional flow within calf perforators taking place both in healthy subjects and in patients with varicose veins enables a quick equilibration of pressure changes between deep and superficial veins of the lower leg. Reflux disturbing the venous hemodynamics is in various degrees dependent on the quantity of retrograde flow; abolition of reflux restores normal venous hemodynamics. Reflux in superficial veins, if large enough, may cause the most severe form of chronic venous insufficiency. Femoral vein incompetence and incompetent calf perforators per se do not produce ambulatory venous hypertension and do not cause hemodynamic disturbance. This study discusses the controversial issues, tries to define and appraise the principal hemodynamic phenomena (ambulatory venous hypertension, ambulatory pressure gradient, venous reflux, superficial and deep vein incompetence, incompetent perforators), mentions a possible relation between deep vein incompetence and varicose veins, and attempts to present, based on proved facts, a comprehensive picture of the venous hemodynamics in the lower extremity.
A new scientific truth does not triumph by convincing its opponents and making them see the light, but rather because its opponents eventually die and a new generation grows up that is familiar with it
- Max Planck
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Postby malden » Tue Nov 09, 2010 6:48 am

Talking about CCSVI and reflux in the same sentence, for me, means reflux in brain and spine caused by chronic cerebro-spinal venous insufficiency, not " reflux in the lower limb", "varicose veins", "venous hemodynamics in the lower extremity" and "deep and superficial veins of the lower leg".

And talking about "last statement" I certainly did not mean article "Conception of the Venous Hemodynamics in the Lower Extremity" from 2006. - that you quoted. I mean:
The 4th World Congress on Controversies in Neurology (CONy)
Barcelona, Spain, Palau de Congressos de Catalunya, October 28-31, 2010
http://comtecmed.com/cony/2010/scientific_prog.aspx
Debate: Does chronic venous insufficiency paly a role in MS pathogenesis?
Yes: P. Zamboni, Italy
No: O. Stuve, USA
Commentator: A. Miller, Israel
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Postby Cece » Tue Nov 09, 2010 8:11 am

This seems polemic. :D

Reflux alone would be enough to get you diagnosed with CCSVI, if it were in two places (the jugulars and the deep cerebral veins; these are two of the five Zamboni criteria).
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Postby LR1234 » Tue Nov 09, 2010 8:59 am

I never had reflux but had slow flow and lots of collaterals.
I don't think CCSVI is all about the reflux because even when its fixed the flow still remains too slow which causes problems.
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