Monday, May 10, 2010

Arteriosclerosis and von Willebrand Disease

As soon as you start to think about arteriosclerosis as a thrombotic, platelet driven process you immediately think about von Willebrand disease (vWD) of course. vWD is a real laugh for a surgeon who makes the diagnosis 10 minutes in to an operation on a young Doberman which won't stop bleeding wherever he cuts it. Giving that NSAID at premed time suddenly seems to have morphed in to a very dumb idea. And the desmopressin seemed too expensive to have on the shelf before today. But I digress.

vWD means your platelets won't stick. Generally this is a Bad Thing.

OK, more pictures. Fuster's group produced this nice early paper "Resistance to arteriosclerosis in pigs with von Willebrand's disease. Spontaneous and high cholesterol diet-induced arteriosclerosis" from which the micrographs are taken.

Similar data were generated by Griggs et al but interpreted somewhat differently. Personally Fuster comes over as by far the more convincing. At least he doesn't inflate a balloon in a coronary artery, then pull on the catheter to induce "arteriosclerosis"!

Happily there is some convergence of opinion, as should happen when both sides are fairly correct and a lot of ifs, buts and maybes are still present in our knowledge base of arteriosclerosis.

So lets look at the micrographs from Fuster. Here's the first set:

These are all taken from normal pigs eating normal crap in a bag. Image A is stained for elastin and was taken from a non damaged area of aorta. Look at the elastin layer. Nice and continuous. Intima is one cell thick.

Image B is from a similar pig but the section is taken through a fibrous plaque. Obviously there's a plaque, which is what Fuster is interested in. But to me there is duplication and fraying of the elastin layer, especially on the left of the picture, but also to the right. Both images A and B are taken at X160 magnification, just eyeball-compare the quality of the elastin in the two areas.

Image C is Sudan IV stained for lipid, so elastin doesn't show. The arrow shows a cell with lipid. There are a few more scattered around but this is certainly not a lipid lesion. It's worth pointing out that platelets are 17% lipid, so some will be floating around from this source.

These next two pictures are from a pig with severe homozygous vWD:

The macroscopic picture is of the fatty areas (Griggs, the rival paper, describes these as "sudanophilia" and implies that they are arteriosclerotic. They're not). The micrograph below in image B is also stained with Sudan IV and shows exactly how shallow this lipid layer is. There is no intimal thickening, no fibrosis and there is absolutely no change in the media below the lesion. At some time I'll have a think about what is going on here, but for the moment let's leave it as non-arteriosclerostic fatty accumulation which does not form an epithelium and does not stop Evans Blue dye from penetrating in to the wall of the aorta.

Finally some fantastic electron micrographs, all from pigs with severe vWD:

First look at the scanning EM image C. This is a non stressed area of aorta. Nice epithelialised surface. Image A is from a stressed area of aorta which would have developed a fibrous plaque, given a few platelets to cover it, but in vWD this is not going to happen. Rough is not the word. Images B and D are the comparable transmission EMs.

Having vWD is no fun. Endothelial injury is normal. vWD patients bruise all over the place, all the time. These injuries also occur in normal people and are repaired without problem in normal people. Duguid considered atherosclerosis to be pathological and Moon came to the same conclusion. I'm not sure it is that simple. The process which causes arteriosclerosis also keeps us alive. Life saving pathology?

Addendum: Eddie Vos, through THINCS, quoted from this book while I was typing the above post.

From a section describing 49 aortas from monkeys SHOT in the wild,(page 248):

"The small elevated plaques are composed predominantly of smooth muscle cells and elastic tissue and are practically devoid of fats. Thus, the resemblance to human fibrous plaques noted grossly is not borne out microscopically."

My own opinion is that this would be true if all human lesions were lipid based. As many humans develop many small non lipid plaques which sound to be of similar nature to those described in chimps I'm tempted to believe these lesions are normal and physiological. Converting these non lipid plaques to unstable plaques full of linoleic acid and cholesterol crystals is the trick needed to keep cardiologists in business.



shawn57187 said...

vWD is something that greatly interests me as I was diagnosed with the condition (type 1) as a youth.

I have noticed that I can control my levels of bruising through diet, specifically with the amount and type of fat I consume. This seems, at least experimentally, to be backed up my the peer reviewed literature.

Omega-3 fatty acids, fish oil, alpha-linolenic acid
""Fish oils appear to decrease platelet aggregation and prolong bleeding time, increase fibrinolysis (breaking down of blood clots), and may reduce von Willebrand factor."

Effect of fish oil concentrates on hemorheological and hemostatic aspects of diabetes mellitus: a preliminary study.
"Before fish oil administration, the diabetics had higher levels of von Willebrand Factor (vWF) (208 +/- 31%) than did controls (117 +/- 26%). There was a statistically significant decrease of serum von Willebrand Factor both in diabetics (p less than 0.01) and in normals (p less than 0.05) after six weeks of treatment."

Plasma levels of von Willebrand factor in non-insulin-dependent diabetes mellitus are influenced by dietary monounsaturated fatty acids.
"In conclusion, three weeks on a diet rich in MUFA lowers vWF as compared with a PUFA rich diet, suggesting a beneficial effect of MUFA on the endothelium in NIDDM patients."

Decrease in von Willebrand factor levels after a high-monounsaturated-fat diet in non-insulin-dependent diabetic subjects.
"The H-MUFA diet caused a decrease in vWF from 1.31 +/- 0.08 to 1.13 +/- 0.08 U/mL (P < .004), whereas an unchanged level was observed after a H-CHO diet (1.19 +/- 0.11 v 1.25 +/- 0.11 U/mL, NS)."

The effects of saturated fat and n-6 polyunsaturated fat on postprandial lipemia and hemostatic activity
"The effect of different fat loads on postprandial lipemia and hemostatic activity was examined in 10 middle-aged men using 3 different meals. One meal was rich in saturated fatty acids (cream), the other rich in n-6 polyunsaturated fatty acids (sunflower oil) and the third was fat-free containing only carbohydrates...Factor VIII activity (F VIII:C) was highest after the polyunsaturated fat meal and lowest after the fat-free meal."

I'm sure there is more research on the influence of dietary fats on vWF, but I just haven't had the time to look. I must be especially conscious of any type of n-3 fat (particularly flax) as I had a terrible bleeding incident following dental surgery and flax supplementation.

My current regimen, which has mostly kept vWD from being prohibitive of normal activities, is to consume 45% fat calories from SFA, 45% fat from MUFA, and 10% from PUFA (roughly split evenly between n3/n-6). I track my dietary intake on the computer and consume mostly fats from pastured animals.

Peter said...

Hi Shawn,

I'd assumed that fish oil might worsen vWD symptoms and conversely omega 6s might improve matters, at the cost of frying your liver and other niceties. I'm surprised at the effect of MUFA and would really be thinking of SFAs for bulk calories under those circumstances and keeping MUFA as low as practical while eating real food... Oh, no I just pubmeded the abstract. The MUFA probably do nothing. Dropping your carbs from 50% to 30% will decrease a pathologically elevated vWD in type 2 diabetes due to better glycaemic control. In a non diabetic, who knows, probably depends on how insulin resistant you are.

Hyperglycaemia activates NF kappa-B so increases expression of all sorts of pro coagulant genes. I suspect vWD factor is included. The Finland study does not tell you enough in the abstract to work out what they actually did, but I suspect the low fat meal failed to generate a glucose spike.

Anyway, at least you have a lever which has helped you live with vWD. I'd still look to avoid pathological glucose levels even if there is some protection from CVD from the vWD... Mind you, stressed aorta under vWD isn't normal, even if it's not really atherosclerotic. Better not damage it in the first place and eating real food seems to be a good start!


gn said...

regarding "high-fat-diet" in general, somewhere you warned against going overboard with fat:

in theory, can anything bad happen (aside from pure digestive issues) from consuming too much fat?

i'm just trying to figure out the reason why my heart aches after a high (in absolute quantities, say some couple of hundred grams of butter) fat meals in particular, and why my heart started to ache since i've started to eat high-fat...

gn said...

oh, and by the way, my "high-fat" means butter, lard, tallow and zero vegetable oil except coconut

David said...

These articles seem to suggest coagulation factors do not play the major role in human atherosclerosis:

"Patients With Type 3 Severe von Willebrand Disease Are Not Protected Against Atherosclerosis"

"Decreased Coagulability Has No Clinically Relevant Effect on Atherogenesis"

Both are from the journal circulation...

Peter said...

Hi gn,

It's possible. A number of people have told me about chest pains on zero carb or very low calorie, protein based diets which probably mimic very high fat diets as most calories come from weight loss fat. There is undoubtedly a higher requirement for oxygen per unit ATP generated from fat and very very low carb diets raise sympathetic nervous system tone so there may be problems on this basis, ie impaired oxygen delivery and increased demand. There might also be a requirement for time to adapt. Lutz suggest weeks to months to adapt to 72g/d of carbs, longest in older people and he does cite cardiac abnormalities as one possible problem in Life Without Bread. I'd go slowly and not be too extreme. Adaption takes time.

Hi David,

Even in Fuster'spaper there wasn't 100% protection in pigs with very extreme vWD. Griggs got very similar results, including a statistically significant reduced amount of fibrous plaque in his homozygote pigs. But protection was not complete, although there was a gradation from normal pigs through heterozygotes to homozygotes. Obviously Griggs' heterozygotes did not make p<0.05 vs normal pigs, but a trend is there.

I'm also rather more interested in what factors might be mimicking platelet adhesion to change the intima thickness (and what intimal thickness represents anyway), which will be in the next couple of posts, but we're off to Skye, with a smidgin of luck, for the next week. While antiplatelet drugs are fashionable at the moment, converting all of us to severe vWD homozygotes may not be an ideal route forward. But platelet granules are quite interesting.

For the individual papers you would have to pick through the methods to see if there is a real effect.


shawn57187 said...

Hi Peter,
I found this article that I surmise will be of interest to you:

Patients With Type 3 Severe von Willebrand Disease Are Not Protected Against Atherosclerosis;109/6/740

The findings in pigs may not translate into a benefit for humans.

On a side note, I do adhere to a carbohydrate restricted diet. I limit carbohydrate to 50-70g daily. Any less and I find it difficult to meet my RDIs for essential vitamins and minerals. Even with most of my fats and protein coming from wild caught marine sources and pastured animals, I fear nutrient deficiencies too much to give up my varied intake of leafy green vegetables (with the occasional tubers or fruits).

blogblog said...
This comment has been removed by the author.
Peter said...

Hi Shawn,

Does the next post start to explain matters?

You can mimic platelet adhesion by eating enough sugar to become chronically hyperinsulinaemic. Again one has to ask about the effect of paleo eating on IMT. My suspicion is that there is an effect of vWD, especially type 3, on plaque formation but feeding a pig or a human on crap-in-a-bag will blunt that effect.

You also have to differentiate fibrous plaque formation from unstable plaque formation, the latter being of rather different origin, though there is some relationship. More posts over the next few weeks on those aspects.


blogblog said...

Hi GN,
I also had chest pain during the early stages of a zero carb diet. However it mimicked the symptoms of gastric reflux rather than than a radiating angina type pain that would be expected from hypoxia. This pain was not relieved short-term by eating carbohydrates.

Aaron said...

Peter, do you have any more to say about what you call "an increase in sympathetic tone" on a high fat/low carb diet?

Increased alertness and trouble sleeping -- coupled with an increase in hemorrhoid-budges (not major) <--- but occur just like they have in the past when I took anything stimulant based. It also occurs if I decided to forgo food for more than 24 hours. May be the increase in dopamine.

Does sympathetic tone get turned down over time -- it seems like I wasn't even able to adapt within 6 weeks when I was hardcore about it.

Also, I experience similar weird chest sensations when I eat really high fat foods without carbs. Such as butter or eggs with bacon. When I add carbs to the meal, it doesn't seem to cause as much of a problem, but it is still slightly there. Does this go away overtime? I saw no such abatement over 6 weeks low carb. Eating fruit or veggies never seem to give me this type of pins and needle like sensations in my arms. Or fullness/tightness in my chest (no pain however)

BTW-- I'm a 30yr male in good shape -- Have done HIIT for years.

blogblog said...

re Aaron.
I had very similar experiences to yours on a zero carb diet. However a small amount of carbs (20-40g/day) prevents all these problems.

The alertness problems are probably due to exess cathecholamines being produced to stimulate fat mobilisation and gluconeogenesis - in other words "fight or flight".

The pins and needles are possible mild angina symptoms.

Complete adaptation to a zero carb diet takes at least 12-18 months from all the information I have read.