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covid19: autopsy analyses, biomarkers, von Willebrand factor

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von Willibrand factor, a multimeric blood protein which plays a central role in blood clotting

Canto: So we’re working hard to get through what has been reported on medcram update 95, even though it’s taking us further behind the times in terms of what’s happening in the fight against this virus – there’s been some controversy on convalescent plasma recently for example – because it’s important to get the most out of every report before going onto the next one.

Jacinta: Yes, which means we need to work harder and faster. So in this study of a number of fatal cases of covid19 they found ‘no endothelial abnormalities on microscopic review, in alignment with previous studies’, which suggests that evidence of endothelial damage just doesn’t seem to be there, but they couldn’t rule out pro-coagulant endothelial dysfunction in the absence of ‘histopathological evidence of cell activation or erosion’, and they referred to another autopsy study with specialised equipment which ‘demonstrated ultrastructural endothelial damage’. So it seems they’re struggling with causes.

Canto: What they call the precise aetiology of the disease. 

Jacinta: Yes that’s what we’re after. So they do mention elevated troponin in covid19, which appears to be found regularly. Troponins are ‘a group of proteins found in skeletal and cardiac muscle fibres that regulate muscular contraction’. As the update tells us, troponin tests measure cardiac-specific troponin in the blood as a sign of heart injury. This Australian site tells us more:

For patients who are hospitalised with COVID-19, mild elevation of troponin is common (19.7%) and frequently correlates with disease severity, acting as a marker for cardiac injury. The cause of troponin elevation in serious infection is multifactorial.

In the study under discussion, they consider that the elevated troponin has to do with ‘thrombosis of the microvasculature and cardiac veins’. This cardiac vein finding is apparently important – they found, they believe for the first time, that thrombosis of a cardiac vein can cause myocardial infarction. They also write about renal findings in their subjects, to ‘shed light on the pathogenesis of acute kidney injury in covid19’. They found virions in proximal tubular cells. A virion is essentially a full, active molecule of a virus (there’s still some disagreement about these definitions, it seems). The proximal tubules are components of nephrons, the most important functional units of kidneys. They found acute tubular necrosis and other damage, and noted that this was common to other covid19 autopsy findings, perhaps unsurprisingly as these tubular cells present ACE2, the receptor for the virus. Dr Seheult then goes on to another study from Switzerland. This study looked at 639 critically ill covid10 patients, to determine which factors were most associated with survival or otherwise. So in general they found that this group suffered a ‘moderate’ mortality rate of 24%. To understand the findings will require quite a bit of medico-immunological knowledge, but here goes: they found that ‘PCT and IL-6 levels remained similar in ICU survivors and non-survivors throughout the ICU stay’. PCT is procalcitonin. According to Medscape:

Procalcitonin (PCT) is a biomarker that exhibits greater specificity than other proinflammatory markers (eg, cytokines) in identifying sepsis and can be used in the diagnosis of bacterial infections. Procalcitonin is also produced by the neuroendocrine cells of the lung and intestine and is released as an acute-phase reactant in response to inflammatory stimuli, especially those of bacterial origin. This raised procalcitonin level during inflammation is associated with bacterial endotoxin and inflammatory cytokines.

IL-6 is interleukin-6. An opinion article in Frontiers in Microbiology  entitled ‘The Role of Interleukin-6 During Viral Infections’ describes IL-6:

IL-6 is a pleiotropic cytokine produced in response to tissue damage and infections…  Multiple cell types including fibroblasts, keratinocytes, mesangial cells, vascular endothelial cells, mast cells, macrophages, dendritic cells, and T and B cells are associated with the production of this cytokine….

Pleiotropic cytokines – a cytokine is a type of small protein – affect the activity of multiple cell types. The complex pleiotropic nature of IL-6 unsurprisingly implicates it in both pro-inflammatory and anti-inflammatory effects. So, PCT and Il-6 levels remained similar for these study subjects, but ‘CRP, creatinine, troponin, D-dimer, lactate, neutrophil count, P/F diverged within the first seven days.’  Okay, C-reactive protein (CRP) is produced in the liver, from which it enters the bloodstream, and its levels ‘start to increase very soon after any inflammation or infection affects the body’, according to Australia’s healthdirect website. Creatinine is a waste product found in everyone’s bloodstream, and it’s produced by muscle metabolism. It’s generally filtered out by the kidneys. Too much blood creatinine may be a sign of kidney dysfunction. D-Dimer, the fibrin degradation product, always contains ‘two D fragments of the fibrin product joined by a cross-link’. I won’t try to explain much further at present. Neutrophils, remember, are infection-fighting white blood cells, and P/F ratio, aka PaO2/FiO2 ratio, is, briefly, an assessment of lung function. So with that, and some more, the study looked at levels of different markers most associated with mortality. To quote from the study: 

In contrast to risk factors in hospitalised patients reported in other studies, the main mortality predictors in these critically ill patients were markers of oxygenation deficit, renal and microvascular dysfunction, and coagulatory activation. Elevated risk of bloodstream infections underscores the need to exercise caution with off-label therapies. 

Canto: That last point seems important- it’s all about the blood. Or mostly..?

Jacinta: They presented a number of graphs which Dr Seheult interprets for us, but basically they are all likely to mark higher levels of microthrombi in the patients who died, and this seemed more clearly so in the D-dimer levels. High lactate levels are a sign of anaerobic metabolism, a problem with oxygenation. Ischemic heart disease was also measured, and this has to do with narrowing of the arteries. So blood oxygenation, or lack thereof, and coagulation, which can happen just about anywhere, seems to be happening early, leading to a wide range of symptoms, especially in patients with comorbidities, some of them previously undetected. 

Canto: So we’re moving on to update 96, which starts again with thrombosis due to endothelial damage causing increased production or release of von Willibrand factor (VWF).

Jacinta: Yes, and they’re apparently finding that different blood groups or types – and that’s a topic we could spend a lot of time on – affect the level and activity of VWF. As do other factors, according to Russian researcher Anna Aksenova:

The level and activity of VWF in the blood in people can be different. The lowest values are associated with von Willebrand disease. It is a hereditary blood disease that is characterized by spontaneous bleeding. Additionally, it differs markedly among healthy people. For example, it is higher among: African Americans than among Europeans; in men than in women; in adults than in children; and in the elderly than in middle-aged people. Also, academic papers have described the VWF and blood group relationship—its level is lower among people with blood group 0, and is higher among those with blood group A. The different amount and activity of VWF in people with different blood groups has a very interesting explanation: this protein is modified by oligosaccharide chains of antigenic determinants of the AB0 system (one of the blood group systems), and this affects its stability and activity.

She points out that ‘to date, the way in which the level of VWF is regulated in the blood has not yet been fully studied’, and then she describes some of what we do know, that it’s stored in special organelles (Weibel-Palade bodies) from where it’s secreted in multimeric form. She argues that, in order to determine the level of involvement of VWF in the progress of covid19, ‘large scale and comprehensive research’ needs to be carried out. Another article which is looking at emergency covid19 treatment has the title ‘targeting raised VWF levels and macrophage activation in severe covid19: consider low volume plasma exchange and low dose steroid’. It points out that VWF is such a large protein that it can only really be removed from the body through plasma exchange. This may be a way to reduce thrombosis in serious cases. Another interesting commentary piece is titled ‘microthrombotic complications of covid19 are likely due to embolism of circulating endothelial-derived ultralarge von Willebrand Factor (eULVWF) decorated-platelet strings’. 

Canto: An embolism being a blockage, caused by an embolus. That embolus could be a blood clot (a thrombus) or a fat globule or an air or gas bubble. 

Jacinta: Yes, and VWF can come in these long strings of platelets. In fact the platelets adhere to the strings. Anyway, that’ll do for now. We’ll go on about ivermectin and the Moderna vaccine trials next time. 

References

Coronavirus Pandemic Update 95: Widespread Clotting on Autopsy; New COVID-19 Prognostic Data

Coronavirus Pandemic Update 96: RNA Vaccine; Ivermectin; von Willebrand Factor and COVID-19

https://labtestsonline.org/tests/troponin#:~:text=Troponins%20are%20a%20group%20of,to%20help%20detect%20heart%20injury.

https://www1.racgp.org.au/ajgp/coronavirus/cardiovascular-conditions-and-covid-19#:~:text=Elevated%20biomarkers%3A%20Troponin%20and%20natriuretic,a%20marker%20for%20cardiac%20injury.&text=The%20cause%20of%20troponin%20elevation%20in%20serious%20infection%20is%20multifactorial.

https://www.medscape.com/answers/2096589-179642/what-is-procalcitonin-pct

https://www.frontiersin.org/articles/10.3389/fmicb.2019.01057/full

https://www.medicinenet.com/script/main/art.asp?articlekey=26197

https://www.healthdirect.gov.au/c-reactive-protein-CRP-test

https://medicalxpress.com/news/2020-07-complications-covid-von-willebrand-factor.html

Written by stewart henderson

September 6, 2020 at 1:44 pm

want to live to 100?

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… It may destroy diseases of the imagination, owing to too deep a sensibility, and it may attach the affections to objects, permanent, important, and intimately related to the interests of the human species.

Humphry Davy,  on the value of science, in ‘Discourse introductory to a  course of lectures on chemistry’, 1802

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A great many of us would like to live a long and healthy life, with a greater emphasis on health than length. But both please, if possible, thanks.

I’ve been reading the issues of New Scientist: the collection as they come out. The first issue dealt with the Big Questions, namely Reality, Existence, God, Consciousness, Life, Time, Self, Sleep and Death. Bit of a roller coaster ride, leaving me dizzy, confused, but often enlightened, and sometimes even exhilarated. So, better than a roller coaster. The second issue, entitled The Unknown Universe, took me far out beyond multiverses, quantum loops, energetic dark matter and the eventful horizons of black holes, and essentially taught me that modern cosmology is a mess of competing theories, often competing, it seemed, to be the most egregious ideas that are compatible with mathematical possibility. However, it may be that the studious avoidance of scary maths in these essays/summaries may have made them seem more loopy (or strangulatingly stringy) than they are.

The third issue was more down to earth, and not only earth but me, and you, dear reader. It’s entitled The scientific guide to a better you, and it’s all about longevity, health and success.

So what’s the secret, at least for the first two? Basically, eat healthily, with not too much meat, make sure you have good genes, don’t be too much of a loner (too late for me, I’ve been a loner for 40 years, and that’s unlikely to change, but I’l try, as I always say), be intelligent, active and exploratory. That’s the message of the first half of this issue anyway.

What interested me, though, was the detail. Measurements. Blood sugar, cholesterol, heart rate and many other factors and parameters, most of which I didn’t know I had to be concerned about. The various essays are peppered with these measures of health or lack thereof, but how does your average Jo like me get a measure of these things without pestering doctors on a weekly basis about wellness instead of sickness?

So, for fun, I thought I’d look into these ways of measuring ourselves and see if we can manage them from home. A sort of practical guide to centenarianism and beyond.

1. Body mass index (BMI)

Your BMI is a very rough-and-ready guide to whether or not you’re a healthy weight for your height. Various websites can calculate this for you instantly if you know your height and weight. My current BMI is 26, according to the Heart Foundation, which it regards as ‘overweight’, though very close to the borderline between ‘overweight’ and ‘healthy’. About three years ago my BMI was 29, well into the overweight category, in fact getting close to obese. I decided to eat less, without fasting or ‘going on a diet’, and to try to up my exercise, and over a 2-year period I brought my BMI down from 29 to 23, well into the healthy range. Since then it has crept back up to 26, and I’m struggling to get it back down again. I just need to lose a couple of kilos, and keep them off. The myriad other ways of measuring your health these days might make the old BMI seem outmoded – it doesn’t measure your fat to muscle ratio, for example, or the amount of fat around your heart and other organs – but I find it a useful guide for me, and the cheapest available.

2. Heart rate/blood pressure

Measured in beats per minute, your heart rate naturally varies with exertion, and also with anxiety, stress, illness, drug use and so on. The normal resting heart rate for an adult human ranges from 60 to 100 bpm. You can measure your own heart rate (your pulse) at any time by finding an artery close to the surface. The radial artery on the wrist, the one you see heading in the direction of the thumb, is commonly used due to ease of location, but don’t try it with your thumb which has its own strong pulse. I’ve just located my own wrist pulse and measured it as 62bpm. That’s the first time I’ve ever done it. However, I imagine it would be harder to measure after a bout of HIIT (high intensity interval training), which I sometimes indulge in, or after a moderately strenuous bike-ride. It would be even harder while you’re in the middle of exercise, so that’s where heart rate monitors, including those that can be worn on the wrist, come in handy. A quick google-glance tells me that such wrist devices are selling at $100 to $150. However, caveat emptor, as doubt is being cast on their accuracy. Electrocardiographs (ECGs, or EKGs), which measure the electrical activity of your heart, provide a much more accurate record than heart rate monitors, which are apparently only really effective when you’re at rest. One of the problems is that these optical monitors use light to track your blood, and to get an ‘accurate’ reading, you need to be very still, which sort of defeats the purpose. Reporter Sharon Profis, with the help of cardiologist Jon Saroff of Kaiser Permanente medical center in San Francisco compared various wrist monitor brands with the gold standard EKG measurements, and found them well off-beam especially at over 100 bpm. However, the Garmin Vivofit chest strap monitor, which measures electrical activity, was very accurate. This device can be bought for around $150 in Australia.

3. Cholesterol

Cholesterol’s an essential organic molecule, a sterol, a structural component of our cell membranes. It’s biosynthesised, mainly by our liver cell, often as a precursor to such vital entities as steroid hormones and vitamin D, and researchers have tracked the 37-step process of its synthesis. Cholesterol is transported through the blood within lipoproteins, and that’s where you get HDL (high-density lipoprotein) and LDL (low-density lipoprotein) cholesterol, of which the former is the one that causes problems. Some 32% of Australian adults have high blood cholesterol, the primary cause of atherosclerosis, leading to clogging of major blood vessels. Ways of lowering your LDL levels include not smoking, avoiding transfats, regular moderate exercise, and healthy eating including fruit, veg, grains and pulses and sterol-enriched foods. But of course you know all that. The big question is, can you measure your cholesterol from home? The current answer appears to be no, according to the Harvard Medical School (though I note that their article is 11 years old). The problem is that home testing kits can’t separate the ‘good’ HDL cholesterol from the ‘bad” (LDL). Measuring your overall cholesterol levels might be useful, but the real issue is the proportion that is LDL, not to mention that cholesterol can also be carried by other molecules such as triglycerides.

 4. Blood sugar/glucose

Glucose is a vital source of energy for the body’s cells, and its levels are associated with the hormone insulin, produced by the pancreas. Blood glucose levels naturally vary throughout the day, and having a level regularly above normal is termed hyperglycemia. Hypoglycemia is the term for low levels. Diabetes (technically Diabetes mellitus) is the disease most commonly associated with high blood sugar. General symptoms are frequent urination, hunger pangs and increased thirst.  The mean normal blood sugar level is around 5.5 mM (millimolars). That’s the international standard measure – the Americans measure it differently, which causes the usual confusion. Not surprisingly, considering the global rise in diabetes, blood glucose meters for use at home are readily available, but they’re mostly specially devised for use by diabetics, supervised by healthcare professionals. You can of course buy one and DIY but you must learn to be inured to pricks, and unless you’re at risk, which I’m not, as I don’t have much of a sweet tooth, don’t have particularly high cholesterol, and have never evinced any diabetic symptoms, it’s probably not worth the investment. The essential test associated with ‘pre-diabetes’ or hypoglycaemia is a glucose-tolerance test (GTT).

5. Sequence your genome

According to the Australian government’s National Health and Medical Research Council (NHMRC):

Rapid advances in DNA sequencing technologies now allow an individual’s whole genome to be sequenced. Although this is still relatively expensive, it is likely that in the near future it will become affordable and readily available.

Ah, that other country, the near future. But it is a fact that the price is coming down, from $10 million in 2005 to a mere $1 million in 2007 when James Watson’s genome was sequenced. The going rate in 2012 was under $10,000, and this year (2014) the Garvan Institute of Medical Research in Sydney became one of only three institutes in the world to deliver whole sequenced genomes at under $1000. However, there’s a problem. Your genome will mean nothing to you without expert analysis and interpretation, at a hefty price tag. So what would be the purpose, from a health perspective, of ‘doing your genome’? If you’re already quite healthy, do you want to spend up to $1000 only to find out that you carry a gene which may pre-dispose you to a disease that’s currently non-preventable? Our genome is very complex, so much so that current thinking on the subject, and especially on the introns, the sections that don’t code for proteins, has become more cloudy than ever. We know, or think we know, that the number of introns an organism has is positively correlated with that organism’s complexity, but that’s about all we know for sure, and  considering the enormous complexity of the interaction between genetics and environment, together with our lack of knowledge of the role of so much of our genome (over 98% of which is non-coding DNA), the question of whether it’s worth sequencing at this time is a live one. Of course if the price comes down to $100, or the price of a latte (which will soon be up around that figure) then it’d be well worth it; you would have it there awaiting scientific breakthroughs on all that non-coding stuff.

6. microbiome

If you’ve been paying attention to the world of human health, you’ll know that the microbiome is all the rage at the moment. the term was coined by Joshua Lederburg, who defined it thus, according to Wikipedia:

A microbiome is “the ecological community of commensal, symbiotic, and pathogenic microorganisms that literally share our body space.”

You may well have heard the impressive statistic that you have ten times more bacterial cells (and, most interestingly, archaean cells) growing on or in you than bodily (eukaryotic) cells, though this might become less impressive when you learn that the combined weight of those cells amounts to only a few hundred grams. Still, recent research on the microbiota has turned up some interesting results, especially for health. One finding, which may make it difficult to assess your own microbiome, is that different sets of microbes appear to perform the same function for different people. So you won’t just need to know the genetic content of your microbiome, but its function. Still, we can learn a lot already from our microbiome, according to Catalyst, the ABC science program. For example, we inherit a lot of bacteria from our mothers, via her breast milk, not only directly but because the sugars in breast milk encourage the growth of particular types of bacteria. Most of this gut bacteria does its work in the large intestine or bowel region. They’re anaerobic beasties, so they die when exposed to air. However, recent technological developments (and how often can that story be told) have allowed us to learn far more about them, by sequencing their genes inside the gut. From this we’ve learned that our gut bacteria are vital components of our immune system. And since these bacteria rely on our own diets for their nourishment, the kind of microbiome we have is profoundly related to what we eat. A diverse microbiome results, apparently, from eating a high-fibre diet, and low-fibre processed food, and the ingesting of antibiotics, is reducing that diversity, and contributing to multiple health problems. It appears that a less diverse microbiome finds itself under stress, leading to inflammation, an immune response that can damage our own tissue. As a sufferer from bronchiectasis, a chronic (and incurable) inflammation of the airways due probably to early childhood damage, I’m particularly concerned to limit the extent of inflammation through diet and exercise, so this is probably the aspect of my health I’m most concerned to monitor. And there’s also the relationship between gut bacteria and obesity. Some 62% of Australians are overweight or obese, and I’m one of that majority, and trying not to be.

It has been shown clearly, in mice at least, that a high-fibre diet reduces bronco-constriction, improving resistance to asthma and other airways conditions such as COPD. This is mainly due to the production of short-chain fatty acids by particular bacteria. The short-chain fatty acids are produced though the digestion of dietary fibre. Interestingly, acetate, found in vinegar, is a short-chain fatty acid, and a natural anti-inflammatory, so that’s something I should include regularly in my diet.

Finding out what your particular microbiome is, and how it might align with your health, is a simple if rather unpalatable and ‘intimate’ process. You can apply for a kit from the American Gut Project, an organisation dedicated to researching microbiota. The kit is for obtaining a sample of your ‘biomass’ as they call it, which you then send back to the AGP for analysis. All of this was spelt out in the above-linked Catalyst program, but since that program was aired two months ago, the AGP has been inundated with more biomass than it can deal with, so there’s been a backlog of logs, as it were. I plan to send for a kit anyway. The AGP sends back the results, apparently, with hopefully an analysis of the microbiome easy enough for a layperson to understand.

 

So there’s six areas to look at, either independently or with the help of your GP or other professionals, in terms of measuring how you’re going in terms of overall health, and there are many more aspects of your bodily chemistry and physiology to check up on – hormones, neurotransmitters, bone density, sight, hearing, lung capacity and so forth. Or you can follow the standard advice on diet and exercise, try to avoid stress and hope for the best. And above all don’t stop laughing and dancing, otherwise life would hardly be worth living.

Written by stewart henderson

November 1, 2014 at 6:36 pm