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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