Cardiovascular and haematological pathology in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): A role for viruses, 2023, Nunes, Pretorius

Cardiovascular and haematological pathology in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): A role for viruses
Nunes, Kell, Pretorius

ME/CFS is a debilitating chronic condition that often develops after viral or bacterial infection. Insight from the study of Long COVID/Post Acute Sequelae of COVID-19 (PASC), the post-viral syndrome associated with SARS-CoV-2 infection, might prove to be useful for understanding pathophysiological mechanisms of ME/CFS. Disease presentation is similar between the two conditions, and a subset of Long COVID patients meet the diagnostic criteria for ME/CFS.

Since Long COVID is characterized by significant vascular pathology – including endothelial dysfunction, coagulopathy, and vascular dysregulation – the question of whether or not the same biological abnormalities are of significance in ME/CFS arises. Cardiac abnormalities have for a while now been documented in ME/CFS cohorts, with recent studies demonstrating major deficits in cerebral blood flow, and hence vascular dysregulation. A growing body of research is demonstrating that ME/CFS is accompanied by platelet hyperactivation, anomalous clotting, a procoagulant phenotype, and endothelial dysfunction.

Endothelial damage and dysregulated clotting can impair substance exchange between blood and tissues, and result in hypoperfusion, which may contribute to the manifestation of certain ME/CFS symptoms.

Here we review the ME/CFS literature to summarize cardiovascular and haematological findings documented in patients with the condition, and, in this context, briefly discuss the potential role of previously-implicated pathogens. Overall, cardiac and haematological abnormalities are present within ME/CFS cohorts. While atherosclerotic heart disease is not significantly associated with ME/CFS, suboptimal cardiovascular function defined by reduced cardiac output, impaired cerebral blood flow, and vascular dysregulation are, and these abnormalities do not appear to be influenced by deconditioning. Rather, these cardiac abnormalities may result from dysfunction in the (autonomic) nervous system.

Plenty of recently published studies are demonstrating significant platelet hyperactivity and endothelial dysfunction in ME/CFS, as well as anomalous clotting processes. It is of particular importance to determine to what extent these cardiovascular and haematological abnormalities contribute to symptom severity, and if these two systems can be targeted for therapeutic purposes. Viral reservoirs of herpesviruses exist in ME/CFS, and most likely contribute to cardiovascular and haematological dysfunction directly or indirectly. This review highlights the potential of studying cardiac functioning, the vasculature, and coagulation system in ME/CFS.

Link | PDF (Blood Reviews)

 

https://twitter.com/user/status/1638964053996367876

 

Over 20 years ago, Berg and colleagues reported hypercoagulability and platelet hyperactivation in an ME/CFS cohort, and alluded to the idea that small (anomalous) fibrin aggregates adhere to the endothelium and impair the exchange of substances between the blood and tissue, subsequently giving rise to symptoms [170]. The latter – in light of our findings [42] – can now be interpreted as fibrinaloids. Fibrin(gen) binds to several endothelial receptors and hence can modulate their activity [[205], [206], [207]] – it is of interest to determine the mechanistic differences between normal fibrin and fibrinaloids/amyloid fibrinogen in an endothelial context. Amyloid-type molecules have a tendency to damage lipid membranes [208] and might account for lipid peroxidation [104] and endothelial dysfunction [24,166,209] observed in ME/CFS. Furthermore, fibrinaloids are proinflammatory and persist more than normal fibrin matter due to their fibrinolytic resistance [192,197]. These are characteristics that can exaggerate any pathological impact on the endothelium. It is known that ME/CFS plasma induces endothelial dysfunction in healthy cells [209,210] – further analysis is required to determine if fibrinaloids are largely responsible for this phenomenon.

They are still circulating this disinformation. No one in my group of several pwME tested positive for hypercoagulation.


It is plausible to hypothesize that viruses (and potentially other microbes) are contributing to the clotting pathology observed in ME/CFS individuals [42,43,[170], [171], [172]]. Herpes viruses, the virus types most implicated in ME/CFS, are known to influence coagulation in a prothrombotic manner [[308], [309], [310]]. EBV infection has been associated with disseminated intravascular coagulation [311,312], and cytomegalovirus can induce hypercoagulation [[313], [314], [315], [316], [317]]. These two herpes viruses also interact with platelets via a number of platelet receptors, including toll-like receptors and complement receptors [[318], [319], [320], [321]]. Hence, there is reason to hypothesize that herpes viruses are responsible, to a certain extent, for clotting dysfunction observed in ME/CFS individuals.

I had my blood drawn for hypercoagulation testing by Bergs Lab during the time period that I had both HHV6+ and EBV+ reactivation from taking immune modulators.
Yes I had difficulty walking, I was breathless, my legs felt frozen stiff, but my tests came back normal. I was not in a hypercoagulative state.

I did develop OI afterwards.

 

Honest question.

Did the pwME who tested positive for hypercoagulation, platelet activation, coagulation cascade stimulation improve or recover from taking LMWH? Are they on social media making such claims? Where are they?

 

Another honest question - How often do PwME (and those with Long COVID) have strokes vs the rest of the population? Wouldn't hypercoagulation increase the risk of strokes and wouldn't PwME/PwLC be more likely to have strokes? Is that documented in reputable studies/articles about ME?

 

As I mentioned in another thread on this topic, I had a massive bilateral unproved PE in 2006--four years after I was diagnosed with ME/CFS. But in the 17 years since, I've not heard of anybody else who has had even DVT despite being hyper attuned to this topic and spending 20 years on various patient fora going back to the Usenet era.

I can't remember the details but it seems like maybe Vance Spence's group tried--and failed--to replicate Berg's study in, like, 2007?

Ah yes, here we are. It was 2006.

Is chronic fatigue syndrome associated with platelet activation?
Gwen Kennedy 1 , Gillian Norris, Vance Spence, Margaret McLaren, Jill J F Belch
Affiliations

• PMID: 16479189
• DOI: 10.1097/01.mbc.0000214705.80997.73

Abstract
Chronic fatigue syndrome (CFS) is a debilitating condition that has no known aetiology or pathophysiology. Recent investigations by other workers have suggested that individuals with CFS may have a hypercoagulable state. This study investigated various aspects of platelet activation and function in 17 patients with CFS and in 16 age-matched and sex-matched healthy controls. Platelet aggregation, platelet volume and coagulation tests were performed. Platelet aggregation was investigated by means of the photometric changes using citrated platelet-rich plasma, whole blood aggregation was calculated as the percentage fall in single platelet counts and the coagulation tests were performed on an automatic microcentrifugal analyser.A trend was observed for the patients to have lower aggregation results and a reduced mean platelet volume. However, this only reached statistical significance for one result; the rate of the aggregation slope by 1.0 microg/ml collagen [CFS patients, 18 (9-28) versus controls, 32.5 (19-36); Mann-Whitney U test, P = 0.029]. No significant differences were found for any of the measurements of coagulation. These results are in contrast to previously reported findings. However, due to the heterogeneous nature of the disease, and the resulting lifestyles of the patients, caution should be taken when comparing one group of patients with another. Nevertheless, we certainly found no evidence of increased platelet activation or of a hypercoagulable state in patients with CFS and, on the basis of these results, anti-platelet or anti-coagulant therapy is not warranted.

 

The review is a lot wider than microclots and I think it reads quite well as an overview of what we do and don't know and the various mechanisms under investigation. They divide the discussion into cardiovascular (heart, vessels, endothelium) and haematological (blood cells and proteins) and then review the role of herpes- and other viruses in these and related systems.

As a literature review I think this paper is pretty comprehensive and good - I certainly would not characterise it as disinformation. Their microclot/amyloid clotting hypothesis suggests a type of prothrombotic state that doesn't inevitably lead to overt venous or arterial thromboembolism, but instead tends to impair microcirculation function and endothelial function more generally in large and small vessels, promoting ongoing inflammation. If borne out, that would represent a new understanding of coagulation, one where the system is in a pathological state but that the established tests do not reveal the abnormality. They do recognise that their measures of platelet hyperactivation and microclot formation in ME are not as abnormal as LC.

 

I think this paper IS disinformation.
The whole tone is much too presumptive that we know something is going on when the reality is that a few groups have reported non-replicated findings.

I see no difference between this and telling people they have craniocervical instability or EDS or mitochondrial malfunction or retroviruses or mast cell disorders or false illness beliefs.

The level of discussion on this forum is many levels higher than in this sort of publication. Why give credence to a poorly balanced review when we have already been through the relevant findings?

 

This review is about as good as the current state of the field. Meaning there are only open questions, pieces of puzzles, and no answers. Not even a guiding path yet.

This is what it looks like when there are only questions and no answers. It's a good overview of the map of the field. This is what a neglected field looks like when it's devoid of resources and is subject to malicious disinformation and a tradition of sabotage.

Most of the thinking aligns with other overall reviews. But multisystemic issues are basically unmapped frontier in medicine, so only questions, no answers. There is no one working on this stuff at this level because everything is done through filtered tunnel vision in isolated siloes where no one collaborates other than through the patient-funded efforts.

A lot is cornering in on the vascular system, whether in the blood, or the piping and neurological machinery. The role of pathogens is indisputable, but it is disputed for traditional reasons, so the whole thing is stuck because the germ theory of disease is such a Debbie downer.

What this is missing is data. Reliable, accurate data. We don't have any of that. On purpose. Can't do good science without good data. We are fully denied the right to have good data. So we are stuck until we can bypass this rotten system and do the whole damn thing ourselves.

 

ME seems to affect immune system function. Could that allow viruses to attack the body more effectively, resulting in some of the observed (yet still unverified) links to viral effects? If so, treating the viral effects won't fix the core dysfunction of ME ... unless it's part of the feedback loop sustaining the ME state.