Open UK: Investigating the presence of Micro Clots and other blood factors in people with ME/CFS, Sheffield, Caroline Dalton, Ryback, Hillier

Andy

Andy

Retired committee member
Link to Simon M's blog about the research:
Remarkable researchers hunting for ‘something in the blood’ of people with ME



"In this research we are looking at microclots in the plasma of ME/CFS patients and healthy controls and we will conduct experiments to look at the effect of patient serum on cellular function and metabolism in the lab. This research could identify a diagnostic test for ME/CFS or help us understand the underlying biology of ME/CFS.

We are looking for ME/CFS patients and healthy controls who are over 18, female or were assigned female sex at birth, and able to attend the laboratory in Sheffield between November 28th and December 8th 2023."

https://docs.google.com/forms/d/e/1FAIpQLSdDhTRH43Sy9Qnb2nJcMzby9rPwHgFwMKoJOaVVFNjUwMN7MQ/viewform

Tweet advertising study from Sheffield ME And FM Group
https://twitter.com/user/status/1727284214884978752
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This is very frustrating as I am not that far away, relatively speaking, but it's far enough there's no way I could get there. I worry that these sorts of studies won't include enough of the severe spectrum patients who could quite possibly give the most meaningful results.

Not a criticism of the study, just a general whinge, and I know it's not a new thought! :)
 
@SallyC

I understand your concern, but if I can offer some consolation, I've had all the blood panels done for micro clots, hypercoagulation et over 20 year ago and the head Hematologist in my city is satisfied that this is not an issue for pwME.

There were several of us that had these tests done.
 
Questions/comments after reading pp form

Why is timeframe so restrictive (2 weeks starting 1 week from now)?

How many pwME would they like ideally?

Would they consider home visits for severe pwME?

Could do with an easy map rather than postcode with car parks and entrances marked. PwME need to factor in logistics before even applying.

I guess Sheffields well organised ME group may liaise??

Im a little concerned that this study will select only a very small cohort and be prohibitive for the severer end of spectrum. Also weather and train strikes have potential to interfere and simply put off many.
 
For anyone who's interested, the centre's about as easy to access as these places ever get. It's next to the bus station and opposite the railway station; there's also a tram stop at the back of the station. The latter is a hike on foot (you have to go through or round the station), but it's not too bad for anyone who has access to a powered wheelie or mobility scooter.

They have disabled parking near the door, but the info says it's best to let them know if you want to use it when you book the slot.

It doesn't mention home visits, so I suspect they don't have the resources. The web pages do give a contact email for the study lead, so I guess it'd be possible to ask?

I visit Sheffield quite often, so I'll do the screening questionnaire and see what happens.
 
I am a part of co-producing this research from the position of a patient researcher, so can comment on some things I think are fair enough to share. It's a valid point that the best case scenario we would have a phlebotomist that could visit people in their homes, but as @Kitty suggests we don't have the resources to do that, so any cohort generated here would be mild/moderate in so far as you define this severity class as 'able to leave their home.'

We hope to get at least 30 patients, preferably more. The timescale is short notice which is largely just down to how various logistical things have lined up and not wanting the recruitment to go into the Christmas holiday period. The participant info sheet does contain the address as well as instructions and considerations of how to get there by train and by car. I don't know the site so can't comment on how straightforward navigating it is, but I know what you mean a map would be useful - good consideration for next time.
 
Mij said:
I've had all the blood panels done for micro clots, hypercoagulation et over 20 year ago and the head Hematologist in my city is satisfied that this is not an issue for pwME.
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Perhaps they're right and it won't be an issue for ME/CFS — maybe it's a unique feature of LC — but I think it would be an error to dismiss the potential role of hypercoagulability in LC or ME/CFS.

Leaving aside the fact that microclots (in their newly described amyloid, degradation-resistant form were first reported in 2016) and also leaving aside whether they are simply an ex vivo artefact of hypercoagulability or handling or genuinely in circulation: relying on the knowledge of coagulation we had 20 years ago would be missing a) much new understanding b) the recognition of significant gaps in our knowledge of clotting mechanisms as well as their importance in other systems.

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General
Blood Coagulation and Beyond: Position Paper from the Fourth Maastricht Consensus Conference on Thrombosis (2023, Thrombosis and Haemostasis)

"Theme 2: Novel mechanisms of thrombosis. Mechanisms linking factor XII to fibrin, including their structural and physical properties, contribute to thrombosis, which is also affected by variation in microbiome status. Virus infection-associated coagulopathies perturb the hemostatic balance resulting in thrombosis and/or bleeding."

Mechanisms of ADAMTS13 regulation (2022, Journal of Thrombosis and Haemostasis)

"we currently do not understand the mechanisms that regulate ADAMTS13 activity in vivo. ADAMTS13 evades canonical means of protease regulation because it is secreted as an active enzyme and has a long half‐life in circulation, suggesting that it is not inhibited by natural protease inhibitors."

Tale of two systems: the intertwining duality of fibrinolysis and lipoprotein metabolism (2023, Journal of Thrombosis and Haemostasis)

"Accumulated evidence indicates the close relationship between the 2 seemingly distinct and complicated systems—fibrinolysis and lipoprotein metabolism."

Cancer
The unfolded protein response links ER stress to cancer-associated thrombosis (2023, JCI Insight)

Neuro
Fibrinogen in neurological diseases: mechanisms, imaging and therapeutics (2018, Nature Reviews Neuroscience)

"The cellular and molecular mechanisms underlying the actions of fibrinogen are beginning to be elucidated, providing insight into its involvement in neurological diseases, such as multiple sclerosis, Alzheimer disease and traumatic CNS injury."

Cardiac
Coronary “Microvascular Dysfunction”: Evolving Understanding of Pathophysiology, Clinical Implications, and Potential Therapeutics (2023, International Journal of Molecular Sciences)

"Dysfunction [...] predisposes both to coronary vasoconstriction and to a propensity for microthrombus formation."

Acute Covid

COVID-19 promotes endothelial dysfunction and thrombogenicity: Role of pro-inflammatory cytokines/SGLT2 pro-oxidant pathway (2023, Journal of Thrombosis and Haemostasis)

Sustained VWF-ADAMTS-13 axis imbalance and endotheliopathy in long COVID syndrome is related to immune dysfunction (2022, Journal of Thrombosis and Haemostasis)

GWAS and meta-analysis identifies 49 genetic variants underlying critical COVID-19 (2023, Nature)

Altered fibrin clot structure and dysregulated fibrinolysis contribute to thrombosis risk in severe COVID-19 (2022, Blood Advances)

A macrophage attack culminating in microthromboses characterizes COVID 19 pneumonia (2021, Immunity, Inflammation and Disease)

Post-acute Covid

Transcriptional reprogramming from innate immune functions to a pro-thrombotic signature by monocytes in COVID-19 (2022, Nature Communications)

Analysis of thrombogenicity under flow reveals new insights into the prothrombotic state of patients with post-COVID syndrome (2022, Journal of Thrombosis and Haemostasis)

Acute blood biomarker profiles predict cognitive deficits 6 and 12 months after COVID-19 hospitalization (2023, Nature Medicine)

Prolonged platelet hyperactivity after COVID-19 infection (2023, British Journal of Haematology)
 
Previous work by our group has explored whether microclots are seen in blood samples from people with Long COVID.
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Has that been published yet? The only thing I recall is the YouTube discussion of the pilot study discussed here. She said they had collected more samples since.

Aim 1 - Replicate the assay to measure microclots in blood samples from people with ME/CFS. We aim to repeat the previous findings in Long COVID in samples from people with ME/CFS and healthy control participants. We will stain the plasma for microclots using a dye and image the plasma samples to analyse the size and number of microclots.
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Aim 2 – Should clots be observed in aim 1 we will conduct untargeted mass spectrometry proteomic analysis of the insoluble clots to identify the primary protein components and sequestered molecules. This will follow standard protocols for amyloid material. Identification of protein in the clots will be hypothesis generating and used to guide the design of a full future study.
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Aims 1 and 2 sound like replication of the Pretorius technique, but perhaps some different handling protocols or analysis may be employed.

Aim 3 – We will investigate how exposure of cells to other factors in blood samples from people with ME/CFS affect cellular metabolism or other functions. We will measure the effect of ME/CFS or healthy control serum on cells using a mitochondrial stress test and microscopy-based methods. We may also study biomolecules with diagnostic potential or that can help us understand the biological basis of ME/CFS. This part of the study is a collaboration between the University of Edinburgh and Sheffield Hallam University and the work will be carried out by Audrey Ryback, under supervision of Chris Ponting and funded by Action for ME.
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Aim 3 looks particularly interesting, thanks @audrey_ryback and Chris P. No pressure, but please do let us know what's-in-the-blood™ and what it's doing :)
 
SNT Gatchaman said:
Perhaps they're right and it won't be an issue for ME/CFS — maybe it's a unique feature of LC — but I think it would be an error to dismiss the potential role of hypercoagulability in LC or ME/CFS.
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I'm not disagreeing with testing pwME for hypercoagulation so that it can be ruled out or investigated further for some patients who might have a genetic predisposition. The hypothesis at the time of my sampling was there was a pathogen that was activating the coagulation system so in this case it could be relevant for pwLC. Not sure about M.E since the viral theory has been recycled over and over for decades.
 
It's great to hear that they're doing studies like this. In case it's of any help to the team for future studies, @chillier, the sort of thing I'd need to know if I weren't local or didn't have access to a powered wheelchair are:
  • Which building is it, and how far is the entrance from the nearest vehice access?

  • Are there any steps or long slopes to approach the building once you've left the car/taxi/etc? How many steps, how long a slope?

  • Is there a door entry system where you have to wait to be let in? If so, is there anywhere to sit next to the door?

  • If you can just walk in, what happens then? Might you have to wait behind another couple of visitors for a receptionist to tell you where to go? If so, is there anywhere to sit where you could still signal to them that you're waiting to be signed in? (So often this is one of the most stressful parts of a visit. Even access officers don't always think it through, because they can't imagine being OK to walk a few metres into the building but not being able to cope with standing at a counter for half a minute.)

  • Once you're checked in, how many metres are there between the door to the street and the clinic? Are there places you could stop for a sit down if you needed to? (Maintenance teams sometimes already have the inexpensive laser devices that make measuring this easy, and may even do it for you if you lack scruples about bribes.)

  • Are there any other places where you might have to stand and wait, such as busy lifts or subsidiary reception desks?

  • Is there an accessible toilet that's big enough to turn a wheelchair around in? (Not a given!)

  • If the schedule got held up, is there anywhere to wait that's not a noisy thoroughfare?
That's only one person's experience of visiting many buildings like this in the course of my former job—there will be different things that other people struggle with. It assumes the buildings have wheelchair access, but I think this campus does.
 
I would be interested to know who will be interpreting these test results. Anyone know?

My experience is that these test results can be interpreted in different ways. Will there be second opinions involved? Will there be additional testing based on results?
 
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Microclots not the only focus

From the patient participation form there are 3 aims, the first 2 relate to microclots.

Aim 3 – We will investigate how exposure of cells to other factors in blood samples from people with ME/CFS affect cellular metabolism or other functions. We will measure the effect of ME/CFS or healthy control serum on cells using a mitochondrial stress test and microscopy- based methods. We may also study biomolecules with diagnostic potential or that can help us understand the biological basis of ME/CFS. This part of the study is a collaboration between the University of Edinburgh and Sheffield Hallam University and the work will be carried out by Audrey Ryback, under supervision of Chris Ponting and funded by Action for ME.
 
It would be interesting to know how recruitment is going in say a week. Perhaps a Facebook post could be boosted for adult women in a small radius centred on Sheffield i.e. a Facebook ad. It’s a pity the timescale is so tight.
 
I've applied for the study and been invited to give a sample. I've got a date booked for this week, have sent in the info needed to book disabled parking, and received information on how to get there.

So I've now just got get there without employing my superpower for getting lost, which works amazingly well even in areas I've known all my life. :rolleyes:
 
Sheffield ME & Fibromyalgia Group

https://www.facebook.com/SheffieldM...wcFpdZJLXJzcaNsjGzNxY94A5eGK21VLNWVKqZCHJLVPl
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UPDATE: The study organisers have been in touch to let us know that they now have enough participants for the study. And to pass on their thanks to everyone who has expressed an interest.

They are working their way through the application forms.

We fed back some of the comments about the design of the study, i.e. that it is females only and in-person blood donations.

Dr Dalton said that this is a pilot study, to see if they see an effect, and it has limited funding. If they do then they can apply for more funding and in this case, they would definitely want to expand from just in-person blood donations. On the question of why the study is only looking at females, she said, “There may be biological differences between men and women, which might obscure seeing differences that are present between ME and healthy groups. By restricting it to just one biological sex our study design is simpler and hopefully, we'll have a better chance of finding a significant result - which would be best for ME research for both men and women. In future studies, we may include male ME patients or recruit male ME patients specifically.”

https://twitter.com/user/status/1729700512751026613
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I gave my samples today. It was very straightforward, and I was only in the building for about 15 minutes.

I could have stayed and rested if I'd wanted to, but as I was visiting a relative afterwards I left as soon as they'd taken the bloods.

Good luck to the team with the study, it's great to hear they've got their numbers.
 
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