+100%-

Talk about being pioneering. Resa Pretorius and Douglas Kell have basically carved out a new field – microclots – for themselves. Their findings have gotten a lot of attention in long COVID, but Pretorius, in particular, has been finding microclots in all sorts of diseases for a decade. The fact that different kinds of microclots, as well as damaged platelets, blood vessel issues, and iron dysregulation have shown up in a wide variety of diseases (lupus, diabetes, rheumatoid arthritis, Alzheimer’s, Parkinson’s disease), makes one wonder if they could have stumbled on an important factor in chronic illnesses in general.

blood clots long COVID

Check out the rounded symmetric nature of a normal blood clot. The one’s Pretorius and Kell are finding look like a bunch of spaghetti.

This all came about after she found what Kell vividly called, “horrible, gunky, dark” fibrin microclots at the bottom of her proteomic samples and decided to investigate. (Proteomic studies are regularly done. Did nobody else notice these?) Pretorius believes the strange shapes of these microclots are impeding their breakdown. Some, they report, are big enough to block the small capillaries feeding our tissues and result in a “defect in oxygen transfer at a capillary level”.

Kell proposed at the Oxford ME Conference that microclots are producing ischemic (low oxygen or hypoxic) events which turn really nasty when the blood flow returns. The sudden combination of oxygen-rich blood flowing into a hypoxic environment produces enormous amounts of free radicals and lots of localized damage (“reperfusion injury”). The antibodies they’ve found trapped in the microclots may signal that an autoimmune reaction to the strangely shaped “fibrinaloids” has taken place.

Why these microclots might be forming is not clear, but the potentially really good news is that because the body will slowly remove the microclots, if they can stop them from forming in the first place, normal blood flows should eventually resume and healing will take place.

The Coagulation Controversy in Long COVID and ME/CFS

The coagulation issue in COVID-19, though, has been nothing if not puzzling. Since the spike protein of the coronavirus induces clotting, it seemed a given that anticoagulants would help, but large-scale studies found them mostly to be a bust. Kell and Pretorius believe, though, the treatments didn’t go far enough. Since multiple problems exist (microclots, platelet activation, inflammation), they believe a multipronged treatment is needed to make a difference, and that’s what they’ve been doing in long COVID.

They’re not the only ones to propose that blood vessel problems lie at the heart of COVID-19 and/or long COVID. A recent review, “Endothelial dysfunction in COVID-19: an overview of the evidence, biomarkers, mechanisms, and potential therapies“, called the blood vessels, or endothelium, “the Achilles heel” for COVID-19 patients. COVID-19, the authors asserted, was a “microvascular and endothelial disease”, and included mitochondrial dysfunction in the long list of pathologies they believed blood vessel problems were causing.

Bruce Patterson puts the blood vessel injury first and foremost in his hypothesis, and his protocol is designed to protect them. Blood vessel problems are also central to Wirth and Scheibenbogen’s ME/CFS hypothesis. They’re the only ones I know of, thus far, that have linked the strange (and strangely disregarded) ACE2 and angiotensin findings in ME/CFS and POTS to blood vessel issues. Since the coronavirus enters into cells through the ACE2 receptor, one wonders if ACE2 receptor damage could provide a potentially important link between COVID-19, long COVID, ME/CFS, and POTS.

Two Treatment Trials

In an earlier paper (a preprint in Dec 2021, full paper Aug. 2022), Pretorius and Kell described the results of their multi-pronged attack on the clotting and blood vessel issues in long COVID. The authors warned that this approach, “must only be followed under strict and qualified medical guidance to obviate any dangers, especially hemorrhagic bleeding, and of the therapy as a whole.”

They reported, though, that the 24 participants in the trial resolved their shortness of breath, brain fog, concentration, and forgetfulness, and their fatigue was relieved over the 3-4 week trial. They also lowered their microclot scores by almost two full units (7.1 → 5.2) leaving them at near-normal levels.

Seven months later, they are back with another preprint and a bigger study, “Treatment of Long COVID symptoms with triple anticoagulant therapy“, that included 91 long-COVID patients.

As before, their triple therapy included Dual Antiplatelet Therapy (DAPT) (Clopidogrel 75 mg/aspirin 75 mg) once a day, plus direct oral anticoagulant (DOAC) (Apixiban) 5 mg twice a day, and a proton pump inhibitor (PPI) (e.g., pantoprazole 40 mg/day for gastric protection) was used over 3-4 weeks.

  • Apixiban reduces coagulation.
  • Clopidogrel and aspirin prevent platelet activation (aspirin by targeting the COX-1 receptor, and clopidogrel the P2Y receptor on platelets).

They divided patients up into ‘short’ long COVID (<6 months of persistent symptoms) and ‘long’ long COVID  (<6 months of persistent symptoms). They had the patients fill out a “Patient Global Impression of Change” (PGIC) scale after treatment and a checklist of symptoms before and after treatment.

Patients with ‘short’ long COVID (symptoms less than 6 months) usually needed treatment for 2–4 months, while those with ‘long’ long COVID (symptoms more than 6 months), needed 4–6 months (or longer) of treatment.

Treatment Response

If an ultimate proof of a hypothesis is a successful treatment, their hypothesis is looking pretty good. We should note, though, that this 91-patient clinical trial was not placebo-controlled or randomized – two crucial factors that will need to be included in future trials – and included rather rudimentary symptom assessment scores.

Symptom improvement

Nice symptom improvement!

Still, some of the results were striking, with the authors reporting core symptoms like fatigue, cognitive dysfunction, muscle, and joint pain, shortness of breath, sleep problems, etc. clearing up in many patients.

When it came to overall effectiveness, the results continued to be positive. When patients were asked, “Since beginning treatment at the clinic, how would you describe the change (if any) in activity limitations, symptoms, emotions, and overall quality of life?”, their median score was 6: “Better, and a definite improvement that has made a real and worthwhile difference”.

If you took all the different responses and looked at the one in the very middle of the pack, that’s the median. This result means that as many people reported they were either:

  • “better” and received “a definite improvement that has made a real and worthwhile difference”; or
  • were a “great deal better” and received “a considerable improvement that has made all the difference”
Improvement meant having no symptoms.

Improvement meant having no symptoms.

as the number of people who reported they received lesser improvements (moderately better, somewhat better, etc.).

It’s hard to interpret this, though, as we don’t know how many people chose 6. If the most common response was 6 – and most people were from 5-7, these results would be impressive indeed. The fact that the median score was the second highest possible suggested that the responses were clustered around the upper end of the benefit scale.

The Gist

  • Resia Pretorius Ph.d. has been calling attention to the dark, misshapen, gunky microclots and related problems (damaged platelets, blood vessel issues, and iron dysregulation) she’s been finding in chronic diseases for years. These clots are apparently hard for the body to break down and may be impeding blood flows to the issues. 
  • Over the past couple of years, though, with at least six papers under their belts, she and Douglas Kell have been publishing furiously on their findings in long COVID. Last year they published the results of a small clinical trial using their multipronged approach. Eight months or so later they’re back with more results from more patients (91). 
  • As before, their triple therapy included Dual Antiplatelet Therapy (DAPT) (Clopidogrel 75 mg/aspirin 75 mg) once a day, plus direct oral anticoagulant (DOAC) (Apixiban) 5 mg twice a day, and a proton pump inhibitor (PPI) (e.g., pantoprazole 40 mg/day for gastric protection) was used over 3-4 weeks.
  • The symptom assessments seemed pretty rudimentary but the results were good. Symptoms such as fatigue, sleep, and cognitive problems reportedly resolved in many patients and when asked about their “global health” approximately 50% of the participants stated that they were at the very least “better” and had received “a definite improvement that has made a real and worthwhile difference”;
  • The authors warned that this protocol should only be taken under the close guidance of a medical professional. Side effects were mostly minimal, however. Out of 91 participants, 75 reported bruising, 5 reported minor nosebleeds, 2 increased menstrual bleeding, and one person had a gastrointestinal bleed that required hospitalization and a 2-unit blood transfusion. The authors believed that the “relatively low bleeding risk” was due to the fact a hypercoagulable state was present that needed to be addressed.
  • Apparently, because it took longer to treat the longer-duration patients, the authors also warned that delaying these treatments might “prolong the duration of pharmacotherapy and also increase the likelihood of permanent hypoxic tissue damage”. (Ouch!).
  • They strongly urged that large, randomized, double-blind, placebo-controlled trials with objective endpoints be done as quickly as possible.
  • The potentially good news is that the body will slowly remove the microclots. That means that if they can stop them from forming in the first place, normal blood flows should eventually resume and healing should take place.
  • They also proposed that when long-COVID or ME/CFS patients rest, they build up “a cellular ‘reservoir’” that helps them feel better. When they exert themselves, that oxygen reservoir becomes depleted – leading to a “crash”.
  • They also proposed that the autonomic nervous system issues in these diseases are caused by damage to the blood vessels. 
  • Their treatment approach has yet to be tested in ME/CFS, fibromyalgia, or postural orthostatic intolerance syndrome (POTS). All three diseases, however, show evidence of clotting, platelet activation, and/or blood vessel issues. 
  • A large placebo-controlled, randomized trial is clearly the next step 
With regard to side effects, out of 91 participants, 75 reported bruising, 5 reported minor nosebleeds, 2 increased menstrual bleeding, and one person had a gastrointestinal bleed that required hospitalization and a 2-unit blood transfusion. The authors stated that they believed that the “relatively low bleeding risk” was due to the fact a hypercoagulable state was present that needed to be addressed.

Apparently, because it took longer to treat the longer-duration patients, the authors also warned that delaying these treatments might “prolong the duration of pharmacotherapy and also increase the likelihood of permanent hypoxic tissue damage”. (Ouch!).

They strongly urged that large, randomized, double-blind, placebo-controlled trials with objective endpoints be done as quickly as possible.

New Ideas

They also proposed that when long-COVID or ME/CFS patients rest, they build up “a cellular ‘reservoir’” that helps them feel better. When they exert themselves, that oxygen reservoir becomes depleted – leading to a “crash”.

They also proposed that autonomic nervous system (ANS) problems result – not from a dysfunctional ANS system (at least initially) – but from blood vessel damage. They believe that damage to the blood vessels prevents them (or rather the smooth muscles lining them) from getting the signal to constrict them and send more blood to the muscles during exercise, or the brain during mental exertion. Unable to constrict the blood vessels enough, the body goes to its next best option – increase the heart rate to get the blood flowing more.

Next?

Pretorius and Kell have certainly done everything they can to open the door. Now the question is whether others are going to step through it and get these trials done. The elephant in the room, of course, is the RECOVER Initiative, which reportedly has allocated $172 million to clinical trials (!?). Thus far, it’s announced just one trial (Paxlovid) and is apparently working on a high-intensity exercise trial.

The sheer scale of the Phase III Paxlovid trial (1,700 people), though, demonstrates what a different world we’re in with the RECOVER Initiative. These kinds of trials should give us definitive results – something we’ve never gotten in ME/CFS. (By far, the biggest clinical trial in ME/CFS – the woeful PACE trial – included 641 patients and was littered with methodological problems).

There is a cost to them, though. With the median cost of a Phase III trial at $19 million, RECOVER may be committing around 10% of its entire clinical trials budget to this one huge trial.

The Paxlovid trial was announced at the end of October of last year and was expected to start recruiting at the end of January, but according to clinicaltrials.gov, it’s still not recruiting (?). Apparently, RECOVER has still not decided which other trials it will fund.

Evidence Building for Coagulation and Platelet Activation in ME/CFS, FM and Dysautonomia

This approach has yet to be tested in ME/CFS or fibromyalgia. Early studies did suggest that hypercoagulation was present in ME/CFS, but that effort faded. One study suggested that clotting problems are present in fibromyalgia. Other studies indicate that standing can produce hypercoagulation in people with orthostatic intolerance but not healthy controls. One review even concluded that “abnormal coagulation is an important component of orthostatic intolerance”. Then, just last year, an “unbiased” proteomic study zeroed in on proteins involved in clotting and platelet activation in postural orthostatic tachycardia syndrome (POTS).

In their large overview, “The potential role of ischaemia–reperfusion injury in chronic, relapsing diseases such as rheumatoid arthritis, Long COVID, and ME/CFS: evidence, mechanisms, and therapeutic implications“, Pretorius and Kell noted that many treatment possibilities exist – most of which have been tried in these diseases.

Ischemia-Reperfusion Hypothesis Opens New Treatment Options for Long COVID, Fibromyalgia and ME/CFS

Nothing like the comprehensive protocols Pretorius is using have been tried in ME/CFS, FM or POTS. Thus far, two studies from Pretorius’s group suggest that microclots are present in lower levels than in long COVID but are still quite present. One study reported:

“ME/CFS samples showed significant hypercoagulability as judged by thromboelastography of both whole blood and platelet-poor plasma. The area of plasma images containing fibrinaloid microclots was commonly more than 10-fold greater in untreated PPP from individuals with ME/CFS than in that of healthy controls.”

And

“We conclude that ME/CFS is accompanied by substantial and measurable changes in coagulability, platelet hyperactivation, and fibrinaloid microclot formation. The discovery of these biomarkers represents an important development in ME/CFS research. It also points to possible uses for treatment strategies using known drugs and/or nutraceuticals that target systemic vascular pathology and endothelial inflammation.”

The Pretorius saga continues. Pretorius, Kell, and Nunes just published a paper on clotting and cardiovascular issues in ME/CFS. A blog on that is coming up.

Update!the ECHO program will produce a webinar on microclots in long COVID on April 12th.

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