Bye-Bye “Microclots”: Hello Microclot Complexes
Dr. Pretorius has identified 4 different kinds of microclots in long COVID – setting the stage for precision blood clot therapies.
Resia Pretorius demonstrated just how rapidly the long COVID field has moved with her presentation on blood clots. First came the microclots, but in what seems like a giant leap forward, Pretorius and her team now believe they’ve identified 4 distinct microclot complexes (cell-debris–seeded complexes, NET-containing immune complexes, misfolded fibrinogen, and amyloidogenic aggregates on intact cells) in long COVID and ME/CFS.
Interestingly, post-vaccination syndrome microclots differ from Long COVID microclots. Plus the microclots in people with pre-COVID POTS, Long COVID, and Long COVID POTS appear similar but differ in their chemistry. So now we have microclot subsets!
The most fascinating part of her presentation, though, focused on the idea that one problem – called a phosphatidylserine “flip” – is producing all the different microclot issues. Phosphatidylserine (PS) “flips” when it moves from the inner side of the cell membrane to the outer side of the cell. Once there, it triggers clot formation.
Health Rising’s Quickie Summer Donation Drive is On!When endothelial cells, red blood cells, tissues, etc., are injured, they release extracellular vesicles, apoptotic bodies, membrane fragments, mitochondria-containing debris, or cellular remnants loaded with PS. Depending on what kind of cell/cellular fragment is present, different kinds of microclots are found.
These suggest that targeting the phosphatidylserine “flip” could eliminate the microclot problem entirely. It’s entirely possible, though, that things happening “upstream” of the flip (persistent antigen, platelet hyperreactivity, endothelial injury, complement activation, autoantibodies, hypoxia, oxidative stress, mast-cell activation, impaired fibrinolysis) – are causing the flip and should be addressed first.
The GIST
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The Chime ME/CFS study will be looking deep in the gut tissues for evidence of enteroviruses.
- The second blog on PolyBio’s 2026 Spring Symposium starts off with a very promising finding: Resia Pretorius has found four different kind of microclots in long COVID – each of which would respond to a different kind of treatment. This is precision medicine for microclots!
- This fits nicely with another finding that “netosis” – a process by which neutrophils blow themselves up and produce “nets” that trap clots and cellular debris is occurring in long COVID. These nets can damage the blood vessels, and, in fact, blood vessel damage was worse in LC patients with higher NET levels.
- The presenters’ hypothesis that the coronavirus or remnants of it were constantly leaking into the gut or the blood vessels mirrored the finding from another study. That study found that healing the gut and preventing it from leaking reduced coronavirus levels in the blood and improved symptoms.
- The idea that the coronavirus, or another virus such as EBV, simply needs to be bottled up better is intriguing.
- Looking back at a cerebrospinal presentation covered in the last blog, I asked how an infection could cause such dramatic damage as seen in craniocervical instability (CCI). When CCI occurs, the skull slams down on the brainstem, causing damage.
- The body, though, has all sorts of ways to prevent this from happening. For one, the brain floats on a cushion of cerebrospinal fluid. It is also protected by thick membranes and is held in place by ligaments and muscles.
- One interesting possibility comes back to blood flow. Because cerebrospinal fluid cushions the skull, the virus could affect it by compromising the blood-brain barrier, damaging blood vessels, and dysregulating the pressure/flow systems that regulate CSF. Time will tell, but it’s yet another way that compromised blood flows may be impacting these diseases.
- There’s a lot of excitement about the role that chronically activated and exhaustged T-cells may be playing in ME/CFS. A ton of work on them is being done in long COVID as well.
- T-cells are amongst the most important immune cells we have. One of the two big players in the adaptive, or later, immune response, they’re responsible for eliminating cells that pathogens have infected. Once they’ve identified the pathogen, they produce massive numbers of specifically targeted clones that then destroy those cells and clean the pathogen from the body.
- There is so much interest in T-cells in general that it’s almost impossible to keep up with the number of T-cell drugs available. That suggests that if a specific T-cell problem is shown to play a major role in these diseases, a treatment may very well be available.
- Two presentations found that the T-cells in long COVID had been activated by three pathogens: the coronavirus, Epstein-Barr virus, and cytomegalovirus. Interestingly, the activation appeared to increase over time.
- This finding suggests several treatment options may be helpful: antivirals to remove the viruses, immune modulators to calm the T-cells, and/or to strengthen them.
- A pilot trial of the Furium microtesla device resulted in improvements in several aspects of cognition (including attention) and emotional well-being. These devices use very small magnetic pulses to strengthen the mitochondria. This device was used to reduce neuroinflammation.
- The device is not yet available in the U.S., but David Putrino, the leader of the study, was jazzed enough about the results to launch a major trial that he hopes will lead to FDA approval.
- Finally, the might UCSF LIINC long COVID project is now studying ME/CFS as well! Besides employing whole-body scanning of T-cells (there they are again) and metagenomics, the project will dig deep into gut tissues to see whether enteroviruses, as Dr. Chia has proposed, are present in ME/CFS. This project is led by researchers who are highly skilled in detecting pathogens in the tissue.
- After many years of promoting the idea that enteroviruses are involved in ME/CFS, Dr. Chia will finally get his due.
Health Rising’s Donation Drive Update
We’re getting down to tissues, specific T-cell sets, specific pathogens….The research seems to be getting more precise – and that’s good news.
Thanks to everyone who has contributed. This is the last blog of the drive, and we are getting very close. We had a bit of a mix-up because the donation tracker was inaccurate, but it is now accurate, and we are close indeed to meeting our goal (and we don’t mind going over it! :))
Tissue studies were a focus of the last PolyBio Symposium blog, but in this overview, something else stood out: precision.
Pretorius’s blood clot findings suggest that precision medicine targeting the specific types of microclots present may be coming.
Similarly, T-cell studies suggest that precisely targeting the T-cell clones specifically triggered by the coronavirus, EBV, and/or CMV may be the way to go.
Lastly, it was great to see LIINC dig deep into gut cells to determine whether the enterovirus is present in ME/CFS.
These fields feel like they’re getting more precise and finding things to really hone in on. This is a complex project and will take time, but it feels like it’s moving in the right direction. The more precise our targets, the better off we will be.
If that floats your boat, please support us in the last days of our drive! 🙂
Health Rising is not a 501 c (3) non-profit
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Pretorius’s group has identified three different intervention approaches — restoring fibrinolysis, targeting platelet-monocyte and NET aggregates, and addressing upstream chemistry with glycation inhibitors or antioxidants — that they believe could impact microclots, and are currently testing them in a clinical trial.
If successful, we could have precise treatments that address the different kinds of microclots present in patients with long COVID or ME/CFS. Pretorius’s progress shows how far one dedicated and persistent research group can move a field.
Check out a PolyBio interview with Dr. Pretorius
Caught in NETS?
More evidence of netosisis – where neutrophils explode themselves into create nets that mop up blood clots and cellular debris – is present in long COVID. These nets can damage the blood vessel walls.
Health Rising recently covered several studies that found evidence that NETosis – a dramatic process in which neutrophils essentially explode in order to form nets that capture cellular debris and clots – was present in the microvascular blood vessels in long COVID (and perhaps ME/CFS). Remarkably, one study found that neutrophils from long COVID patients did not require any outside triggers to go on their suicide spree.
A 94-person study from Lael Yonker seconded that finding. Neutrophils exposed to long COVID plasma exhibited high rates of NETosis. The highest NETosis rates were seen in patients with detectable coronavirus spike protein.
However, more analyses indicated that the spike protein alone wasn’t the problem; instead, immune complexes (antibodies plus the spike) were driving the neutrophils to blow themselves up. We’ve seen evidence before that it’s the immune complexes – not the spike protein itself that are the big deal.
Not surprisingly, given the NETs’ ability to damage endothelial cells lining blood vessels, long COVID patients showed evidence of endothelial injury.
Yonker proposed that SARS‑CoV‑2 or its remnants persisting in the gut and/or blood vessels chronically leak into the circulation. The immune reaction that results – including these NETS – further damages the blood vessels. This suggests that neutrophils may play a major role in long COVID, and potentially opens the door for a variety of treatment possibilities.
This fits in nicely with another Symposium presentation suggesting that larazotide may be able to help by healing the gut barrier (larazotide) and preventing the coronavirus (or EBV or another virus?) or other toxic factors from spilling into the blood.
Other drugs that reduce immune complex formation (FcyR/complement), inhibit NET formation (DNase‑based approaches), or protect the endothelium (antiplatelet/anticoagulant regimens) might be called for.
Craniocervical Instability Pt. II
Four sets of neck muscles help to stabilize the skull
Getting back to Murakami’s presentation on craniocervical instability. One question concerns how a viral infection could create a condition as dramatic as craniocervical instability.
Stabilizing the brain so that it doesn’t smash down on the spinal cord is something the body clearly takes very seriously. Most of the stabilizing actually comes from the cerebrospinal fluid, which cushions the head so that it kind of floats above the spinal cord. Allowing the head to float in a liquid greatly reduces its downward thrust.
Three layers of tough membranes covering the brain and the spinal cord provide further support, and four ligaments keep the skull from moving in ways that could kink or compress the crucial junction between the spine and the skull. Four sets of neck muscles also keep the skull centered properly. (Deconditioning could contribute to weak neck muscles.)
A SARS-CoV-2 infection might particularly affect people who already had weakened ligaments or joint hypermobility but were largely asymptomatic because they were able to compensate by using their muscles, their healthy autonomic system, and abundant cerebrospinal fluid flow. The virus may also unleash mast cells, which attack ligaments that were perhaps already weakened and were helping to hold the skull in place. If COVID-19 produces extensive bed rest, that could weaken the muscular “guy wires” in the neck that help to hold the skull in place.
Because cerebrospinal fluid cushions the skull, the virus could affect it by compromising the blood-brain barrier, damaging blood vessels, and dysregulating the pressure/flow systems that regulate CSF.
If the same blood flow problems found in the body exist in the brain – and it looks like they do – that may be all that’s needed. Because one of the major waste removal systems in the brain – the glymphatic system – runs in the perivascular spaces found right next to the blood vessels, anything that affects blood vessel functioning could impair the brain’s ability to get rid of its waste products.
That, of course, suggests finding ways to return the blood flows to normal could be helpful in many ways.
Increased cerebral spinal fluid pressure – which appears to be common on ME/CFS – can impact the foramen magnum – the small opening at the bottom of the skull through which the spinal cord, arteries. ligaments and nerves pass through
Low cerebrospinal fluid (CSF) levels or pressures can cause the brain to sag downward, producing intracranial hypotension (low CSF pressure). High CSF pressures, which studies suggest are common in these diseases, can cause the small hole (foramen magnum) through which a variety of structures (lower medulla, upper spinal cord, arteries, meninges, ligaments, membranes, nerve roots) make their way through to the brain, to become compressed and produce a wide variety of problems.
The virus can also produce CCI-like symptoms by producing neuroinflammation in the brainstem and/or vagus nerve, by restricting venous outflows of blood from the jugular vein, by producing Chiari-like crowding of the cerebrospinal fluid, via POTS/dysautonomia, vestibular dysfunction, small fiber neuropathy, cervical muscle spasms, and MCAS-related inflammation/swelling.
Immune Functioning
The T-cells Are Back!
Actually, they’ve never left. Health Rising just reported on the exciting T-cell work in ME/CFS being carried out by Selin, Kumar, and Kohlbruger in Boston. Two presentations in the Polybio Symposium feature T-cells. Over the past couple of months, more than 10 long COVID studies have featured T-cells.
Since it looks like T-cells are here to stay in the long COVID/ME/CFS space, let’s take a brief look at what these powerhouses of the adaptive immune system do and why so many researchers are interested in them.
A Short T-cell Interlude
T-cells are responsible for finding and destroying pathogen-infected cells.
T-cells are a major target in the drug space. From T-cell activation inhibitors, immune checkpoint inhibitors, intracellular signaling inhibitors, immunosuppressants, cytokine pathway modulators, CAR‑T products, T‑cell engagers, TCR‑based therapies, and Treg‑targeters, probably hundreds of different T-cell-affecting drugs exist. In fact, the T-cell space is so dynamic, and so many T-cell-affecting drugs are being assessed, that any attempt to come up with a solid number is likely to be quickly outdated.
One would think that if specific T-cell problems are validated in these diseases, drugs targeting them would be available.
T and B cells are the mainstays of the adaptive immune response, which is responsible for eliminating infection once and for all. When activated – a process which takes enormous energy – both send out armies of clones specifically designed to find the pathogen and kill it
B-cells hunt extracellular pathogen hunters (free-floating pathogens not inside a cell). They produce clones that bind to the pathogen, preventing it from entering cells and replicating. As they’re doing that, they place a tag on it which is like catnip to macrophages and neutrophils, which then rush in and engulf (eat up) the pathogen.
CAR-T-cell therapy is just one of the many T-cell therapies present. CAR-T weaponizes T-cells by aiming them at specific targets such as autoreactive B-cells. If autoimmunity is present, it’s a possibility.
T-cells, on the other hand, hunt for intracellular pathogens – pathogens found inside cells. They do this by examining MHC molecules on the cell surface, which cells produce to communicate their state to the immune system. If a pathogen is present, these molecules exhibit a piece of the pathogen – an antigen – on the outside of the cell, for all to see.
If a cytotoxic or killer T-cell determines that a pathogen is present, it kills the cell itself by boring a hole into it and dropping in a suicide program. Note, though, that pathogens have developed several ways to prevent MHC complexes from appearing on the cell surface. If that happens, the cell can still be destroyed by cytotoxic T-cells, which detect the low levels of MHC complexes on the cell, suspect a pathogen is present, and then move in and kill the cell in exactly the same way that T-cells do.
Coronavirus / EBV Activated T-cells Take I
In Nadia Roan’s presentation, “A type of cell-killing immune cell stays abnormally active in Long COVID — especially in women — which may help explain why Long COVID disproportionately affects women“, she looked at T-cells from a different angle and ended with a familiar result.
T-cells specifically activated by the Epstein-Barr virus were found.
First, she used mass cytometry to identify T-cells associated with a variety of pathogens (SARS-CoV-2-, EBV-, CMV-, and influenza-specific CD8 T cells) to determine their state. The recovered COVID-19 participants’ T-cells had low levels of exhaustion markers (their T-cells were not activated and were ready to pounce on the next invader), whereas the T-cells in long COVID patients were highly activated and showed evidence of exhaustion.
Note that the longer these killer T-cells are chronically activated, the more likely they are to trigger an autoimmune reaction and/or damage the blood vessels, nerves, produce fibrosis, etc.
An analysis found clusters of T-cells had become activated by SARS-CoV-2, EBV, and/or CMV (but not the flu). Each of these pathogen-specific clusters showed increased cytotoxic T-cell CD29⁺/Granzyme B⁺ frequencies, indicating that even years after the initial exposure, these T cells were still on high alert and primed to act. In fact, the level of activation even seemed to increase over time, perhaps indicating that further bits of SARS-CoV-2 and/or herpesviruses were continuing to escape. This was more prominently seen in women.
Impaired cytotoxic NK cell exhaustion was found in ME/CFS many years ago. So now we appear to have problems with both of the cells (cytotoxic T and NK cells) responsible for going after intracellular pathogens. If that’s true, it’s no wonder that EBV reactivation, in some form, remains a problem, or that the innate immune system is highly activated, trying to fill the gap.
Validating this finding could open a wide variety of treatment approaches which might a) target EBV via antivirals or monoclonal antibodies, b) seek to calm the T-cells, c) seek to revive the exhausted T-cells,
Coronavirus / EBV Activated T-cells Take II
Mark Painter ·of the J. Craig Venter Institute, provided more evidence of T-cell exhaustion caused by coronavirus (or remnants of it) and/or EBV in his “Virus-specific CD8 T cells as biosensors of antigen persistence” talk.
Painter assessed cytotoxic T-cells that have been specifically primed to attack SARS-CoV-2, EBV, CMV, and the flu. The basic question was – are they still reacting to the virus? If they are, that suggests the virus (or bits of it) is still present and driving the T-cell activation.
More evidence of cytotoxic T-cell exhaustion was found.
Lo and behold, he found that the cytotoxic T-cells in about a third of long COVID patients were still reacting to the virus, were in an activated/exhausted state, had trouble producing cytokines, and proliferating. These and past findings suggest that the coronavirus is tweaking the immune system in a substantial subset of long COVID patients, but certainly not in all.
He also found signs of EBV reactivation in a subset of long COVID patients. No signs of CMV or flu-activated T-cells were found.
These EBV findings track well with a recent German study, which found that cytotoxic T-cells lost the ability to effectively rein in EBV early in a COVID-19 infection.
They also align perfectly with Selin-Kumar-Kohlbuger’s pilot ME/CFS work, which found that T-cells in ME/CFS are activated by a pathogen or an autoimmune response. They’re now on the hunt to identify the specific T-cell triggers in ME/CFS.
MicroTesla Therapy to the Fore?
(Elon Musk supporters or non-supporters and everyone in between, please note that this MicroTesla device has nothing to do with Musk’s Tesla enterprise.)
Now for a completely different treatment approach. The Furium microtesla device used in this long COVID study is gentle (check), can be used at home (double-check), and appears to have no side effects (double-double-check). It’s being trialed by David Putrino at Mt Sinai, who seems to be checking out just about any treatment that makes sense.
So far so good. Magnetic devices have already proved themselves to various degrees in disease, but this one is decidedly different. It produces low‑energy, low‑frequency magnetic fields (hence the “micro-Tesla”) that are ~100,000× weaker than those used in rTMS devices being trialed for fibromyalgia.
The mictoTesla device gives the brain’s mitochondria a gentle nudge to combat neuroinflammation.
The magnetic fields are far too weak to cause neurons to fire. Instead, the goal is to engage hormetic mechanisms. These treatments give the brain’s mitochondria a gentle nudge, prompting them to rebound, produce more mitochondria, clean up damaged mitochondria, and exert an anti-inflammatory effect.
These devices are aimed at the head. The goal is to reduce neuroinflammation. A 2025 paper, “Transcranial microtesla magnetic fields suppress neuroinflammation and neuronal oxidative stress burden” appearing in Science, found that in various disease animal models, this electromagnetic therapy had “robust anti-inflammatory, antioxidant, and neuroprotective effects”,
It was a small trial, just 30 persons with long COVID, but it was triple‑blinded, randomized, and sham‑controlled. The participants used the device for 15 minutes every three days for four weeks.
People with the active device showed improvements in visual attention, processing speed, attention/inhibition, and emotional well‑being. That processing speed and attention improvements are biggies, as delayed processing speed (“what did you just say?”) and attention (“what was I doing again?”) are prime cognitive issues in these diseases. Better emotional well-being is an obvious help as well.
This device is being trialed in other neuroinflammatory diseases, but this is the first time it’s been tested in long COVID. It’s not yet available on the US market, and it should be noted that this was a pilot trial, but Putrino was excited enough about the results to report that a multi‑site pivotal trial for FDA approval was underway. I was unable to find a website associated with this product.
The Mighty UCSF LIINC Project Takes on ME/CFS
“research on enterovirus persistence as a driver of ME/CFS has stalled over the past decade due to a lack of teams in the field with the infrastructure needed to collect tissue samples from patients with the condition or to identify viruses in such samples using cutting-edge methods.” Chime
Saving the best (for ME/CFS patients) for last, Michael Peluso, UCSF professor and co-founder of the mighty LIINC long COVID project, reported that, thanks to PolyBio, the LIINC project is now taking on ME/CFS (yah!).
The Chime ME?CFS study will be looking deep in the tissues for evidence of enteroviruses.
It looks like Dr. John Chia, after pounding the enterovirus drum for decades, is finally going to get his study. Despite the fact that enteroviral RNA has been found in the brains, muscles, and guts of ME/CFS patients, the last ME/CFS enteroviral study (by Chia) I could find was in 2010.
In 2021, though, O’Neal and Hanson’s ME/CFS enterovirus review asserted that “further studies of appropriate biological samples with the latest molecular methods are urgently needed.”
Enter three experts (Mike Peluso, Steven Deeks, Tim Henrich) with deep experience in ferreting out viruses (HIV) that hide deep within tissues. They will use the same ultrasensitive methods (single-molecule assays, peptide arrays, bacteriophage display, and transcriptomics) they’ve used in HIV and are using in long COVID to search for enteroviruses in ME/CFS.
In the “Chronic Infections and Inflammation in Myalgic Encephalomyelitis (CHIIME): study, preCOVID ME/CFS patients will receive intensive in-house visits that will include providing a wide range of biospecimens (all biobanked), including gut biopsies (enteroviruses), brain imaging, neurocognitive tests, and metagenomic analyses.
Plus, an advanced whole-body PET (positron emission tomography) will use a special tracer they’ve developed to map the location of the activated T cells throughout the bodies and brains of the ME/CFS study participants. (There are those T-cells again!).
When I emailed Peluso several months ago, he said the CHIME ME/CFS study was immediately filled.
Conclusion
The four big things that popped out for me in this Symposium were the creation of the Long COVID Cure Initiative, the tissue findings, the pathogen/T-cell findings, and, of course, as a long-term ME/CFS patient, the CHIME project.
The arterial plaque, retinal, gut, lymph, spinal, and brainstem findings suggest that, as Amy Proal asserted, the tissues may be where we’ll find the “most signal”.
We saw more evidence that persistent pathogens are playing a role in long COVID.
If there’s one thing that PolyBio has been focused on, it’s been viral persistence; i.e., the idea that the coronavirus and/or EBV are continuing to tweak the immune systems of long COVID patients.
With two presentations finding evidence of T-cell exhaustion due to chronic responses to the coronavirus and/or EBV, T-cells are clearly going to continue to spark strong interest.
It appears that the immune system is activated but is unable to clear the remnants of SARS-CoV-2 infection and/or tamp down EBV in a significant subset of long COVID patients.
Two other presentations suggested that the problem may not be the pathogen itself, but its ability to escape into the bloodstream from the gut or to trigger immune cells to attack the blood vessels. This suggests that gut lining support/immune modulation may be helpful.
Finally, LIINC’s CHIME project is a breath of fresh air for a field that is making progress but has struggled to gain the traction one would have thought it would after long COVID showed up on the scene.
Health Rising’s Donation Drive Update
We’re getting down to tissues, specific T-cell sets, specific pathogens….The research seems to be getting more precise – and that’s good news.
Thanks to everyone who has contributed. This is the last blog of the drive, and we are getting very close. We had a bit of a mix-up because the donation tracker was inaccurate, but it is now accurate, and we are close indeed to meeting our goal (and we don’t mind going over it! :))
Tissue studies were a focus of the last PolyBio Symposium blog, but in this overview, something else stood out: precision. Pretorius’s blood clot findings suggest that precision medicine targeting the specific types of microclots present may be coming. Similarly, T-cell studies suggest that precisely targeting the T-cell clones specifically triggered by the coronavirus, EBV, and/or CMV may be the way to go. Lastly, it was great to see LIINC digging deep into gut cells to see if the enterovirus is present in ME/CFS.
These fields feel like they’re getting more precise and finding things to really hone in on. This is a complex project and will take time, but it feels like it’s moving in the right direction. The more precise our targets, the better off we will be.
If that floats your boat, please support us in the last days of our drive! 🙂
Health Rising is not a 501 c (3) non-profit
