Ischemia–reperfusion injury, hypoxia–reperfusion injury, or reoxygenation injury – whatever name you wish to call it – occurs when a low oxygen state in the tissues is followed by a resumption of normal oxygen flows. Oddly enough, it’s during the resumption or reperfusion of oxygen flows that the big problems – high amounts of inflammation and oxidative stress – occur.
In their 56-page page review paper, “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 propose that infections are triggering a chronic state of reperfusion injury in diseases like rheumatoid arthritis, chronic fatigue syndrome (ME/CFS) and long COVID. In fact, while the authors don’t emphasize it, they suggest that all chronic inflammatory diseases may have an infectious origin.
These diseases have three things that stand out for Pretorius and Kell: they cause a wide variety of symptoms, crashes – periods of exacerbated symptoms – are common, they’re all associated with high degrees of fatigue, and they all affect more women than men.
The possibility that blood clots, strangely deformed red blood cells, and possibly other factors, are impairing blood flows to the tissues, leaving behind an on-again, off-again ischemic environment, seems to make sense. Ischemia-reperfusion popped up in Wirth and Scheibenbogen’s hypothesis, and has been proposed to be behind the muscle pain and fatigue in fibromyalgia as well.
A 2006 study, for instance, found that muscle ischemia-induced pain played a key role in FM patients’ activity limitations. Elvin felt that the reduced muscle blood flows following exercise that he found in FM could be explained by deconditioning and sympathetic nervous system issues. A 2015 study found that an ischemia-hyperpnea test effectively diagnosed people with fibromyalgia.
The Lights proposed that vasoconstriction was decreasing blood flows to multiple parts of the body and causing the buildup of metabolites and inflammatory agents in ME/CFS and FM. The Lights believed that the huge buildup of muscle injury-sensing receptors may have been caused by the need to constantly monitor the muscles for signs of ischemia-reperfusion injury.
Kell and Pretorius assert that it’s not uncommon for intracellular pathogens such as Mycobacterium tuberculosis, Helicobacter pylori, herpes viruses, and enteroviruses to lie dormant until they get reactivated by high levels of free iron. Iron is usually tightly sequestered in the cell – leaving free iron levels low. Cell death, however, releases free iron – which can then trigger the pathogen to grow – and also has a nasty characteristic of triggering one of the most potent free radicals of all – the hydroxyl (OH-) radical.
Unusual Microclots Are Key
There’s a problem, though. Viral or bacterial reactivation usually happens in fairly small quantities and doesn’t produce a lot of viral or bacterial products. How to translate, then, a relatively small infectious event into chronic and even disabling illness?
Enter microclots. The authors believe that an abnormal or anomalous clotting process has taken place in long COVID and ME/CFS. The fibrin amyloid or ‘fibrinaloids’ produced in these illnesses causes three problems:
- the production of autoantibodies that end up attacking the body,
- unusually long clot persistence times due to the difficulty breaking them down,
- blockage of the capillaries – last and most importantly, blockage of the capillaries when the strangely formed and hard-to-break down clots get stuck in them. That blockage could result in low oxygen uptake and a hypoxic (low oxygen) condition that results in a chronic ischemia-reperfusion injury as well as reduced energy production by the mitochondria. (The commonly used pulse oximeters would not pick up this condition.)
The capillaries are very small. In fact, most of them are so small (5–10 μm) that red blood cells largely pass through them in single file. The fibrin amyloid microclots that Pretorius’s team has uncovered in ME/CFS (blog coming up) and long COVID are from 5 to 200 μm in diameter – easily large enough to block up the capillaries.
Plus, the fibrin amyloids in microclots are also less deformable – making it more difficult for them to move through the capillaries. (Other kinds of cellular debris such as exosomes could be blocking up the capillaries in ME/CFS and long COVID as well.)
Reaching way back to 1989, they referred to Les Simpson’s paper finding altered red blood cell shapes in ME/CFS, and then reaching forward thirty years later, the San Jose State University team found altered red blood cell deformability. One wonders if a major cause of ME/CFS has been readily visible all this time. Ron Davis and the Open Medicine Foundation are exploring the red blood cell deformability issue further in ME/CFS with UC Davis researchers.
More evidence of coagulation issues exists in fibromyalgia. A 2019 paper found evidence of a prothrombotic or coagulatory state, and two plasma proteomic studies pointed fingers at coagulation and inflammation.
Evidence of ischemia-reperfusion injury
The hydroxyl radical causes most of the damage in ischemia-reperfusion injury. The hydroxyl radical is so unbalanced, though, that it doesn’t last long enough to measure. Therefore, its by-products (malondialdehyde TBARS), nitrotyrosine, 8-isoprostane) are – and all have been found – increased in ME/CFS, and several in fibromyalgia as well.
An ongoing state of platelet hyperactivation – caused by an ischemic reperfusion injury and/or inflammatory state – is a possible scenario.
In platelet hyperactivation, blood platelets form platelet complexes that drive pathological clotting states and damage the endothelial cells lining the blood vessels. Platelet hyperactivation has been found in long COVID.
The authors hypothesize that untreated platelet hyperactivation and microclots could lead to 5 scenarios – many of which apparently can overlap:
- Return to health – Patients recover spontaneously, where their fibrinolytic system returns to healthy clotting and lysis cycles.
- Hypercoagulable state forms that triggers more platelet activation and blood vessel damage – Patients do not spontaneously recover, but instead develop a persistent hypercoagulable state with the persistent triggering of hyperactivated platelets and persistent endotheliitis, that may lead to more widespread endothelial damage.
- Microclots trigger immune dysfunction and/or autoimmunity – Microclots trap inflammatory molecules and distort them, causing the production of autoantibodies that may mistakenly attack the body as well.
- An increase in free iron causes past viral/bacterial infections to flare up – Some individuals, who previously might have suffered from EBV, Herpes simplex virus or Lyme disease, might suffer from a flare of those original symptoms, caused by reinfection, or even by the vaccine.
- Spike/COVID-driven ME/CFS – In some individuals, the persistent microclots and widespread endothelial pathology may culminate in eventually COVID triggering ‘spike/COVID-driven ME/CFS’.
- Ischemia-reperfusion injury occurs during reductions in blood flow when the blood flow is resumed causing an explosion of oxidative stress and inflammation.
- The authors believe that long COVID, ME/CFS and rheumatoid arthritis are ischemia-reperfusion diseases.
- Unusual microclots found in long COVID and ME/CFS that are of irregular shape and are difficult to break down – which clog the small capillaries that carry blood to the tissues – are a main feature.
- A possible complication of ischemia-reperfusion injury is something called “platelet hyperactivation” which results in hypercoagulation (more clotting), possibly autoimmunity, and an explosion in free iron which, in turn, promotes viral and bacterial reactivation.
- This new focus on reperfusion injury and clotting is leading to a range of new treatment possibilities including anti-clotting drugs and supplements, drugs like fenofibrate, metformin, lactoferrin, biologics, and treatments like apheresis and hyperbaric oxygen therapy.
- This is actually just the tip of the iceberg. Long-COVID patients and their doctors are trying many more things. A future blog will focus on those.
The authors start off the treatment section by noting that, as with any complex illness, multiple treatments will probably be needed in ME/CFS and long COVID. Lots of treatments new to the ME/CFS/FM communities are being tried to long COVID, and a future blog is going to address them, but I think this idea – that multiple treatments are going to be needed to really move the needle on these illnesses – is probably spot on. We need assessments of treatment protocols more than anything.
Potential treatments for long COVID already in common use in chronic fatigue syndrome (ME/CFS).
Low-dose naltrexone, N-acetyl cysteine NAC), curcumin, flavonoids, melatonin – are all well known supplements that have anti-inflammatories/antioxidant properties. Niacin (B3) was also mentioned. Green tea catechins (epigallocatechin-3-gallate, as well. One warning: As mentioned above, vitamin C is to be recommended only if one is sure that free or poorly liganded iron is absent.
Magnesium – Magnesium is, of course, very well known, but the authors provided a new slant on it stating that “‘Magnesium’ was experimentally one of the earliest substances that the authors found to inhibit fibrin amyloid microclotting (then known as dense matted deposit formation). People with low magnesium ion levels were found to be more susceptible to COVID-19, and magnesium supplementation has shown benefits in SARS-CoV-2 therapy, ME/CFS [93,897], and in maintaining endothelial cell function.”
New, or less used, treatments in ME/CFS.
Anticoagulants and platelet inhibitors – The authors mentioned heparin (unfractionated heparin (UFH)) and low molecular mass heparin (LMWH), and specifically recommended the LMWH form, but quite a few other possibilities exist. Dr. Holtorf has reportedly been using heparin successfully in some ME/CFS patients for years, though the vast majority of ME/CFS experts have not. With a recent paper from Dr. Pretorius’s group demonstrating the presence of microclots in ME/CFS (blog coming up shortly), anti-clotting treatments are receiving more and more interest.
Thrombolytics (clot-busting supplements): nattokinase, serrapeptase, and lumbrokinase – the authors noted that the fibrin amyloid microclots contain compounds (antiplasmin) that make them difficult to break up via the normal processes.
- Nattokinase – Nattokinase leads the list of fibrinolytic and amyloid-degrading compounds. Found naturally in the Japanese fermented soybean food natto, it may have antiviral, antiplatelet, anti-inflammatory, and anti-hypertensive (high blood pressure) properties. It’s a supplement, that has not, however, been well studied.
- Serrapeptase (serratiopeptidase) – the authors reported that serrapeptase has similar properties as well as having anti-mucus effects. It also has not received much study.
- Lumbrokinase – another fibrinolytic (fibrin-degrading) enzyme, lumbrokinase is apparently under study in long COVID.
Biologics – (Enbrel), and infliximab (Remicade) have been very effective with RA (rheumatoid arthritis) – and with fatigue in RA. RA was mentioned in conjunction with ME/CFS and long COVID several times in this paper. A potential RA / ME/CFS connection is fascinating. Fatigue, exercise intolerance, jacked-up sympathetic nervous systems, and similar metaboreflex problems appear to be present in all three diseases. A hypothesis that inflammatory factors are sensitizing the metabolic receptors in the muscles in RA seems entirely possible in ME/CFS.
The authors stated they were surprised that these biologics have not been trialed in ME/CFS. A small trial is underway. Dr. Klimas’s modeling studies suggested that Enbrel be used first to tamp down neuroinflammation, followed by mifepristone to reset the HPA axis, and a small trial, long delayed by the coronavirus epidemic, is hopefully underway. A recent case series found that a perispinal application of Enbrel produced rather amazing results in a long-COVID patients. On a positive note, the authors reported that as biosimilars begin to come in, the costs of these expensive drugs are expected to fall.
Colchicine – has long been used in various inflammatory diseases. One of Dr. Montoya’s ME/CFS patients apparently did well on it.
Metformin – Metformin is a first-line drug for type II diabetes that was first suggested for fibromyalgia for its mitochondria-enhancing effects. Numerous studies suggest that mitochondrial problems exist in FM, and several animal studies suggest that metformin may, by increasing mitochondrial and antioxidant activity, reduce pain; and one found that FM patients with mitochondrial problems did well on metformin.
A prediabetes connection may also exist in FM and chronic fatigue syndrome as well. Marco’s 2014 blog, “The Energy Disorders: Diabetes, ME/CFS and FM – Can Diabetes Tell Us Anything About Chronic Fatigue Syndrome and Fibromyalgia?” noted that small fiber neuropathy is common in diabetes, that Type II diabetes patients also suffer from fatigue, early onset of muscle pain, reduced oxygen uptake during exercise, exercise intolerance, endothelial cell problems, and delayed recovery.
Different forms of diabetes exist. Could a form of diabetes be present in ME/CFS, fibromyalgia, and long COVID? Peter Attia, MD, believes that our testing procedures are terrible at picking up pre-diabetic conditions and that they are vastly underdiagnosed in the U.S.
Fenofibrate – is usually used to treat abnormal lipid levels, but the authors stated that it appears to be at least somewhat protective against reperfusion injury. It’s been used in diabetes type II, reduces high levels of uric acid, and get this, it may also enhance the proliferation of the peroxisomes that have recently become of such interest in ME/CFS. Vijay reported that he’s been doing well on it.
Ergothioneine – is a new, to me, at least, anti-inflammatory, and antioxidant that has been shown to help prevent ischemia-reperfusion injury. The authors noted that it is not easily obtained in pure form, but its “availability via mushrooms can provide a convenient supply.”
Lactoferrin – since lactoferrin binds iron effectively, if higher amounts of free iron are triggering viral and bacterial reactivation, then lactoferrin could be helpful.
Other, Non-Pharmacological Methods
H.E.L.P.: apheresis – removes factors that impair blood vessel health such as lipoproteins, fibrinogen, and inflammatory factors. It also may improve blood flows in the microcirculation. The authors noted that heparin-mediated LDL precipitation (H.E.L.P.) apheresis may be best for long-COVID patients as it may remove fibrin amyloid microclots with high efficiency”.
Hyperbaric oxygen therapy and 02 nanobubbles – could, by increasing oxygen levels, stop or slow down the reperfusion-ischemia reaction. Several fibromyalgia studies suggest hyperbaric oxygen could be helpful.
The possibility that unusual, hard to break down, and less deformable microclots are impairing blood flows and causing a chronic ischemia-reperfusion (read free radical rich, inflammatory) state in chronic fatigue syndrome (ME/CFS), long-COVID and fibromyalgia (FM) are spurring interest in many treatments that are mostly new to the ME/CFS and FM communities. This blog touches on a few of them – many more things are being tried in long COVID. A future blog will dig into those.