Long COVID and the role of fibrin amyloid (fibrinaloid) microclots

Together with Professor Resia Pretorius from Stellenbosch University, we have been studying the role of fibrin amyloid microclots in the phenomena of Long COVID (and related post-infection diseases). All of the papers (including many on iron dysregulation and the role of infections) are on the group’s Publications page. Following considerable earlier work using electron microscopy (that uncovered ‘dense matted deposits’, that are equivalent), we discovered the ability of tiny amounts (1 molecule per 100,000,000 fibrinogen molecules) of bacterial lipopolysaccharide to cause blood to clot into an anomalous ‘amyloid’ type form that could simply be stained with fluorogenic dyes such as thioflavin T. Similar phenomena can be observed in the blood of individuals with various chronic, inflammatory diseases such as Alzheimer’s, Parkinson’s, type 2 diabetes, and rheumatoid arthritis. These kinds of fibrinaloid microclots are significantly more resistant to breakdown than are normal clots, so D-dimer measurements do not alone detect their presence, and the phenomena bear similarities to other more classical ‘amyloidoses’ (which are different in that they are not normally detected in blood and do not involve fibrinogen), and especially in some aspects around cross-reactivity to the properties of prions. More specifically, although it was once believed that proteins whose amino acid sequence was sufficient to determine their 3D conformations always folded into their state of lowest free energy, this was always an assumption as there were far too many possibilities for it to be calculated. It turns out that more stable states (of the identical, unchanged amino acid sequence but of lower free energy) do in fact exist, that these can be formed in some circumstances, and that they typically contain ‘cross-beta’ structures that are referred to as amyloid structures. We consider that this is highly pertinent to the mechanisms and causes of long COVID. (Similar findings pertain in Myalgic Encephalopathy/Chronic Fatigue Syndrome (ME/CFS).)

It was clear early on (see also a superb early video by Drs Jaco Laubscher & Johan Lourens) that COVID-19 was essentially a coagulopathy. We then discovered extensive amyloid blood clots in ‘unclotted‘ plasma of acute COVID patients (i.e. even without adding thrombin in vitro), that these could be induced in ‘normal’ blood from uninfected controls simply by the addition of small amounts of purified (virus-free) SARS-CoV-2 (‘alpha’) spike protein, and that this amyloidogenesis was also true for the plasma of individuals with Post-Acute Sequelae of COVID-19 (PASC, i.e. Long COVID). A more recent paper expands on this. Thus the SARS-CoV-2 spike protein alone was sufficient to induce this anomalous microclotting that was more resistant to the normal means of removal (‘fibrinolysis’, mainly catalysed by the enzyme plasmin).

This led to the view that careful assessment and prevention of clotting could be of clinical value in both acute and Long COVID. The latter study showed the presence of fibrinaloids in all individuals with long COVID (70/70 tested), and provided some encouraging preliminary results from clinical practice using a treatment based around anticoagulants and platelet inhibitors. Note that this was not a clinical trial; there were purposely no controls. We do stress additionally, however, that anyone contemplating medication  for Long COVID or anything else MUST do so ONLY with the full cooperation and involvement of their physicians. In particular we note the importance of assessing potential coagulation status before and during any therapy, by using thromboelastography, since there is a potential risk of bleeding. A preprinted follow-up is now available (2023).

Our present thinking, summarised in a February 2022 review in the Biochemical Journal, is that these hard-to-remove fibrin amyloid or fibrinaloid microclots (also containing other proteins), that can inhibit blood flow to capillaries and hence O2 transfer to tissues, are involved in, and can help account for, most (if not all) of the symptoms of Long COVID, and we are presently working hard to improve both the diagnostics and (with clinical colleagues) the therapeutics based on this thinking. Note that a recent paper (preprint here) shows that the omicron variant is both far less able to produce fibrinaloid microclots and is far less potent in terms of causing severe disease; this is an important ‘control’ that indicates that fibrinaloid microclots are indeed on the disease pathway and not a side effect. Phenomena such as over-exercise causing relapses might then be seen as the microclots temporarily blocking some capillaries and then reverting, leading to a kind of hypoxia-reperfusion injury. A newer paper reviews fibrin amyloid microclots (including from omicron) and surgery, while a further proteomics paper and a much more detailed review on ischaemia-reperfusion injury and one on abnormalities of coagulation and metabolism have been published. We have also demonstrated that increased levels of inflammatory molecules in blood of Long COVID patients point to thrombotic endotheliitis as a major mechanism of Long Covid. A paper with similar findings on ME/CFS is also available, implying that both ME/CFS (reviewed by us here in 2024) and Long COVID share endothelial damage as a key part of their aetiology Our work catalysed a 2-page review in Nature. A picture of typical microclots stained with thioflavin T is shown at the right. A third BiochemJ review developed the extensive evidence for how fibrinaloids can catalyse the production of autoantibodies, a common feature of post-infection, chronic, inflammatory diseases. A 2023 perspective covers more detailed diagnostic features of the microclots that may be exploited; some may be observed using imaging flow cytometry. A 2024 paper by Wüst and colleagues shows amyloid deposition in muscle tissues in Long COVID, while Cheng-Hock Toh and colleagues showed that they were exceptionally predictive of disseminated intravascular coagulation and mortality in patients in intensive care. Caroline Dalton and colleagues have also developed (preprint) an automated microscopic methods for detecting the fibrinaloid microclots, and we have used it (preprint) to assess their kinetics. The microclots are also closely linked to (raised levels of) Neutrophil Extracellular Traps (NETs) (preprint here).

We have also explained how fibrinaloid microclots can account for other phenomena such as POTS, atrial fibrillation and fibromyalgia (that also often accompany Long COVID).

Systems view. As systems biologists, we recognise that the role of the systems biologist is to trace the major routes in a complex network. Consequently our focus here on platelets and microclots as mediators or proximate causes says nothing about the external triggers, that likely include spike protein (whether left from infection, or shed via viral persistence, or produced by mRNA). External triggers commonly include infectious agents. Seemingly some folk fail to recognise how the systems view work. A tutorial on MCA and distributed causes (of parameters) is here,  while recentish reviews (including the role of infectious agents and their latent/dormant forms) of the systems analysis of Alzheimer’s disease and of pre-eclampsia (here and here) are also available. If in doubt about our views and the evidence on which they are based, and before commenting on them, do please read the papers first. Having said this, we are being attacked by a variety of individuals, some involved in discredited psychological ‘explanations’, who seemingly choose not to, and either ignore, misunderstand, or grossly misrepresent the evidence in a scientifically indefensible manner. We always try to rebut such efforts so as to set the record straight: some rebuttals are published (usually in diluted form) by the offending journals; others have to appear in a blog, viz about a Cochrane Review, a JTH piece, and an RPTH opinion.

Absent of the availability of treatment with pharmaceutical anticoagulants, a number of nutraceutical enzymes have been proposed as able to remove microclots. These are available online as supplements and include nattokinase (from the Japanese fermented food natto), serra(tia)peptase (from a bacterial symbiont of the silkworm), lumbricase (originally from earthworms) and bromelain (available in fresh pineapple). Links to youtube video on nattokinase here. We have shown that nattokinase can indeed break down the fibrinaloid microclots (preprint here). Surveys of their benefits, and discussions of suitable and adequate dosing, including combinations, can be found for example in the excellent timelines of LongCovidPharmD, for instance this survey for nattokinase dosing and efficacy, along with some reasonably clear evidence that coating to allow enzyme to pass through stomach may help. A superb FAQ from @organichemusic is here. These enzymes are also mentioned in our review on PESE, and in a superb blog of a recoveree. As there is mixed quality control in the production of such supplements, one guideline might be to consider trying those that have at least been shown to work in some folk. Antioxidants, that are helpful against ischaemia-reperfusion injury, include ergothioneine, which is obtainable from eating culinary mushrooms,  and many polyphenols such as quercetin, baicalein, and rutin, and are abundant in coloured fruit juices such as Acai juice, cranberry juice, and goji juice. We note that some of these foodstuffs such as mushrooms contain histamines, so may not suit those with MAST cell activation syndrome. Vedicinals 9 is a cocktail (mainly of antioxidants) that some longhaulers have found very helpful. Vasodilators may also offer a suitable approach to assisting blood flow. A useful survey highlighting anticoagulant nutraceuticals and treatments for occult infection is here. All of this said, Long Covid and ME/CFS sufferers are likely to come upon a variety of ‘snake oil’ remedies that claim to work for everyone; everyone is different, and we counsel against ‘miracle cures’ – caveat emptor.

Warning: we have become aware of various organisations offering so-called “microclot” testing that use methods (e.g. in whole blood) (and bizarreley even an ‘online’ version) that bear absolutely no relationship whatsoever to what is discussed above. To be clear, we have absolutely nothing whatsoever to do with them. Any suggestion that we are in any way involved in these would be libellous. Caveat emptor. When we are able to offer proper measurements of fluorescent microclots in platelet-poor plasma based on our own published methods we’ll announce it or make contact directly with individuals who have explicitly expressed interest.

Mostly UK-based links: Long COVID prevalence in the UK. Funding portals such as COVID-CIRCLE. The APPG on coronavirus and how to submit evidence to it. POST report on LC.; UK CV Family; International coalition for vaccine-injured;

Some useful resources for microclots and Long COVID: video interview between Dr Amy Proal & Prof Resia Pretorius; BBC discussion of Dr Beate Jaeger’s HELP apheresis; Long COVID Foundation video with Dr Marek Fabrowski on his treatment including H.E.L.P. apheresis; an op-ed in The Guardian; an excellent talk by Dr  Proal on the causes of Long COVID; a podcast with Resia Pretorius and myself;

My own twitter feeds and those of Prof Resia Pretorius, Dr Amy Proal, Dr Anna Brooks, Dr Asad KhanBody Politic, CovidSupportGroupSA, Dr Jennifer Curtin, Long Covid Advocacy, Long Covid Austria, Long Covid France, Long Covid Italia, Long Covid Kids, Long Covid News, Long Covid Podcast, Long Covid Scotland, Long Covid Support, Long Covid Wales, Dr Rae Duncan, RTHM, Ruth Liptrot. Some twitter feeds with hashtags such as Long COVID, Long Covid Canada, Long COVID Deutschland, Long COVID Europe, Long COVID Ireland, Long Covid Kids, Long Covid Nederland, Long Covid Nurses and Midwives, Long Covid Patient Action Group UK, Long Covid Wales, Long Haulers Pakistan, pwLC, pwME, TeamClots, Treat Long Covid.

Other web links: Action for ME, C19-YRS symptom questionnaire, Doctors with ME. LongCovid.org, Long Covid Finland (in Finnish; use translate), Long Covid Foundation, Long Covid Research Initiative. Long COVID Support, NHS Long COVID Support, My Long Covid Diaries blog, NIH Long COVID through an ME/CFS lens. RTHM link to sign up for microclot tests in USA. Nicely done blog summary by Janna Moen.

Broadcasts: Amy Proal interview with Resia Pretorius 18 December 2021. 7-minute Inside Science segment with Resia and DBK. 11 August 2022. Longish rehearsal of microclots with Mark Walsh, Resia and Doug moderated by Asad Khan 25 August 2022. TLC sessions Sept 14 with Doug, starting ca 6 min in. A talk on ME/CFS (Doug from ca 1.03.27) in Parliament Square for #MEAction42 min of Doug on ischaemia-reperfusion injury from an Action for ME Research Summit in Edinburgh. A four-parter on microclots with Gez Medinger and Asad Khad: part 1 with Dr Jaco Laubscher, part 2 on the general microclot discoveries, part 3 on post-exertional symptom exacerbation (aka post-exertional malaise), and part 4 on the possible utility of nutraceutical clotbuster enzymes such as nattokinase, serrapaptase and umbricase. 15 min piece by Ruth Liptrot on Channel 5 News. There’s a nice if somewhat polemic (and 49-minute…) introduction to the clotting story (and discussion of an anti-vax movie called Died Suddenly) more generally by Dr Chris Martenson here, with links to a related blog. Superb piece on microclots and Long Covid by Dr Jordan Vaughn here.