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

Together with Professor Resia Pretorius, 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 kind 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 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 preprint 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.

Our present thinking, summarised in a February 2022 review in the Biochemical Journal, is that these hard-to-remove fibrin amyloid 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 have been published. A paper with similar findings on ME/CFS is also available. Our work catalysed a 2-page review in Nature.

Absent of the availability of treatment with pharmaceutical anticoagulants, a number of nutraceuticals 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). Surveys of their benefits, and discussions of suitable and adequate dosing, including combinations, can be found for example in the timelines of LongCovidPharmD. 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.

Warning: we have become aware of various organisations offering so-called “microclot” testing that use methods (e.g. in whole blood) that bear absolutely no relationship whatsoever to what is discussed above, and we have absolutely nothing 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. 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.

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.