A misdirected agenda seemingly seeking to provide more misinformation about microclots

Yet again in a series of blog posts such as https://dbkgroup.org/drawing-wrong-conclusions-by-doing-the-wrong-experiments-and-or-failing-to-do-the-correct-ones/ I find I have to write a rebuttal a paper [1] that self-evidently set out to try and discredit our fibrinaloid microclot complex (‘microclot’) work but that – like the others I have criticised in this blog – misses out important details, makes no attempt to reproduce our amyloid microclot experiments, and draws conclusions that seemingly bear little or no relation to what was observed (however artefactual, as seems in many ways to be in this case). The purposely declarative title is “No evidence of hypercoagulability, altered fibrinolysis, or increased fibrin(ogen) microaggregates in never-hospitalized long COVID”. As in the above blog, one has to point out that absence of evidence is not evidence of absence.

An equally risible endorsement of the paper appears at https://meassociation.org.uk/2026/10/research-the-controversial-microclot-theory-and-the-use-of-anticoagulant-medication-to-treat-long-covid/ who also seem to believe that ME is a psychological disorder so are necessarily ideologically opposed to people who find biochemical differences (such as [2] and a huge multitude of others) that can actually explain these disorders.

Frankly, the journal should have rejected this paper out of hand.

We do not really understand the agenda of people who criticise our work in this way (some not for the first time). Hopefully it is not an attempt to try to discredit thrombotic properties as a cause of (both acute and) Long COVID in an attempt to draw attention away from the appalling and frankly insulting fiction about ME/CFS and Long COVID (LC) being purely psychological.

Although it is quite hard to tell precisely what was done and why, the paper in question [1] uses samples that were “processed within 4 h of collection” and then frozen. If they were left that long the counts would drop, so if most of the longer delays were in samples from clinics and so biased towards the LC group that alone would explain the lack of a difference (as they do actually recognise, which hardly then justifies the declarative title). More importantly, though, it is practically impossible to know what is being measured as in contrast to those in our very our extensive papers (linked at https://dbkgroup.org/longcovid/) and that of Dalton and colleagues [3], no attempt was made to reproduce our findings by adding thioflavin T or Amytracker dyes. So until folk actually set out to do the same experiments as we (and others, e.g. [4, 5]) have, any claims about (fibrinaloid) microclots are simply rubbish as they are not seeking to measure them.

The comment is made that “Fibrin structure in LC has not previously been reported.” A very bold claim to priority, but one very easily shown to be false by simply pointing at where they have been (and some of these were even cited by Fraser et al…), e.g. [6-9].

The claim is then made that the failure of STIMULATE-ICP to find a benefit in the anti-coagulant rivaroxaban somehow makes the microclot theory false. Apart from the complete lack of patient stratification in that study, which almost guaranteed that they would fail, we and others have pointed out COUNTLESS times that BOTH arms of the clotting cascade have to be blocked to expect any benefit, as should be known by anyone who considers themselves even vaguely expert in the field. Continuing to trot out such misinformation is completely unworthy, but if authors choose to do so they can expect to be criticised.

It is then stated that “Plasma exchange has been proposed as a potential treatment as hypothetically it could remove ‘microclots/microaggregates’ from the circulation” but again the fact that no benefit was found only shows that it was a daft hypothesis. If you only remove a small fraction of plasma the remaining microclots will still temporarily block up capillaries, as again a moment’s rational thought would have made obvious.

Table 1 has three classes of individual (breathless, non-breathless and control), but only one p-value so what is actually being compared with what is opaque, albeit no comparisons were seemingly ‘significant’.

Then we come to the (single) figure (whose construction seemingly required 18 coauthors plus whoever is in EXPLAIN). I find this figure completely uninterpretable. There are pictures of various aggregates that are red, but the methods (in Supplementary figure 4 of [1]) state that (as in [10]) this was from Alexa-labelled fibrinogen that was ADDED to the samples, so what is being measured here, and what they were created from, is quite beyond me. This assay may be measuring the propensity of plasma samples to recruit or incorporate an exogenous fibrinogen tracer into aggregates under the experimental conditions, but it tells one nothing about the origin of the aggregates. Also the hydrophobic dye used is stated to be measuring membranes, but I have seen no independent evidence of that: hydrophobic molecules (such as general anaesthetics [11, 12]) will bind to hydrophobic patches on proteins too [13-18], as is in fact conceded in the original paper [10] but now seemingly forgotten.

Also, the statement [1] that ‘no measured biomarker differed between groups’ makes one wonder whether the patient and control classes they defined were in fact functionally different at all. It is simply stated that LC was diagnosed according to a NICE guideline, and that “all LC participants had significant persistent symptom burden” but no symptomological or severity data were in fact provided to back up that claim, nor any attempt made to compare their observations with disease severity (with which – given the lack of differences – there would presumably have been no correlation). By contrast we have shown that illness severity, virulence and amyloidogenicity are clearly related as the strain of SARS-CoV-2 and its spike protein vary [19, 20], providing strong evidence that the fibrinaloid microclot complexes are on the disease pathway (evidence completely ignored by Fraser et al. [1]).

The Table below summarises the substantial differences between the fibrinaloid microclot complexes that we have observed and studied in detail (e.g. [21] and references therein) and whatever is claimed to be being measured by Fraser et al. [1]. Obviously they are completely unrelated.

As the previous blog remarked “…we would suggest that the first job of authors claiming findings that purport to contradict a substantial literature (even if they choose to ignore it) is actually to try and do the same experiments.” Failing to do so is simply anti-intellectual, and will be called out every time.

References

1. Fraser, E., Ng, K., Hasan, N., Dunstan, I., Laws, A., Macrae, F., Abu-Hanna, J., Ariens, R., Harris, V., Oke, J., Saunders, L., Grist, J., Collier, G., Hughes, P., Wild, J., Thompson, R., Gleeson, F., Shapiro, S. and EXPLAIN Investigators. (2026) No evidence of hypercoagulability, altered fibrinolysis, or increased fibrin(ogen) microaggregates in never-hospitalized long COVID. Hemasphere. 10, e70501. https://doi.org/10.1002/hem3.70501
2. Cervia-Hasler, C., Bruningk, S. C., Hoch, T., Fan, B., Muzio, G., Thompson, R. C., Ceglarek, L., Meledin, R., Westermann, P., Emmenegger, M., Taeschler, P., Zurbuchen, Y., Pons, M., Menges, D., Ballouz, T., Cervia-Hasler, S., Adamo, S., Merad, M., Charney, A. W., Puhan, M., Brodin, P., Nilsson, J., Aguzzi, A., Raeber, M. E., Messner, C. B., Beckmann, N. D., Borgwardt, K. and Boyman, O. (2024) Persistent complement dysregulation with signs of thromboinflammation in active Long Covid. Science. 383, eadg7942. https://doi.org/10.1126/science.adg7942
3. Dalton, C. F., de Oliveira, M. I. R., Stafford, P., Peake, N., Kane, B., Higham, A., Singh, D., Jackson, N., Davies, H., Price, D., Duncan, R., Tattersall, N., Barnes, A. and Smith, D. P. (2024) Increased fibrinaloid microclot counts in platelet-poor plasma are associated with Long COVID. medRxiv, 2024.2004.2004.24305318. https://doi.org/10.1101/2024.04.04.24305318
4. Okuducu, Y. K., Boribong, B., Ellett, F., Hajizadeh, S., VanElzakker, M., Haas, W., Pillai, S., Fasano, A., Irimia, D. and Yonker, L. (2024) Evidence Circulating Microclots and Activated Platelets Contribute to Hyperinflammation Within Pediatric Post Acute Sequala of COVID. Am J Respir Crit Care Med. 209, A2247.
5. Steifman, C. B., Alvarez-Carcamo, B., Verma, S., McCarthy, R., Guthrie, L. B., Gill, K. K., Swank, Z., Walt, D. R., Grabowski, E. F., Fasano, A., VanElzakker, M. B., Irimia, D. and Yonker, L. M. (2026) Endovascular profiles linked to neutrophil activation in children and young adults with long COVID. Pediatr Reshttps://doi.org/10.1038/s41390-026-05024-1
6. Pretorius, E., Vlok, M., Venter, C., Bezuidenhout, J. A., Laubscher, G. J., Steenkamp, J. and Kell, D. B. (2021) Persistent clotting protein pathology in Long COVID/ Post-Acute Sequelae of COVID-19 (PASC) is accompanied by increased levels of antiplasmin. Cardiovasc Diabetol. 20, 172. https://doi.org/10.1186/s12933-021-01359-7
7. Pretorius, E., Venter, C., Laubscher, G. J., Kotze, M. J., Oladejo, S., Watson, L. R., Rajaratnam, K., Watson, B. W. and Kell, D. B. (2022) Prevalence of symptoms, comorbidities, fibrin amyloid microclots and platelet pathology in individuals with Long COVID/ Post-Acute Sequelae of COVID-19 (PASC) Cardiovasc Diabetol. 21, 148. https://doi.org/10.1186/s12933-022-01579-5
8. Kruger, A., Vlok, M., Turner, S., Venter, C., Laubscher, G. J., Kell, D. B. and Pretorius, E. (2022) Proteomics of fibrin amyloid microclots in Long COVID/ Post-Acute Sequelae of COVID-19 (PASC) shows many entrapped pro-inflammatory molecules that may also contribute to a failed fibrinolytic system. Cardiovasc Diabetol. 21, 190. https://doi.org/10.1186/s12933-022-01623-4
9. Turner, S., Laubscher, G. J., Khan, M. A., Kell, D. B. and Pretorius, E. (2023) Accelerating discovery: A novel flow cytometric method for detecting fibrin(ogen) amyloid microclots using long COVID as a model Heliyon. 9, e19605. https://doi.org/10.1016/j.heliyon.2023.e19605
10. Baker, S. R., Halliday, G., Ząbczyk, M., Alkarithi, G., Macrae, F. L., Undas, A., Hunt, B. J. and Ariëns, R. A. S. (2023) Plasma from patients with pulmonary embolism show aggregates that reduce after anticoagulation. Commun Med (Lond). 3, 12. https://doi.org/10.1038/s43856-023-00242-8
11. Franks, N. P. and Lieb, W. R. (1984) Do general anaesthetics act by competitive binding to specific receptors? Nature. 310, 599-601.
12. Franks, N. P., Jenkins, A., Conti, E., Lieb, W. R. and Brick, P. (1998) Structural basis for the inhibition of firefly luciferase by a general anesthetic. Biophys J. 75, 2205-2211.
13. Dixon, N. M. and Kell, D. B. (1989) The inhibition by CO2 of the growth and metabolism of microorganisms. J. Appl. Bacteriol. 67, 109-136. https://doi.org/10.1111/j.1365-2672.1989.tb03387.x
14. Kell, D. B., Dobson, P. D., Bilsland, E. and Oliver, S. G. (2013) The promiscuous binding of pharmaceutical drugs and their transporter-mediated uptake into cells: what we (need to) know and how we can do so. Drug Disc Today. 18, 218-239. https://doi.org/10.1016/j.drudis.2012.11.008
15. Kell, D. B. (2015) What would be the observable consequences if phospholipid bilayer diffusion of drugs into cells is negligible? Trends Pharmacol Sci. 36, 15-21. https://doi.org/10.1016/j.tips.2014.10.005
16. Kell, D. B. (2015) The transporter-mediated cellular uptake of pharmaceutical drugs is based on their metabolite-likeness and not on their bulk biophysical properties: Towards a systems pharmacology Perspect Sci. 6, 66-83. https://doi.org/10.1016/j.pisc.2015.06.004
17. Kell, D. B. and Oliver, S. G. (2014) How drugs get into cells: tested and testable predictions to help discriminate between transporter-mediated uptake and lipoidal bilayer diffusion. Front Pharmacol. 5, 231. https://doi.org/10.3389/fphar.2014.00231
18. Kell, D. B. (2021) The transporter-mediated cellular uptake and efflux of pharmaceutical drugs and biotechnology products: how and why phospholipid bilayer transport is negligible in real biomembranes. Molecules. 26, 5629. https://doi.org/10.3390/molecules26185629
19. Grobbelaar, L. M., Venter, C., Vlok, M., Ngoepe, M., Laubscher, G. J., Lourens, P. J., Steenkamp, J., Kell, D. B. and Pretorius, E. (2021) SARS-CoV-2 spike protein S1 induces fibrin(ogen) resistant to fibrinolysis: implications for microclot formation in COVID-19. Biosci Rep. 41, BSR20210611. https://doi.org/10.1042/BSR20210611
20. Grobbelaar, L. M., Kruger, A., Venter, C., Burger, E. M., Laubscher, G. J., Maponga, T. G., Kotze, M. J., Kwaan, H. C., Miller, J. B., Fulkerson, D., Huff, W., Chang, E., Wiarda, G., Bunch, C. M., Walsh, M. M., Raza, S., Zamlut, M., Moore, H. B., Moore, E. E., Neal, M. D., Kell, D. B. and Pretorius, E. (2022) Relative hypercoagulopathy of the SARS-CoV-2 Beta and Delta variants when compared to the less severe Omicron variants is related to TEG parameters, the extent of fibrin amyloid microclots, and the severity of clinical illness. Semin Thromb Haemost. 48, 858-868. https://doi.org/10.1055/s-0042-1756306
21. Grixti, J. M., Pretorius, E. and Kell, D. B. (2026) Uncovering the hidden biology of fibrinaloid microclot complexes in complex, inflammatory diseases. QRB Discovery. 7, e9. https://doi.org/10.1017/qrd.2026.10022