Single article

DOI: 10.47026/2413-4864-2021-3-1-9

Kozlov V.A., Sapozhnikov S.P.

Rapid Amyloid Formation and Thrombi Formation in COVID-19 (A brief literature review)

Keywords: COVID-19, amyloid, clotting, factor XII, thrombosis, disseminated intravascular coagulation syndrome

The course of COVID-19 in patients is often complicated by hypercoagulation and thrombosis of the great vessels. Vaccination against COVID-19 with ChAdOx1 nCoV-19 (AstraZeneca) in a number of patients turned out to cause thrombocytopenia and thrombi formation in atypical (cerebral venous sinus, portal, abdominal, and hepatic veins) and typical (deep femoral and sural veins, pulmonary artery thromboembolia, acute arterial thrombosis) places. And the use of mRNA vaccines (Moderna and Pfizer) was sometimes accompanied by thrombocytopenia and hemorrhage, but without thrombi formation. This circumstance gave rise to the search for mechanisms of thrombi formation when using previously never-used vaccines developed against COVID-19. The purpose of the paper is to inform the medical community about the mechanisms of thrombi formation in COVID-19; to discuss possible pathogenetic ways of rapid amyloid formation and amyloidogenic stimulation of the coagulation hemostasis system. The only study completed to date provides information on the launch of rapid amyloid formation with the formation of dense large fibrin clots in the whole blood of both healthy people and those who were in the acute period of COVID‑19 disease by the spike protein of the COVID-19 virus capsid. The authors, having discovered the fact of the direct influence of spike protein on the formation of blood clots, nevertheless did not investigate possible pathogenetic ways of triggering thrombi formation by the spike protein. Since the authors directly pointed out the role of rapid amyloid formation in triggering coagulation, the mechanism of which is unknown to practitioners, it makes sense to discuss the issues of rapid amyloid formation in the vascular bed and the role of amyloid as a factor in triggering coagulation hemostasis. The publication under discussion is confirmed by previous studies of other authors on the influence of b‑amyloid and AA‑amyloid on the formation of blood clots in Alzheimer's disease and systemic amyloidosis. Based on the literature sources studied, we suggested that some of the patients who recovered from COVID-19 in its severe form may subsequently develop systemic amyloidosis.


  1. Ismailov D.D., Isaev T.A., Shustov S.B., Sveklina T.S., Kozlov V.A. Sravnitel’nyi analiz laboratornykh dannykh patsientov, stradayushchikh pnev-moniei, vyzvannoi SARS-COV-2, i bakterial’noi pnevmonie [Comparative analysis of laboratory data of patients suffering from pneumonia caused by SARS-COV-2 and bacterial pneumonia]. Vestnik Rossiiskoi Voenno-meditsinskoi akademii, 2020, no. 4(72), pp. 53–59.
  2. Kozlov V.A., Sapozhnikov S.P., Golenkov A.V. Epidemiologiya amiloidoza (preobladanie etiologicheskogo myshleniya) [Epidemiology of amyloidosis (predominance of etiological thinking)] Patologicheskaya fiziologiya i eksperimental’naya terapiya, 2021, vol. 65, no. 2, pp. 94–108. DOI: 10.25557/0031-2991.2021.02.94-108.
  3. Kozlov V.A., Sapozhnikov S.P., Sheptukhina A.I., Golenkov A.V. Sravni-tel’nyi analiz razlichnykh modelei amiloidoza [Comparative analysis of various models of amyloidosis] Vestnik Rossiiskoi akademii meditsinskikh nauk. 2015. T. 70. № 1. pp. 5–11. DOI: 15690/vramn.v70i1.1225
  4. Kuznik B.I., Khavinsonc V.Kh., Lin’kovac N.S. COVID-19: vliyanie na im-munitet, sistemu gemostaza i vozmozhnye puti korrektsii [COVID-19: impact on the immune system, hemostasis system and possible ways of correction]. Uspekhi fiziologi-cheskikh nauk, 2020, vol. 51, no. 4, pp. 51–63. DOI: 10.31857/S0301179820040037
  5. Lobastov K.V., Schastlivtsev I.V., Porembskaya O.Ya., Dzhenina O.V., Bargandzhiya A.B., Tsaplin S.N. COVID-19-assotsiirovannaya koagulopatiya: ob-zor sovremennykh rekomendatsii po diagnostike, lecheniyu i profilaktike [COVID-19-associated coagulopathy: an overview of current recommendations for diagnosis, treatment and prevention]. Ambulatornaya khirurgiya, 2020, no. 3–4, pp. 36–51. DOI:
  6. Yavelov I.S., Drapkina O.M. COVID-19: sostoyanie sistemy gemostaza i osobennosti antitromboticheskoi terapii [COVID-19: the state of the hemostasis system and features of antithrombotic therapy]. Kardiovaskulyarnaya terapiya i profilaktika, 2020, vol. 19, no. 3, pp. 310–318. DOI: 10.15829/1728-8800-2020-2571.
  7. Ahn H.J., Chen Z.L., Zamolodchikov D., Norris E.H., Strickland S. Interactions of β-amyloid peptide with fibrinogen and coagulation factor XII may contribute to Alzheimer’s disease. Opin. Hematol., 2017, vol. 24, no. 5, pp. 427–431. DOI: 10.1097/MOH.0000000000000368.
  8. Cajamarca S.A., Norris E.H., van der Weerd L., Strickland S., Ahn H.J. Cerebral amyloid angiopathy-linked β-amyloid mutations promote cerebral fibrin deposits via increased binding affinity for fibrinogen. Natl. Acad. Sci. USA, 2020, vol. 117, no. 25, pp. 14482–14492. DOI: 10.1073/pnas.1921327117.
  9. Cines D.B., Bussel J.B. SARS-CoV-2 Vaccine-Induced Immune Thrombotic Thrombocytopenia. Engl. J. Med., 2021, vol. 384, no. 23, pp. 2254–2256. DOI: 10.1056/NEJMe2106315.
  10. Cortes-Canteli M., Zamolodchikov D., Ahn H.J., Strickland S., Norris E.H. Fibrinogen and altered hemostasis in Alzheimer’s disease. Alzheimers Dis., 2012, vol. 32, no. 3, pp. 599–608. DOI: 10.3233/JAD-2012-120820.
  11. De Jager M., Boot M.V., Bol J.G., Brevé J.J., Jongenelen C.A., Drukarch B., Wilhelmus M.M. The blood clotting Factor XIIIa forms unique complexes with amyloid-beta (Aβ) and colocalizes with deposited Aβ in cerebral amyloid angiopathy. Neuropathol. Neurobiol., 2016, vol. 42, no. 3. pp. 255–272. DOI: 10.1111/nan.12244.
  12. Domagk G. Untersuchungen über die Bedeutung des retikuloendothelial Systems für die Entstehung d. Amyloids. Virchows Archiv. B. , 1924, vol. 253, pp. 594–638.
  13. Dovidchenko N.V., Finkelstein A.V., Galzitskaya O.V. How to determine the size of folding nuclei of protofibrils from the concentration dependence of the rate and lag-time of aggregation. I. Modeling the amyloid protofibril formation. Phys. Chem. B, 2014, vol. 118, no. 5, pp. 1189–1197. DOI: 10.1021/jp4083294.
  14. Ferguson N., Berriman J., Petrovich M., Sharpe T.D., Finch J.T., Fersht A.R. Rapid amyloid fiber formation from the fast-folding WW domain FBP28. Natl. Acad. Sci. USA, 2003, vol. 100, no. 17, pp. 9814–9819. DOI: 10.1073/pnas.1333907100.
  15. Fernández J.A., Deguchi H., Elias D.J., Griffin J.H. Serum amyloid A4 is a procoagulant apolipoprotein that it is elevated in venous thrombosis patients. Pract. Thromb. Haemost., 2019, vol. 4, no. 2, pp. 217–223. DOI: 10.1002/rth2.12291.
  16. Grobbelaar L.M., Venter C., Vlok M., Ngoepe M., Laubscher G.J., Lourens P.J., Steenkamp J., Kell D.B., Pretorius E. SARS-CoV-2 spike protein S1 induces fibrin(ogen) resistant to fibrinolysis: Implications for microclot formation in COVID-19. medRxiv03.05.21252960; DOI: 10.1101/2021.03.05.21252960.
  17. Hur W.S., Mazinani N., Lu X.J.D., Yefet L.S., Byrnes J.R., Ho L., Yeon J.H., Filipenko S., Wolberg A.S., Jefferies W.A., Kastrup C.J. Coagulation factor XIIIa cross-links amyloid β into dimers and oligomers and to blood proteins. Biol. Chem., 2019, vol. 294, no. 2, pp. 390–396. DOI: 10.1074/jbc.RA118.005352.
  18. Kitamura Y., Usami R., Ichihara S., Kida H., Satoh M., Tomimoto H., Murata M., Oikawa S. Plasma protein profiling for potential biomarkers in the early diagnosis of Alzheimer’s disease. Res., 2017, vol. 39, no. 3, pp. 231–238. DOI: 10.1080/01616412.2017.1281195.
  19. Li F. Structure, Function, and Evolution of Coronavirus Spike Proteins. Annu Rev. Virol., 2016, vol. 3, no. 1, pp. 237– DOI: 10.1146/annurev-virology-110615-042301.
  20. Li Q.X., Whyte S., Tanner J.E., Evin G., Beyreuther K., Masters C.L. Secretion of Alzheimer’s disease Abeta amyloid peptide by activated human platelets. Lab Invest., 1998, vol. 78, no. 4, pp. 461– PMID: 9564890.
  21. Maas C., Govers-Riemslag J.W., Bouma B., Schiks B., Hazenberg B.P., Lokhorst H.M., Hammarström P., ten Cate H., de Groot P.G., Bouma B.N., Gebbink M.F. Misfolded proteins activate factor XII in humans, leading to kallikrein formation without initiating coagulation. Clin. Invest., 2008, vol. 118, no. 9, pp. 3208–3218. DOI: 10.1172/JCI35424.
  22. Mahase E. Covid-19: UK offers under 40s alternative to AstraZeneca vaccine to boost confidence. BMJ. 2021. no 373:n1185. DOI: 10.1136/bmj.n1185.
  23. Noguchi M., Sato T., Nagai K., Utagawa I., Suzuki I., Arito M., Iizuka N., Suematsu N., Okamoto K., Kato T., Yamaguchi N., Kurokawa M.S. Roles of serum fibrinogen α chain-derived peptides in Alzheimer’s disease. Int. J. Geriatr. Psychiatry., 2014, vol. 29, no. 8, pp. 808–8 DOI: 10.1002/gps.4047.
  24. Page M.J., Thomson G.J.A., Nunes J.M., Engelbrecht A.M., Nell T.A., de Villiers W.J.S., de Beer M.C., Engelbrecht L., Kell D.B., Pretorius E. Serum amyloid A binds to fibrin(ogen), promoting fibrin amyloid formation. Rep., 2019, vol. 9, no. 1, p. 3102. DOI: 10.1038/s41598-019-39056-x.
  25. Poissy J., Goutay J., Caplan M., Parmentier E., Duburcq T., Lassalle F., Jeanpierre E., Rauch A., Labreuche J., Susen S. Lille ICU Haemostasis COVID-19 Group. Pulmonary Embolism in Patients With COVID-19: Awareness of an Increased Prevalence. Circulation., 2020, vol. 142, no. 2, pp. 184– DOI: 10.1161/CIRCULATIONAHA.120.047430.
  26. Sipe J.D., Benson M.D., Buxbaum J.N., Ikeda S., Merlini G., Saraiva M.J., Westermark P. Nomenclature 2014: Amyloid fibril proteins and clinical classification of the amyloidosis. Amyloid., 2014, vol. 21, no. 4, pp. 221– DOI: 10.3109/13506129.2014.964858
  27. Sipe J.D., Benson M.D., Buxbaum J.N., Ikeda S.I., Merlini G., Saraiva M.J., Westermark P. Amyloid fibril proteins and amyloidosis: chemical identification and clinical classification International Society of Amyloidosis 2016 Nomenclature Guidelines. , 2016, vol. 23, no. 4, pp. 209–213. DOI: 10.1080/13506129.2016.1257986.
  28. Sudol M., McDonald C.B., Farooq A. Molecular insights into the WW domain of the Golabi-Ito-Hall syndrome protein PQBP1. FEBS Lett., 2012, vol. 586, no. 17, pp. 2795– DOI: 10.1016/j.febslet.2012.03.041.
  29. Tjendra Y., Al Mana A.F., Espejo A.P., Akgun Y., Millan N.C., Gomez-Fernandez C., Cray C. Predicting Disease Severity and Outcome in COVID-19 Patients: A Review of Multiple Biomarkers. Pathol. Lab. Med., 2020, vol. 144, no. 12, pp. 1465–1474. DOI: 10.5858/arpa.2020-0471-SA. PMID: 32818235.
  30. Zamolodchikov D., Renné T., Strickland S. The Alzheimer’s disease peptide β-amyloid promotes thrombin generation through activation of coagulation factor XII. Thromb. Haemost., 2016, vol. 14, no. 5, pp. 995–1007. DOI: 10.1111/jth.13209.

About authors

Kozlov Vadim A.
Doctor of Biological Sciences, Candidate of Medical Sciences, Professor of the Department of Medical Biology with a course in Microbiology and Virology, Chuvash State University, Russia, Cheboksary (; ORCID:
Sapozhnikov Sergey P.
Doctor of Medical Sciences, Head of the Department of Medical Biology with a course in Microbiology and Virology, Chuvash State University, Russia, Cheboksary (; ORCID:

Article link

Kozlov V.A., Sapozhnikov S.P. Rapid Amyloid Formation and Thrombi Formation in COVID-19 (A brief literature review) [Electronic resource] // Acta medica Eurasica. – 2021. – №3. P. 1-9. – URL: DOI: 10.47026/2413-4864-2021-3-1-9.