Pathogenetic continuum of coagulopathies and the complexity of their therapy in COVID‐19: 616-005.6:616.151.5

Abstract

Summary. In aspect of displaying the mosaic of potential COVID-19 pathogenesis mechanisms, its coagulopathy more seems as the manifestation of pathogenicity continuum with participation of many factors. It is illustrated by confirming an active role of the system complement in the immunoinflammatory pathogenesis of coagulopathy in COVID-19. The complement system and hemostasis are structurally and evolutionary related and also are functionally closely connected. Their activation is mutually dependent. In case of disturbed regulation the mutual coactivation can have the potential of becoming a pathologic vicious cycle complicating COVID-19 course and its therapy. The relationship of complement activation and severe COVID-19 forms, the rever- sion of thrombotic microangiopathy by complement inhibitors, decreasing acute lung lesions by inhibiting complement serve as indication for using immunotherapy in case of coagulopathy in COVID-19 taking into account its side effects.

References:

1. Connors J.M., Levy J.H. COVID‐19 and its implications for throm‐ bosis and anticoagulation. Blood. 2020;135(23):2033–40. DOI: 10.1182/blood.2020006000. 

2. KharchenkoE.P.Arterialhypertension:аnexpandingpathogenic continuum and therapeutic limitations. Terapevticheskij arhiv. 2015;87(1):100–4. (In Russ.). DOI: 10.17116/terarkh2015871100–104. 

3. Perico L., Benigni A., Casiraghi F. et al. Immunity, endothelial injury and complement‐induced coagulopathy in COVID‐ Nat Rev Nephrol. 2021;17(1):46–64. DOI: 10.1038/s41581–020–00357–4. 

4. Santiesteban‐Lores L.E., Amamura T.A., da Silva T.F. et al. A dou‐ ble edged‐sword — the complement system during SARS‐CoV‐2 infection. Life Sci. 2021;272:119245. DOI: 10.1016/j.lfs.2021.119245. 

5. Benmansour N.C., Carvelli J., Vivier E. Complement cascade in severe forms of COVID‐19: recent advances in therapy. Eur J Immu- nol. 2021;51(7):1652–9. DOI: 10.1002/eji.202048959. 

6. van der Lee R., Buljan M., Lang B. et al. Classification of intrinsi‐ cally disordered regions and proteins. Chem Rev. 2014;114(13):6589– DOI: 10.1021/cr400525m. 

7. Kharchenko E.P. The coronavirus SARS‐CoV‐2: the characteris‐ tics of structural proteins, contagiousness, and possible immune collisions. Epidemiologiya i vakcinoprofilaktika. 2020;19(2):13–30. (In Russ.). DOI: 10.31631/2073–3046–2020–19–2–13–30. 

8. Kharchenko E.P. The coronavirus SARS‐CoV‐2: the complexity of infection pathogenesis, the search of vaccines and possible future pandemics. Epidemiologiya i vakcinoprofilaktika. 2020;19(3):4–20. (In Russ.). DOI: 10.31631/2073–3046–2020–19–3–4–20. 

9. KharchenkoE.P.Thecomplexityofcoagulopathypathogenesisin COVID‐19. Tromboz, gemostaz i reologiya. 2020;(4):41–51. (In Russ.). DOI: 10.25555/THR.2020.4.0944. 

10. Liu L., Wang P., Nair M.S. et al. Potent neutralizing antibod‐ ies directed to multiple epitopes on SARS‐CoV‐2 spike. Nature. 2020;584(7821):450–6. DOI: 10.1038/s41586–020–2571–7. 

11. Peeling R.W., Wedderburn C.J., Garcia P.J. et al. Serology testing in the COVID‐19 pandemic response. Lancet Infect Dis. 2020;20(9): e245‐ DOI: 10.1016/S1473–3099(20)30517‐X. 

12. Ahmed S.S., Volkmuth W., Duca J. et al. Antibodies to influenza nucleoprotein cross‐react with human hypocretin receptor 2. Sci Transl Med. 2015;7(294).ra105. DOI: 10.1126/scitranslmed.aab2354. 

13. Kharchenko E.P. The possible collisions in virus infection immuno‐ diagnostics and vaccination. Infekciya i immunitet. 2016;6(2):157– 64. (In Russ.). DOI: 10.15789/2220–7619–20162–157–164.

1. Taquet M., Geddes J.R., Husain M. et al. 6‐month neurological and psychiatric outcomes in 236 379 survivors of COVID‐19: a retro‐ spective cohort study using electronic health records. Lancet Psy- chiatry. 2021;8(5):416–27. DOI: 10.1016/S2215–0366(21)00084–5.
2. Kharchenko E.P. Vaccines against Covid‐19: the comparative esti‐ mates of risks in adenovirus vectors. Epidemiologiya i vakcinopro- filaktika. 2020;19(5):4–17. (In Russ.). DOI: 10.31631/2073–3046– 2020–19–5–4–17.

1. Eriksson O., Hultstrom M., Persson B. et al. Mannose‐binding lec‐ tin is associated with thrombosis and coagulopathy in critically ill COVID‐19 patients. Thromb Haemost. 2020;120(12):1720–4. DOI: 1055/s‐0040–1715835.
2. Oncula S., Afshar‐Kharghan V. The interaction between the complement system and hemostatic factors. Curr Opin Hema- tol. 2020;27(5):341–52. DOI: 10.1097/MOH.0000000000000605.
3. Huang T., Garcia‐Carreras B., Hitchings M.D.T. et al. A syste‐ matic review of antibody mediated immunity to coronaviruses: antibody kinetics, correlates of protection, and association of antibody responses with severity of disease. medRxiv. 2020 Apr 17;2020.04.14.20065771. DOI: 10.1101/2020.04.14.20065771. Pre‐
4. Ouldali N., Pouletty M., Mariani P. et al. Emergence of Kawa‐ saki disease related to SARS‐CoV‐2 infection in an epicentre of the French COVID‐19 epidemic: a time‐series analysis. Lan- cet Child Adolesc Health. 2020;4(9):662–8. DOI: 10.1016/S2352– 4642(20)30175–9.
5. KharchenkoE.P.Immunepitopecontinuumoftheproteinrela‐ tionships, poly and autoreactivity of antibodies. Medicinskaya immunologiya. 2015;17(4):335–46. (In Russ.). DOI: 10.15789/1563– 0625–2015–4–335–346.
6. COVID‐19 Vaccine Janssen: EMA finds possible link to very rare cases of unusual blood clots with low blood platelets. European Medicines Agency. News 20/04/2021. Available at: https://www. ema.europa.eu/en/news/covid‐19‐vaccine‐janssen‐ema‐finds‐ possible‐link‐very‐rare‐cases‐unusual‐blood‐clots‐low‐
7. Greinacher A., Thiele T., Warkentin T.E., Weisser K. et al. Throm‐ botic thrombocytopenia after ChAdOx1 nCov‐19 vaccination. N Engl J Med. 2021;384(22):2092–101. DOI: 10.1056/NEJMoa210484
8. Cines D.B., Bussel J.B. SARS‐CoV‐2 Vaccine‐induced immune thrombotic thrombocytopenia. N Engl J Med. 2021;384(23):2254– 6. DOI: 10.1056/NEJMe2106315.
9. Lee E.J., Cines D.B., Gernsheimer T. et al. Thrombocytopenia fol‐ lowing Pfizer and Moderna SARS‐CoV‐2 vaccination. Am J Hema- tol. 2021;96(5):534–47. DOI:10.1002/ajh.26132.
10. Theofilopoulos A.N., Kono D.H., Baccala R. The multiple pathways to autoimmunity. Nat Immunol. 2017;18(7):716–24. DOI: 10.1038/ni.3731.
11. Zabolotskikh I.B., Kirov M. Yu., Lebedinskii K.M. et al. Anesthesia and intensive care for patients with COVID‐19. Russian Federa‐ tion of anesthesiologists and reanimatologists guidelines. Vestnik intensivnoj terapii imeni A.I. Saltanova. 2022;(1):5–140. (In Russ.). DOI: 10.21320/1818–474X‐2022–1–5–140.

1. Kudlay D.A., Bakirov B.A., Pavlov V.N. The nature of the mono‐ clonal antibody eculizumab and its potential for corona‐virus infection COVID‐19. Tromboz, gemostaz i reologiya. 2020;(2):27– 32. (In Russ.). DOI: 10.25555/THR.2020.2.0915.

1. Van Regenmortel M. An outdated notion of antibody specificity is one of the major detrimental assumptions of the structure‐based reverse vaccinology paradigm, which prevented it from helping to develop an effective HIV‐1 vaccine. Front Immunol. 2014;5:593. DOI: 10.3389/fimmu.2014.00593.