Pathogenetically substantiated prevention of cerebrovascular disorders in patients with coronavirus disease


  • M.A. Treshchinskaia Shupyk National Medical Academy of Postgraduate Education, Kyiv, Ukraine
  • O.Ye. Kononov Shupyk National Medical Academy of Postgraduate Education, Kyiv, Ukraine
  • I.V. Belskaia Shupyk National Medical Academy of Postgraduate Education, Kyiv, Ukraine



coronavirus infection, COVID-19, SARS-CoV-2, acute stroke, Disgren


The paper deals with the basic pathogenic mechanisms of thrombosis development both arterial and venous in patients with COVID-19. These patients developed critical complications in cases of vascular risk factors that significantly enhances the risk of occurrence of such vascular events as acute ischemic stroke. The thrombophilia mechanism in a patient with COVID-19 disease turns on the direct activation of coagulation, so antiplatelet drugs cannot prevent the development of thrombosis while the vascular risk factors and prominent inflammatory reaction cause vascular events. The optimization of antiplatelet therapy in patients with
COVID-19 disease with vascular risk factors is relevant. Triflusal is an antiplatelet drug with the best characteristics for the treatment of these patients.


Download data is not yet available.


Ameriso S.F., Wong V.L., Quismorio F.P. Jr, Fisher M. Immunohematologic characteristics of infection-associated cerebral infarction. Stroke. 1991. 22. 1004. doi: 10.1161/01.STR.22.8.1004.

Asadi-Pooya A.A., Simani L. Central nervous system manifestations of COVID-19: A systematic review. J. Neurol. Sci. 2020. 413. 116832. doi: 10.1016/j.jns.2020.116832.

Baig A.M., Khaleeq A., Ali U., Syeda H. Evidence of the COVID-19 virus targeting the CNS: tissue distribution, host-virus interaction, and proposed neurotropic mechanisms. ACS Chem. Neu-rosci. 2020. 11. 995-8. doi: 10.1021/acschemneuro.0c00122.

Baig A.M. Neurological manifestations in COVID-19 caused by SARS-CoV-2. CNS Neurosci Ther. 2020. 26. 499-501. doi: 10.1111/cns.13372.

Beyrouti R., Adams M.E., Benjamin L., Cohen H., Far­mer S.F., Goh Y.Y. et al. Characteristics of ischaemic stroke associated with COVID-19. J. Neurol. Neurosurg. Psychiatry. 2020. 91. 889-91. doi: 10.1136/jnnp-2020-323586.

Bogdanov V.Y., Balasubramanian V., Hathcock J., Vele O., Lieb M., Nemerson Y. Alternatively spliced human tissue factor: a circulating, soluble, thrombogenic protein. Nat. Med. 2003. 9. 458-462.

Broze G.J. Jr. Tissue factor pathway inhibitor. Thromb. Haemost. 1995. 74. 90-93.

Chen G., Wu D., Guo W., Cao Y., Huang D., Wang H. et al. Clinical and immunological features of severe and moderate coronavirus disease 2019. J. Clin. Invest. 2020. 130. 2620-9. doi: 10.1172/JCI137244.

Cochrane Database of Systematic Reviews Triflusal for preven­ting serious vascular events in people at high risk Cochrane Systematic Review — Intervention Version published: 20 July 2005.

Das G., Mukherjee N., Ghosh S. Neurological insights of COVID-19 pandemic. ACS Chem. Neurosci. 2020. 11. 1206-9. doi: 10.1021/acschemneuro.0c00201.

Desforges M., Le Coupanec A., Dubeau P., Bourgouin A., Lajoie L., Dubé M. et al. Human coronaviruses and other respiratory viruses: underestimated opportunistic pathogens of the central nervous system? Viruses. 2019. 12. 14. doi: 10.3390/v12010014.

Eguchi S., Kawai T., Scalia R., Rizzo V. Understanding angiotensin II type 1 receptor signaling in vascular pathophysiology. Hypertension. 2018. 71. 804-10. doi: 10.1161/HYPERTENSIONAHA. 118.10266.

Ellul M.A., Benjamin L., Singh B. et al. Neurological associations of COVID-19. Lancet Neurol. 2020. 19. 767-83.

Escher R., Breakey N., Lämmle B. Severe COVID-19 infection associated with endothelial activation. Thromb. Res. 2020. 190. 62. doi: 10.1016/j.thromres.2020.04.014.

Furumoto T., Fujii S., Saito N., Mikami T., Kitabatake A. Relationships between brachial artery flow mediated dilation and carotid artery intima-media thickness in patients with suspected coronary artery disease. Jpn. Heart J. 2002. 43. 117-125.

Garcia-Rafanell J., Ramis J., Gomez L. et al. Effect of triflusal and other salicylic acid derivatives on cyclic AMP levels in rat platelets. Arch. Int. Pharmacodyn. 1986. 284. 155-65.

Gheblawi M., Wang K., Viveiros A., Nguyen Q., Zhong J.C., Turner A.J. et al. Angiotensin-converting enzyme 2: SARS-CoV-2 receptor and regulator of the renin-angiotensin system: celebrating the 20th anniversary of the discovery of ACE2. Circ. Res. 2020. 126. 1456-74. doi: 10.1161/CIRCRESAHA.120.317015.

Giacomelli A., Pezzati L., Conti F., Bernacchia D., Siano M., Oreni L. et al. Self-reported olfactory and taste disorders in patients with severe acute respiratory coronavirus 2 infection: a cross-sectional study. Clin. Infect. Dis. 2020. 71. 889-90. doi: 10.1093/cid/ciaa330.

Goshua G., Pine A.B., Meizlish M.L., Chang C.H., Zhang H., Bahel P., Baluha A., Bar N., Bona R.D., Burns A.J. et al. Endothelio-pathy in COVID-19-associated coagulopathy: evidence from a single-centre, cross-sectional study. Lancet Haematol. 2020. 7. e575-e582. doi: 10.1016/S2352-3026(20)30216-7.

Grau A.J., Urbanek C., Palm F. Common infections and the risk of stroke. Nat. Rev. Neurol. 2010. 6. 681-94. doi: 10.1038/nrneurol.2010.163.

Guan W.J., Ni Z.Y., Hu Y., Liang W.H., Ou C.Q., He J.X. et al. Clinical characteristics of coronavirus disease 2019 in China. N. Engl. J. Med. 2020. 382. 1708-720. doi: 10.1056/NEJMoa2002032.

Guzik T.J., Mohiddin S.A., Dimarco A., Patel V., Savvatis K., Marelli-Berg F.M. et al. COVID-19 and the cardiovascular system: implications for risk assessment, diagnosis, treatment options. Cardiovasc. Res. 2020. 116. 1666-87. doi: 10.1093/cvr/cvaa106.

Hankey G.J. Stroke. Lancet. 2017. 389. 641-54. doi: 10.1016/S0140-6736(16)30962-X.

Hirano T., Murakami M. COVID-19: a new virus, but a familiar receptor and cytokine release syndrome. Immunity. 2020. 52. 731-3. doi: 10.1016/j.immuni.2020.04.003.

Hurlimann D., Enseleit F., Ruschitzka F. Rheumatoid Arthritis, Inflammation, and Atherosclerosis. Herz. 2004. 29. 760-768.

Inciardi R.M., Adamo M., Lupi L., Cani D.S., Di Pasquale M., Tomasoni D. et al. Characteristics and outcomes of patients hospitalized for COVID-19 and cardiac disease in Northern Italy. Eur. Heart J. 2020. 41. 1821-9. doi: 10.1093/eurheartj/ehaa388.

José Alvarez-Sabín, Anna Penalba, Manolo Quintana, Jerzy Krupinski, Lidia García-Bonilla, Joan Montaner. Triflusal and aspirin have different effects on inflammatory biomarkers measured in patients with acute ischemic stroke. Cerebrovasc. Dis. 2009. 28(4). 371-7. doi: 10.1159/000230711. Epub 2009 Jul 30.

Kallirroi I. Kalantzi, Ioannis V. Ntalas, Vasileios G. Chantzichristos, Maria E. Tsoumani, Dimitrios Adamopoulos, Christos Asimakopoulos, Adamantios Bourdakis. Comparison of Triflusal with Aspirin in the Secondary Prevention of Atherothrombotic Events; Α Randomised Clinical Trial. Curr. Vasc. Pharmacol. 2019. 17(6). 635-643.

Kansagra A.P., Goyal M.S., Hamilton S., Albers G.W. Collateral effect of COVID-19 on stroke evaluation in the United States. N. Engl. J. Med. 2020. 383. 400-01.

Kim I., Oh J.L., Ryu Y.S., So J.N., Sessa W.C., Walsh K., Koh G.Y. Angiopoietin-1 negatively regulates expression and activity of tissue factor in endothelial cells. FASEB J. 2002. 16. 126-128.

Kirchhofer D., Tschopp T.B., Hadvary P., Baumgartner H.R. Endothelial cells stimulated with tumor necrosis factor-alpha express varying amounts of tissue factor resulting in inhomogenous fibrin deposition in a native blood flow system. Effects of thrombin inhibitors. J. Clin. Invest. 1994 May. 93(5). 2073-2083.

Klok F.A., Kruip M., van der Meer N.J.M., Arbous M.S., Gommers D., Kant K.M. et al. Incidence of thrombotic complications in critically ill ICU patients with COVID-19. Thromb. Res. 2020. 191. 145-7. doi: 10.1016/j.thromres.2020.04.013.

Klok F.A., Kruip M.J.H.A., van der Meer N.J.M., Arbous M.S., Gommers D., Kant K.M., Kaptein F.H.J., van Paassen J., Stals M.A.M., Huisman M.V. et al. Confirmation of the high cumulative incidence of thrombotic complications in critically ill ICU patients with COVID-19: an updated analysis. Thromb. Res. 2020. 191. 148-150. doi: 10.1016/j.thromres.2020.04.041.

Kuba K., Imai Y., Rao S., Gao H., Guo F., Guan B. et al. A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury. Nat. Med. 2005. 11. 875-9. doi: 10.1038/nm1267.

Laia Acarin, Berta González and Bernardo Castellano. Decrease of Proinflammatory Molecules Correlates With Neuroprotective Effect of the Fluorinated Salicylate Triflusal After Postnatal Excitotoxic Damage. Stroke. 1 October 2002. 33(10). 2499-2505.

Lechien J.R., Chiesa-Estomba C.M., De Siati D.R., Horoi M., Le Bon S.D., Rodriguez A. et al. Olfactory and gustatory dysfunctions as a clinical presentation of mild-to-moderate forms of the coronavirus disease (COVID-19): a multicenter European study. Eur. Arch. Otorhinolaryngol. 2020. 277. 2251-61. doi: 10.1007/s00405-020-05965-1.

Li Y., Li M., Wang M., Zhou Y., Chang J., Xian Y. et al. Acute cerebrovascular disease following COVID-19: a single center, retrospective, observational study. Stroke Vasc. Neurol. 2020. 5. 279-84. doi: 10.1136/svn-2020-000431.

Liu K., Pan M., Xiao Z., Xu X. Neurological manifestations of the coronavirus (SARS-CoV-2). pandemic 2019-2020. J. Neurol. Neurosurg. Psychiatry. 2020. 91. 669-70. doi: 10.1136/jnnp-2020-323177.

Lodigiani C., Iapichino G., Carenzo L., Cecconi M., Ferrazzi P., Sebastian T. et al. Venous and arterial thromboembolic complications in COVID-19 patients admitted to an academic hospital in Milan, Italy. Thromb. Res. 2020. 191. 9-14. doi: 10.1016/j.thromres.2020.04.024.

Lowenstein C.J., Solomon S.D. Severe COVID-19 Is a Microvascular Disease Circulation. 2020. 142. 1609-1611. DOI: 10.1161/CIRCULATIONAHA.120.050354.

Mao L., Jin H., Wang M., Hu Y., Chen S., He Q. et al. Neurologic manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan, China. JAMA Neurol. 2020. 77. 1-9. doi: 10.1001/jamaneurol.2020.1127.

Marchetti M., Vignoli A., Bani M.R., Balducci D., Barbui T., Falanga A. All-trans retinoic acid modulates microvascular endothelial cell hemostatic properties. Haematologica. 2003. 88. 895-905.

Menni C., Valdes A., Freydin M.B., Ganesh S., El-Sayed Moustafa J., Visconti A. et al. Loss of smell and taste in combination with other symptoms is a strong predictor of COVID-19 infection. medRxiv. 2020. doi: 10.1101/2020.04.05.20048421.

Merad M., Martin J.C. Pathological inflammation in patients with COVID-19: a key role for monocytes and macrophages. Nat. Rev. Immunolo. 2020. 20. 355-62. doi: 10.1038/s41577-020-0331-4.

Montalvan V., Toledo J.D., Nugent K. Mechanisms of stroke in coronavirus disease 2019. J. Stroke. 2020. 22. 282-3. doi: 10.5853/jos.2020.01802.

Moriguchi T., Harii N., Goto J., Harada D., Sugawara H., Takamino J. et al. A first case of meningitis/Encephalitis associated with SARS-Coronavirus-2. Int. J. Infect. Dis. 2020. 94. 55-8. doi: 10.1016/j.ijid.2020.03.062.

Muhlfelder T.W., Teodorescu V., Rand J., Rosman A., Niemetz J. Human atheromatous plaque extracts induce tissue factor activity (TFa) in monocytes and also express constitutive TFa. Thromb. Haemost. 1999. 81. 146-150.

Nemerson Y. Tissue factor and hemostasis. Blood. 1988. 71. 1-8.

O’Sullivan J.M., Gonagle D.M., Ward S.E., Preston R.J.S., O’Donnell J.S. Endothelial cells orchestrate COVID-19 coagulopathy. Lancet Haematol. 2020. 7. e553-e555. doi: 10.1016/S2352-3026(20)30215-5.

Oxley T.J., Mocco J., Majidi S., Kellner C.P., Shoirah H., Singh I.P. et al. Large-Vessel stroke as a presenting feature of covid-19 in the young. N. Engl. J. Med. 2020. 382. 60. doi: 10.1056/NEJMc2009787.

Paniz-Mondolfi A., Bryce C., Grimes Z., Gordon R.E., Rei-dy J., Lednicky J. et al. Central nervous system involvement by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). J. Med. Virol. 2020. 92. 699-702. doi: 10.1002/jmv.25915.

Pedersen S.F., Ho Y.C. SARS-CoV-2: a storm is raging. J. Clin. Invest. 2020. 130. 2202-5. doi: 10.1172/JCI137647.

Pérez-Gómez F., Salvador A., Zumalde J., Iriarte J.A., Berjón J., Alegría E., Almería C., Bover R., Herrera D., Fernández C. Cochrane Central Register of Controlled Trials. Effect of antithrombotic therapy in patients with mitral stenosis and atrial fibrillation: a sub-analysis of NASPEAF randomized trial European heart journal. 2006. 27(8). 960-967.

Poyiadji N., Shahin G., Noujaim D., Stone M., Patel S., Griffith B. COVID-19-associated acute hemorrhagic necrotizing encephalopathy: CT and MRI features. Radiology. 2020. 292. 119-20. doi: 10.1148/radiol.2020201187.

Salom R.N., Maguire J.A., Hancock W.W. Endothelial activation and cytokine expression in human acute cardiac allograft rejection. Pathology. 1998. 30. 24-29.

Sanchez de Miguel L., Rico L., Jimenez A. et al. Effect of oral triflusal treatment on nitric oxide production and endothelial nitric oxide synthase protein expression in neutrophils from healthy donors [abstract no.P10/10172]. Eur. J. Heart Fail. 2000 Jun. 2(2) 43.

Sanghoon Shin, Kwang-Joon Kim, In-Jeong Cho, Geu-Ru Hong, Yangsoo Jang, Namsik Chung, Young Min Rah, Hyuk-Jae Chang Yonsei. Effect of Triflusal on Primary Vascular Dysregulation Compared with Aspirin: A Double-Blind, Randomized, Crossover Trial Med. J. 2015 Sep. 56(5). 1227-1234.

Santos R.A.S., Oudit G.Y., Verano-Braga T., Canta G., Steckelings U.M., Bader M. The renin-angiotensin system: going beyond the classical paradigms. Am. J. Physiol. Heart Circ. Physiol. 2019. 316. 958-70. doi: 10.1152/ajpheart.00723.2018.

Schecter A.D., Spirn B., Rossikhina M., Giesen P.L., Bogdanov V., Fallon J.T., Fisher E.A., Schnapp L.M., Nemerson Y., Taubman M.B. Release of active tissue factor by human arterial smooth muscle cells. Circ. Res. 2000. 87. 126-132.

Seung-Woo Kim, Kyu-Jin Choi, Ju-Young Park, Sung-Hwa Yoon, Ja-Kyeong Lee. Neuroprotective effect of triflusal and its main metabolite, 2-hydroxy-4-trifluoromethylbenzoic acid (HTB), in the postischemic brain. Neurosci Lett. 2017 Mar 16. 643. 59-64. doi: 10.1016/j.neulet.2017.02.018. Epub 2017 Feb 9.

Siegler J.E., Heslin M.E., Thau L., Smith A., Jovin T.G. Falling stroke rates during COVID-19 pandemic at a Comprehensive Stroke Center: cover title: falling stroke rates during COVID-19. J. Stroke Cerebrovasc. Dis. 2020. 29. 104953.

Simes J., Robledo K.P., White H.D., Espinoza D., Ste­wart R.A., Sullivan D.R. et al. D-Dimer predicts long-term cause-specific mortality, cardiovascular events, and cancer in patients with stable coronary heart disease: LIPID study. Circulation. 2018. 138. 712-23. doi: 10.1161/CIRCULATIONAHA.117.029901.

Szotowski B., Antoniak S., Poller W., Schultheiss H., Rauch U. Procoagulant Soluble Tissue Factor Is Released From Endothelial Cells in Response to Inflammatory Cytokines. Circulation Research. 2005. 96. 1233-1239.

Tang N., Li D., Wang X., Sun Z. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J. Thromb. Haemost. 2020. 18. 844-7. doi: 10.1111/jth.14768.

Tentolouris C., Tousoulis D., Antoniades C., Bosinakou E., Kotsopoulou M., Trikas A., Toutouzas P., Stefanadis C. Endothelial function and proinflammatory cytokines in patients with ischemic heart disease and dilated cardiomyopathy. Int. J. Cardiol. 2004. 94. 301-305.

Van Den Hengel L.G., Versteeg H.H. Tissue factor signaling: a multi-faceted function in biological processes. Front. Biosci. 2011. 3. 240. doi: 10.2741/240.

Varga Z., Flammer A.J., Steiger P., Haberecker M., Andermatt R., Zinkernagel A.S., Mehra M.R., Schuepbach R.A., Ruschitzka F., Moch H. Endothelial cell infection and endotheliitis in COVID-19. Lancet. 2020. 395. 1417-1418. doi: 10.1016/S0140-6736(20)30937-5.

Wang B., Li R., Lu Z., Huang Y. Does comorbidity increase the risk of patients with COVID-19: evidence from meta-analysis. ­Aging. 2020. 12. 6049-57. doi: 10.18632/aging.103000.

Wang D., Hu B., Hu C., Zhu F., Liu X., Zhang J. et al. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA. 2020. 323. 1061-9. doi: 10.1001/jama.2020.1585.

Wang H.Y., Li X.L., Yan Z.R., Sun X.P., Han J., Zhang B.W. Potential neurological symptoms of COVID-19. Ther. Adv. Neurol. ­Disord. 2020. 13. 1756286420917830. doi: 10.1177/1756286420917830.

Wang Z., Yang Y., Liang X., Gao B., Liu M., Li W., Chen Z., Wang Z. COVID-19 Associated Ischemic Stroke and Hemorrhagic Stroke: Incidence, Potential Pathological Mechanism, and Management. Front. Neurol. 2020. 11. 571996. doi: 10.3389/fneur.2020.571996.

Wu Y., Xu X., Chen Z., Duan J., Hashimoto K., Yang L. et al. Nervous system involvement after infection with COVID-19 and other coronaviruses. Brain Behav. Immun. 2020. 87. 18-22. doi: 10.1016/j.bbi.2020.03.031.

Xia H., Lazartigues E. Angiotensin-converting enzyme 2 in the brain: properties and future directions. J. Neurochem. 2008. 107. 1482-94. doi: 10.1111/j.1471-4159.2008.05723.x.

Xu J., Zhong S., Liu J., Li L., Li Y., Wu X. et al. Detection of severe acute respiratory syndrome coronavirus in the brain: potential role of the chemokine mig in pathogenesis. Clin. Infect. Dis. 2005. 41. 1089-96. doi: 10.1086/444461.

Yao Z., Zheng Z., Wu K., Junhua Z. Immune environment modulation in pneumonia patients caused by coronavirus: SARS-CoV, MERS-CoV and SARS-CoV-2. Aging. 2020. 12. 7639-51. doi: 10.18632/aging.103101.

Zhou P., Yang X.L., Wang X.G., Hu B., Zhang L., Zhang W. et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature. 2020. 579. 270-3. doi: 10.1038/s41586-020-2012-7.

Zotowski B., Antoniak S., Poller W., Schultheiss H.P., Rauch U. Procoagulant soluble tissue factor is released from endothelial cells in response to inflammatory cytokines. Circ. Res. 2005. 96. 1233-9. doi: 10.1161/01.RES.0000171805.247 99.fa.



How to Cite

Treshchinskaia, M., Kononov, O., & Belskaia, I. (2021). Pathogenetically substantiated prevention of cerebrovascular disorders in patients with coronavirus disease. INTERNATIONAL NEUROLOGICAL JOURNAL, 16(7), 23–31.



Original Researches