Please wait a minute...
Reviews in Cardiovascular Medicine  2020, Vol. 21 Issue (3): 315-319     DOI: 10.31083/j.rcm.2020.03.126
Special Issue: Utilizing Technology in the COVID 19 era
Review | Next articles
Endothelial dysfunction contributes to COVID-19-associated vascular inflammation and coagulopathy
Jun Zhang1, *(), Kristen M. Tecson1, Peter A. McCullough1, 2, 3
1Baylor Heart and Vascular Institute, Dallas, TX 75226, USA
2Baylor University Medical Center, Dallas, TX 75226, USA
3Baylor Jack and Jane Hamilton Heart and Vascular Hospital, Dallas, TX 75226, USA
Download:  PDF(923KB)  ( 1778 ) Full text   ( 200 )
Export:  BibTeX | EndNote (RIS)      
Abstract:

Great attention has been paid to endothelial dysfunction (ED) in coronavirus disease 2019 (COVID-19). There is growing evidence to suggest that the angiotensin converting enzyme 2 receptor (ACE2 receptor) is expressed on endothelial cells (ECs) in the lung, heart, kidney, and intestine, particularly in systemic vessels (small and large arteries, veins, venules, and capillaries). Upon viral infection of ECs by severe acute respiratory syndrome coronarvirus 2 (SARS-CoV-2), ECs become activated and dysfunctional. As a result of endothelial activation and ED, the levels of pro-inflammatory cytokines (interleukin -1, interleukin-6 (IL-6), and tumor necrosis factor-α), chemokines (monocyte chemoattractant protein-1), von Willebrand factor (vWF) antigen, vWF activity, and factor VIII are elevated. Higher levels of acute phase reactants (IL-6, C-reactive protein, and D-dimer) are also associated with SARS-CoV-2 infection. Therefore, it is reasonable to assume that ED contributes to COVID-19-associated vascular inflammation, particularly endotheliitis, in the lung, heart, and kidney, as well as COVID-19-associated coagulopathy, particularly pulmonary fibrinous microthrombi in the alveolar capillaries. Here we present an update on ED-relevant vasculopathy in COVID-19. Further research for ED in COVID-19 patients is warranted to understand therapeutic opportunities.

Key words:  COVID-19      coagulation      cytokines      endothelial dysfunction      SARS-CoV-2      von Willebrand factor      thrombosis     
Submitted:  02 July 2020      Revised:  10 August 2020      Accepted:  12 August 2020      Published:  30 September 2020     
Fund: Baylor Health Care System Foundation
*Corresponding Author(s):  Jun Zhang     E-mail:  Zhangj37@gmail.com

Cite this article: 

Jun Zhang, Kristen M. Tecson, Peter A. McCullough. Endothelial dysfunction contributes to COVID-19-associated vascular inflammation and coagulopathy. Reviews in Cardiovascular Medicine, 2020, 21(3): 315-319.

URL: 

https://rcm.imrpress.com/EN/10.31083/j.rcm.2020.03.126     OR     https://rcm.imrpress.com/EN/Y2020/V21/I3/315

Fig. 1.  Schematic diagram depicting endothelial dysfunction (ED) contributing to COVID-19-associated vascular inflammation and coagulopathy. The angiotensin converting enzyme 2 (ACE2) receptor is widely expressed on endothelial cells in the lung, heart, kidney, and intestine, allowing endothelial cells (EC) to be infected by severe acute respiratory syndrome coronarvirus 2 (SARS-CoV-2). The sequence of cellular events leading to ED begins (as early as) immediately for type I EC activation, followed by type II EC activation, EC apoptosis, and EC necrosis. Type I EC activation does not require de novo protein synthesis by means of immediately releasing pro-stored proteins such as von Willebrand factor (vWF), P-selectin, thrombin, and histamine. Conversely, type II EC activation requires de novo protein synthesis by means of releasing new proteins such as vWF, Tissue factor, fibrinogen, E-selectin, intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), interleukin-1 (IL-1), monocyte chemoattractant protein-1, (MCP-1), and C-reactive protein. Endothelial apoptosis results in endothelial detachment by anoikis & denudation of basement membrane, whereas endothelial necrosis results in further release of thrombomudulin and vWF. Finally, leukocyte adhesion molecules, pro-inflammatory cytokines (IL-1, IL-6, and TNF), chemokines (MCP-1), together with pro-coagulant molecules contribute to COVID-19 –associated inflammation and coagulopathy.

[1] Ackermann, M., Verleden, S. E., Kuehnel, M., Haverich, A., Welte, T., Laenger, F., Vanstapel, A., Werlein, C., Stark, H., Tzankov, A., Li, W. W., Li, V. W., Mentzer, S. J. and Jonigk, D. (2020) Pulmonary Vascular endothelialitis, thrombosis, and angiogenesis in Covid-19. New England Journal of Medicine 383, 120-128.
[2] Adachi, T., Chong, J., Nakajima, N., Sano, M., Yamazaki, J., Miyamoto, I., Nishioka, H., Akita, H., Sato, Y., Kataoka, M., Katano, H., Tobiume, M., Sekizuka, T., Itokawa, K., Kuroda, M. and Suzuki, T. (2020) Clinicopathologic and immunohistochemical findings from autopsy of patient with COVID-19, Japan. Emerging Infectious Diseases 26, 2157-2161.
[3] Becker, R. C. (2020) COVID-19 update: Covid-19-associated coagulopathy. Journal of Thrombosis and Thrombolysis 50, 54-67.
[4] Buja, L. M., Wolf, D. A., Zhao, B., Akkanti, B., McDonald, M., Lelenwa, L., Reilly, N., Ottaviani, G., Elghetany, M. T., Trujillo, D. O., Aisenberg, G. M., Madjid, M. and Kar, B. (2020) The emerging spectrum of cardiopulmonary pathology of the coronavirus disease 2019 (COVID-19): Report of 3 autopsies from Houston, Texas, and review of autopsy findings from other United States cities. Cardiovascular Pathology 48, 107233.
[5] Chen, G., Wu, D., Guo, W., Cao, Y., Huang, D., Wang, H., Wang, T., Zhang, X., Chen, H., Yu, H., Zhang, X., Zhang, M., Wu, S., Song, J., Chen, T., Han, M., Li, S., Luo, X., Zhao, J. and Ning, Q. (2020) Clinical and immunological features of severe and moderate coronavirus disease 2019. Journal of Clinical Investigation 130, 2620-2629.
[6] Escher, R., Breakey, N. and Lämmle, B. (2020) Severe COVID-19 infection associated with endothelial activation. Thrombosis Research 190, 62.
[7] Fox, S. E., Akmatbekov, A., Harbert, J. L., Li, G., Quincy Brown, J. and Vander Heide, R. S. (2020) Pulmonary and cardiac pathology in African American patients with COVID-19: an autopsy series from New Orleans. The Lancet Respiratory Medicine 8, 681-686.
[8] Gimbrone, M. A. and García-Cardeña, G. (2016) Endothelial cell dysfunction and the pathobiology of atherosclerosis. Circulation Research 118, 620-636.
[9] Klok, F. A., Kruip, M. J. H. A., van der Meer, N. J. M., Arbous, M. S., Gommers, D. A. M. P. J., Kant, K. M., Kaptein, F. H. J., van Paassen, J., Stals, M. A. M., Huisman, M. V. and Endeman, H. (2020) Incidence of thrombotic complications in critically ill ICU patients with COVID-19. Thrombosis Research 191, 145-147.
[10] La Mura, V., Artoni, A., Martinelli, I., Rossio, R., Gualtierotti, R., Ghigliazza, G., Fusco, S., Ierardi, A. M., Andrisani, M. C., Carrafiello, G. and Peyvandi, F. (2020) Acute portal vein thrombosis in SARS-CoV-2 infection. American Journal of Gastroenterology (inpress).
[11] Léonard-Lorant, I., Delabranche, X., Séverac, F., Helms, J., Pauzet, C., Collange, O., Schneider, F., Labani, A., Bilbault, P., Molière, S., Leyendecker, P., Roy, C. and Ohana, M. (2020) Acute pulmonary embolism in patients with COVID-19 at CT angiography and relationship to D-dimer levels. Radiology 296, E189-E191.
[12] Llitjos, J., Leclerc, M., Chochois, C., Monsallier, J., Ramakers, M., Auvray, M. and Merouani, K. (2020) High incidence of venous thromboembolic events in anticoagulated severe COVID-19 patients. Journal of Thrombosis and Haemostasis 18, 1743-1746.
[13] Lyss, A. D. (2020) Endothelial injury may play a major role in COVID-19-associated-coagulopthy. Medscape. Available at: https://www.medscape.com/viewarticle/933141 (Accessed: June 29, 2020)
[14] Magro, C., Mulvey, J. J., Berlin, D., Nuovo, G., Salvatore, S., Harp, J., Baxter-Stoltzfus, A. and Laurence, J. (2020) Complement associated microvascular injury and thrombosis in the pathogenesis of severe COVID-19 infection: A report of five cases. Translational Research 220, 1-13.
[15] Nunes Duarte-Neto, A., de Almeida Monteiro, R. A., da Silva, L., Malheiros, D., de Oliveira, E. P., Theodoro Filho, J., Pinho, J., Soares Gomes-Gouvêa, M., Salles, A., de Oliveira, I., Mauad, T., do Nascimento Saldiva, P. H. and Dolhnikoff, M. (2020) Pulmonary and systemic involvement of COVID-19 assessed by ultrasound-guided minimally invasive autopsy. Histopathology (in press).
[16] Pons, S., Fodil, S., Azoulay, E. and Zafrani, L. (2020) The vascular endothelium: the cornerstone of organ dysfunction in severe SARS-CoV-2 infection. Critical Care 24, 353.
[17] Sonzogni, A., Previtali, G., Seghezzi, M., Grazia Alessio, M., Gianatti, A., Licini, L., Morotti, D., Zerbi, P., Department of Biomedical and Clinical Sciences University of Milan Milano Italy, Carsana, L., Rossi, R., Lauri, E., Pellegrinelli, A., Nebuloni, M. and Department of Biomedical and Clinical Sciences University of Milan Milano Italy (2020) Liver histopathology in severe COVID 19 respiratory failure is suggestive of vascular alterations. Liver International 40, 2110-2116.
[18] Tang, N., Li, D., Wang, X. and Sun, Z. (2020) Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. Journal of Thrombosis and Haemostasis 18, 844-847.
[19] Teuwen, L., Geldhof, V., Pasut, A. and Carmeliet, P. (2020) COVID-19: the vasculature unleashed. Nature Reviews Immunology 20, 389-391.
[20] Varga, Z., Flammer, A. J., Steiger, P., Haberecker, M., Andermatt, R., Zinkernagel, A. S., Mehra, M. R., Schuepbach, R. A., Ruschitzka, F. and Moch, H. (2020) Endothelial cell infection and endotheliitis in COVID-19. the Lancet 395, 1417-1418.
[21] Virzì, G., Zhang, J., Nalesso, F., Ronco, C. and McCullough, P. (2018) The role of dendritic and endothelial cells in cardiorenal syndrome. Cardiorenal Medicine 8, 92-104.
[22] Wichmann, D., Sperhake, J., Lütgehetmann, M., Steurer, S., Edler, C., Heinemann, A., Heinrich, F., Mushumba, H., Kniep, I., Schröder, A. S., Burdelski, C., de Heer, G., Nierhaus, A., Frings, D., Pfefferle, S., Becker, H., Bredereke-Wiedling, H., de Weerth, A., Paschen, H., Sheikhzadeh-Eggers, S., Stang, A., Schmiedel, S., Bokemeyer, C., Addo, M. M., Aepfelbacher, M., Püschel, K. and Kluge, S. (2020) Autopsy findings and venous thromboembolism in patients with COVID-19. Annals of Internal Medicine 173, 268-277.
[23] Zhang, J., Bottiglieri, T. and McCullough, P. A. (2017) The central role of endothelial dysfunction in cardiorenal syndrome. Cardiorenal Medicine 7, 104-117.
[24] Zhang, J., DeFelice, A. F., Hanig, J. P. and Colatsky, T. (2010) Biomarkers of endothelial cell activation serve as potential surrogate markers for drug-induced vascular injury. Toxicologic Pathology 38, 856-871.
[25] Zhang, J., Hanig, J. P. and De Felice, A. F. (2012) Biomarkers of endothelial cell activation: Candidate markers for drug-induced vasculitis in patients or drug-induced vascular injury in animals. Vascular Pharmacology 56, 14-25.
[1] Niloofar Deravi, Mobina Fathi, Kimia Vakili, Shirin Yaghoobpoor, Marzieh Pirzadeh, Melika Mokhtari, Tara Fazel, Elahe Ahsan, Samad Ghaffari. SARS-CoV-2 infection in patients with diabetes mellitus and hypertension: a systematic review[J]. Reviews in Cardiovascular Medicine, 2020, 21(3): 385-397.
[2] Ramesh K. Goyal, Jaseela Majeed, Rajiv Tonk, Mahaveer Dhobi, Bhoomika Patel, Kalicharan Sharma, Subbu Apparsundaram. Current targets and drug candidates for prevention and treatment of SARS-CoV-2 (COVID-19) infection[J]. Reviews in Cardiovascular Medicine, 2020, 21(3): 365-384.
[3] Jun Zhang, Peter A. McCullough, Kristen M. Tecson. Vitamin D deficiency in association with endothelial dysfunction: Implications for patients withCOVID-19[J]. Reviews in Cardiovascular Medicine, 2020, 21(3): 339-344.
[4] Allison Zimmerman, Dinesh Kalra. Usefulness of machine learning in COVID-19 for the detection and prognosis of cardiovascular complications[J]. Reviews in Cardiovascular Medicine, 2020, 21(3): 345-352.
[5] Ajay K. Mahenthiran, Ashorne K. Mahenthiran, Jo Mahenthiran. Cardiovascular system and COVID-19: manifestations and therapeutics[J]. Reviews in Cardiovascular Medicine, 2020, 21(3): 399-409.
[6] Kimia Vakili, Mobina Fathi, Aiyoub Pezeshgi, Ashraf Mohamadkhani, Mohammadreza Hajiesmaeili, Mostafa Rezaei-Tavirani, Fatemeh Sayehmiri. Critical complications of COVID-19: A descriptive meta-analysis study[J]. Reviews in Cardiovascular Medicine, 2020, 21(3): 433-442.
[7] Matteo Cameli, Maria Concetta Pastore, Michael Henein, Hatem Soliman Aboumarie, Giulia Elena Mandoli, Flavio D'Ascenzi, Paolo Cameli, Federico Franchi, Sergio Mondillo, Serafina Valente. Safe performance of echocardiography during the COVID-19 pandemic: a practical guide[J]. Reviews in Cardiovascular Medicine, 2020, 21(2): 217-223.
[8] Gayatri Setia, Jeffrey Tyler, Alan Kwan, Josh Faguet, Shilpa Sharma, Siddharth Singh, Babak Azarbal, Rose Tompkins, Dinora Chinchilla, Sara Ghandehari. High thrombus burden despite thrombolytic therapy in ST-elevation myocardial infarction in a patient with COVID-19[J]. Reviews in Cardiovascular Medicine, 2020, 21(2): 289-295.
[9] Peter A. McCullough, John Eidt, Janani Rangaswami, Edgar Lerma, James Tumlin, Kevin Wheelan, Nevin Katz, Norman E. Lepor, Kris Vijay, Sandeep Soman, Bhupinder Singh, Sean P. McCullough, Haley B. McCullough, Alberto Palazzuoli, Gaetano M. Ruocco, Claudio Ronco. Urgent need for individual mobile phone and institutional reporting of at home, hospitalized, and intensive care unit cases of SARS-CoV-2 (COVID-19) infection[J]. Reviews in Cardiovascular Medicine, 2020, 21(1): 1-7.
[10] Kailash Prasad. AGE-RAGE stress play a role in aortic aneurysm: A comprehensive review and novel potential therapeutic target[J]. Reviews in Cardiovascular Medicine, 2019, 20(4): 201-208.
[11] Vikrant Rai, Marcus W. Balters, Devendra K. Agrawal. Factors IX, XI, and XII: Potential Therapeutic Targets for Anticoagulant Therapy in Atherothrombosis[J]. Reviews in Cardiovascular Medicine, 2019, 20(4): 245-254.
[12] Akanksha Agrawal, Deepanshu Jain, Pradhum Ram, Jorge Luis Penalver Leon, Janani Rangaswami. Anticoagulation for intra-cardiac thrombi in peripartum cardiomyopathy: A review of the literature[J]. Reviews in Cardiovascular Medicine, 2019, 20(2): 53-58.
[13] Jing Jin, Yufeng Liu, Lihong Huang, Hong Tan. Advances in epigenetic regulation of vascular aging[J]. Reviews in Cardiovascular Medicine, 2019, 20(1): 19-25.
[14] Huaying Cai, Xiaobin Ye, Weiliang Zheng, Li Ma, Xingyue Hu, Xing Jin. Pitfalls in the diagnosis and initial management of acute cerebral venous thrombosis[J]. Reviews in Cardiovascular Medicine, 2018, 19(4): 129-133.
[15] Michael S. Lee, Jeremy Kong. Heparin: Physiology, Pharmacology, and Clinical Application[J]. Reviews in Cardiovascular Medicine, 2015, 16(3): 189-199.
No Suggested Reading articles found!