Thromb Haemost 2022; 122(01): 123-130
DOI: 10.1055/a-1551-9911
Blood Cells, Inflammation and Infection

Mild COVID-19 and Impaired Blood Cell–Endothelial Crosstalk: Considering Long-Term Use of Antithrombotics?

Arthur Melkumyants
1   Cell Adhesion Department, National Medical Research Center of Cardiology, Moscow, Russia
2   Department of Physics of Living Systems, Institute of Physics and Technology, Moscow, Russia
Ludmila Buryachkovskaya
1   Cell Adhesion Department, National Medical Research Center of Cardiology, Moscow, Russia
Nikita Lomakin
3   Cardiology Division, Central Clinical Hospital of Presidential Administration, Moscow, Russia
Olga Antonova
1   Cell Adhesion Department, National Medical Research Center of Cardiology, Moscow, Russia
Victor Serebruany
4   Division of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States
› Author Affiliations
Funding This study was supported by the Russian Foundation for Basic Research (grant No. 19–015–00213) to Dr. Melkumyants.


Background Current coronavirus disease 2019 (COVID-19) pandemic reveals thrombotic, vascular, and endothelial dysfunctions at peak disease. However, the duration, degree of damage, and appropriate long-term use of antithrombotic strategies are unclear. Most COVID data are yielded from random clinical observations or autopsy of postmortem samples, while precise blood cellular data in survivors are insufficient.

Methods We analyzed erythrocytes, circulating endothelial cells, and echinocytes by electron microscopy and flow cytometry in patients with confirmed COVID-19 (n = 31) and matched healthy controls (n = 32) on admission and at hospital discharge.

Results All patients experienced mild disease, none required pulmonary support, and all survived. Admission number of circulating endothelial cells was significantly (40–100 times) higher in COVID-19 patients. Cells were massively damaged by multiple fenestrae in membranes with diameter comparable to the size of supercapsid in SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) virus. COVID-19 also provoked formation of stacked aggregated erythrocytes capable of clogging microvascular bed and of diminishing oxygen supply. In some patients, such abnormalities persisted at hospital discharge revealing remaining intracellular penetration of SARS-CoV-2 where it may be replicated and returned to circulation.

Conclusion These observational and descriptive data suggest that persistent viral cell injury may cause blood vessel damage; their increased permeability resulted in tissue edema, inflammation, platelet activation, and augmented thrombosis. There is a residual blood cell damage following the acute phase in some COVID-19 survivors. Controlled outcome-driven trials are urgently needed for exploring optimal use of long-term antithrombotics and vascular protection strategies even after mild COVID-19.

Publication History

Received: 28 April 2021

Accepted: 13 July 2021

Accepted Manuscript online:
16 July 2021

Article published online:
05 September 2021

© 2021. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

  • References

  • 1 Ackermann M, Verleden SE, Kuehnel M. et al. Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in Covid-19. N Engl J Med 2020; 383 (02) 120-128
  • 2 Puelles VG, Lütgehetmann M, Lindenmeyer MT. et al. Multiorgan and renal tropism of SARS-CoV-2. N Engl J Med 2020; 383 (06) 590-592
  • 3 Shafi AMA, Shaikh SA, Shirke MM, Iddawela S, Harky A. Cardiac manifestations in COVID-19 patients-A systematic review. J Card Surg 2020; 35 (08) 1988-2008
  • 4 Gupta A, Madhavan MV, Sehgal K. et al. Extrapulmonary manifestations of COVID-19. Nat Med 2020; 26 (07) 1017-1032
  • 5 Connors JM, Levy JH. Thromboinflammation and the hypercoagulability of COVID-19. J Thromb Haemost 2020; 18 (07) 1559-1561
  • 6 Batlle D, Soler MJ, Sparks MA. et al; COVID-19 and ACE2 in Cardiovascular, Lung, and Kidney Working Group. Acute kidney injury in COVID-19: emerging evidence of a distinct pathophysiology. J Am Soc Nephrol 2020; 31 (07) 1380-1383
  • 7 Zhang C, Shi L, Wang FS. Liver injury in COVID-19: management and challenges. Lancet Gastroenterol Hepatol 2020; 5 (05) 428-430
  • 8 Hadi A, Werge M, Kristiansen KT. et al. Coronavirus disease-19 (COVID-19) associated with severe acute pancreatitis: case report on three family members. Pancreatology 2020; 20 (04) 665-667
  • 9 Aghagoli G, Marin BG, Katchur NJ, Chaves-Sell F, Asaad WF, Murphy SA. Neurological involvement in COVID-19 and potential mechanisms: a review. Neurocrit Care 2021; 34 (03) 1062-1071
  • 10 Sepehrinezhad A, Shahbazi A, Negah SS. COVID-19 virus may have neuroinvasive potential and cause neurological complications: a perspective review. J Neurovirol 2020; 26 (03) 324-329
  • 11 Varga Z, Flammer AJ, Steiger P. et al. Endothelial cell infection and endotheliitis in COVID-19. Lancet 2020; 395 (10234): 1417-1418
  • 12 Escher R, Breakey N, Lämmle B. Severe COVID-19 infection associated with endothelial activation. Thromb Res 2020; 190: 62
  • 13 O'Sullivan JM, Gonagle DM, Ward SE, Preston RJS, O'Donnell JS. Endothelial cells orchestrate COVID-19 coagulopathy. Lancet Haematol 2020; 7 (08) e553-e555
  • 14 Perrotta F, Matera MG, Cazzola M, Bianco A. Severe respiratory SARS-CoV2 infection: does ACE2 receptor matter?. Respir Med 2020; 168: 105996
  • 15 Loganathan S, Kuppusamy M, Wankhar W. et al. Angiotensin-converting enzyme 2 (ACE2): COVID 19 gate way to multiple organ failure syndromes. Respir Physiol Neurobiol 2021; 283: 103548
  • 16 Hoffmann M, Kleine-Weber H, Schroeder S. et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell 2020; 181 (02) 271.e8-280.e8
  • 17 Hamming I, Timens W, Bulthuis MLC, Lely AT, Navis G, van Goor H. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis. J Pathol 2004; 203 (02) 631-637
  • 18 Mancuso P, Gidaro A, Gregato G. et al. Circulating endothelial progenitors are increased in COVID-19 patients and correlate with SARS-CoV-2 RNA in severe cases. J Thromb Haemost 2020; 18 (10) 2744-2750
  • 19 Moussa MD, Santonocito C, Fagnoul D. et al. Evaluation of endothelial damage in sepsis-related ARDS using circulating endothelial cells. Intensive Care Med 2015; 41 (02) 231-238
  • 20 Khider L, Gendron N, Goudot G. et al. Curative anticoagulation prevents endothelial lesion in COVID-19 patients. J Thromb Haemost 2020; 18 (09) 2391-2399
  • 21 Nizzoli ME, Merati G, Tenore A. et al. Circulating endothelial cells in COVID-19. Am J Hematol 2020; 95 (08) E187-E188
  • 22 Guervilly C, Burtey S, Sabatier F. et al. Circulating endothelial cells as a marker of endothelial injury in severe COVID-19. J Infect Dis 2020; 222 (11) 1789-1793
  • 23 Lanuti P, Simeone P, Rotta G. et al. A standardized flow cytometry network study for the assessment of circulating endothelial cell physiological ranges. Sci Rep 2018; 8 (01) 5823
  • 24 Bouvier CA, Gaynor E, Cintron JR, Bernhardt B, Spaet TH. Circulating endothelium as an indication of vascular injury in vascular factors and thrombosis. Thromb Diath Haemorrh 1970; 40: 163
  • 25 Al-Aly Z, Xie Y, Bowe B. High-dimensional characterization of post-acute sequelae of COVID-19. Nature 2021; 594 (7862): 259-264