Platelets in COVID-19: “innocent by-standers” or active participants?

Cover Page

Cite item

Full Text

Abstract

One of the most dangerous features of the new coronavirus infection caused by the SARS-CoV-2 virus is the tendency of the hemostasis system of patients to excessive thrombus formation. Among the possible causes of this pathology, both the activation of vascular endothelial cells, leading to the exposure of tissue factor by these cells, and direct activation of the plasma hemostasis were named. Besides, there is a significant change in platelet responses to activation, which is not accompanied by significant thrombocytopenia. The mechanism of platelet dysfunction is rather controversial. On the one hand, there are suggestions that platelets can act as a direct “container” for the virus, thus spreading it throughout the body. On the other hand, the presence of viral RNA in platelets has been demonstrated in only one study, while other authors have obtained the opposite result. Another mechanism of the virus's direct effect on platelets is the penetration of the virus into megakaryocytes and the subsequent violation of thrombocytopoiesis. However, three of the four published works show that platelets from patients with SARS-CoV-2 are in an activated state (the so-called platelet pre-activation). This phenomenon can be caused by the direct influence of the virus and the effect of thromboinflammation in the lungs on platelet functions. Here we review the known data and possible causes of the platelet functionality changes observed in patients with SARS-CoV-2. 

About the authors

O. I. An

I.M. Sechenov First Moscow State Medical University of the Ministry of Healthcare of the Russian Federation

ORCID iD: 0000-0002-9023-901X

Moscow

Russian Federation

A. A. Martyanov

Center for Theoretical Problems of Physicochemical Pharmacology, RAS;
Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of the Ministry of Healthcare of the Russian Federation;
Lomonosov Moscow State University;
N.M. Emanuel Institute of Biochemical Physics, RAS

ORCID iD: 0000-0003-0211-6325

Moscow

Russian Federation

M. G. Stepanyan

Center for Theoretical Problems of Physicochemical Pharmacology, RAS;
Lomonosov Moscow State University

ORCID iD: 0000-0001-7509-6316

Moscow

Russian Federation

A. E. Boldova

Center for Theoretical Problems of Physicochemical Pharmacology, RAS;
Lomonosov Moscow State University

ORCID iD: 0000-0003-4252-5588

Moscow

Russian Federation

S. A. Rumyantsev

Hospital of the Russian Academy of Sciences (Troitsk)

Moscow, Troitsk

Russian Federation

M. A. Panteleev

Center for Theoretical Problems of Physicochemical Pharmacology, RAS;
Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of the Ministry of Healthcare of the Russian Federation;
Lomonosov Moscow State University

ORCID iD: 0000-0002-8128-7757

Moscow

Russian Federation

F. I. Ataullakhanov

Center for Theoretical Problems of Physicochemical Pharmacology, RAS;
Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of the Ministry of Healthcare of the Russian Federation;
Lomonosov Moscow State University

ORCID iD: 0000-0002-6668-0948

Moscow

Russian Federation

A. G. Rumyantsev

Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of the Ministry of Healthcare of the Russian Federation

ORCID iD: 0000-0002-1643-5960

Moscow

Russian Federation

A. N. Sveshnikova

I.M. Sechenov First Moscow State Medical University of the Ministry of Healthcare of the Russian Federation;
Center for Theoretical Problems of Physicochemical Pharmacology, RAS;
Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of the Ministry of Healthcare of the Russian Federation;
Lomonosov Moscow State University

Author for correspondence.
Email: a.sveshnikova@physics.msu.ru
ORCID iD: 0000-0003-4720-7319

head of the Intracellular signalling and systems biology laboratory, Center for Theoretical Problems of Physicochemical Pharmacology, RAS;
30 Srednyaya Kalitnikovskaya st., 109029 Moscow

Russian Federation

References

  1. Yang M., Li C.K., Li K., Hon K.L.E., Ng M.H.L., Chan P.K.S., et al. Hematological findings in SARS patients and possible mechanisms (review). Int J Mol Med 2004; 14 (2): 311–5. doi: 10.3892/ijmm.14.2.311
  2. Yin Y., Wunderink R.G. MERS, SARS and other coronaviruses as causes of pneumonia. Respirol. Carlton Vic 2018; 23 (2): 130–7. doi: 10.1111/resp.13196
  3. Park S.E. Epidemiology, virology, and clinical features of severe acute respiratory syndrome -coronavirus-2 (SARSCoV-2; Coronavirus Disease-19). Clin Exp Pediatr 2020; 63 (4): 119–24. doi: 10.3345/cep.2020.00493
  4. Richardson S., Hirsch J.S., Narasimhan M., Crawford J.M., McGinn T., Davidson K.W., et al. Presenting Characteristics, Comorbidities, and Outcomes Among 5700 Patients Hospitalized With COVID-19 in the New York City Area. JAMA 2020; 323 (20): 2052–9. doi: 10.1001/jama.2020.6775
  5. Peck T.J., Hibbert K.A. Recent advances in the understanding and management of ARDS. F1000Research 2019; 8: F1000 Faculty Rev-1959. doi: 10.12688/f1000research.20411.1
  6. Hu B., Huang S., Yin L. The cytokine storm and COVID-19. J Med Virol 2020. doi: 10.1002/jmv.26232
  7. Chousterman B.G., Swirski F.K., Weber G.F. Cytokine storm and sepsis disease pathogenesis. Semin Immunopathol 2017; 39 (5): 517–28. doi: 10.1007/s00281-017-0639-8
  8. Terpos E., Ntanasis-Stathopoulos I., Elalamy I., Kastritis E., Sergentanis T.N., Politou M. Hematological findings and complications of COVID‐19. Am J Hematol 2020; 95 (7): 834–47. DOI: 10.1002/ ajh.25829
  9. Makatsariya A.D., Grigoreva K.N., Mingalimov M.A., Bitsadze V.O., Khizroeva J.Kh., Tretyakova M.V., et al. Coronavirus disease (COVID-19) and disseminated intravascular coagulation syndrome. Obstetr Gynecol Reproduct 2020; 14 (2). Доступно по: https://www.gynecology.su/jour/article/view/633. Дата обращения 05.06.2020.
  10. Iba T., Levy J.H., Connors J.M., Warkentin T.E., Thachil J., Levi M. The unique characteristics of COVID-19 coagulopathy. Crit Care 2020; 24 (1): 360. doi: 10.1186/s13054-020-03077-0
  11. Mucha S.R., Dugar S., McCrae K., Joseph D., Bartholomew J., Sacha G.L., et al. Coagulopathy in COVID-19: Manifestations and management. Cleve Clin J Med 2020; 87 (8): 461–8. doi: 10.3949/ccjm.87a.ccc024
  12. Seitz R., Schramm W. DIC in COVID-19: Implications for prognosis and treatment? J Thromb Haemost JTH 2020; 18 (7): 1798–9. doi: 10.1111/jth.14878
  13. Connors J.M., Levy J.H. COVID-19 and its implications for thrombosis and anticoagulation. Blood 2020; 135 (23): 2033– 40. doi: 10.1182/blood.2020006000
  14. Connors J.M., Levy J.H. Thromboinflammation and the hypercoagulability of COVID‐19. J Thromb Haemost 2020; 18 (7): 1559–61.
  15. Jayarangaiah A., Kariyanna P.T., Chen X., Jayarangaiah A., Kumar A. COVID-19-Associated Coagulopathy: An Exacerbated Immunothrombosis Response. Clin Appl Thromb Hemost 2020; 26: 107602962094329.
  16. Schattner M., Jenne C.N., Negrotto S., Ho-Tin-Noe B. Editorial: Platelets and Immune Responses During Thromboinflammation. Front Immunol 2020; 11: 1079.
  17. Rayes J., Watson S.P., Nieswandt B. Functional significance of the platelet immune receptors GPVI and CLEC-2. J Clin Invest 2019; 129 (1): 12–23. doi: 10.1172/JCI122955
  18. Cao X. COVID-19: immunopathology and its implications for therapy. Nat Rev Immunol 2020; 20 (5): 269–70.
  19. Roschewski M., Lionakis M.S., Sharman J.P., Roswarski J., Goy A., Monticelli M.A., et al. Inhibition of Bruton tyrosine kinase in patients with severe COVID19. Sci Immunol 2020; 5 (48).
  20. Martyanov A.A., Balabin F.A., Dunster J.L., Panteleev M.A., Gibbins J.M., Sveshnikova A.N. Control of platelet CLEC-2-mediated activation by receptor clustering and tyrosine kinase signalling. Biophys J 2020. DOI: 10.1016/j. bpj.2020.04.023
  21. Nicolson P.L.R., Welsh J.D., Chauhan A., Thomas M.R., Kahn M.L., Watson S.P. A rationale for blocking thromboinflammation in COVID-19 with Btk inhibitors. Platelets 2020; 31 (5): 685–90.
  22. Wool G.D., Miller J.L. The Impact of COVID-19 Disease on Platelets and Coagulation. Pathobiology 2021; 88 (1): 15–27. doi: 10.1159/000512007
  23. Yang X., Yang Q., Wang Y., Wu Y., Xu J., Yu Y., Shang Y. Thrombocytopenia and its association with mortality in patients with COVID-19. J Thromb Haemost 2020; 18 (6): 1469–72. doi: 10.1111/jth.14848
  24. Manne B.K., Denorme F., Middleton E.A., Portier I., Rowley J.W., Stubben C., et аl. Platelet gene expression and function in patients with COVID-19. Blood 2020; 136 (11): 1317–29.
  25. Manne B.K., Denorme F., Middleton E.A., Portier I., Rowley J.W., Stubben C.J., еt аl. Platelet Gene Expression and Function in COVID-19 Patients. Blood 2020. Доступно по: https://ashpublications.org/blood/article/doi/10.1182/blood.2020007214/461106/Platelet-Gene-Expression-and-Function-in-COVID-19. Ссылка активна на 12.03.2021.
  26. Taus F., Salvagno G., Canè S., Fava C., Mazzaferri F., Carrara E., et al. Promote Thromboinfl ammation in SARSCoV-2 Pneumonia. Arterioscler Thromb Vasc Biol 2020; 40 (12): 2975–89. doi: 10.1161/ATVBAHA.120.315175
  27. Zaid Y., Puhm F., Allaeys I., Naya A., Oudghiri M., Khalki L., et al. Platelets can contain SARS-CoV-2 RNA and are hyper activated in COVID-19. Circ Res 2020; 127 (11): 1404–18. doi: 10.1161/CIRCRESAHA.120.317703
  28. Rampotas A., Pavord S. Platelet aggregates, a marker of severe COVID19 disease. J Clin Pathol 2020 jclinpath-2020-206933. doi: 10.1136/jclinpath-2020-206933
  29. Pryzdial E.L.G., Lin B.H., Sutherland M.R. Virus–Platelet Associations. In: Platelets in Thrombotic and Non-Thrombotic Disorders: Pathophysiology, Pharmacology and Therapeutics: an Update. Gresele P., Kleiman N.S., Lopez J.A., Page C.P., eds. Cham: Springer International Publishing; 2017. Рр. 1085–1102.
  30. Koupenova M., Corkrey H.A., Vitseva О., Manni G., Pang C.J., Clancy L., et al. The role of platelets in mediating a response to human influenza infection. Nat Commun 2019; 10 (1). doi: 10.1038/s41467- 019-09607-x
  31. Chaipan C., Soilleux E.J., Simpson P., Hofmann H., Gramberg T., Marzi A., et al. DC-SIGN and CLEC-2 Mediate Human Immunodeficiency Virus Type 1 Capture by Platelets. J Virol 2006; 80 (18): 8951– 60. doi: 10.1128/JVI.00136-06
  32. Real F., Capron С., Sennepin А., Arrigucci R., Zhu А., Sannier G., et al. Platelets from HIV-infected individuals on antiretroviral drug therapy with poor CD4+ T cell recovery can harbor replication-competent HIV despite viral suppression. Sci Transl Med 2020; 12 (535). doi: 10.1126/scitranslmed.aat6263
  33. Rapkiewicz A.V., Mai X., Carsons S.E., Pittaluga S., Kleiner D.E., Berger J.S., et al. Megakaryocytes and platelet-fibrin thrombi characterize multi-organ thrombosis at autopsy in COVID-19: A case series. EClinicalMedicine 2020; 24: 100434.
  34. Valdivia-Mazeyra M.F., Salas C., NievesAlonso J.M., Martín-Fragueiro L., Bárcena C., Muñoz-Hernández P., еt al. Increased number of pulmonary megakaryocytes in COVID-19 patients with diffuse alveolar damage: an autopsy study with clinical correlation and review of the literature. Virchows Arch 2020; 1–10. doi: 10.1007/s00428-020-02926-1
  35. Burkhart J.M., Vaude М., Gambaryan S., Radau S., Walter U., Martens L., et al. The first comprehensive and quantitative analysis of human platelet protein composition allows the comparative analysis of structural and functional pathways. Blood 2012; 120 (15): e73–82. doi: 10.1182/blood-2012-04-416594
  36. Chang L., Yan Y., Wang L. Coronavirus Disease 2019: Coronaviruses and Blood Safety. Transfus Med Rev 2020; 34 (2): 75–80. doi: 10.1016/j.tmrv.2020.02.003
  37. Zaid Y., Puhm F., Allaeys I., Naya A., Oudghiri M., Khalki L., et al. Platelets Can Associate with SARS-Cov-2 RNA and Are Hyperactivated in COVID-19. Circ Res 2020; 127 (11): 1404–18. doi: 10.1161/CIRCRESAHA.120.317703
  38. Ferrando C., Suarez-Sipmann F., Mellado-Artigas R., Hernández M., Gea A., Arruti E., et al on behalf of the COVID-19 Spanish ICU Network. (2020) Clinical features, ventilatory management, and outcome of ARDS caused by COVID-19 are similar to other causes of ARDS. Intensive Care Med 2020; 46 (12): 2200–11.
  39. Umbrello M., Formenti P., Bolgiaghi L., Chiumello D. Current Concepts of ARDS: A Narrative Review. Int J Mol Sci 2016; 18 (1): 64. doi: 10.3390/ijms18010064
  40. Grobler C., Maphumulo S.C., Grobbelaar L.M., Bredenkamp J.C., Laubscher G.J., Lourens P.J., et al. Covid-19: The Rollercoaster of Fibrin(Ogen), D-Dimer, Von Willebrand Factor, P-Selectin and Their Interactions with Endothelial Cells, Platelets and Erythrocytes. Int J Mol Sci 2020; 21 (14): 5168. doi: 10.3390/ijms21145168
  41. Frantzeskaki F., Armaganidis A., Orfanos S.E. Immunothrombosis in Acute Respiratory Distress Syndrome: Cross Talks between Inflammation and Coagulation. Respiration 2017; 93 (3): 212–25.
  42. Fuchs T.A., Brill A., Wagner D.D. Neutrophil Extracellular Trap (NET) Impact on Deep Vein Thrombosis. Arterioscler Thromb Vasc Biol 2012; 32 (8): 1777–83.
  43. Martinod K., Wagner D.D. Thrombosis: tangled up in NETs. Blood 2014; 123 (18): 2768–76.
  44. Kimball A.S., Obi A.T., Diaz J.A., Henke P.K. The Emerging Role of NETs in Venous Thrombosis and Immunothrombosis. Front Immunol 2016; 7: 236.
  45. Engelmann B., Massberg S. Thrombosis as an intravascular effector of innate immunity. Nat Rev Immunol 2013; 13 (1): 34–45.
  46. Liaw P.C., Ito T., Iba T., Thachil J., Zeerleder S. DAMP and DIC: The role of extracellular DNA and DNA-binding proteins in the pathogenesis of DIC. Blood Rev 2016; 30 (4): 257–61.
  47. Delabranche X., Stiel L., Severac F., Galoisy A.-C., Mauvieux L., Zobairi F., et al. Evidence of Netosis in Septic Shock-Induced Disseminated Intravascular Coagulation. Shock 2017; 47 (3): 313– 7. doi: 10.1097/SHK.0000000000000719
  48. Middleton E.A., He X.-Y., Denorme F., Campbell R.A., Ng D., Salvatore S.P., еt al. Neutrophil extracellular traps contribute to immunothrombosis in COVID19 acute respiratory distress syndrome. Blood 2020; 136 (10): 1169–79.
  49. Zimmerman G.A., McIntyre T.M., Prescott S.M., Stafforini D.M. The platelet-activating factor signaling system and its regulators in syndromes of inflammation and thrombosis. Crit Care Med 2002; 30 (5 Suppl): S294–301.
  50. Yeaman M.R. Platelets in defense against bacterial pathogens. Cell Mol Life Sci 2010; 67 (4): 525–44. SP
  51. Semple J.W., Italiano J.E., Freedman J. Platelets and the immune continuum. Nat Rev Immunol 2011; 11 (4): 264–74.
  52. Rampotas A., Pavord S. Platelet aggregates, a marker of severe COVID19 disease. J Clin Pathol 2020; jclinpath-2020-206933. DOI: 10.1136/ jclinpath-2020-206933
  53. Hottz E.D., Azevedo-Quintanilha I.G., Palhinha L., Teixeira L., Barreto E.A., Pão C.R.R., et al. Platelet activation and platelet-monocyte aggregate formation trigger tissue factor expression in patients with severe COVID-19. Blood 2020; 136 (11): 1330–41. doi: 10.1182/blood.2020007252
  54. Celi A., Pellegrini G., Lorenzet R., De Blasi A., Ready N., Furie B.C., Furie B. P-selectin induces the expression of tissue factor on monocytes. Proc Natl Acad Sci U S A 1994; 91 (19): 8767.
  55. Koupenova M., Clancy L., Corkrey H.A., Freedman J.E. Circulating Platelets as Mediators of Immunity, Inflammation, and Thrombosis. Circ. Res 2018; 122 (2): 337–51.
  56. Jenne C.N., Kubes P. Platelets in inflammation and infection. Platelets 2015; 26 (4): 286–92.

Supplementary files

Supplementary Files
Action
1. JATS XML
Download

Copyright (c) 2021 An O.I., Martyanov A.A., Stepanyan M.G., Boldova A.E., Rumyantsev S.A., Panteleev M.A., Ataullakhanov F.I., Rumyantsev A.G., Sveshnikova A.N.

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.