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DOI: 10.1055/s-0043-1769939
Effects of Recombinant SARS-CoV-2 Spike Protein Variants on Platelet Morphology and Activation
Abstract
Platelets are central elements of hemostasis and also play a pivotal role in the pathogenesis of thrombosis in coronavirus disease 2019. This study was planned to investigate the effects of different severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) recombinant spike protein variants on platelet morphology and activation. Citrated whole blood collected from ostensibly healthy subjects was challenged with saline (control sample) and with 2 and 20 ng/mL final concentration of SARS-CoV-2 recombinant spike protein of Ancestral, Alpha, Delta, and Omicron variants. Platelet count was found to be decreased with all SARS-CoV-2 recombinant spike protein variants and concentrations tested, achieving the lowest values with 20 ng/mL Delta recombinant spike protein. The mean platelet volume increased in all samples irrespective of SARS-CoV-2 recombinant spike protein variants and concentrations tested, but especially using Delta and Alpha recombinant spike proteins. The values of both platelet function analyzer-200 collagen-adenosine diphosphate and collagen-epinephrine increased in all samples irrespective of SARS-CoV-2 recombinant spike protein variants and concentrations tested, and thus reflecting platelet exhaustion, and displaying again higher increases with Delta and Alpha recombinant spike proteins. Most samples where SARS-CoV-2 recombinant spike proteins were added were flagged as containing platelet clumps. Morphological analysis revealed the presence of a considerable number of activated platelets, platelet clumps, platelet-monocyte, and platelet-neutrophils aggregates, especially in samples spiked with Alpha and Delta recombinant spike proteins at 20 ng/mL. These results provide support to the evidence that SARS-CoV-2 is capable of activating platelets through its spike protein, though such effect varies depending on different spike protein variants.
* These authors contributed equally to this article.
Publication History
Article published online:
16 June 2023
© 2023. Thieme. All rights reserved.
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References
- 1 Sampath S, Khedr A, Qamar S. et al. Pandemics throughout the history. Cureus 2021; 13 (09) e18136
- 2 Lippi G, Sanchis-Gomar F, Henry BM. COVID-19: unravelling the clinical progression of nature's virtually perfect biological weapon. Ann Transl Med 2020; 8 (11) 693
- 3 Levi M, Thachil J. Coronavirus disease 2019 coagulopathy: disseminated intravascular coagulation and thrombotic microangiopathy-either, neither, or both. Semin Thromb Hemost 2020; 46 (07) 781-784
- 4 Mattiuzzi C, Lippi G. Timeline analysis of clinical severity of COVID-19 in the general population. Eur J Intern Med 2023; 110: 97-98
- 5 di Gennaro C, Galdiero M, Scherillo G. et al. Editorial COVID-19 and thrombosis 2023: new waves of SARS-CoV-2 infection, triage organization in emergency department and the association of VOCs/VOI with pulmonary embolism. Viruses 2022; 14 (11) 2453
- 6 Bouzid D, Visseaux B, Kassasseya C. et al; IMProving Emergency Care (IMPEC) FHU Collaborators Group. Comparison of patients infected with delta versus omicron COVID-19 variants presenting to Paris Emergency Departments: a retrospective cohort study. Ann Intern Med 2022; 175 (06) 831-837
- 7 Manzur-Pineda K, O'Neil CF, Bornak A. et al. COVID-19-related thrombotic complications experience before and during delta wave. J Vasc Surg 2022; 76 (05) 1374-1382.e1
- 8 Law N, Chan J, Kelly C, Auffermann WF, Dunn DP. Incidence of pulmonary embolism in COVID-19 infection in the ED: Ancestral, Delta, Omicron variants and vaccines. Emerg Radiol 2022; 29 (04) 625-629
- 9 Shulman AH, Jacobson B, Segal BM. et al. D-dimers in omicron versus delta: a retrospective analysis. S Afr J Infect Dis 2022; 37 (01) 484
- 10 Ronderos Botero DM, Omar AMS, Pengo MF. et al. D-dimer trends elaborate the heterogeneity of risk in hospitalized patients with COVID-19: a multi-national case series from different waves. Front Med (Lausanne) 2023; 10: 1103842
- 11 Iba T, Wada H, Levy JH. Platelet activation and thrombosis in COVID-19. Semin Thromb Hemost 2023; 49 (01) 55-61
- 12 Wang SSY, Chee K, Wong SW. et al; COVID-19 Clotting and Bleeding Investigators. Increased platelet activation demonstrated by elevated CD36 and P-selectin expression in 1-year post-recovered COVID-19 patients. Semin Thromb Hemost 2023; 49 (05) 561-564
- 13 Craddock V, Mahajan A, Spikes L. et al. Persistent circulation of soluble and extracellular vesicle-linked spike protein in individuals with postacute sequelae of COVID-19. J Med Virol 2023; 95 (02) e28568
- 14 Ogata AF, Cheng CA, Desjardins M. et al. Circulating severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine antigen detected in the plasma of mRNA-1273 vaccine recipients. Clin Infect Dis 2022; 74 (04) 715-718
- 15 Favaloro EJ. Clinical utility of the PFA-100. Semin Thromb Hemost 2008; 34 (08) 709-733
- 16 Favaloro EJ, Pasalic L, Lippi G. Towards 50 years of platelet function analyser (PFA) testing. Clin Chem Lab Med 2022; 61 (05) 851-860
- 17 Assinger A, Capron C, Real F, Bomsel M. Editorial: Platelet and megakaryocyte dysfunctions in infectious diseases. Front Immunol 2023; 14: 1175200
- 18 Lippi G, Mattiuzzi C, Henry BM. Updated picture of SARS-CoV-2 variants and mutations. Diagnosis (Berl) 2021; 9 (01) 11-17
- 19 Chatterjee S, Bhattacharya M, Nag S, Dhama K, Chakraborty C. A detailed overview of SARS-CoV-2 omicron: its sub-variants, mutations and pathophysiology, clinical characteristics, immunological landscape, immune escape, and therapies. Viruses 2023; 15 (01) 167
- 20 Zhang J, Cai Y, Lavine CL. et al. Structural and functional impact by SARS-CoV-2 Omicron spike mutations. Cell Rep 2022; 39 (04) 110729
- 21 De Michele M, d'Amati G, Leopizzi M. et al. Evidence of SARS-CoV-2 spike protein on retrieved thrombi from COVID-19 patients. J Hematol Oncol 2022; 15 (01) 108
- 22 Perico L, Morigi M, Galbusera M. et al. SARS-CoV-2 spike protein 1 activates microvascular endothelial cells and complement system leading to platelet aggregation. Front Immunol 2022; 13: 827146
- 23 Lippi G, Plebani M, Henry BM. Thrombocytopenia is associated with severe coronavirus disease 2019 (COVID-19) infections: a meta-analysis. Clin Chim Acta 2020; 506: 145-148
- 24 Len P, Iskakova G, Sautbayeva Z. et al. Meta-analysis and systematic review of coagulation disbalances in COVID-19: 41 studies and 17,601 patients. Front Cardiovasc Med 2022; 9: 794092
- 25 Zinellu A, Mangoni AA. A systematic review and meta-analysis of the association between the neutrophil, lymphocyte, and platelet count, neutrophil-to-lymphocyte ratio, and platelet-to-lymphocyte ratio and COVID-19 progression and mortality. Expert Rev Clin Immunol 2022; 18 (11) 1187-1202
- 26 Ishikura H, Maruyama J, Nakashio M. et al. Daily combined measurement of platelet count and presepsin concentration can predict in-hospital death of patients with severe coronavirus disease 2019 (COVID-19). Int J Hematol 2023; 117 (06) 845-855
- 27 Meletis G, Tychala A, Ntritsos G. et al. Variant-related differences in laboratory biomarkers among patients affected with alpha, delta and omicron: a retrospective whole viral genome sequencing and hospital-setting cohort study. Biomedicines 2023; 11 (04) 1143
- 28 Li Q, Liu X, Li L. et al. Comparison of clinical characteristics between SARS-CoV-2 Omicron variant and Delta variant infections in China. Front Med (Lausanne) 2022; 9: 944909
- 29 Zhang Y, Zeng X, Jiao Y. et al. Mechanisms involved in the development of thrombocytopenia in patients with COVID-19. Thromb Res 2020; 193: 110-115
- 30 Lippi G, Henry BM, Favaloro EJ. Mean platelet volume predicts severe COVID-19 illness. Semin Thromb Hemost 2021; 47 (04) 456-459
- 31 Zein AFMZ, Sulistiyana CS, Raffaelo WM. et al. The association between mean platelet volume and poor outcome in patients with COVID-19: systematic review, meta-analysis, and meta-regression. J Intensive Care Soc 2022;
- 32 Lippi G, Sanchis-Gomar F, Favaloro EJ. Mean platelet volume in arterial and venous thrombotic disorders. J Lab Med 2020; 44 (05) 305-312
- 33 Knight R, Walker V, Ip S. et al; CVD-COVID-UK/COVID-IMPACT Consortium and the Longitudinal Health and Wellbeing COVID-19 National Core Study. Association of COVID-19 with major arterial and venous thrombotic diseases: a population-wide cohort study of 48 million adults in England and Wales. Circulation 2022; 146 (12) 892-906
- 34 Thachil J, Lisman T. Pulmonary megakaryocytes in coronavirus disease 2019 (COVID-19): roles in thrombi and fibrosis. Semin Thromb Hemost 2020; 46 (07) 831-834
- 35 O'Kennedy N, Duttaroy AK. Platelet hyperactivity in COVID-19: can the tomato extract Fruitflow® be used as an antiplatelet regime?. Med Hypotheses 2021; 147: 110480
- 36 Gorog DA, Storey RF, Gurbel PA. et al. Current and novel biomarkers of thrombotic risk in COVID-19: a consensus statement from the International COVID-19 Thrombosis Biomarkers Colloquium. Nat Rev Cardiol 2022; 19 (07) 475-495
- 37 Taus F, Salvagno G, Canè S. et al. Platelets promote thromboinflammation in SARS-CoV-2 pneumonia. Arterioscler Thromb Vasc Biol 2020; 40 (12) 2975-2989
- 38 Zaid Y, Puhm F, Allaeys I. et al. Platelets can associate with SARS-Cov-2 RNA and are hyperactivated in COVID-19. Circ Res 2020; 127 (11) 1404-1418
- 39 Garishah FM, Huskens D, Pramudo SG. et al. Hyperresponsive platelets and a reduced platelet granule release capacity are associated with severity and mortality in COVID-19 patients. Thromb Haemost 2022; 122 (12) 2001-2010
- 40 Zhang S, Liu Y, Wang X. et al. SARS-CoV-2 binds platelet ACE2 to enhance thrombosis in COVID-19. J Hematol Oncol 2020; 13 (01) 120
- 41 Kuhn CC, Basnet N, Bodakuntla S. et al. Direct Cryo-ET observation of platelet deformation induced by SARS-CoV-2 spike protein. Nat Commun 2023; 14 (01) 620
- 42 Maugeri N, De Lorenzo R, Clementi N. et al. Unconventional CD147-dependent platelet activation elicited by SARS-CoV-2 in COVID-19. J Thromb Haemost 2022; 20 (02) 434-448
- 43 Bye AP, Hoepel W, Mitchell JL. et al. Aberrant glycosylation of anti-SARS-CoV-2 spike IgG is a prothrombotic stimulus for platelets. Blood 2021; 138 (16) 1481-1489
- 44 Appelbaum J, Arnold DM, Kelton JG. et al. SARS-CoV-2 spike-dependent platelet activation in COVID-19 vaccine-induced thrombocytopenia. Blood Adv 2022; 6 (07) 2250-2253
- 45 Grobbelaar LM, Venter C, Vlok M. et al. SARS-CoV-2 spike protein S1 induces fibrin(ogen) resistant to fibrinolysis: implications for microclot formation in COVID-19. Biosci Rep 2021; 41 (08) BSR20210611
- 46 Favaloro EJ, Pasalic L, Lippi G. Autoimmune diseases affecting hemostasis: a narrative review. Int J Mol Sci 2022; 23 (23) 14715
- 47 Favaloro EJ, Pasalic L, Lippi G. Antibodies against platelet factor 4 and their associated pathologies: from HIT/HITT to spontaneous HIT-like syndrome, to cOVID-19, to VITT/TTS. Antibodies (Basel) 2022; 11 (01) 7
- 48 Quartuccio L, Sonaglia A, Casarotto L, McGonagle D, Di Loreto C, Pegolo E. Clinical, laboratory and immunohistochemical characterization of in situ pulmonary arterial thrombosis in fatal COVID-19. Thromb Res 2022; 219: 95-101
- 49 Nishikawa M, Kanno H, Zhou Y. et al. Massive image-based single-cell profiling reveals high levels of circulating platelet aggregates in patients with COVID-19. Nat Commun 2021; 12 (01) 7135
- 50 Zong X, Wang X, Liu Y. et al. Antiplatelet therapy for patients with COVID-19: Systematic review and meta-analysis of observational studies and randomized controlled trials. Front Med (Lausanne) 2022; 9: 965790
- 51 Hottz ED, Azevedo-Quintanilha IG, Palhinha L. et al. Platelet activation and platelet-monocyte aggregate formation trigger tissue factor expression in patients with severe COVID-19. Blood 2020; 136 (11) 1330-1341
- 52 Manne BK, Denorme F, Middleton EA. et al. Platelet gene expression and function in patients with COVID-19. Blood 2020; 136 (11) 1317-1329
- 53 Grobbelaar LM, Kruger A, Venter C. et al. Relative hypercoagulopathy of the SARS-CoV-2 Beta and Delta variants when compared to the less severe Omicron variants is related to TEG parameters, the extent of fibrin amyloid microclots, and the severity of clinical illness. Semin Thromb Hemost 2022; 48 (07) 858-868
- 54 Matsuoka A, Koami H, Shinada K, Sakamoto Y. Investigation of differences in coagulation characteristics between hospitalized patients with SARS-CoV-2 Alpha, Delta, and Omicron variant infection using rotational thromboelastometry (ROTEM): A single-center, retrospective, observational study. J Clin Lab Anal 2022; 36 (12) e24796
- 55 Lenharo M. WHO declares end to COVID-19's emergency phase. Nature 2023; . Epub ahead of print