Autoantibodies to protein S may explain rare cases of coagulopathy following COVID-19 vaccination.
Humans
Autoantibodies
/ immunology
Middle Aged
Male
Female
COVID-19
/ immunology
Aged
COVID-19 Vaccines
/ adverse effects
Sweden
Adult
SARS-CoV-2
/ immunology
Protein S
/ immunology
Vaccination
/ adverse effects
Blood Coagulation Disorders
/ immunology
Platelet Factor 4
/ immunology
Aged, 80 and over
Autoantibodies
Blood coagulation disorders
COVID-19
Protein S
Vaccines/adverse effects
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
18 Oct 2024
18 Oct 2024
Historique:
received:
06
07
2024
accepted:
07
10
2024
medline:
19
10
2024
pubmed:
19
10
2024
entrez:
18
10
2024
Statut:
epublish
Résumé
While Coronavirus disease 2019 (COVID-19) vaccines have proven to be both effective and generally safe, rare but severe adverse events following immunization (AEFIs) are described. Autoantibodies to platelet factor-4 are associated with catastrophic thrombotic AEFIs, but comprehensive investigations of other autoantibodies are lacking. We aimed to detect and describe autoantibodies targeting coagulation-related proteins in a population-wide cohort (SWEDEGENE) including AEFIs attributed to COVID-19 vaccines in Sweden. Subjects were recruited from December 2020 to October 2022 and were stratified based on diagnosis and COVID-19 exposure. Screening was carried out in two phases, with a multiplex bead-based assay in the first subset (until September 2021) and with targeted assays for the second (until October 2022). Positivity was defined based on absolute, relative, and biological/technical thresholds. Patients with coagulation-related AEFIs were older and the Vaxzevria vaccine was overrepresented in this group. Two cases had antiphospholipid antibodies but none had PF4 antibodies. We identified six positives for protein S autoantibodies. Protein S concentrations were negatively correlated with autoantibody response in patients with immunoreactivity and functional analysis revealed low protein S activity in three subjects. Our population-wide analysis reveals cases with autoantibodies against protein S which possibly underlie coagulopathic AEFIs.
Identifiants
pubmed: 39424883
doi: 10.1038/s41598-024-75514-x
pii: 10.1038/s41598-024-75514-x
doi:
Substances chimiques
Autoantibodies
0
COVID-19 Vaccines
0
Protein S
0
Platelet Factor 4
37270-94-3
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
24512Informations de copyright
© 2024. The Author(s).
Références
Flanagan, K. L., MacIntyre, C. R., McIntyre, P. B. & Nelson, M. R. SARS-CoV-2 vaccines: Where are we now?. J. Allergy Clin. Immunol. Pract. 9, 3535–3543. https://doi.org/10.1016/j.jaip.2021.07.016 (2021).
doi: 10.1016/j.jaip.2021.07.016
pubmed: 34400116
pmcid: 8363243
Wu, Q. et al. Evaluation of the safety profile of COVID-19 vaccines: A rapid review. BMC Med. 19, 173. https://doi.org/10.1186/s12916-021-02059-5 (2021).
doi: 10.1186/s12916-021-02059-5
pubmed: 34315454
pmcid: 8315897
Luo, C. et al. Comparability of clinical trials and spontaneous reporting data regarding COVID-19 vaccine safety. Sci. Rep. 12, 10946. https://doi.org/10.1038/s41598-022-13809-7 (2022).
doi: 10.1038/s41598-022-13809-7
pubmed: 35768434
pmcid: 9243073
Vera-Lastra, O. et al. New onset autoimmune diseases after the sputnik vaccine. Biomedicines 11, 1898. https://doi.org/10.3390/biomedicines11071898 (2023).
doi: 10.3390/biomedicines11071898
pubmed: 37509537
pmcid: 10377489
Tsoi, J. Y. H. et al. Autoantibodies against angiotensin-converting enzyme 2 (ACE2) after COVID-19 infection or vaccination. J. Med. Virol. 95, e29313. https://doi.org/10.1002/jmv.29313 (2023).
doi: 10.1002/jmv.29313
pubmed: 38100626
Reuben, R. C. & Adogo, L. Y. SARS-CoV-2 vaccines-induced thrombotic thrombocytopenia: Should we consider immuno-hypersensitivity?. Rev. Saude Publica 55, 70. https://doi.org/10.11606/s1518-8787.2021055003855 (2021).
doi: 10.11606/s1518-8787.2021055003855
pubmed: 34730750
pmcid: 8522756
Gardner, A. J. et al. Antithrombin III deficiency-induced coagulopathy in the context of COVID-19: A case series. British Journal of Haematology 194, 1007–1009. https://doi.org/10.1111/bjh.17575 (2021).
doi: 10.1111/bjh.17575
pubmed: 34053064
pmcid: 8239505
de la Morena-Barrio, M. E. et al. A pilot study on the impact of congenital thrombophilia in COVID-19. Eur. J. Clin. Invest. 51, e13546. https://doi.org/10.1111/eci.13546 (2021).
doi: 10.1111/eci.13546
pubmed: 33738814
pmcid: 8250296
Silva, B. R. S. et al. Downregulation of the protein C signaling system is associated with COVID-19 hypercoagulability-a single-cell transcriptomics analysis. Viruses 14, 2753. https://doi.org/10.3390/v14122753 (2022).
doi: 10.3390/v14122753
pubmed: 36560757
pmcid: 9785999
Chirumamilla, Y., Almerstani, Y., Marcus, H. & Bachuwa, G. Protein S deficiency and COVID-19: A brutal combination leading to acute submassive bilateral pulmonary embolism. Cureus 15, e41560. https://doi.org/10.7759/cureus.41560 (2023).
doi: 10.7759/cureus.41560
pubmed: 37554606
pmcid: 10405865
Joan, L., Daniella, A. S. & Michael, N. COVID-19, immunothrombosis and venous thromboembolism: Biological mechanisms. Thorax 76, 412. https://doi.org/10.1136/thoraxjnl-2020-216243 (2021).
doi: 10.1136/thoraxjnl-2020-216243
Sim, M. M. S. & Wood, J. P. Dysregulation of Protein S in COVID-19. Best Pract. Res. Clin. Haematol. 35, 101376. https://doi.org/10.1016/j.beha.2022.101376 (2022).
doi: 10.1016/j.beha.2022.101376
pubmed: 36494145
pmcid: 9395234
Nguyen, P. et al. Varicella and thrombotic complications associated with transient protein C and protein S deficiencies in children. Eur. J. Pediatr. 153, 646–649 (1994).
doi: 10.1007/BF02190684
pubmed: 7957422
Lamprinou, M., Sachinidis, A., Stamoula, E., Vavilis, T. & Papazisis, G. COVID-19 vaccines adverse events: Potential molecular mechanisms. Immunol. Res. 71, 356–372. https://doi.org/10.1007/s12026-023-09357-5 (2023).
doi: 10.1007/s12026-023-09357-5
pubmed: 36607502
pmcid: 9821369
Bustamante, J. G., Goyal, A. & Singhal, M. in StatPearl (StatPearls Publishing, St. Petersburg, 2024).
Abdel-Wahab, N., Talathi, S., Lopez-Olivo, M. A. & Suarez-Almazor, M. E. Risk of developing antiphospholipid antibodies following viral infection: A systematic review and meta-analysis. Lupus 27, 572–583. https://doi.org/10.1177/0961203317731532 (2018).
doi: 10.1177/0961203317731532
pubmed: 28945149
Zuo, Y. et al. Prothrombotic autoantibodies in serum from patients hospitalized with COVID-19. Sci. Transl. Med. 12, 3876. https://doi.org/10.1126/scitranslmed.abd3876 (2020).
doi: 10.1126/scitranslmed.abd3876
Castillo-Martínez, D., Torres, Z., Amezcua-Guerra, L. M. & Pineda, C. Are antiphospholipid antibodies just a common epiphenomenon or are they causative of immune-mediated coagulopathy in COVID-19?. Clin. Rheumatol. 40, 3015–3019. https://doi.org/10.1007/s10067-021-05724-5 (2021).
doi: 10.1007/s10067-021-05724-5
pubmed: 33826045
pmcid: 8024929
Devreese, K. M. J., Linskens, E. A., Benoit, D. & Peperstraete, H. Antiphospholipid antibodies in patients with COVID-19: A relevant observation?. J. Thromb. Haemost. 18, 2191–2201. https://doi.org/10.1111/jth.14994 (2020).
doi: 10.1111/jth.14994
pubmed: 32619328
pmcid: 7361253
Gkrouzman, E., Barbhaiya, M., Erkan, D. & Lockshin, M. D. Reality check on antiphospholipid antibodies in COVID-19–associated coagulopathy. Arthritis Rheumatol. 73, 173–174. https://doi.org/10.1002/art.41472 (2021).
doi: 10.1002/art.41472
pubmed: 32901454
Scully, M. et al. Pathologic antibodies to platelet factor 4 after ChAdOx1 nCoV-19 vaccination. N. Engl. J. Med. 384, 2202–2211. https://doi.org/10.1056/NEJMoa2105385 (2021).
doi: 10.1056/NEJMoa2105385
pubmed: 33861525
Schultz, N. H. et al. Thrombosis and Thrombocytopenia after ChAdOx1 nCoV-19 Vaccination. N. Engl. J. Med. 384, 2124–2130. https://doi.org/10.1056/NEJMoa2104882 (2021).
doi: 10.1056/NEJMoa2104882
pubmed: 33835768
Welsh, K. J., Baumblatt, J., Chege, W., Goud, R. & Nair, N. Thrombocytopenia including immune thrombocytopenia after receipt of mRNA COVID-19 vaccines reported to the vaccine adverse event reporting system (VAERS). Vaccine 39, 3329–3332. https://doi.org/10.1016/j.vaccine.2021.04.054 (2021).
doi: 10.1016/j.vaccine.2021.04.054
pubmed: 34006408
pmcid: 8086806
Cines, D. B. & Bussel, J. B. SARS-CoV-2 vaccine-induced immune thrombotic thrombocytopenia. N. Engl. J. Med. 384, 2254–2256. https://doi.org/10.1056/NEJMe2106315 (2021).
doi: 10.1056/NEJMe2106315
pubmed: 33861524
Greinacher, A. et al. Thrombotic thrombocytopenia after ChAdOx1 nCov-19 vaccination. N. Engl. J. Med. 384, 2092–2101. https://doi.org/10.1056/NEJMoa2104840 (2021).
doi: 10.1056/NEJMoa2104840
pubmed: 33835769
Favas, T. T. et al. Thrombotic and thromboembolic complications after vaccination against COVID-19: A systematic review. Cureus 15, e37275. https://doi.org/10.7759/cureus.37275 (2023).
doi: 10.7759/cureus.37275
pubmed: 37182082
pmcid: 10167937
Hallberg, P. et al. SWEDEGENE—a Swedish nation-wide DNA sample collection for pharmacogenomic studies of serious adverse drug reactions. Pharmacogenomics J. 20, 579–585. https://doi.org/10.1038/s41397-020-0148-3 (2020).
doi: 10.1038/s41397-020-0148-3
pubmed: 31949290
pmcid: 7375949
Nordström, P., Ballin, M. & Nordström, A. Risk of infection, hospitalisation, and death up to 9 months after a second dose of COVID-19 vaccine: A retrospective, total population cohort study in Sweden. Lancet 399, 814–823. https://doi.org/10.1016/S0140-6736(22)00089-7 (2022).
doi: 10.1016/S0140-6736(22)00089-7
pubmed: 35131043
pmcid: 8816388
Lundberg-Morris, L. et al. Covid-19 vaccine effectiveness against post-covid-19 condition among 589 722 individuals in Sweden: Population based cohort study. BMJ 383, e076990. https://doi.org/10.1136/bmj-2023-076990 (2023).
doi: 10.1136/bmj-2023-076990
pubmed: 37993131
pmcid: 10666099
Karlstad, Ø. et al. SARS-CoV-2 vaccination and myocarditis in a nordic cohort study of 23 million residents. JAMA Cardiol. 7, 600–612. https://doi.org/10.1001/jamacardio.2022.0583 (2022).
doi: 10.1001/jamacardio.2022.0583
pubmed: 35442390
pmcid: 9021987
Pomara, C. et al. COVID-19 vaccine and death: Causality algorithm according to the WHO eligibility diagnosis. Diagnostics (Basel) 11, 955. https://doi.org/10.3390/diagnostics11060955 (2021).
doi: 10.3390/diagnostics11060955
pubmed: 34073536
Le Voyer, T. et al. Autoantibodies against type I IFNs in humans with alternative NF-κB pathway deficiency. Nature 623, 803–813. https://doi.org/10.1038/s41586-023-06717-x (2023).
doi: 10.1038/s41586-023-06717-x
pubmed: 37938781
pmcid: 10665196
Yalcinkaya, A. et al. No link between type I interferon autoantibody positivity and adverse reactions to COVID-19 vaccines. npj Vaccines 9, 42. https://doi.org/10.1038/s41541-024-00829-9 (2024).
doi: 10.1038/s41541-024-00829-9
pubmed: 38388530
pmcid: 10883980
Abolhassani, H. et al. X-linked TLR7 deficiency underlies critical COVID-19 pneumonia in a male patient with ataxia-telangiectasia. J. Clin. Immunol. 42, 1–9. https://doi.org/10.1007/s10875-021-01151-y (2022).
doi: 10.1007/s10875-021-01151-y
pubmed: 34686943
Platton, S. et al. Evaluation of laboratory assays for anti-platelet factor 4 antibodies after ChAdOx1 nCOV-19 vaccination. J. Thromb. Haemost. 19, 2007–2013. https://doi.org/10.1111/jth.15362 (2021).
doi: 10.1111/jth.15362
pubmed: 33973336
pmcid: 8236994
R Foundation for Statistical Computing. R: A language and environment for statistical computing (R Foundation for Statistical Computing, Vienna, Austria, 2023).
Knight, R. et al. 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 146, 892–906. https://doi.org/10.1161/CIRCULATIONAHA.122.060785 (2022).
doi: 10.1161/CIRCULATIONAHA.122.060785
pubmed: 36121907
pmcid: 9484653
Núria, M.-B. et al. The role of COVID-19 vaccines in preventing post-COVID-19 thromboembolic and cardiovascular complications. Heart https://doi.org/10.1136/heartjnl-2023-323483 (2024).
doi: 10.1136/heartjnl-2023-323483
Cari, L. et al. Thrombotic events with or without thrombocytopenia in recipients of adenovirus-based COVID-19 vaccines. Front. Cardiovasc. Med. 9, 967926. https://doi.org/10.3389/fcvm.2022.967926 (2022).
doi: 10.3389/fcvm.2022.967926
pubmed: 36247442
pmcid: 9556888
Fujinami, R. S., von Herrath, M. G., Christen, U. & Whitton, J. L. Molecular mimicry, bystander activation, or viral persistence: Infections and autoimmune disease. Clin. Microbiol. Rev. 19, 80–94. https://doi.org/10.1128/cmr.19.1.80-94.2006 (2006).
doi: 10.1128/cmr.19.1.80-94.2006
pubmed: 16418524
pmcid: 1360274
Sher, E. K. et al. Covid-19 a triggering factor of autoimmune and multi-inflammatory diseases. Life Sci 319, 121531. https://doi.org/10.1016/j.lfs.2023.121531 (2023).
doi: 10.1016/j.lfs.2023.121531
pubmed: 36858313
pmcid: 9969758
Peng, K. et al. Risk of autoimmune diseases following COVID-19 and the potential protective effect from vaccination: A population-based cohort study. eClinicalMedicine 63, 102154. https://doi.org/10.1016/j.eclinm.2023.102154 (2023).
doi: 10.1016/j.eclinm.2023.102154
pubmed: 37637754
pmcid: 10458663
Greinacher, A. et al. Anti–platelet factor 4 antibodies causing VITT do not cross-react with SARS-CoV-2 spike protein. Blood 138, 1269–1277. https://doi.org/10.1182/blood.2021012938 (2021).
doi: 10.1182/blood.2021012938
pubmed: 34280256
pmcid: 8294553
Schönborn, L. et al. Anti-PF4 immunothrombosis without proximate heparin or adenovirus vector vaccine exposure. Blood 142, 2305–2314. https://doi.org/10.1182/blood.2023022136 (2023).
doi: 10.1182/blood.2023022136
pubmed: 37883798
pmcid: 10862238
Warkentin, T. E. et al. Adenovirus-associated thrombocytopenia, thrombosis, and VITT-like antibodies. N. Engl. J. Med. 389, 574–577. https://doi.org/10.1056/NEJMc2307721 (2023).
doi: 10.1056/NEJMc2307721
pubmed: 37590457
Campello, E., Biolo, M. & Simioni, P. More on Adenovirus-Associated Thrombocytopenia, Thrombosis, and VITT-like Antibodies. N. Engl. J. Med. 389, 1729. https://doi.org/10.1056/NEJMc2310644 (2023).
doi: 10.1056/NEJMc2310644
pubmed: 37913522
Wang, J. J. et al. Antibody fingerprints linking adenoviral anti-PF4 disorders. N. Engl. J. Med. 390, 1827–1829. https://doi.org/10.1056/NEJMc2402592 (2024).
doi: 10.1056/NEJMc2402592
pubmed: 38749041
See, I. et al. Case series of thrombosis with thrombocytopenia syndrome after COVID-19 vaccination-United States, december 2020 to august 2021. Ann. Intern. Med. 175, 513–522. https://doi.org/10.7326/m21-4502 (2022).
doi: 10.7326/m21-4502
pubmed: 35038274
Dautaj, A. et al. Hereditary thrombophilia. Acta Biomed. 90, 44–46. https://doi.org/10.23750/abm.v90i10-S.8758 (2019).
doi: 10.23750/abm.v90i10-S.8758
pubmed: 31577252
pmcid: 7233636
Sorice, M. et al. Inhibition of protein S by autoantibodies in patients with acquired protein S deficiency. Thromb. Haemost. 75, 555–559 (1996).
doi: 10.1055/s-0038-1650320
pubmed: 8743177
Andersson, H. M. et al. Activated protein C cofactor function of protein S: A critical role for Asp95 in the EGF1-like domain. Blood 115, 4878–4885. https://doi.org/10.1182/blood-2009-11-256610 (2010).
doi: 10.1182/blood-2009-11-256610
pubmed: 20308596
pmcid: 2884152
Regnault, V. et al. Anti-protein S antibodies following a varicella infection: Detection, characterization and influence on thrombin generation. J. Thromb. Haemost. 3, 1243–1249. https://doi.org/10.1111/j.1538-7836.2005.01270.x (2005).
doi: 10.1111/j.1538-7836.2005.01270.x
pubmed: 15946215
Montserrat, B. et al. IgM anti-protein S antibodies as a risk factor for venous thrombosis. Haematologica 93, 1115–1117. https://doi.org/10.3324/haematol.12575 (2008).
doi: 10.3324/haematol.12575
Levin, M. et al. Postinfectious purpura fulminans caused by an autoantibody directed against protein S. J. Pediatr. 127, 355–363. https://doi.org/10.1016/S0022-3476(95)70063-3 (1995).
doi: 10.1016/S0022-3476(95)70063-3
pubmed: 7658262
Stanne, T. M., Pedersen, A., Gisslén, M. & Jern, C. Low admission protein C levels are a risk factor for disease worsening and mortality in hospitalized patients with COVID-19. Thromb. Res. 204, 13–15. https://doi.org/10.1016/j.thromres.2021.05.016 (2021).
doi: 10.1016/j.thromres.2021.05.016
pubmed: 34102452
pmcid: 8163729
Dinarvand, P. & Moser, K. A. Protein C deficiency. Arch. Pathol. Lab. Med. 143, 1281–1285. https://doi.org/10.5858/arpa.2017-0403-RS (2019).
doi: 10.5858/arpa.2017-0403-RS
pubmed: 30702334
Panigada, M. et al. Hypercoagulability of COVID-19 patients in intensive care unit: A report of thromboelastography findings and other parameters of hemostasis. J. Thromb. Haemost. 18, 1738–1742. https://doi.org/10.1111/jth.14850 (2020).
doi: 10.1111/jth.14850
pubmed: 32302438
pmcid: 9906150
Tin, A. et al. Association between circulating protein C levels and incident dementia: The atherosclerosis risk in communities study. Neuroepidemiology 55, 306–315. https://doi.org/10.1159/000516287 (2021).
doi: 10.1159/000516287
pubmed: 34077937
Muhanad, T. & Lobelia, S. Antiphospholipid antibodies in COVID-19: A meta-analysis and systematic review. RMD Open 7, e001580. https://doi.org/10.1136/rmdopen-2021-001580 (2021).
doi: 10.1136/rmdopen-2021-001580
Pineton de Chambrun, M. et al. High frequency of antiphospholipid antibodies in critically ill COVID-19 patients: A link with hypercoagulability?. J. Intern. Med. 289, 422–424. https://doi.org/10.1111/joim.13126 (2021).
doi: 10.1111/joim.13126
pubmed: 32529774
Siguret, V. et al. Are antiphospholipid antibodies associated with thrombotic complications in critically ill COVID-19 patients?. Thromb. Res. 195, 74–76. https://doi.org/10.1016/j.thromres.2020.07.016 (2020).
doi: 10.1016/j.thromres.2020.07.016
pubmed: 32663703
pmcid: 7342042
Bowles, L. et al. Lupus anticoagulant and abnormal coagulation tests in patients with COVID-19. N. Engl. J. Med. 383, 288–290. https://doi.org/10.1056/NEJMc2013656 (2020).
doi: 10.1056/NEJMc2013656
pubmed: 32369280
Fonseca, D. L. M. et al. Severe COVID-19 patients exhibit elevated levels of autoantibodies targeting cardiolipin and platelet glycoprotein with age: A systems biology approach. npj Aging 9, 21. https://doi.org/10.1038/s41514-023-00118-0 (2023).
doi: 10.1038/s41514-023-00118-0
pubmed: 37620330
pmcid: 10449916
Dabit, J. Y., Valenzuela-Almada, M. O., Vallejo-Ramos, S. & Duarte-García, A. Epidemiology of antiphospholipid syndrome in the general population. Curr. Rheumatol. Rep. 23, 85. https://doi.org/10.1007/s11926-021-01038-2 (2022).
doi: 10.1007/s11926-021-01038-2
pubmed: 34985614
pmcid: 8727975