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Covid-19: European countries suspend use of Oxford-AstraZeneca vaccine after reports of blood clots

BMJ 2021; 372 doi: (Published 11 March 2021) Cite this as: BMJ 2021;372:n699

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Re: COVID vaccines and thrombotic events: is mRNA translation and spike protein synthesis by platelets a real possibility?

Dear Editor,

We wish to comment on the Rapid Response by Dr. Hamid Merchant to the BMJ Research News on “Covid-19: European countries suspend use of Oxford-AstraZeneca vaccine after reports of blood clots” [1], suggesting that immune thrombocytopenia (ITP) secondary to COVID-19 might be induced by infection of platelets by SARS-CoV-2 with subsequent translation by platelets of viral mRNA, production of viral proteins and consequent triggering of an autoimmune response against platelets. Dr. Merchant also hypothesizes that it is not unreasonable to think that genetic COVID-19 vaccines may directly infect platelets and megakaryocytes, and this might be the reason of COVID-19 vaccination–induced thrombocytopenia.

The infection of platelets by SARS-CoV-2 is not an unfounded hypothesis, indeed HIV [2], influenza [3] and Dengue [4] viruses infect platelets and four recent studies explored the possible presence of SARS-CoV-2 in platelets [5-7]. Viral RNA was found in 2/25 (8%) [5], 15/241 (6.22%) [6], 0/24 (0%) [8] and 11/49 (22%) [7] COVID-19 patient platelets, however in this latter study platelets were not ultrapurified [9] raising the suspicion that the presence of the virus in white blood cells might have affected the results [7]. In particular, we analyzed serum and ultrapurified platelet samples from 24 patients with COVID-19, with both high and low viral load, including patients with thrombocytopenia, and we did not detect SARS-CoV-2 mRNA in any of our samples even when using the very sensitive technique of digital drop PCR [8]. Of note, none of these studies identified a correlation between the presence of SARS-CoV-2 mRNA in platelets and thrombocytopenia [5-8]. Thus, if SARS-CoV-2 enters platelets this seems to be a rare and possibly poorly relevant phenomenon. Indeed, other viruses are found in platelets from a significant fraction of infected patients: 52% for Dengue, upto 55% for influenza, 66% for HIV [2-4].

Exploitation of the platelet translational machinery by a virus has been reported only for Dengue which is able to enter platelets and to replicate its viral RNA by sequestering platelet translational machinery, then viral particles assemble and are released by platelets [4]. However, there is no evidence that platelets expose on their surface Dengue proteins and are thus cleared by the immune system, as suggested by Dr. Merchant for SARS-CoV-2. At most, viral replication in platelets, if present, may induce platelet activation and formation of platelet-leukocyte aggregates that are cleared from circulation [10,11] and/or apoptosis, that are more plausible hypotheses.

Thus, the hypothesis of the triggering of an autoimmune response against platelets by viral entry does not appear to be supported by any scientific evidence currently.

Finally, that genetic vaccines may “infect” platelets appears also an unlikely hypothesis. We presume that Dr. Merchant refers to the AstraZeneca vaccine, which is the object of the BMJ article [12]. However, platelets although possessing a transcriptome and protein synthesis ability [13], are anuclear and can not transcribe genetic DNA information into mRNA. The AstraZeneca ChAdOx1 nCoV-19 vaccine (AZD1222) consists of a replication-deficient chimpanzee adenoviral vector ChAdOx1 containing the SARS-CoV-2 spike protein gene [14]. Therefore, it would be very unlikely that a platelet could transcribe and then translate into a spike-protein a DNA vector. Moreover, it seems improbable that a replication-deficient adenoviral vector vaccine administered intramuscularly could directly interact and “transfect” circulating platelets, because it would hardly circulate as such [15,16].

Although the hypothesis raised by Dr. Merchant may seem fascinating we believe that disseminating the doubt, not corroborated by experimental evidence, that indeed the direct interaction of the AstraZeneca vaccine with platelets may lead to platelet consumption may be very dangerous and disorient patients and medical practitioners with a possibly very negative impact on this crucial initial phase of SARS-CoV-2 mass vaccination.

2. Real F, Capron C, Sennepin A, 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):eaat6263.
3. Koupenova M, Corkrey HA, Vitseva O, et al. The role of platelets in mediating a response to human influenza infection. Nat Commun. 2019;10(1):1780.
4. Simon AY, Sutherland MR, Pryzdial EL. Dengue virus binding and replication by platelets. Blood. 2015;126(3):378-85.
5. Manne BK, Denorme F, Middleton EA, et al. Platelet Gene Expression and Function in COVID-19 Patients. Blood. 2020:136(11):1317-1329.
6. 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(1):120.
7. 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. doi: 10.1161/CIRCRESAHA.120.317703. Online ahead of print. DOI: 10.1161/CIRCRESAHA.120.317703.
8. Bury L, Camilloni B, Castronari R, et al. Search for SARS-CoV-2 RNA in platelets from COVID-19 patients. Platelets. 2021;32(2):284-287. doi: 10.1080/09537104.2020.1859104.
9. Cecchetti L, Tolley ND, Michetti N, Bury L, Weyrich AS, Gresele P. Megakaryocytes differentially sort mRNAs for matrix metalloproteinases and their inhibitors into platelets: a mechanism for regulating synthetic events. Blood. 2011;118(7):1903-11.
10. Petito E, Falcinelli E, Paliani U et al. J Infect Dis. 2020:jiaa756. doi: 10.1093/infdis/jiaa756.
11. Falcinelli E, Petito E, Becattini C, et al. Role of endothelial dysfunction in the thrombotic complications of COVID-19 patients. J Infect. 2020:S0163-4453(20)30760-X. doi: 10.1016/j.jinf.2020.11.041.
12. BMJ 2021;372:n699. doi:
13. Weyrich AS, Schwertz H, Kraiss LW, Zimmerman GA. Protein synthesis by platelets: historical and new perspectives. J Thromb Haemost. 2009;7(2):241-6. doi: 10.1111/j.1538-7836.2008.03211.x.
14. Voysey M, Clemens SAC, Madhi SA, et al. Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK. Lancet. 2021;397(10269):99-111. doi: 10.1016/S0140-6736(20)32661-1.
15. Dupuis M, Denis-Mize K, Woo C, et al. Distribution of DNA vaccines determines their immunogenicity after intramuscular injection in mice. J Immunol. 2000;165(5):2850-8. doi: 10.4049/jimmunol.165.5.2850.
16. Pardi N, Hogan MJ, Porter FW, Weissman D. mRNA vaccines - a new era in vaccinology. Nat Rev Drug Discov. 2018;17(4):261-279. doi: 10.1038/nrd.2017.243.

Competing interests: No competing interests

19 March 2021
Paolo Gresele
Full Professor of Internal Medicine
Loredana Bury, Marco Malvestiti (University of Perugia, Section of Internal and Cardiovascular Medicine)
University of Perugia
Section of Internal and Cardiovascular Medicine