Review

. 2021 Jul 13;11(7):1020.

doi: 10.3390/biom11071020.

COVID-19 Vaccines and Thrombosis-Roadblock or Dead-End Street?

Kenneth Lundstrom¹, Debmalya Barh^{2

3}, Bruce D Uhal⁴, Kazuo Takayama⁵, Alaa A A Aljabali⁶, Tarek Mohamed Abd El-Aziz^{7

8}, Amos Lal⁹, Elrashdy M Redwan¹⁰, Parise Adadi¹¹, Gaurav Chauhan¹², Samendra P Sherchan¹³, Gajendra Kumar Azad¹⁴, Nima Rezaei^{15

16}, Ángel Serrano-Aroca¹⁷, Nicolas G Bazan¹⁸, Sk Sarif Hassan¹⁹, Pritam Kumar Panda²⁰, Pabitra Pal Choudhury²¹, Damiano Pizzol²², Ramesh Kandimalla^{23

24}, Wagner Baetas-da-Cruz²⁵, Yogendra Kumar Mishra²⁶, Giorgio Palu²⁷, Adam M Brufsky²⁸, Murtaza M Tambuwala²⁹, Vladimir N Uversky³⁰

Affiliations

¹ PanTherapeutics, CH 1095 Lutry, Switzerland.
² Centre for Genomics and Applied Gene Technology, Institute of Integrative Omics and Applied Biotechnology (IIOAB), Purba Medinipur 721172, India.
³ Departamento de Genética, Ecologia e Evolução, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte 31270-901, Brazil.
⁴ Department of Physiology, Michigan State University, East Lansing, MI 48824, USA.
⁵ Center for iPS Cell Research and Application, Kyoto University, Kyoto 606-8397, Japan.
⁶ Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, Yarmouk University, P.O. Box 566, Irbid 21163, Jordan.
⁷ Zoology Department, Faculty of Science, Minia University, El-Minia 61519, Egypt.
⁸ Department of Cellular and Integrative Physiology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
⁹ Department of Medicine, Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, MN 55902, USA.
¹⁰ Biological Science Department, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia.
¹¹ Department of Food Science, University of Otago, Dunedin 9054, New Zealand.
¹² School of Engineering and Sciences, Tecnológico de Monterrey, Av. Eugenio Garza Sada 2501 Sur, Monterrey 64849, Mexico.
¹³ Department of Environmental Health Sciences, Tulane University, New Orleans, LA 70112, USA.
¹⁴ Department of Zoology, Patna University, Patna 800005, India.
¹⁵ Research Center for Immunodeficiency, Children's Medical Center, Tehran University of Medical Sciences, Tehran 1416753955, Iran.
¹⁶ Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), 17177 Stockholm, Sweden.
¹⁷ Biomaterials and Bioengineering Lab, Centro de Investigación Traslacional San Alberto Magno, Universidad Católica de Valencia San Vicente Mártir, c/Guillem de Castro 94, 46001 Valencia, Spain.
¹⁸ Neuroscience Center of Excellence, School of Medicine, LSU Health New Orleans, New Orleans, LA 70112, USA.
¹⁹ Department of Mathematics, Pingla Thana Mahavidyalaya, Maligram 721140, India.
²⁰ Condensed Matter Theory Group, Materials Theory Division, Department of Physics and Astronomy, Uppsala University, Box 516, 75120 Uppsala, Sweden.
²¹ Applied Statistics Unit, Indian Statistical Institute, Kolkata 700108, India.
²² Italian Agency for Development Cooperation-Khartoum, Sudan Street 33, Al Amarat 11111, Sudan.
²³ Applied Biology, CSIR-Indian Institute of Technology, Uppal Road, Tarnaka, Hyderabad 500007, India.
²⁴ Department of Biochemistry, Kakatiya Medical College, Warangal 506007, India.
²⁵ Translational Laboratory in Molecular Physiology, Centre for Experimental Surgery, College of Medicine, Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro 21941-901, Brazil.
²⁶ Mads Clausen Institute, University of Southern Denmark, NanoSYD, Alsion 2, 6400 Sønderborg, Denmark.
²⁷ Department of Molecular Medicine, University of Padova, 35122 Padova, PD, Italy.
²⁸ UPMC Hillman Cancer Center, Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
²⁹ School of Pharmacy and Pharmaceutical Science, Ulster University, Coleraine BT52 1SA, UK.
³⁰ Department of Molecular Medicine and USF Health Byrd Alzheimer's Institute, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA.

PMID: 34356644
PMCID: PMC8301964
DOI: 10.3390/biom11071020

Review

COVID-19 Vaccines and Thrombosis-Roadblock or Dead-End Street?

Kenneth Lundstrom et al. Biomolecules. 2021.

. 2021 Jul 13;11(7):1020.

doi: 10.3390/biom11071020.

Authors

Affiliations

¹ PanTherapeutics, CH 1095 Lutry, Switzerland.
² Centre for Genomics and Applied Gene Technology, Institute of Integrative Omics and Applied Biotechnology (IIOAB), Purba Medinipur 721172, India.
³ Departamento de Genética, Ecologia e Evolução, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte 31270-901, Brazil.
⁴ Department of Physiology, Michigan State University, East Lansing, MI 48824, USA.
⁵ Center for iPS Cell Research and Application, Kyoto University, Kyoto 606-8397, Japan.
⁶ Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, Yarmouk University, P.O. Box 566, Irbid 21163, Jordan.
⁷ Zoology Department, Faculty of Science, Minia University, El-Minia 61519, Egypt.
⁸ Department of Cellular and Integrative Physiology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
⁹ Department of Medicine, Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, MN 55902, USA.
¹⁰ Biological Science Department, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia.
¹¹ Department of Food Science, University of Otago, Dunedin 9054, New Zealand.
¹² School of Engineering and Sciences, Tecnológico de Monterrey, Av. Eugenio Garza Sada 2501 Sur, Monterrey 64849, Mexico.
¹³ Department of Environmental Health Sciences, Tulane University, New Orleans, LA 70112, USA.
¹⁴ Department of Zoology, Patna University, Patna 800005, India.
¹⁵ Research Center for Immunodeficiency, Children's Medical Center, Tehran University of Medical Sciences, Tehran 1416753955, Iran.
¹⁶ Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), 17177 Stockholm, Sweden.
¹⁷ Biomaterials and Bioengineering Lab, Centro de Investigación Traslacional San Alberto Magno, Universidad Católica de Valencia San Vicente Mártir, c/Guillem de Castro 94, 46001 Valencia, Spain.
¹⁸ Neuroscience Center of Excellence, School of Medicine, LSU Health New Orleans, New Orleans, LA 70112, USA.
¹⁹ Department of Mathematics, Pingla Thana Mahavidyalaya, Maligram 721140, India.
²⁰ Condensed Matter Theory Group, Materials Theory Division, Department of Physics and Astronomy, Uppsala University, Box 516, 75120 Uppsala, Sweden.
²¹ Applied Statistics Unit, Indian Statistical Institute, Kolkata 700108, India.
²² Italian Agency for Development Cooperation-Khartoum, Sudan Street 33, Al Amarat 11111, Sudan.
²³ Applied Biology, CSIR-Indian Institute of Technology, Uppal Road, Tarnaka, Hyderabad 500007, India.
²⁴ Department of Biochemistry, Kakatiya Medical College, Warangal 506007, India.
²⁵ Translational Laboratory in Molecular Physiology, Centre for Experimental Surgery, College of Medicine, Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro 21941-901, Brazil.
²⁶ Mads Clausen Institute, University of Southern Denmark, NanoSYD, Alsion 2, 6400 Sønderborg, Denmark.
²⁷ Department of Molecular Medicine, University of Padova, 35122 Padova, PD, Italy.
²⁸ UPMC Hillman Cancer Center, Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
²⁹ School of Pharmacy and Pharmaceutical Science, Ulster University, Coleraine BT52 1SA, UK.
³⁰ Department of Molecular Medicine and USF Health Byrd Alzheimer's Institute, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA.

PMID: 34356644
PMCID: PMC8301964
DOI: 10.3390/biom11071020

Abstract

Two adenovirus-based vaccines, ChAdOx1 nCoV-19 and Ad26.COV2.S, and two mRNA-based vaccines, BNT162b2 and mRNA.1273, have been approved by the European Medicines Agency (EMA), and are invaluable in preventing and reducing the incidence of coronavirus disease-2019 (COVID-19). Recent reports have pointed to thrombosis with associated thrombocytopenia as an adverse effect occurring at a low frequency in some individuals after vaccination. The causes of such events may be related to SARS-CoV-2 spike protein interactions with different C-type lectin receptors, heparan sulfate proteoglycans (HSPGs) and the CD147 receptor, or to different soluble splice variants of the spike protein, adenovirus vector interactions with the CD46 receptor or platelet factor 4 antibodies. Similar findings have been reported for several viral diseases after vaccine administration. In addition, immunological mechanisms elicited by viral vectors related to cellular delivery could play a relevant role in individuals with certain genetic backgrounds. Although rare, the potential COVID-19 vaccine-induced immune thrombotic thrombocytopenia (VITT) requires immediate validation, especially in risk groups, such as the elderly, chronic smokers, and individuals with pre-existing incidences of thrombocytopenia; and if necessary, a reformulation of existing vaccines.

Keywords: COVID-19; SARS-CoV-2; chronic smokers; thrombosis; vaccines.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Figures

**Figure 1**
Schematic illustration of ChAdOx1 nCoV-19 and Ad26.COV2.S constructs and the potential association of tPA and thrombocytopenia. Both ChAdOx nCoV-19 and Ad26.COV2.S contain the tPA leader sequence and the full-length SARS-CoV-2 protein. Ad26.COV2.S additionally has a mutated furin site. The translation of only the tPA leader sequence is unlikely to cause thrombocytopenia as previously reported in ischemic stroke and acute myocardial infarction patients treated with recombinant tPA. Figure was created with Biorender.

**Figure 2**
Potential Mechanisms for Upregulation of Complementary Pathways by the SARS-CoV-2 S Protein. Schematic presentation of the stages for alternative, classic and lectin pathways: 1. Binding of complement proteins to SARS-CoV-2; 2. Formation of C3 convertase; 3. Cleavage of C3 by C3 convertase; 4. Formation of C5 convertase. Figure was created with Biorender.

**Figure 3**
Heparin-induced Thrombocytopenia. Proposed mechanism of thrombocytopenia induced after Ad-based vaccine administration. Figure was created with Biorender.

See this image and copyright information in PMC

References

1. Sahin U., Muik A., Derhovanessian E., Vogler I., Kranz L.M., Vormehr M., Baum A., Pascal K., Quandt J., Maurus D., et al. COVID-19 vaccine BNT162b1 elicits human antibody and TH1 T cell responses. Nature. 2020;586:594–599. doi: 10.1038/s41586-020-2814-7. - DOI - PubMed
1. Jackson L.A., Anderson E.J., Rouphael N.G., Roberts P.C., Makhene M., Coler R.N., McCullough M.P., Chappell J.D., Denison M.R., Stevens L.J., et al. An mRNA Vaccine against SARS-CoV-2—Preliminary Report. N. Engl. J. Med. 2020;383:1920–1931. doi: 10.1056/NEJMoa2022483. - DOI - PMC - PubMed
1. Mercado N.B., Zahn R., Wegmann F., Loos C., Chandrashekar A., Yu J., Liu J., Peter L., McMahan K., Tostanoski L.H., et al. Single-shot Ad26 vaccine protects against SARS-CoV-2 in rhesus macaques. Nature. 2020;586:583–588. doi: 10.1038/s41586-020-2607-z. - DOI - PMC - PubMed
1. Arashkia A., Jalilvand S., Mohajel N., Afchangi A., Azadmanesh K., Salehi-Vaziri M., Fazlalipour M., Pouriayevali M.H., Jalali T., Nasab D.D.M., et al. Severe acute respiratory syndrome-coronavirus-2 spike (S) protein based vaccine candidates: State of the art and future prospects. Rev. Med. Virol. 2020:e2183. doi: 10.1002/rmv.2183. - DOI - PMC - PubMed
1. Galloway S.E., Paul P., MacCannell D.R., Johansson M.A., Brooks J.T., MacNeil A., Slayton R.B., Tong S., Silk B.J., Armstrong G.L., et al. Emergence of SARS-CoV-2 B.1.1.7 Lineage—United States, 29 December 2020–12 January 2021. Morb. Mortal. Wkly Rep. 2021;70:95–99. doi: 10.15585/mmwr.mm7003e2. - DOI - PMC - PubMed

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COVID-19 Vaccines and Thrombosis-Roadblock or Dead-End Street?

Affiliations

COVID-19 Vaccines and Thrombosis-Roadblock or Dead-End Street?

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Substances

LinkOut - more resources

Full Text Sources

Medical

Research Materials

Miscellaneous