Farideh Najafi, Mohammad S. Abdelaal, Javad Parvizi.
Response/Recommendation: The risk of venous thromboembolism (VTE) in individuals receiving the severe acute respiratory syndrome-related coronavirus (SARS-CoV [COVID – 19]) vaccination is similar to the general population. A rare but drastic side effect of adenoviral COVID – 19 vector vaccines is the development of venous thrombosis at unusual sites, such as the brain or abdomen, accompanied by thrombocytopenia. Because the mechanism is still unclear and similarity was observed with heparin-induced thrombocytopenia (HIT), treatment of such thrombus should include non-heparin anticoagulants and intravenous immunoglobulin.
Strength of Recommendation: Limited.
Rationale: Vaccination against COVID – 19 has proven its efficacy in preventing infection contraction and spreading, and has significantly reduced the risk of severe illness, hospitalization, and mortality1–3. Diversity of technology landscapes were developed to create vaccines that offer a way out of the COVID – 19 crisis. Most platforms utilized the virus spike protein and its variants as the main antigen of COVID – 19 infection. These projects involved nucleic acid technologies (nucleoside-modified messenger RNA and DNA), non-replicating viral vectors, peptides, recombinant proteins, live attenuated viruses, and inactivated viruses approaches4. Though generally safe and efficacious, some temporary adverse effects have been reported including pain at the injection site, myalgia, headaches, fatigue, and tiredness, which is not uncommon with an inoculant that stimulates the immune system and usually resolves in a few days. However, few reports addressed a rare but devastating complication of thrombotic events in combination with thrombocytopenia observed after the administration of COVID – 19 vaccination5-7.
The thrombotic disorder was described to be clinically similar to severe HIT, which is caused by anti-PF4/heparin antibodies and occurs almost 5 – 24 days after the 1st dose of vaccination8,9. Vaccine-induced prothrombotic immune thrombotic thrombocytopenia (VIPTT) were found to be associated with unusual sites of thromboembolism, such as cerebral venous sinus thrombosis in (CVST) or abdominal venous thromboses. Apprehension remains relative to the safety of two vaccines that were associated with most cases of thrombosis; Vaxzevria ( previously AstraZeneca) and Janssen vaccines (Johnson and Johnson; also known as J&J)10. Both vaccines contain recombinant adenoviral vectors based on a chimpanzee adenovirus (Vaxzevria) or a human adenovirus (Janssen vaccine) that encodes the SARS-CoV-2 spike protein immunogen. It is well known that adenovirus binds to platelets and that this interaction causes platelet activation which can initiate the thrombosis process11. The American Society of Hematology and the Expert Hematology Panel (UK) suggest four diagnostic criteria in patients presenting within 4 – 30 days after vaccination with thrombotic symptoms. This includes receipt of a COVID – 19 vaccine (Janssen/Vaxzevria) 4 to 30 days previously; thrombosis (often cerebral or abdominal); thrombocytopenia; and positive PF4-HIT test using enzyme-linked immunosorbent assay (ELISA)12,13. While fewer cases were reported to have thrombotic events after the lipid nanoparticle encapsulated mRNA vaccine (Moderna and Comirnaty), no reports were found about thrombocytopenia after these vaccines13.
The majority of the large-scale studies consisting of individuals receiving COVID – 19 vaccination have reported that the thrombotic risk associated with vaccination was not elevated relative to the risk in the general population14,15. Huh et al., used the Korean claim database to determine the incidence of VIPTT among 8’548,231 patients vaccinated with Vaxzevria and it was found to be 0.23/1’000,00016. In a multinational study of 21,720 persons receiving the Comirnaty (Pfizer/BioNTech) vaccine, half of them followed for 2 months and reported no deep venous thrombosis (DVT) or pulmonary embolism (PE)17. Shazley et al., reported on a patient who developed DVT and PE which culminated in disseminated intravascular coagulation (DIC) in a COVID – 19 positive patient following the administration of the J&J vaccine18. Smadja et al., assessed clinical features of venous and arterial thrombotic events after injection of three COVID – 19 vaccines (Comirnaty, Moderna, and Vaxzevria). They recorded more arterial thrombosis occurring with mRNA vaccines compared to venous thrombosis. For Vaxzevria, the proportion of venous and arterial thromboses was more evenly distributed10.
An observed-to-expected analysis performed by the marketing authorization holder reported that the number of DVT or PE cases observed was indeed significantly lower than expected, suggesting no causal association between VTEs and Vaxzevria19. This interpretation however needs to be taken cautiously due to concerns related to quality, sensitivity, and appropriate stratification in the report.
Although the main pathogenic mechanisms behind the rare thrombotic phenomenon known to occur after COVID – 19 vaccination have not yet been identified, both host factors (thrombosis history, specific haplotypes, smoking and taking specific medications) and vaccine-related factors might be involved, with pathology being at least in part related to the vaccine-triggered autoimmune reaction1. Furthermore, COVID – 19 infection has been proven to be prothrombotic20, it is unclear whether the patients who developed VTE after vaccination were infected with COVID – 19 (i.e., asymptomatic) prior to or immediately before immunity developed.
Based on the reports available, the rate of VTE in individuals receiving COVID – 19 vaccination appears to be similar to the general population.
1. Lee GM, Romero JR, Bell BP. Postapproval Vaccine Safety Surveillance for COVID-19 Vaccines in the US. JAMA. 2020;324(19):1937-1938. doi:10.1001/jama.2020.19692
2. Shah A, Challener DW, O’Horo JC, Badley AD. Vaccination Safety. Mayo Clin Proc. 2021;96(7):1712-1713. doi:10.1016/j.mayocp.2021.05.004
3. Wise J. Covid-19: Is vaccination roll out reducing cases and deaths in the UK? BMJ. 2021;372:n506. doi:10.1136/bmj.n506
4. Thanh Le T, Andreadakis Z, Kumar A, et al. The COVID-19 vaccine development landscape. Nature Reviews Drug Discovery. 2020;19(5):305-306. doi:10.1038/d41573-020-00073-5
5. Elrashdy F, Tambuwala MM, Hassan SkS, et al. Autoimmunity roots of the thrombotic events after COVID-19 vaccination. Autoimmunity Reviews. Published online September 9, 2021:102941. doi:10.1016/j.autrev.2021.102941
6. De Michele M, Iacobucci M, Chistolini A, et al. Malignant cerebral infarction after ChAdOx1 nCov-19 vaccination: a catastrophic variant of vaccine-induced immune thrombotic thrombocytopenia. Nat Commun. 2021;12:4663. doi:10.1038/s41467-021-25010-x
7. Greinacher A, Thiele T, Warkentin TE, Weisser K, Kyrle PA, Eichinger S. Thrombotic Thrombocytopenia after ChAdOx1 nCov-19 Vaccination. N Engl J Med. Published online April 9, 2021:NEJMoa2104840. doi:10.1056/NEJMoa2104840
8. Greinacher A, Thiele T, Warkentin TE, Weisser K, Kyrle P, Eichinger S. A Prothrombotic Thrombocytopenic Disorder Resembling Heparin-Induced Thrombocytopenia Following Coronavirus-19 Vaccination. Published online September 20, 2021. doi:10.21203/rs.3.rs-362354/v1
9. Greinacher A. CLINICAL PRACTICE. Heparin-Induced Thrombocytopenia. N Engl J Med. 2015;373(3):252-261. doi:10.1056/NEJMcp1411910
10. Hwang J, Lee SB, Lee SW, et al. Comparison of vaccine-induced thrombotic events between ChAdOx1 nCoV-19 and Ad26.COV.2.S vaccines. J Autoimmun. 2021;122:102681. doi:10.1016/j.jaut.2021.102681
11. Stone D, Liu Y, Shayakhmetov D, Li ZY, Ni S, Lieber A. Adenovirus-platelet interaction in blood causes virus sequestration to the reticuloendothelial system of the liver. J Virol. 2007;81(9):4866-4871. doi:10.1128/JVI.02819-06
12. Thrombosis with Thrombocytopenia Syndrome – Hematology.org. Accessed September 23, 2021. http://www.hematology.org/covid-19/vaccine-induced-immune-thrombotic-thrombocytopenia
13. Islam A, Bashir MS, Joyce K, Rashid H, Laher I, Elshazly S. An Update on COVID-19 Vaccine Induced Thrombotic Thrombocytopenia Syndrome and Some Management Recommendations. Molecules. 2021;26(16):5004. doi:10.3390/molecules26165004
14. Malik B, Kalantary A, Rikabi K, Kunadi A. Pulmonary embolism, transient ischaemic attack and thrombocytopenia after the Johnson & Johnson COVID-19 vaccine. BMJ Case Rep. 2021;14(7):e243975. doi:10.1136/bcr-2021-243975
15. Scully M, Singh D, Lown R, et al. Pathologic Antibodies to Platelet Factor 4 after ChAdOx1 nCoV-19 Vaccination. N Engl J Med. 2021;384(23):2202-2211. doi:10.1056/NEJMoa2105385
16. Huh K, Na Y, Kim YE, Radnaabaatar M, Peck KR, Jung J. Predicted and Observed Incidence of Thromboembolic Events among Koreans Vaccinated with ChAdOx1 nCoV-19 Vaccine. J Korean Med Sci. 2021;36(27):e197. doi:10.3346/jkms.2021.36.e197
17. Polack FP, Thomas SJ, Kitchin N, et al. Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine. N Engl J Med. Published online December 10, 2020:NEJMoa2034577. doi:10.1056/NEJMoa2034577
18. Shazley O, Alshazley M. A COVID-Positive 52-Year-Old Man Presented With Venous Thromboembolism and Disseminated Intravascular Coagulation Following Johnson & Johnson Vaccination: A Case-Study. Cureus. 2021;13(7):e16383. doi:10.7759/cureus.16383
19. PINHO AC. COVID-19 Vaccine AstraZeneca: PRAC investigating cases of thromboembolic events – vaccine’s benefits currently still outweigh risks Update. European Medicines Agency. Published March 11, 2021. Accessed September 23, 2021. https://www.ema.europa.eu/en/news/covid-19-vaccine-astrazeneca-prac-investigating-cases-thromboembolic-events-vaccines-benefits
20. Al-Ani F, Chehade S, Lazo-Langner A. Thrombosis risk associated with COVID-19 infection. A scoping review. Thromb Res. 2020;192:152-160. doi:10.1016/j.thromres.2020.05.039