Since December 2019, the SARS-CoV-2 virus spread around the globe and caused a COVID-19 pandemic. The crisis threatened millions of lives, prompting the pharmaceutical industry to develop novel anti-viral drugs and potential vaccines. Many countries dived in such domain and five vaccines against COVID-19 were approved by the European Medicines Agency (EMA) thus far. However, to combat the rapidly deteriorating condition of COVID-19, governments permitted the distribution of the vaccine under emergency use. The safety and effectiveness of those vaccines were therein still under current controversy.

ChAdOx1 nCoV-19 vaccine (AstraZeneca) is a non-replicating adenovirus vector vaccine containing the SARS-CoV-2 virus spike protein gene. The vaccine entered cells and produced spike protein, stimulating T cells to attack the virus-infected cell. Urgently, the vaccine was authorised by the British Medicines and Health Products Administration and EMA respectively on 30 December 2020 and 30 January 2021. The convenience in storage and transportation established its global distribution. The vaccine was indicated for over 18 years of age and required two doses with a 12-week interval. Individuals with a history of severe allergic reaction and pregnant or breastfeeding female were not recommended for vaccine injection due to insufficient safety evidence. Common adverse events included but were not limited to local swelling or redness at the injection site, fatigue, headache, muscle pain, arthralgia, fever, nausea, and vomiting. These symptoms were reported to be predominantly self-limited within a few days.

Nevertheless, by February 2021, a series of unusual thromboembolic events with concomitant thrombocytopenia was reported days or weeks after injected with the ChAdOx1 nCoV-19 vaccine. A 42-year-old woman presented with headache and worsening consciousness 1 week after vaccination. The platelet count was 14 000 per cubic millimetre. Venous thromboembolism was identified in the transverse and sigmoid sinuses. Albeit being treated with dalteparin, methylprednisolone, and intravenous immune globulin, the patient expired two weeks later due to intracranial haemorrhage and cerebral swelling [1]. Among 5 million recipients of the ChAdOx1 nCoV-19 vaccine in Europe, a total of 30 thromboembolic events had been reported by 10 March 2021 [2]. Disseminated intravascular coagulation and cerebral venous sinus thrombosis were encountered, nearly two-thirds of which occured in young and middle-aged women [3].

  Subsequent studies suggested the platelet-activating antibody mediates the thrombotic thrombocytopenia, resembling heparin-induced thrombocytopenia (HIT) [4]. HIT is an immune-mediated disorder and is caused by antibodies binding to the heparin-PF4 complex, which activates platelets and initiates the thrombotic cascade. Up to 50% of HIT cases were associated with thromboembolism, and the mortality rate was high [5,6].

Whether the blood clot directly results from the ChAdOx1 nCoV-19 vaccine remained controversial. AstraZeneca and EMA stated to find no elevation in the risk of blood clots caused by the vaccine. A study based on Denmark nationwide population concluded that the thromboembolic events were not elevated in those receiving this vaccination as compared with the general population. Still, limitation in the cohort characteristics and underestimation of the target events might confound the statistics [2]. Under such uncertainty, several countries temporarily halted the injection.

On 18 March 2021, EMA’s safety committee announced the vaccine may be related to very rare cases of thromboembolism but did not escalate its overall risk. The unusual blood clots with low blood platelets ought to be listed as a rare side effect. Overall, the benefits of the vaccine still outweigh the potential risk.

To clarify the relationship between vaccination and blood clotting, further prospective studies with real-world data are warranted. Additionally, detailed elucidation on the pathophysiologic mechanism of thromboembolism is mandatory to assure the safety profile of this vaccination. The current bottom line is those high-risk subjects are advised to postpone vaccination until further evidence is available [7]. To emphasise, individuals with the otherwise clinical background are still urged to receive the vaccination, regardless of the brand. Only with the adequate coverage of vaccination will the pandemic be better managed.

Acknowledgements: The authors would like to acknowledge all those frontline medical personnel and the logistics in combating this pandemic.

Disclosures: The authors declare no conflicts of interest.

References

• 1. Schultz, N. H., Sørvoll, I.H., Michelsen, A. E., et al. (2021). Thrombosis and Thrombocytopenia after ChAdOx1 nCoV-19 Vaccination. N Engl J Med. https://doi.org/10.1056/nejmoa2104882. Epub ahead of print.

• 2. Østergaard, S. D., Schmidt, M., Horváth-Puhó, E., et al. (2021). Thromboembolism and the Oxford-AstraZeneca COVID-19 vaccine: side-effect or coincidience? The Lancet. https://doi.org/10.1016/s0140-6736(21)00762-5. Epub ahead of print.

• 3. Nick Triggle. (2021, April 7) Covid: Under-30s offered alternative to Oxford- AstraZeneca jab.

• 4. Greinacher, A., Thiele, T., Warkentin, T. E., et al. (2021). Thrombotic Thrombocytopenia after ChAdOx1 nCov-19 Vaccination. N Engl J Med. https://doi.org/10.1056/nejmoa2104840. Epub ahead of print.

• 5. Arepally, G. M., & Padmanabhan, A. (2021). Heparin-Induced Thrombocytopenia: A Focus on Thrombosis. Arteriosclerosis, Thrombosis, and Vascular Biology, 41(1), 141- 152. https://doi.org/10.1161/ATVBAHA.120.315445

• 6. Nicolas D, Nicolas S, Hodgens A, Reed M. (2020, July 13) Heparin Induced Thrombocytopenia. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan–. PMID: 29493955.

• 7. World Health Organization (2021, February 11) The Oxford/AstraZeneca COVID-19 vaccine: what you need to know.

http://www.who.int/news-room/feature-stories/detail/the-oxford-astrazeneca-COVID-19- vaccine-what-you-need-to-know

Written by:

En-Lin Su

Ting-Wei Kao M.D.

AMSA Taiwan