LONDON – The U.K. Medicines and Healthcare products Regulatory Agency (MHRA) stood by its view that the benefits of Astrazeneca plc’s COVID-19 vaccine “continue to outweigh the risks,” as it published the latest summary of reported adverse events. These include 22 cases of cerebral venous sinus thrombosis (CVST) associated with thrombocytopenia, and eight reports of other thromboses that also were characterized by low platelet counts. Of the 30 reports of rare clotting disorders seen up to and including March 24, seven people have died. After the MHRA and the Commission on Human Medicines examined the cases in detail, they reached the same conclusion as the EMA, which on March 31 concluded “there is no evidence to support restricting the use of the vaccine in any population. The 30 reports in the U.K. are out of a total of 18.1 million doses of Astrazeneca vaccine administered. There have been two reported cases of CVST seen in people who received the Pfizer Inc./Biontech SE vaccine, but those were not associated with thrombocytopenia. Neither agency considers the matter closed, with the MHRA saying it is continuing its investigation, while the EMA is due to publish a fuller report next week. Occurrences of CVST in people vaccinated with the Astrazeneca vaccine are causing concern in Europe, and several countries have suspended its use in people below the age of 65. A British Society of Hematology expert team that has been involved in diagnosing and managing the U.K. cases, said no causal association with COVID-19 vaccination has been established. The cases are unusual because, despite the thrombocytopenia, there is progressive thrombosis, primarily venous, though some arterial thrombotic events have also been noted. Testing typically shows low fibrinogen and very raised levels of the fibrin degradation product, D-Dimer, above the level typically expected in venous thromboembolism. Antibodies to platelet factor 4 (PF4) have been identified, pointing to similarities to heparin-induced thrombocytopenia. However, none of the cases had prior exposure to heparin treatment. Samples from patients that are positive for anti-PF4 antibodies are being sent for whole genome sequencing. Setting out treatment guidelines on April 2, the Society of Hematologists noted anti-PF4 antibodies can be detected by the ELISA Heparin-induced thrombocytopenia assay, but not always by the Accustar assay. David Werring, professor of clinical neurology at University College London, said the absolute risk of CVST after receiving the Astrazeneca vaccine remains extremely low, at about 1.5 per million. “It’s not clear if this is any higher than the usual expected incidence of CVST, [at] probably around five to 15 per million people per year, though the figures vary as it can be difficult to diagnose in some cases,” he said. However, the latest evidence published by the MHRA does point to some unusual features, including the low blood platelets; the number of cases in the U.K. that have occurred in men, given CVST usually is more common in women; the finding of anti-PF4 antibodies in patients not previously treated with heparin; and a high risk of severe clots, said Werring. “This raises the possibility that the vaccine could be a causal factor in these rare and unusual cases of CVST, though we don’t know this yet, so more research is urgently needed,” he said. Most reports of CVST following vaccination with Astrazeneca’s vaccine has been in people under the age of 50, and David Spiegelhalter, chair of the Winton Centre for Risk and Evidence Communication at Cambridge University, said it is important to know whether that risk is substantially higher in younger age groups in the U.K., as has been found elsewhere. “Vaccinating younger people is as much for the wider community as for their direct benefit, and so it is reasonable to try to avoid causing harm, even if extremely rarely,” he said.

Reporting bias?

The U.K. started its vaccination program with people over age 80, progressively going down in age, and currently is calling all people ages 50 to 54 to make an appointment. Peter English, a retired consultant in communicable disease control, who formerly was editor of the journal Vaccines in Practice, noted it is only possible to tell whether there are excess cases of CVST if the background rate is known. He suggested that with CVST being so hard to diagnose, there may be some reporting bias, with the condition being diagnosed and reported in more people who have had the vaccine, just because it is being looked for. “Remember, it is a difficult diagnosis, suggesting it may often be missed, and if you look for it more carefully in one group than another, you are likely to find more cases in the group where you look more carefully,” English said. The latest safety update, published by the MHRA on April 1, shows that as of March 21, there were 40,883 adverse events reported for the Pfizer/Biontech vaccine after 10.8 million doses were administered, and 99,817 for AstraZeneca’s vaccine. The overwhelming majority relate to the normal immune response that would be expected shortly after vaccination. The MHRA has received 283 U.K. reports of suspected adverse events with the Pfizer/Biontech vaccine in which the patient died shortly after vaccination and 421 reports for Astrazeneca’s vaccine. The majority of those reports were in elderly people, or people with underlying illness. Since the MHRA issued guidance in December 2020 saying Pfizer/Biontech’s vaccine should not be given to anyone with a previous history of anaphylaxis, severe allergic reactions have been very rare, with 246 reports for Pfizer/Biontech and 390 for Astrazeneca. “The total number and the nature of [adverse events] reported so far is not unusual for a new vaccine for which members of the public and health care professionals are encouraged to report any suspected adverse event,” MHRA said.

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ISSN: 2155-9864| NLM ID: 101630198