Even as a host of vaccines have been rolled out to counter the coronavirus disease 2019 (COVID-19) pandemic, some serious adverse effects have been reported, in the form of thrombocytopenia. A new study in the journal Vaccine reports the results of an evaluation of reported cases of this condition, using data from the Vaccine Adverse Event Reporting System (VAERS).
Background
Starting with the Pfizer and Moderna vaccines in December 2020, many different vaccines have received Emergency Use Authorization (EUA) from the US Food and Drugs Administration (FDA). Both these vaccines are built on a messenger ribonucleic acid (mRNA) platform, the mRNA being encapsulated within lipid nanoparticles.
The mRNA encodes the spike glycoprotein of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and expresses it within the host cell, to induce an immune reaction.
The FDA-designed VAERS system envisages the monitoring of adverse events of special interest like thrombocytopenia that are passively reported. Soon after the EUA, several reports of immune thrombocytopenia (ITP) came in. This condition, in which the platelet count drops to below 100 x109/L as a result of an autoimmune attack on the platelets, causing their destruction or reduced platelet production within the bone marrow.
Vaccine-associated events
The association of ITP with measles, rubella, and with several vaccines, led to the suspicion that the current outbreak was also related to the new COVID-19 vaccines, especially since SARS-CoV-2 infection has been linked to ITP in a few cases.
The mechanism of COVID-19-related platelet destruction has been hypothesized to be immunologic, directly due to the virus, reduced production of the platelet production factor thrombopoietin because of liver damage, or increased platelet consumption due to a disruption of normal coagulation function.
Earlier, the measles-mumps-rubella (MMR) vaccine was found to increase the risk of ITP within six weeks of vaccination. In almost 80% of these cases, antibodies were found to be present on platelets.
However, both the Pfizer and Moderna vaccines continued to be used.
Study details
The researchers examined VAERS data for any evidence of altered platelet counts to pathological levels. However, they excluded all cases where the low platelet count was reported on the same day. The FDA physicians also chose to ignore potential cases reported a day or more after vaccination, citing possibly insufficient information for etiological study.
What are the findings?
Of the approximately 19 million and 16 million doses of Pfizer and Moderna vaccine administered in the USA, respectively, these careful selection criteria identified 15 and 13 cases of thrombocytopenia, corresponding to less than one reported case per million doses of either vaccine. No sex difference was observed, and the median age was 49 years, though the condition was reported from 22 to 82 years.
The median duration from vaccination to onset of thrombocytopenia was 5.5 days, with a range of 1-23 days. Earlier reports on ITP in COVID-19 cases indicated a median time of onset at 13 days. Typically, however, the presentation occurred at 2-3 weeks from symptom onset, with only one in five patients presenting within a week or less.
The short period to onset of thrombocytopenia is not clear since immune reactions typically take longer to set in. Another explanation could be that these patients had previously been infected by the virus, which produced sensitization. In this case, the vaccine acted to produce a hypersensitivity reaction.
However, given the lack of data on a history of COVID-19 in these patients, this can only be hypothetical.
In most reports, symptomatic thrombocytopenia was described, with only one asymptomatic case discovered accidentally on routine laboratory testing.
Two patients died, one of a hemorrhagic stroke and the other of a heart attack with pulmonary embolism. Both had thrombocytopenia.
Only three patients had a history of ITP, and a few had other underlying inflammatory or autoimmune conditions. These included Crohn’s disease, Hashimoto’s disease and psoriasis, all being associated with inflammation and thus plausibly connected to the development of ITP.
What are the implications?
In the US, there are 1-6 cases of ITP/100,000 adults per year. At a median incidence rate of 3.3 cases per 100,00, this would come to an expected incidence of about 900 cases of ITP among the almost 28 million people who have received one or more doses of the vaccine over a year, or 57 cases in the 45 days since the vaccines began to be administered on a large scale.
The cases of thrombocytopenia included in this study number 28, and not all may actually have been ITP. “Reports of ITP were not higher than expected.”
The use of the AstraZeneca and the Johnson & Johnson COVID-19 vaccines have led to reports of serious thrombotic events in rare sites, often with thrombocytopenia. Most occurred in women, below 60 years of age, within 14 days of vaccination. This possible vaccine-related adverse reaction is being evaluated at present.
However, thrombosis in the presence of thrombocytopenia is postulated to be the result of an immunologic process like that, which is responsible for heparin-induced thrombocytopenia (HIT). In the current study, thrombosis was not reported in most cases.
The study relies on passive surveillance rather than an active search for such side effects, which may have introduced biases due to under-reporting and delayed reporting. Moreover, all cases may not have been captured due to the limitations of the search methodology used.
Several active surveillance studies are being carried out, and so far, fewer than expected cases of thrombocytopenia have been found. The researchers conclude that post-vaccination ITP does not seem to be an issue with COVID-19 vaccines, based on this data.
Given that COVID-19 vaccines will continue to be administered in increasingly diverse populations, and new vaccines for COVID-19 may be authorized in the future, continuing surveillance for thrombocytopenia including ITP is warranted.”
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