Conclusion
Natural viral infections such as influenza, varicella, measles, mumps and rubella are associated with immune thrombocytopenic purpura (ITP). Thus, influenza, varicella, measles, mumps and rubella vaccines prevent ITP by protecting against natural infection. Measles-containing vaccines can very rarely cause ITP within 6 weeks of vaccination in children. However, these vaccines prevent many more cases of ITP than they cause. Influenza vaccines do not cause ITP. Other vaccines currently routinely recommended to the general population in the U.S.* have not been shown to cause ITP.
Epidemiological Evidence
Rates of ITP after MMR vaccination have been estimated at 1-3 cases per 100,000 doses 1-3. However, this is significantly lower than rates of ITP after natural infection otherwise prevented by the vaccine; the incidence of ITP after natural rubella infection is an estimated 1 per 3,000, and incidence after natural measles infection is estimated to be even higher 2.
The 2012 report by the Institute of Medicine (IOM), now called the National Academy of Medicine (NAM), found no relevant studies of quality in the literature assessing an association between ITP and diphtheria, tetanus, pertussis and varicella vaccines, since the only applicable studies available used passive surveillance systems and therefore lacked an unvaccinated comparison group 4.
Studies published since this report have consistently shown an increased risk of thrombocytopenic purpura in children within 6 weeks of measles-containing vaccination 1,2,5,6. However, several studies published since this report have found no association between influenza vaccines and ITP 7-9, and early childhood vaccines other than MMR or MMRV (ProQuad®) have not been shown to cause ITP 1,2.
A 2013 study examining the safety of trivalent inactivated seasonal influenza vaccination in pregnant individuals reported a null association with thrombocytopenia 10.
A 2016 VSD study of 438,487 live births between 2007 and 2013 found slightly decreased rates of venous thromboembolic events and thrombocytopenia among pregnant individuals receiving Tdap vaccination 11.
A 2016 retrospective observational study of California infants found no cases of ITP during the 30-day risk interval after 46,486 doses of DTaP-IPV/Hib vaccine administered 12.
A 2017 South Korean nationwide cohort study found no associations between HPV vaccination and 33 predefined serious adverse events (including venous thromboembolism and ITP) 13.
A 2018 US cohort study found no increased risk of thrombocytopenia in infants receiving rotavirus vaccine 14.
A 2020 self-controlled risk interval analysis of Taiwanese children using nationwide data found no increased risk of ITP after varicella vaccination, unless given concomitantly with MMR vaccine (incidence rate ratio: 1.70; 95% CI: 1.19-2.43) 15.
A 2020 systematic review and meta-analysis found HPV vaccines to have no association with venous thrombocytopenia and a potential protective effect against ITP 16.
A 2021 Cochrane review determined that the evidence supports an association between MMR vaccines and ITP, at an estimated attributable risk of 1 per 40,000 doses, about half that of natural infection 17.
Case-control and self-controlled case series analyses of a Scottish national prospective cohort found an increased risk of ITP within 27 days of receiving the ChAdOx1nCoV-19, a viral vector COVID-19 vaccine not used in the US, but no increased risk was found between vaccination with Comirnaty and any thrombocytopenic, thromboembolic, or hemorrhagic events 18.
A self-controlled case series analysis using national UK data found an increased risk of thrombocytopenia and venous thromboembolism 8-14 days after vaccination with ChAdOx1nCoV-19 but not Comirnaty; however, an increased risk of arterial thromboembolism was found 15-21 days after vaccination with Comirnaty (IRR: 1.06; 95%CI: 1.01-1.10) 19.
Analyses of safety surveillance data from the Vaccine Safety Datalink found no significant associations between mRNA COVID-19 vaccines and 23 serious health outcomes (including immune thrombocytopenia) 20.
Proposed Biological Mechanism
ITP has been associated with natural viral infections such as influenza, varicella, measles, mumps and rubella 2,21. Patients with ITP have antibodies to platelets. Measles virus has an affinity for platelets and measles vaccine results in a transient decrease in platelet counts in the first few days following vaccination. ITP occurs later, within the first 6 weeks following vaccination. The most likely pathogenesis for ITP involves altered immune processing of the measles virus-platelet aggregations and induction of anti-platelet antibodies 22. The IOM found only weak mechanistic evidence for an association between ITP and varicella vaccine, even when considering knowledge about the natural infection, as the only post-vaccination case documented provided little evidence beyond recurrence of symptoms after vaccine re-challenge 23. The IOM also concluded that there was no mechanistic evidence for an association between ITP and diphtheria, tetanus or pertussis vaccines 4.
* These conclusions do not necessarily consider vaccines recommended only for special populations in the United States such as Yellow Fever vaccine (international travelers) or Smallpox vaccine (military personnel), or vaccines no longer recommended to the public such as the Janssen (J&J) COVID-19 vaccine.
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