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Vaccine-associated thrombocytopenia

Published:September 26, 2022DOI:https://doi.org/10.1016/j.thromres.2022.09.017

      Abstract

      Vaccination is the most cost-effective means of preventing and even eliminating infectious diseases. However, adverse reactions after vaccination are inevitable. In addition to common vaccine-related adverse reactions, some rare but serious adverse reactions have been reported, including secondary immune thrombocytopenia (ITP). The measles-mumps-rubella (MMR) vaccine is currently the only vaccine for which a cause-effect relationship with immune thrombocytopenia has been demonstrated with an incidence of approximately 0.087–4 per 100,000 doses, and the complication is mostly observed in children. In addition, thrombocytopenia can be induced by coronavirus disease 2019 (COVID-19) vaccines following COVID-19 vaccination primarily occurs within a few weeks post-vaccination. The condition mostly occurs in elderly individuals with no sex differences. Its incidence is approximately 0.80 to 11.3 per million doses. Some patients have previously suffered from chronic ITP likely to develop exacerbation of ITP after COVID-19 vaccines, especially those who have undergone splenectomy or are being treated with >5 medications. Based on clinical practice, first-line treatments for vaccine-associated thrombocytopenia are essentially limited to those used for primary ITP, including glucocorticoids and intravenous immunoglobulin (IVIg).

      Keywords

      Abbreviations:

      ITP (immune thrombocytopenia), MMR (measles-mumps-rubella), COVID-19 (coronavirus disease 2019), IVIg (intravenous immunoglobulin), AIDS (acquired immunodeficiency syndrome)
      Since ancient times, numerous infectious diseases that have struck humans have been recorded. Some of these diseases have been particularly life-threatening, such as leprosy, plague, smallpox and influenza. As time progressed, more infectious diseases, such as acquired immunodeficiency syndrome (AIDS), tuberculosis, severe acute respiratory syndrome (SARS) and coronavirus disease 2019 (COVID-19), have been rampant to varying degrees and have generated a notorious reputation. Humans have paid a heavy price for these infectious diseases repeatedly; these diseases have caused population declines, social instability, or even changes in dynasties. Early in the 20th century, smallpox had claimed an estimated 375 million lives. It is only in the last hundred years that some scientific understanding of infectious diseases has been developed. In the battle against these infectious diseases, a natural enemy combating them was gradually discovered - vaccines. In 1796, the British physician Edward Jenner first successfully inoculated cowpox in people, thus finding an eradicative method to eliminate smallpox. It was not until 1979 that the World Health Organization (WHO) officially declared smallpox to be completely eradicated. At present, >70 vaccines have been licensed for use against approximately 30 microbes, saving countless lives. Given that more vaccines have been successively utilized in modern medical administration, many infectious diseases have been eradicated, such as poliomyelitis and smallpox, which have claimed million lives or potentially disabled infectious people. As evidenced by numerous examples, an indisputable fact has been demonstrated that vaccination is the most effective, safe and economical means of preventing and eliminating infectious diseases [
      • Hammoudi D.
      • Sanyaolu A.O.
      • Orish V.N.
      • Onyeabor O.S.
      • Benayache I.
      • Hammoudi D.A.-S.
      • et al.
      Induction of autoimmune diseases following vaccinations: a review.
      ,
      • Toussirot É.
      • Bereau M.
      Vaccination and induction of autoimmune diseases.
      ].
      In the early 2020s, coronavirus disease 2019 (COVID-19), an acute respiratory infection caused by SARS-CoV-2, quickly swept the world. According to Johns Hopkins University, as of February 21st, 2022, there were a total of 424,718,523 diagnoses and 5,889,150 deaths of COVID-19 worldwide, with a mortality rate of 1.4 %. Seriously ill patients manifest respiratory distress or hypoxemia, which can progress rapidly to acute respiratory distress syndrome, septic shock, uncorrectable metabolic acidosis, hemorrhage and coagulation disorders and even multiple organ failure (MOF). Severe cases have a distinctly higher mortality rate and therefore require special attention during the treatment. However, no specific drug has been developed for COVID-19. Vaccines are urgently needed as the only effective method of controlling serious diseases. Subsequently, the most rapid and widespread vaccination campaign in history has been implemented through the combined efforts of all scientific researchers. Although vaccines cannot completely prevent infection with SARS-CoV-2, the risk of severe illness and death after infection can be reduced significantly, and the rate of breakthrough infection with mutant strains of SARS-CoV-2 is also significantly reduced. In addition to the benefits of vaccines, there are also potential adverse effects, including autoimmune reactions.
      Consistent across all vaccines, common adverse reactions following vaccination include pain at the injection site and generalized flu-like symptoms [
      Medicines &ampHealthcare products Regulatory Agency
      Research and analysis. Coronavirus vaccine - weekly summary of Yellow Card reporting.
      ]. These adverse reactions are believed to be an acute immune response to vaccines but mostly present as mild or moderate forms that are usually self-limiting and more frequently in young people. In addition, vaccines have been suspected of playing a role in inducing autoimmune diseases for a long time, such as Guillain–Barré syndrome (GBS) with swine flu vaccine in 1976 and immune thrombocytopenia purpura (ITP) with measles-mumps-rubella (MMR) vaccine. Some rare complications, including arthritis, vasculitis, central or peripheral nervous system symptoms, myopericarditis, primary ovarian failure, systemic lupus erythematosus (SLE) and acute disseminated encephalomyelitis (ADEM), are all autoimmune conditions with reported links to vaccinations since the global rollout of vaccination campaigns [
      • Hammoudi D.
      • Sanyaolu A.O.
      • Orish V.N.
      • Onyeabor O.S.
      • Benayache I.
      • Hammoudi D.A.-S.
      • et al.
      Induction of autoimmune diseases following vaccinations: a review.
      ]. The following is a review of vaccine-associated thrombocytopenia.

      1. Vaccine-associated thrombocytopenia

      Immune thrombocytopenia (ITP) is an acquired autoimmune bleeding disorder. Patients with ITP have a low platelet count that is clinically defined as <100,000 platelets per microliter and produce of immunoglobulin G autoantibodies against platelet surface glycoproteins IIb-IIIa. ITP is widely believed to be caused by antiplatelet autoantibodies that bind to antigens on platelets and megakaryocytes, which leads to platelet destruction and impaired platelet production. Its clinical manifestation is highly variable, ranging from asymptomatic thrombocytopenia, bleeding of the skin and mucous membranes to severe visceral bleeding, even presenting with fatal intracranial hemorrhage. The term severe ITP should only be used to describe patients with clinically relevant bleeding. People over 60 years are more likely to ITP, and ITP is noted slightly more women of childbearing age than men. Older patients are at significantly higher risk of fatal bleeding than younger patients. The incidence of ITP is estimated to range from 2 to 10 per 100,000 persons in the general population (2–10/100,000). ITP exists as two distinct clinical syndromes: acute ITP and chronic ITP. Acute ITP is commonly noted in children, often follows infection and resolves spontaneously within two months. In contrast, chronic ITP is common in adults and persists longer than 6 months. Following the new standardization, cases with an initial diagnosis of ITP are called newly diagnosed ITP. Patients whose platelet counts remain below than the lower limit 3–12 months after diagnosis are considered to be diagnosed with persistent ITP, including those not achieving spontaneous remission or not maintaining a response after stopping treatment. Chronic ITP is noted in patients with ITP lasting for >12 months. Eighty percent of patients with ITP have no obvious causes, which is called primary ITP. Others ITP cases can occur secondary to underlying diseases, including immune diseases (e.g., systemic lupus erythematosus, antiphospholipid syndrome, immunodeficiency disorders, etc.), infections (e.g., human immunodeficiency virus (HIV), H. pylori (HP), cytomegalovirus (CMV) and hepatitis C virus (HCV)); exposure to drugs, such as heparin and quinidine; and lymphoproliferative disorders (e.g., chronic lymphocytic leukemia, large granular lymphocytic leukemia, lymphoma, and autoimmune lymphoproliferative syndrome) [
      • Bussel J.
      • Cooper N.
      • Boccia R.
      • et al.
      Immune thrombocytopenia.
      ,
      Thrombosis and Hemostasis Group, Chinese Society of Hematology, Chinese Medical Association, [Chinese guideline on the diagnosis and management of adult primary immune thrombocytopenia (version 2020)].
      ,
      • Neunert C.
      • Terrell D.R.
      • Arnold D.M.
      • et al.
      American Society of Hematology 2019 guidelines for immune thrombocytopenia. Blood Adv. 2019;3(23):3829-3866.
      ,
      • Guillaume Moulis
      • Aurore Palmaro
      • Jean-Louis Montastruc
      • et al.
      Epidemiology of incident immune thrombocytopenia: a nationwide population-based study in France.
      ,
      • Yun Lee Ji
      • Ju-Hyun Lee
      • Heeyoung Lee
      • et al.
      Epidemiology and management of primary immune thrombocytopenia: a nationwide population-based study in Korea.
      ,
      • Lambert Michele P.
      • Gernsheimer Terry B.
      Clinical updates in adult immune thrombocytopenia.
      ]. Vaccine-associated thrombocytopenia is classified as secondary ITP and is attributed to abnormal autoimmunity.
      Although studies have assessed the genetic background of patients with autoimmune diseases in the context of the administration of vaccines with or without their adjuvants, reliable data concerning absolute links between ITP and vaccines are limited. The chance of developing ITP following the administration of any vaccine and the mechanism of vaccine-associated ITP remain unclear. Reports from surveillance systems are also subject to substantial reporting bias including varied vaccination schedules of different countries, inconsistent surveillance forms, unattended cases and difficulties in the exclusionary diagnosis of ITP. The MMR vaccine is currently the only vaccine for which an association with thrombocytopenia is widely documented. In 1966, Oski et al. [
      • Yun Lee Ji
      • Ju-Hyun Lee
      • Heeyoung Lee
      • et al.
      Epidemiology and management of primary immune thrombocytopenia: a nationwide population-based study in Korea.
      ] first described the development of ITP after vaccination with live attenuated measles vaccine. Subsequently, ITP was reported following the administration of live attenuated MMR vaccination either isolated or combined [
      • Autret E.
      • Jonville-Béra A.P.
      • Galy-Eyraud C.
      • et al.
      Thrombocytopenic purpura after isolated or combined vaccination against measles, mumps and rubella.
      ]. The data from surveillance systems reported that 115 cases developed ITP after vaccination in Canada between 1992 and 2007. In total, 77 of cases (74.7 %) occurred after the administration of the MMR vaccines; 28 occurred after diphtheria, tetanus and pertussis (DTP) or diphtheria, tetanus and acellular pertussis (DTaP) vaccination; and 10 occurred after varicella vaccination. Most of these patients had mild symptoms and did not experience severe complications [
      • Sauvé L.J.
      • Scheifele D.
      Do childhood vaccines cause thrombocytopenia?.
      ]. Similarly, the US Vaccine Adverse Events Reporting System (VAERS) reported 478 cases of ITP after MMR alone or in combination with other vaccines between 1990 and 2008. In total, 47 cases occurred after varicella vaccination, 32 occurred after hepatitis A (HA) vaccination, and 8 occurred after DTaP vaccination. It appears as if all vaccines have been associated with the development of ITP at least once.
      Furthermore, data from passive surveillance systems clearly indicate that MMR vaccines may exhibit a reliable relationship with the development of ITP. Black et al. [
      • Miller E.
      • Waight P.
      • Farrington C.P.
      • et al.
      Idiopathic thrombocytopenic purpura and MMR vaccine.
      ,
      • Corri Black
      • Kaye James A.
      • Hershel Jick
      MMR vaccine and idiopathic thrombocytopaenic purpura.
      ] retrospectively noted a causal association between the MMR vaccine and ITP in children within six weeks of administration. These children were at a higher risk of developing ITP than those who did not receive the MMR vaccine or were vaccinated for >26 weeks. Rajantie et al. [
      • Rajantie J.
      • Zeller B.
      • Treutiger I.
      • Rosthöj S.
      NOPHO ITP working group and five national study groups
      Vaccination associated thrombocytopenic purpura in children.
      ] prospectively collected population data concerning 35 consecutive pediatric patients living in North European countries who presented with ITP within one month of vaccination. In total, 24 pediatric patients were diagnosed with ITP after MMR. The authors reported an estimated incidence of MMR-associated ITP of approximately 1 in 30,000 vaccine inoculations, a value significantly lower than that reported after natural infections. O'Leary et al. [
      • O'Leary Sean T.
      • Glanz Jason M.
      • McClure David L.
      • Aysha Akhtar
      • Daley Matthew F.
      • Cynthia Nakasato
      • Roger Baxter
      • Davis Robert L.
      • Izurieta Hector S.
      • Lieu Tracy A.
      • Robert Ball
      The risk of immune thrombocytopenic purpura after vaccination in children and adolescents.
      ] then collected data from five managed care organizations in the USA. With a total study population of 1.8 million subjects, a significant association was noted between ITP and the MMR vaccine in children aged 12–19 months with an incidence rate ratio (IRR) of 5.48 (95 % confidence interval (CI): 1.61–18.64). Their estimated incidence was reported as approximately 1.9/100,000 doses. The time period is just when children would normally be receiving the MMR vaccine as per the immunization schedule recommendations. Although they did find a significantly high risk of ITP after HA vaccination at 7–17 years of age (95 % CI 3.59–149.30), and after V and DTaP vaccine at 11–17 years of age (95 % CI 1.10–133.96, 95 % CI 3.12–131.83), it was confirmed that there was no high risk of ITP after any early childhood vaccine other than MMR in the 12–29 month age group (95 % CI: 1.61–18.64). Thus, the MMR vaccine is currently the only vaccine that has a cause-effect relationship with the development of ITP. Other vaccines have also been reported to be associated with elevated risks of ITP following vaccination, including BCG, polio, encephalitis B, influenza, hepatitis B virus, diphtheria-tetanus-acellular pertussis, varicella and enterovirus, both domestically and internationally [
      • Yuh-Lin Hsieh
      • Lung-Huang Lin
      Thrombocytopenic purpura following vaccination in early childhood: experience of a medical center in the past 2 decades.
      ,
      • Sinan Akbayram
      • Kamuran Karaman
      • İbrahim Ece
      • Tuba Hatice Akbayram
      Acute immune thrombocytopenic purpura following oral polio vaccination.
      ,
      • Ryuichi Ohta
      • Chiaki Sano
      Severe immune thrombocytopenic purpura following influenza vaccination:a case report.
      ,
      • Nicholas Schmidt
      • Hillary Maitland
      Acute Immune Thrombocytopenia following administration of Shingrix recombinant zoster vaccine.
      ,
      • Alessandro Allegra
      • Giuseppa Penna
      • Andrea Alonci
      • et al.
      Exacerbation of chronic idiopathic thrombocytopenic purpura following reactivation of an occult hepatitis B.
      ]. A significantly elevated risk has also been recorded for the varicella vaccine and tetanus-diphtheria-acellular pertussis vaccine in adolescents aged 11–17 years [
      • Sauvé L.J.
      • Bettinger J.
      • Scheifele D.
      • Halperin S.
      • Vaudry W.
      • Law B.
      Canadian Immunization Monitoring Program, and Active (IMPACT). Postvaccination thrombocytopenia in Canada.
      ,
      • O'Leary S.T.
      • Glanz J.M.
      • McClure D.L.
      • Akhtar A.
      • Daley M.F.
      • Nakasato C.
      • Baxter R.
      • Davis R.L.
      • Izurieta H.S.
      • Lieu T.A.
      • Ball R.
      The risk of immune thrombocytopenic purpura after vaccination in children and adolescents.
      ]. Another significantly elevated risk of ITP has been noted following HA vaccinations in children/adolescents between the ages of 7–17 years [
      • O'Leary S.T.
      • Glanz J.M.
      • McClure D.L.
      • Akhtar A.
      • Daley M.F.
      • Nakasato C.
      • Baxter R.
      • Davis R.L.
      • Izurieta H.S.
      • Lieu T.A.
      • Ball R.
      The risk of immune thrombocytopenic purpura after vaccination in children and adolescents.
      ].
      Since the beginning of COVID-19 vaccination campaigns in December 2020, thrombocytopenia with or without hemorrhage was observed soon afterward [
      • Abi Watts
      • Kavin Raj
      • Pooja Gogia
      • et al.
      Secondary immune thrombocytopenic purpura triggered by COVID-19.
      ,
      • Omar Fueyo Rodriguez
      • Benjamin Valente Acosta
      • Rodolfo Jimenez Soto
      • Yvette Neme Yunes
      • Ignacio Inclán Alarcón Sergio
      • Roxana Trejo Gonzalez
      • Ángel García Salcido Miguel
      Secondary immune thrombocytopenia supposedly attributable to COVID-19 vaccination.
      ,
      • Idogun Precious O.
      • Ward Mindy C.
      • Yeshanew Teklie
      • Wilhelmine Wiese Rometsch
      • Joel Baker
      Newly diagnosed idiopathic thrombocytopenia post COVID-19 vaccine administration.
      ,
      • Angelo Gardellini
      • Francesca Guidotti
      • Elena Maino
      • et al.
      Severe immune thrombocytopenia after COVID-19 vaccination: report of four cases and review of the literature.
      ,
      • King Eleanor R.
      • Elizabeth Towner
      A case of immune thrombocytopenia after BNT162b2 mRNA COVID-19 vaccination.
      ,
      • Gyungah Kim
      • Eun-Ji Choi
      • Han-Seung Park
      • et al.
      A case report of immune thrombocytopenia after ChAdOx1 nCoV-19 vaccination.
      ,
      • Finn-Ole Paulsen
      • Christoph Schaefers
      • Florian Langer
      • et al.
      Immune thrombocytopenic purpura after vaccination with COVID-19 vaccine (ChAdOx1 nCov-19).
      ,
      • Martin Koch
      • Sybille Fuld
      • Middeke Jan M.
      • Julia Fantana
      • von Bonin Simone
      • Jan Beyer Westendorf
      Secondary immune thrombocytopenia (ITP) associated with ChAdOx1 COVID-19 vaccination - a case report.
      ,
      • Bader Al Rawahi
      • Hashem Ba Taher
      • Zoheb Jaffer
      • et al.
      Vaccine-induced immune thrombotic thrombocytopenia following AstraZeneca (ChAdOx1 nCOV19) vaccine-a case report.
      ,
      • Noppacharn Uaprasert
      • Krissana Panrong
      • Songphol Tungjitviboonkun
      • et al.
      ChAdOx1 nCoV-19 vaccine-associated thrombocytopenia: three cases of immune thrombocytopenia after 107 720 doses of ChAdOx1 vaccination in Thailand.
      ,
      • Rubén Alonso Beato
      • Alejandro Morales Ortega
      • la Hera Fernández Francisco Javier De
      • Parejo Morón Ana Isabel
      • Raquel Ríos Fernández
      • Callejas Rubio José Luis
      • Ortego Centeno Norberto
      Immune thrombocytopenia and COVID-19: case report and review of literature.
      ,
      • Bhattacharjee S.
      • Banerjee M.
      Immune thrombocytopenia secondary to COVID 19: a systematic review.
      ,
      • Raphael Battegay
      • Ioanna Istampoulouoglou
      • Andreas Holbro
      • et al.
      Immune thrombocytopenia associated with COVID-19 mRNA vaccine tozinameran - a clinical case and global pharmacovigilance data.
      ,
      • Ali Shah Syed Raza
      • Sherpa Dolkar
      • Jacob Mathew
      • et al.
      COVID-19 vaccination associated severe immune thrombocytopenia.
      ,
      • Paula David
      • Arad Dotan
      • Naim Mahroum
      • et al.
      Immune Thrombocytopenic Purpura (ITP) triggered by COVID-19 infection and vaccination.
      ,
      • Vrushali Saudagar
      • Satish Patil
      • Shaun Goh
      • et al.
      Vigilance regarding immune thrombocytopenic purpura after COVID-19 vaccine.
      ,
      SARS-CoV-2 vaccine-induced immune thrombotic Thrombocytopenia.
      ,
      • Yi Wong Jessica Sue
      • Hong-En Kang James
      • Zin Maw Kyaw
      Acute immune thrombocytopenic purpura post first dose of COVID-19 vaccination.
      ,
      • Elrazi A.Ali
      • Qusai Al-Maharmeh
      • Mohammed Rozi Waail
      • et al.
      Immune thrombocytopenia purpura flare post COVID-19 vaccine.
      ,
      • Cooper Katherine M.
      • Bradley Switzer
      Severe immune thrombocytopenic purpura after SARS-CoV-2 vaccine.
      ,
      • Asuka Ogai
      • Ryuto Yoshida
      • Chiaki Yuasa
      • et al.
      Acute immune thrombocytopenia following SARS-CoV-2 vaccination in chronic ITP patients and a healthy individual.
      ,
      • Gordon Sally F.
      • Clothier Hazel J.
      • Hannah Morgan
      • et al.
      Immune thrombocytopenia following immunisation with Vaxzevria ChadOx1-S (AstraZeneca) vaccine, Victoria, Australia.
      ,
      • Johannes Oldenburg
      • Robert Klamroth
      • Florian Langer
      • Manuela Albisetti
      • von Auer Charis
      • Cihan Ay
      • Wolfgang Korte
      • Scharf Rüdiger E.
      • Bernd Pötzsch
      • Andreas Greinacher
      Diagnosis and management of vaccine-related thrombosis following AstraZeneca COVID-19 vaccination: guidance statement from the GTH.
      ,
      • Pishko Allyson M.
      • Bussel James B.
      • Cines Douglas B.
      COVID-19 vaccination and immune thrombocytopenia.
      , ,
      Medicines &ampHealthcare products Regulatory Agency
      Decision summary of product characteristics for COVID-19 vaccine Pfizer/BioNTech.
      ,
      • Jacqui Wise
      COVID-19: AstraZeneca vaccine linked with small risk of ITP, real world data show.
      ,
      • Claudia Serrano
      • Ignacio Español
      • Almudena Cascales
      • Moraleda José M.
      Frequently relapsing post-COVID-19 immune thrombocytopenia.
      ]. On January 6th, 2021, The New York Times reported that a 56-year-old doctor died of severe thrombocytopenia complicated by intracranial hemorrhage 16 days after receiving the Pfizer vaccine [
      • Weintraub K.
      Death of Florida doctor after receiving COVID-19 vaccine under investigation.
      ]. In February 2021, the editors of the New England Journal of Medicine indicated that such an association is plausible between thrombocytopenia and COVID-19 vaccines, given that this condition is noted as a rare side effect of other vaccines [
      • NEJM Journal Watch
      Offcial's investigating reports of thrombocytopenia after COVID-19 vaccine.
      ].

      2. Exploration of mechanism exploration of vaccine-associated thrombocytopenia

      A vaccine typically contains an agent that resembles a disease-causing microorganism and is often made from weakened or killed forms of the microorganism, its toxins or one of its surface proteins, which ultimately stimulates the immune system of an individual to develop adaptive immunity to a specific pathogen [
      • Hammoudi D.
      • Sanyaolu A.O.
      • Orish V.N.
      • Onyeabor O.S.
      • Benayache I.
      • Hammoudi D.A.-S.
      • et al.
      Induction of autoimmune diseases following vaccinations: a review.
      ]. Vaccines possess specific and similar antigenicity to the pathogen being inoculated against and then activate antigen-presenting cells (APCs), which stimulate autoreactive T helper cells. These autoreactive T cells together with macrophages secrete cytokines, creating a superimposed effect that activates the specific immune response [
      • Wraith D.C.
      • Goldman M.
      • Lambert P.H.
      Vaccination and autoimmune disease: what is the evidence?.
      ]. Therefore, the immune cells generated by vaccination are similar to the immune cells that would be generated by the natural pathogen [
      • Salemi S.
      • D'Amelio R.
      Could autoimmunity be induced by vaccination?.
      ].
      It is now generally accepted that ITP is primarily induced by autoimmunity. Autoimmune reactions linked to vaccines have been reported, and chronic conditions and diseases that interfere with the immune response, such as diabetes, HIV, steroid use for autoimmune diseases or inflammatory diseases, and aging, can alter the effectiveness of vaccines [
      • Hammoudi D.
      • Sanyaolu A.O.
      • Orish V.N.
      • Onyeabor O.S.
      • Benayache I.
      • Hammoudi D.A.-S.
      • et al.
      Induction of autoimmune diseases following vaccinations: a review.
      ]. Therefore, it has been hypothesized that vaccine-associated thrombocytopenia is mediated by autoimmunity.
      Multiple factors are thought to contribute to the development of the immune response to the self, including differences in the vaccine itself, genetic susceptibility, and environmental factors. There are several mechanisms through which pathogens can initiate or perpetuate autoimmunity. The most common mechanism appears to be antigen-induced specific autoimmunity, including molecular mimicry, epitope spreading, bystander activation and polyclonal activation (Fig. 3).

      2.1 Molecular mimicry

      Molecular mimicry is based on the structural similarity between epitopes on microorganisms and host cells. The similarities have the potential to cause autoimmune diseases because immune cells can share specificity with both pathogens and host cells [
      • Francis L.
      • Perl A.
      Infection in systemic lupus erythematosus: friend or foe?.
      ]. For example, the antibodies specific recognition of Epstein–Barr virus (EBV) epitope cross react with host antigens in systemic lupus erythematosus [
      • Hammoudi D.
      • Sanyaolu A.O.
      • Orish V.N.
      • Onyeabor O.S.
      • Benayache I.
      • Hammoudi D.A.-S.
      • et al.
      Induction of autoimmune diseases following vaccinations: a review.
      ,
      • Francis L.
      • Perl A.
      Infection in systemic lupus erythematosus: friend or foe?.
      ]. EBV protein shares immunological similarities with a target lupus autoantigen given the same peptide, which can also induce cross-reactive autoantibodies (Fig. 1) [
      • Francis L.
      • Perl A.
      Infection in systemic lupus erythematosus: friend or foe?.
      ].
      Fig. 1
      Fig. 1Molecular mimicry in virus induced autoimmunity
      [
      • Francis L.
      • Perl A.
      Infection in systemic lupus erythematosus: friend or foe?.
      ]
      .
      Cited from Francis L [
      • Francis L.
      • Perl A.
      Infection in systemic lupus erythematosus: friend or foe?.
      ]. EBV can influence adaptive immunity through molecular mimicry. Autoantigenic peptide sequences can be common to a viral peptide and then induce autoantibodies by antibodies cross reactivity. EBV: Epstein–Barr virus.
      In addition, studies have found that a new Lyme disease vaccine contains an immunodominant epitope of the outer surface protein A of Borrelia burgdorferi that displays significant homology to human lymphocyte function-associated antigen-1. Bogdanos and his colleagues have also demonstrated significant antigenic similarities between hepatitis B surface antigen (HBsAg) and specific myelin antigens [
      • Hammoudi D.
      • Sanyaolu A.O.
      • Orish V.N.
      • Onyeabor O.S.
      • Benayache I.
      • Hammoudi D.A.-S.
      • et al.
      Induction of autoimmune diseases following vaccinations: a review.
      ,
      • Bogdanos D.P.
      • Smith H.
      • Ma Y.
      • Baum H.
      • Mieli-Vergani G.
      • Vergani D.
      A study of molecular mimicry and immunological cross-reactivity between hepatitis B surface antigen and myelin mimics.
      ]. Okazaki et al. [
      • Naho Okazaki
      • Masahiro Takeguchi
      • Kohji Sonoda
      • et al.
      Detection of platelet-binding anti-measles and anti-rubella virus IgG antibodies in infants with vaccine-induced thrombocytopenic purpura.
      ] detected both anti-measles and anti-rubella virus IgG antibodies in the isolated platelets of children who developed ITP 4 weeks after MMR vaccination. This finding also suggested that thrombocytopenia following MMR vaccination may be induced by platelet destruction by the above antibodies. Valerio et al. [
      • Cecinati V.
      • Principi N.
      • Brescia L.
      • Giordano P.
      • Esposito S.
      Vaccine administration and the development of immune thrombocytopenic purpura in children.
      ] indicated that antibodies can be detected on platelets in approximately 79 % of cases vaccinated with the MMR vaccine and then pointed to the concept of MMR-related ITP. Vrushali et al. [
      • Vrushali Saudagar
      • Satish Patil
      • Shaun Goh
      • et al.
      Vigilance regarding immune thrombocytopenic purpura after COVID-19 vaccine.
      ] also noted that hemagglutinin (HA) on the surface of the influenza vaccine was structurally similar to the antigen on platelets. Kanduc D et al. [
      • Kanduc D.
      • Shoenfeld Y.
      Molecular mimicry between SARS-CoV-2 spike glycoprotein and mammalian proteomes: implications for the vaccine.
      ] recently demonstrated that the SARS-CoV-2 virus has several primary sequences homologous to the human genome.
      It is now generally accepted that the mechanism for vaccine-associated thrombocytopenia most likely involves molecular mimicry.

      2.2 Bystander activation

      Bystander activation represents a second mechanism that has been proposed in an effort to explain autoimmune disease development following vaccination. Damage caused by certain harmful factors is not limited to the target cells themselves but can also extend to surrounding normal cells. In bystander activation, normal host cells become bystander cells induced by target cells that are directly damaged by harmful factors, such as cell death, gene mutation and chromosomal instability [
      • Horwitz M.S.
      • Bradley L.M.
      • Harbertson J.
      • Krahl T.
      • Lee J.
      • Sarvetnick N.
      Diabetes induced by Coxsackie virus: initiation by bystander damage and not molecular mimicry.
      ]. Nonspecifically damaged tissues can lead to enhanced processing and presentation of self-antigens, which induces the expansion of the immune response toward different self-antigens. This last process is also known as epitope spreading [
      • Sfriso P.
      • Ghirardello A.
      • Botsios C.
      • Tonon M.
      • Zen M.
      • Bassi N.
      • Bassetto F.
      • Doria A.
      Infections and autoimmunity: the multifaceted relationship.
      ]. The presence of the bystander effect perpetuates and amplifies the effects of the damage on the target cells, thus making the damage significantly worse [
      • Hammoudi D.
      • Sanyaolu A.O.
      • Orish V.N.
      • Onyeabor O.S.
      • Benayache I.
      • Hammoudi D.A.-S.
      • et al.
      Induction of autoimmune diseases following vaccinations: a review.
      ,
      • Horwitz M.S.
      • Bradley L.M.
      • Harbertson J.
      • Krahl T.
      • Lee J.
      • Sarvetnick N.
      Diabetes induced by Coxsackie virus: initiation by bystander damage and not molecular mimicry.
      ,
      • Lam R.K.
      • Fung Y.K.
      • Han W.
      • Yu K.N.
      Rescue effects: irradiated cells helped by unirradiated bystander cells.
      ].
      The bystander effect in oncogene therapy and radiation-induced bystander effect are more widely recognized. When cells are affected by radiotherapy or chemotherapy, various chemical signals are released to the surrounding cells, including growth signals or death signals, which cause the surrounding cells to either undergo apoptosis or proliferation even though they have not been exposed to any chemotherapy drugs or radiation directly [
      • Lam R.K.
      • Fung Y.K.
      • Han W.
      • Yu K.N.
      Rescue effects: irradiated cells helped by unirradiated bystander cells.
      ]. In oncology gene therapy, a distinctive feature of suicide gene therapy is the production of a bystander effect. The treatment not only kills already transfected tumor cells but also causes the death of adjacent untransfected tumor cells by transferring toxic metabolites from transfected tumor cells to adjacent tumor cells (Fig. 2) [
      • Horwitz M.S.
      • Bradley L.M.
      • Harbertson J.
      • Krahl T.
      • Lee J.
      • Sarvetnick N.
      Diabetes induced by Coxsackie virus: initiation by bystander damage and not molecular mimicry.
      ].
      Fig. 2
      Fig. 2Bystander signals in radioimmunotherapy
      [
      • Lam R.K.
      • Fung Y.K.
      • Han W.
      • Yu K.N.
      Rescue effects: irradiated cells helped by unirradiated bystander cells.
      ]
      .
      Cited from R. K. K. Lam [
      • Lam R.K.
      • Fung Y.K.
      • Han W.
      • Yu K.N.
      Rescue effects: irradiated cells helped by unirradiated bystander cells.
      ]. When cells affected by radiotherapy, irradiated cells release bystander signals to surrounding unirradiated cells. The irradiated cells can be irradiated by either self-irradiation (targeted cells) or crossfire irradiation (non-targeted cells) from the application of radioimmunotherapeutic agents.
      Bystander activation was also reported by Horwitz and colleagues [
      • Horwitz M.S.
      • Bradley L.M.
      • Harbertson J.
      • Krahl T.
      • Lee J.
      • Sarvetnick N.
      Diabetes induced by Coxsackie virus: initiation by bystander damage and not molecular mimicry.
      ] in their study of type 1 diabetes induced by Coxsackie B4 virus. Coxsackie virus infection leads to direct inflammation, tissue damage, the release of sequestered islet antigens and the stimulation of resting autoreactive T cells. Thus, vaccines may cause the release of sequestered self-antigens by bystander activation from host tissue-induced autoimmune responses [
      • Hammoudi D.
      • Sanyaolu A.O.
      • Orish V.N.
      • Onyeabor O.S.
      • Benayache I.
      • Hammoudi D.A.-S.
      • et al.
      Induction of autoimmune diseases following vaccinations: a review.
      ].

      2.3 Epitope spreading

      Epitope spreading is a characteristic feature of autoimmune diseases, leading to a broad immune attack on other tissues. Antigenic epitopes can be divided into dominant epitopes and cryptic epitopes. Dominant epitopes are strongly immunogenic and stimulate the immune response when the antigen initially contacts the immune cells, whereas the cryptic epitopes are low density or hidden inside the macromolecule and activate the immune cells only during the subsequent response. The cryptic epitope has been found to show that when a specific antigen stimulates the body, the immune system first responds to the dominant epitopes, but this is often not sufficient to clear the antigen. As the immune response continues, the body can respond to more antigenic epitopes in succession, including cryptic epitopes [
      • Degn S.E.
      • van der Poel C.E.
      • Firl D.J.
      • Ayoglu B.
      • Al Qureshah F.A.
      • Bajic G.
      • Mesin L.
      • Reynaud C.A.
      • Weill J.C.
      • Utz P.J.
      • Victora G.D.
      • Carroll M.C.
      Clonal evolution of autoreactive germinal centers.
      ].

      2.4 Polyclonal activation

      Polyclonal activation is a nonspecific immune reaction. It is often observed with a high concentration of antigen that activates polyclonal B cells by binding to the LPS receptor on the surface of B cells, producing low affinity IgM-like antibodies. LPS is a polyclonal activator. In addition, adjuvants and superantigens can also activate autoreactive immune cells via polyclonal activation, promoting autoimmune responses and even developing autoimmune diseases. For example, Fuchs' complete adjuvant in combination with tissue homogenates or purified autoantigens has been widely used to induce experimental autoimmune diseases.
      In addition to the active vaccine itself, the following chemicals are commonly present in vaccine preparations (Fig. 3), including mineral compounds, proteins, nucleic acids, gels, emulsions, lipids, particulates, virosomes and polymeric structures. These substances are termed adjuvants and added to augment immunogenicity and program the durable immunity of nonreplicating, inactivated and subunit antigens [
      • Toussirot É.
      • Bereau M.
      Vaccination and induction of autoimmune diseases.
      ]. These substances are also known as immunomodulators or immunopotentiators. Adjuvants are not antigenic themselves but are frequently added to vaccines to initiate the immune response to vaccine as well as to boost the immune response to the vaccine. For example, aluminum hydroxide is a common adjuvant that acts as a repository for the vaccine antigen, which slowly presents the antigen to the immune system over a long period of time and prevents the immune system from clearing the vaccine rapidly.
      Fig. 3
      Fig. 3Schematic of vaccination-associated autoimmune diseases [
      • Toussirot É.
      • Bereau M.
      Vaccination and induction of autoimmune diseases.
      ,
      • Sfriso P.
      • Ghirardello A.
      • Botsios C.
      • Tonon M.
      • Zen M.
      • Bassi N.
      • Bassetto F.
      • Doria A.
      Infections and autoimmunity: the multifaceted relationship.
      ].
      Cited and modified by Toussirot É [
      • Toussirot É.
      • Bereau M.
      Vaccination and induction of autoimmune diseases.
      ] and Santoro D [
      • Sfriso P.
      • Ghirardello A.
      • Botsios C.
      • Tonon M.
      • Zen M.
      • Bassi N.
      • Bassetto F.
      • Doria A.
      Infections and autoimmunity: the multifaceted relationship.
      ]. Multiple factors are thought to contribute to the development of immune response to self, including vaccine itself and other components, sometimes with the involvement of adjuvants. There are several mechanisms through which pathogens can initiate or perpetuate autoimmunity. The most common appears to be antigen-induced specific autoimmunity, including molecular mimicry, epitope spreading, bystander activation and polyclonal activation. (A) Molecular mimicry: Pathogens bear similar structure to self-antigen. The immune response can eventually turn toward the self-peptide as a result of cross-reactivity, leading to the activation of naive and specific immunity to self. (B) Epitope spreading: Following several infections and other damage injury of host cells, that are normally sequestered and shielded from immune recognition can be exposed to the immune system and become immunogenic and induce an autoimmune response. (C) Polyclonal activation: Superantigens can bind TCR irrespective of its antigenic specificity and result in the polyclonal T lymphocytes of different antigenic specificity. (D) Bystander activation: The non-specific damaged cells can enhance processing and presentation of self-antigens induces the expansion or spreading of immune response toward surrounding cells.
      Genetic factors are also an important factor in autoimmune diseases. The diversity and heterogeneity of the immune response originates from the genetic history of each individual; hence, it is believed to be partly related to polymorphisms in immune response genes [
      • Castiblanco J.
      • Anaya J.M.
      Genetics and vaccines in the era of personalized medicine.
      ]. Many individuals suffering from autoimmune diseases have specific human leukocyte antigen (HLA) proteins in common. Certain HLA proteins tend to have a predilection for activating the immune system against ‘self’ cells. It has been suggested that specific HLA proteins can also explain why certain people are more prone to autoimmune conditions that are induced or exacerbated by vaccines. Santoro [
      • Santoro D.
      • Vita G.
      • Vita R.
      • Mallamace A.
      • Savica V.
      • Bellinghieri G.
      • Benvenga S.
      • Gangemi S.
      HLA haplotype in a patient with systemic lupus erythematosus triggered by hepatitis B vaccine.
      ] and colleagues reported that the HLA haplotype influences antigenic presentation, which, in predisposed individuals, leads to an increase in the immune response against self-antigens and could explain why only a few individuals are prone to develop autoimmune reactions after vaccinations.
      Vaccine-associated thrombocytopenia has been proposed for almost one century. The data on MMR vaccine-associated thrombocytopenia only suggest an association. Its pathophysiological mechanism remains unclear and is presumed to be most likely due to molecular mimicry. On the one hand, vaccines activate the autoimmune response with cytotoxic T cells and antibodies being activated by vaccine antigens that entered the body. The antibodies can cross react with similar structures on the surface of platelets and megakaryocytes and then directly destroy platelets or activate macrophage phagocytosis of antibody-coated platelets, resulting in thrombocytopenia. Autoantibodies against GPIIb-IIIa, GPIa-IIa and GPIV have also been reported using immunoprecipitation, immunoblotting and antigen-capture techniques [
      • Provan D.
      Characteristics of immune thrombocytopenic purpura: a guide for clinical practice.
      ]. Patients with ITP display antiplatelet antibodies approximately 4–8 weeks following infection or immunization. On the other hand, vaccines may act directly on megakaryocytes and inhibit megakaryocyte maturation, leading to insufficient platelet production [
      • Sylvain Audia
      • Matthieu Mahévas
      • Martin Nivet
      • et al.
      Immune thrombocytopenia: recent advances in pathogenesis and treatments.
      ,
      • Cines Douglas B.
      • Howard Liebman
      • Roberto Stasi
      Pathobiology of secondary immune thrombocytopenia.
      ,
      • Qiaozhu Zeng
      • Xiaohui Zhang
      Current and emerging treatments based on novel mechanisms for immune thrombocytopenia.
      ,
      • Anne Zufferey
      • Rick Kapur
      • Semple John W.
      Pathogenesis and therapeutic mechanisms in immune thrombocytopenia (ITP).
      ]. Some cases negative for antiplatelet antibodies are believed to be caused by an alternate mechanism. Complementary T-cell immune-mediated destruction or a reduction in the formation of platelets is suspected [
      • Toltl L.J.
      • Nazi I.
      • Jafari R.
      • Arnold D.M.
      Piecing together the humoral and cellular mechanisms of immune thrombocytopenia.
      ]. With presentation of glycoprotein antigens to APCs, autoantibody generation is stimulated, and ITP can occur [
      • Kuwana M.
      • Okazaki Y.
      • Ikeda Y.
      Splenic macrophages maintain the anti-platelet autoimmune response via uptake of opsonized platelets in patients with immune thrombocytopenic purpura.
      ]. In addition, vaccine adjuvants/additives, such as aluminum salts, DNA and lipids, may also enhance the immune response of the body [
      • Hammoudi D.
      • Sanyaolu A.O.
      • Orish V.N.
      • Onyeabor O.S.
      • Benayache I.
      • Hammoudi D.A.-S.
      • et al.
      Induction of autoimmune diseases following vaccinations: a review.
      ].

      3. Characteristics of vaccine-associated thrombocytopenia

      3.1 Data in children

      Thrombocytopenia following vaccine administration depends on the development of autoantibodies that more likely cross-react with the naturally present antigenic targets on platelets. Thrombocytopenia is more frequent and acute in young children. Thus, acute ITP is a common acquired autoimmune bleeding disorder in preschool children. The condition is less common in adults, and no sex differences are noted. Thrombocytopenia occurs frequently during the peak seasons of infection in winter and spring. The rapid onset of the disease is often accompanied by a history of infection for the previous 1–2 weeks and symptoms, including fever, chills, and generalized cutaneous mucosal bleeding. Greater than 80 % of acute ITP resolves spontaneously. Of acute ITP cases, approximately 1 % are classified as secondary to vaccines. Vaccine-associated thrombocytopenia has also been reported in children. The available data clearly indicate that ITP is very rare. The only vaccine for a demonstrated cause-effect relationship with ITP is the MMR vaccine, the incidence of which has been reported to be 0.087–4/100,000 and 0.11–9,33/100,000 in China [
      • Megan Letourneau
      • George Wells
      • Wikke Walop
      • et al.
      Improving global monitoring of vaccine safety: a survey of national centres participating in the WHO Programme for International Drug Monitoring.
      ,
      • Elpis Mantadakis
      • Evangelia Farmaki
      • Buchanan George R.
      Thrombocytopenic purpura after measles-mumps-rubella vaccination: a systematic review of the literature and guidance for management.
      ].
      In 2010, Elpis [
      • Elpis Mantadakis
      • Evangelia Farmaki
      • Buchanan George R.
      Thrombocytopenic purpura after measles-mumps-rubella vaccination: a systematic review of the literature and guidance for management.
      ] and colleagues systematically evaluated the association between the MMR vaccine and ITP. They showed that the MMR vaccine could result in acute ITP, predominantly presenting with cutaneous mucosal hemorrhage. In most cases, ITP is mild and presents with only bruising and petechiae. Platelet counts are higher than that noted in the case of nonvaccine-associated ITP. Severe bleeding requiring hospitalization and/or transfusion is rare. Acute ITP mostly occurs within 6 weeks post-vaccination and is common in children (93 % of cases). The condition is almost self-limited in these patients, and patients are sensitive to glucocorticoids and intravenous immunoglobulin (IVIg). More than 90 % of these patients can be completely cured within 6 months of diagnosis. However, the other approximately 10 % of patients fail to control their disease and eventually develop chronic disease with a relatively poor prognosis. France et al. [
      • France E.K.
      • Glanz J.
      • Xu S.
      • Hambidge S.
      • Yamasaki K.
      • Black S.B.
      • et al.
      Vaccine Safety Datalink Team. Risk of immune thrombocytopenic purpura after measlesmumps-rubella immunization in children.
      ] found that among children aged 12–23 months with ITP, the percentage of those who had developed chronic conditions was quite similar among those who had been vaccinated and those who had not (10 % vs. 7 %). However, the prognosis is significantly better than that of ITP following viral infections, which becomes chronic in 25–28 % of cases [
      • Rodeghiero F.
      • Stasi R.
      • Gernsheimer T.
      • Michel M.
      • Provan D.
      • Arnold D.M.
      • et al.
      Standardization of terminology, definitions and outcome criteria in immune thrombocytopenic purpura of adults and children: report from an international working group.
      ].
      Interestingly, it is intriguing to note that administration of the MMR vaccine to unimmunized patients with ITP or revaccination to patients with prior ITP did not lead to recurrence or progression of thrombocytopenia, either primary ITP or MMR-associated ITP [
      • Cecinati V.
      • Principi N.
      • Brescia L.
      • Giordano P.
      • Esposito S.
      Vaccine administration and the development of immune thrombocytopenic purpura in children.
      ]. Although there have been individual reports of isolated cases of relapse, studies also indicate that the first dose of MMR does not generally reactivate previous acute ITP [
      • Vlacha V.
      • Forman E.N.
      • Miron D.
      • Peter G.
      Recurrent thrombocytopenic purpura after repeated measlesmumps-rubella vaccination.
      ,
      • Drachtman R.A.
      • Murphy S.
      • Ettinger L.J.
      Exacerbation of chronic idiopathic thrombocytopenic purpura following measles-mumps-rubella immunization.
      ].

      3.2 Data on COVID-19 vaccines

      Vaccines are classified into six main categories: inactivated vaccines, virus-like particle vaccines, live attenuated vaccines, protein subunit vaccines, adenovirus-based vaccines, and nucleic acid vaccines [
      • Gabriel Dagotto
      • Jingyou Yu
      • Barouch Dan H.
      Approaches and challenges in SARS-CoV-2 vaccine development.
      ]. Five main categories of COVID-19 vaccines have recently been approved for use. Three major classes, including inactivated vaccines, recombinant protein subunit vaccines and adenovirus-based vector vaccines, are currently in use. Established studies have reported the safety of the Oxford-AstraZeneca adenovirus vector vaccine (ChAdOx1 nCoV-19), the Pfizer/BioNTech vaccine, the Moderna vaccine and others in over tens of thousands of subjects.
      Shortly after the launch of the COVID-19 vaccination campaign, Welsh et al. [
      • Welsh Kerry J.
      • Jane Baumblatt
      • Wambui Chege
      • et al.
      Thrombocytopenia including immune thrombocytopenia after receipt of mRNA COVID-19 vaccines reported to the Vaccine Adverse Event Reporting System (VAERS).
      ] identified 15 adverse events of thrombocytopenia, including ITP for Pfizer vaccine and 13 reports for Modena vaccine within 18,841,309 doses of Pfizer BioNTech COVID-19 Vaccine and 16,260,102 doses of Moderna through the Centers for Disease Control and Prevention (CDC) Vaccine Adverse Event Reporting System (VAERS). Thrombocytopenia in these subjects occurred within 1–23 days after vaccination (average 5.5 days). The patients were on average 48.5 years old (ranging from 22 to 82), and there were slightly more females than male s(15:11). Their clinical symptoms mainly included petechial ecchymosis of the cutaneous and mucous. Two patients had severely life-threatening intracranial hemorrhage. Tracing their past medical history, it was found that three patients had a history of chronic ITP, and one patient each had Crohn's disease, Hashimoto's thyroiditis, psoriasis, and type 1 diabetes, all of which represent underlying an inflammatory status. The incidence of COVID-19 vaccine-associated thrombocytopenia (Pfizer and Modena) was reported to be approximately 0.80 per million, significantly less than that of primary ITP. However, the cause-effect relationship cannot be completely explained between COVID-19 vaccines and thrombocytopenia. Considering the sensitivity of subjects to glucocorticoids and IVIg and the similar presence of thrombocytopenia caused by other vaccines, the possibility of a specific association cannot be excluded between COVID-19 vaccines and thrombocytopenia.
      As the reports of vaccine-associated thrombocytopenia increased and awareness grew, Kamal Sharma [
      • Sharma K.
      • Patel S.
      • Patel Z.
      • Patel K.B.
      • Shah D.B.
      • Doshi J.
      • Chokshi P.
      • Sharma C.
      • Amdani M.M.
      • Parabtani A.
      • Benani U.
      • Konat A.
      Immune thrombocytopenia in previously healthy individuals following SARS-CoV-2 vaccination (COVID-19 Immunization): a descriptive research of 70 instances with a focus on biomarkers, predictive outcomes, and consequences.
      ] looked at a number of studies and compiled evidence of COVID-19 vaccine-induced ITP based on the exclusion of other related adverse events with COVID-19 vaccines that had been published. They found that the existing data suggest that the frequency of ITP following COVID-19 vaccine immunization is roughly equivalent to contemporaneous cases after vaccination. In this research of 70 published studies, ITP incidences followed vaccination with a variety of COVID-19 vaccines from Pfizer, Moderna, Oxford, AstraZeneca, and Johnson & Johnson. The typical age of presentation was 50 years (interquartile range [IQR]: 38.25–61). Males accounted for 36.7 % of reported cases, whereas females accounted for 63.33 %. The average time interval between the day of immunization and the onset of illness was 5 days (IQR: 3–9 days). The patients also had preexisting comorbidities, including diabetes, hypertension, hypercholesterolemia, cancer, renal diseases, liver problems, blood disorders, and others. However, they also discovered that the PF-4 antibody was synthesized or present in 30 % of the patients.
      Lee et al. [
      • Eun-Ju Lee
      • Marina Beltrami Moreira
      • Hanny Al-Samkari
      • et al.
      SARS-CoV-2 vaccination and immune thrombocytopenia in de novo and pre-existing ITP patients.
      ] then summarized the information of patients with de novo ITP with COVID-19 vaccines reported on the VAERS up to April 2021 and found a total of 77 yellow cards, indicating possible adverse drug effects. In total, 37 of these patients received the Pfizer vaccine, and 40 received the Modena vaccine. Their mean age was 63 years, and slightly more women were noted than men (6:4). Seventy-five percent of these patients had manifestations of cutaneous-mucosal hemorrhage, a few had genitourinary and gastrointestinal bleeding, and only one had central nervous system bleeding. Thirty-two percent of the subjects also had a history of lying autoimmune diseases. Their thrombocytopenia occurred within 3–13 days (average 7 days) after vaccination. Most cases occurred with the first dose (77 %), whereas others occurred with the second dose. All subjects were treated with glucocorticoids and/or IVIg, and 90 % responded effectively. In those who respond poorly, platelet counts and bleeding can be improved through other regimens, including thrombopoietin receptor agonist (TPO-RA), rituximab, and vincristine.
      Visser [
      • Visser C.
      • Swinkels M.
      • van Werkhoven E.D.
      • Croles F.N.
      • Noordzij-Nooteboom H.S.
      • Eefting M.
      • Last-Koopmans S.M.
      • Idink C.
      • Westerweel P.E.
      • Santbergen B.
      • Jobse P.A.
      • Baboe F.
      • Te Boekhorst P.A.W.
      • Leebeek F.W.G.
      • Levin M.D.
      • Kruip M.J.H.A.
      • Jansen A.J.G.
      RECOVAC-IR Consortium
      COVID-19 vaccination in patients with immune thrombocytopenia.
      ] also observed that 63 % of healthy controls experienced decreased platelet counts 4 weeks after COVID-19 vaccine vaccination, but only 1 (0.5 %) had a platelet count <100 ∗ 10^9/L.
      To assess the incidence of COVID-19 vaccine-associated ITP, Simpson et al. [
      • Simpson C.R.
      • Shi T.
      • Vasileiou E.
      • et al.
      First-dose ChAdOx1 and BNT162b2 COVID-19 vaccines and thrombocytopenic, thromboembolic and hemorrhagic events in Scotland.
      ] conducted a prospective cohort study in Scotland. They observed and analyzed 2.53 million subjects who developed thrombocytopenia and/or abnormal hemorrhage with first-time use of the COVID-19 vaccines from December 8th, 2020 to April 14th, 2021. This finding indicated a strong association between the AstraZeneca vaccine and thrombocytopenia within 0 to 27 days after vaccination (aRR = 5.77), which was most pronounced within 21–27 days (aRR = 14.07). As the study showed, the incidence of AstraZeneca vaccine-associated thrombocytopenia was 1.13 per 100,000 doses. Compared to unvaccinated patients, the subjects were older (average 69 years) with no significant difference in gender. Their increased risk of hemorrhage was positively associated with age, chronic comorbidities, and smoking, which is similar to that noted for primary ITP. Pfizer vaccines did not lead to an increased risk of thrombocytopenia and bleeding according to the study (aRR = 0.540).
      In addition, ITP can be induced following the first or second doses of vaccination. Another national prospective cohort study by Simpson [
      • Simpson C.R.
      • Kerr S.
      • Katikireddi S.V.
      • McCowan C.
      • Ritchie L.D.
      • Pan J.
      • Stock S.J.
      • Rudan I.
      • Tsang R.S.M.
      • de Lusignan S.
      • Hobbs F.D.R.
      • Akbari A.
      • Lyons R.A.
      • Robertson C.
      • Sheikh A.
      Second-dose ChAdOx1 and BNT162b2 COVID-19 vaccines and thrombocytopenic, thromboembolic and hemorrhagic events in Scotland.
      ] assessed the incidence of developing ITP after a second vaccination dose injection and showed no increased risk of thrombocytopenia following the second dose (0–27 days incidence rate ratio or BNT162b2 vaccine during any of the postvaccination time periods). The incidence of ITP after the second dose of ChAdOx1 was 0.59 (0.37–0.89) per 100,000 doses (95 % CI 0.37–0.89).
      With profound awareness of the side effects of the COVID-19 vaccines, we found another note-worthy phenomenon called vaccine-induced immune thrombotic thrombocytopenia (VITT) [
      • Sue Pavord
      • Marie Scully
      • Hunt Beverley J.
      • William Lester
      • Catherine Bagot
      • Brian Craven
      • Alex Rampotas
      • Gareth Ambler
      • Mike Makris
      Clinical features of vaccine-induced immune thrombocytopenia and thrombosis.
      ,
      • Angela Huynh
      • Kelton John G.
      • Arnold Donald M.
      • Mercy Daka
      • Ishac Nazy
      Antibody epitopes in vaccine-induced immune thrombotic thrombocytopenia.
      ,
      • Rizk J.G.
      • Gupta A.
      • Sardar P.
      • Henry B.M.
      • Lewin J.C.
      • Lippi G.
      • Lavie C.J.
      Clinical characteristics and pharmacological management of COVID-19 vaccine-induced immune thrombotic thrombocytopenia with cerebral venous sinus thrombosis: a review.
      ,
      • Cines D.B.
      • Bussel J.B.
      SARS-CoV-2 Vaccine-Induced Immune Thrombotic Thrombocytopenia.
      ,
      • Woodruff R.K.
      • Grigg A.P.
      • Firkin F.C.
      • Smith I.L.
      Fatal thrombotic events during treatment of autoimmune thrombocytopenia with intravenous immunoglobulin in elderly patients.
      ]. The condition first appeared in different reports as a prothrombotic syndrome in a small number of individuals after AstraZeneca vaccine administration. VITT is another COVID-19 vaccine-related reaction characterized by thrombocytopenia, thrombosis, and positive PF4 antibodies within weeks (5-30 d, within an average of 2 w) after vaccination [
      • Sue Pavord
      • Marie Scully
      • Hunt Beverley J.
      • William Lester
      • Catherine Bagot
      • Brian Craven
      • Alex Rampotas
      • Gareth Ambler
      • Mike Makris
      Clinical features of vaccine-induced immune thrombocytopenia and thrombosis.
      ,
      • Rizk J.G.
      • Gupta A.
      • Sardar P.
      • Henry B.M.
      • Lewin J.C.
      • Lippi G.
      • Lavie C.J.
      Clinical characteristics and pharmacological management of COVID-19 vaccine-induced immune thrombotic thrombocytopenia with cerebral venous sinus thrombosis: a review.
      ]. IVIg in combination with steroids have been used to inhibit the production antibodies. Not all patients have thrombosis. Sue [
      • Sue Pavord
      • Marie Scully
      • Hunt Beverley J.
      • William Lester
      • Catherine Bagot
      • Brian Craven
      • Alex Rampotas
      • Gareth Ambler
      • Mike Makris
      Clinical features of vaccine-induced immune thrombocytopenia and thrombosis.
      ] et al. found that some patients without thrombosis but abnormal coagulation were classified as probable, rather than definite VITT. It is likely that the absence of thrombosis reflects the early identification and treatment of VITT. There may have been misdiagnosis in the past. Early data reported may lack relevant results of coagulation and PF4 antibodies for further diagnosis. For example, one of the ITP diagnosed by Welsh [
      • Welsh Kerry J.
      • Jane Baumblatt
      • Wambui Chege
      • et al.
      Thrombocytopenia including immune thrombocytopenia after receipt of mRNA COVID-19 vaccines reported to the Vaccine Adverse Event Reporting System (VAERS).
      ] died from pulmonary embolism. Currently, patients considered for vaccine-related ITP all excluded thrombosis. But even in those who do not present with thrombosis, positive anti-platelet antibodies may be present, such as found in studies by Visser [
      • Visser C.
      • Swinkels M.
      • van Werkhoven E.D.
      • Croles F.N.
      • Noordzij-Nooteboom H.S.
      • Eefting M.
      • Last-Koopmans S.M.
      • Idink C.
      • Westerweel P.E.
      • Santbergen B.
      • Jobse P.A.
      • Baboe F.
      • Te Boekhorst P.A.W.
      • Leebeek F.W.G.
      • Levin M.D.
      • Kruip M.J.H.A.
      • Jansen A.J.G.
      RECOVAC-IR Consortium
      COVID-19 vaccination in patients with immune thrombocytopenia.
      ] and Sue [
      • Sue Pavord
      • Marie Scully
      • Hunt Beverley J.
      • William Lester
      • Catherine Bagot
      • Brian Craven
      • Alex Rampotas
      • Gareth Ambler
      • Mike Makris
      Clinical features of vaccine-induced immune thrombocytopenia and thrombosis.
      ]. And early identification of VITT may show thrombocytopenia alone. Therefore, it may be misdiagnosed as ITP at the early stage of VITT.

      3.3 Chronic ITP and COVID-19 vaccines

      The data presented above show most patients with underlying inflammatory conditions before vaccination, including primary chronic ITP, and these patients have more potential risks of activating the body's immune response and relapse of thrombocytopenia both in terms of the clinical phenomena and by inferring the possible pathological mechanisms.
      Kuter et al. [
      • Kuter David J.
      Exacerbation of immune thrombocytopenia following COVID-19 vaccination.
      ] conducted a prospective clinical study in 52 patients with chronic ITP treated with three COVID-19 vaccines, including Modena, Pfizer, and Johnson & Johnson. They observed their hemorrhagic manifestations and platelet counts post vaccination and noted that 12 % of them experienced a significant decrease in platelet count (average reduction of 96 % of baseline) within 2–5 days after vaccination complicated by neo bleeding. In contrast, the other 88 % showed no significant worsening of reduction in platelet count or hemorrhage, which may be exacerbation of ITP. Conversely, the exacerbation of thrombocytopenia was not associated with age, sex, duration of ITP, baseline platelet count, remission status, or vaccine type.
      Lee et al. [
      • Eun-Ju Lee
      • Marina Beltrami Moreira
      • Hanny Al-Samkari
      • et al.
      SARS-CoV-2 vaccination and immune thrombocytopenia in de novo and pre-existing ITP patients.
      ] also compared subjects with prior ITP with COVID-19 vaccines published by a 10-center retrospective study, the Platelet Disease Support Association of America (PDSA) and the UK ITP Support Association. Approximately 20 % of subjects with chronic ITP may develop exacerbation of ITP with COVID-19 vaccines. Chronic ITP can manifest as the following: 1) greater than a 50 % reduction in platelet count; 2) greater than a 20 % decline from prevaccination baseline and platelet nadir <30 ∗ 10^9/L; 3) receipt of rescue therapy for ITP. A review of their therapeutic methods suggested that patients with chronic ITP who underwent splenectomy or were treated with >5 medications had a significantly higher risk of disease progression [RR (splenectomy) = 1.8, RR (≥5 medications) = 2.2], signifying that this potential lack of acute immune response is directly favorable for platelet counts in these individuals. In addition, no significant associations with age, sex, vaccine type, and autoimmune disease were noted.
      In the study by Visser [
      • Visser C.
      • Swinkels M.
      • van Werkhoven E.D.
      • Croles F.N.
      • Noordzij-Nooteboom H.S.
      • Eefting M.
      • Last-Koopmans S.M.
      • Idink C.
      • Westerweel P.E.
      • Santbergen B.
      • Jobse P.A.
      • Baboe F.
      • Te Boekhorst P.A.W.
      • Leebeek F.W.G.
      • Levin M.D.
      • Kruip M.J.H.A.
      • Jansen A.J.G.
      RECOVAC-IR Consortium
      COVID-19 vaccination in patients with immune thrombocytopenia.
      ], among 218 patients with ITP (50.9 % female) aged 55 (17) years at the time of vaccination, thirty (13.8 %; 95 % CI, 9.5–19.1) patients with ITP experienced an exacerbation of thrombocytopenia who had a >50 % decline in platelet count compared with baseline, platelet nadir<30*10^9/L or rescue administration. The risk factors for exacerbation of ITP after vaccination were low baseline platelet count, time of treatment received and younger age. Additionally, previous splenectomy was positively associated with platelet counts over time.

      3.4 Latest data on COVID-19 vaccines

      We also searched for reports of thrombocytopenia with or without hemorrhage after COVID-19 vaccination through VAERS to the lock period from 2020 to 2022 with the following preferred terms: AUTOIMMUNE THROMBOCYTOPENIA, IDIOPATHIC THROMBOCYTOPENIC, PURPURA, IMMUNE THROMBOCYTOPENIA, IMMUNE THROMBOCYTOPENIC PURPURA, THROMBOCYTOPENIA, and THROMBOCYTOPENIC PURPURA. Cases with thrombocytopenia or bleeding identified on the same day of vaccination were excluded. It is believed that onset of <24 h was deemed to not be biologically attributable to vaccine-induced an immune-mediated response [
      • Welsh Kerry J.
      • Jane Baumblatt
      • Wambui Chege
      • et al.
      Thrombocytopenia including immune thrombocytopenia after receipt of mRNA COVID-19 vaccines reported to the Vaccine Adverse Event Reporting System (VAERS).
      ]. In addition, all known reports of vaccine-associated ITP have an onset time of <60 days. We chose to include all potential thrombocytopenia cases presenting ≥1 day and <60 days after vaccination and to evaluate cases that may be plausibly consistent with a vaccine etiology.
      As of February 11th, 2022, 125 yellow card warnings have been reported worldwide on VAERS for thrombocytopenia or bleeding manifestations following vaccination with COVID-19 vaccines (Table 1). Of the 125 cases of thrombocytopenia after COVID-19 vaccines, 9 cases after the Janssen vaccine, 29 cases after Moderna vaccine and 87 cases after Pfizer-BioNTech vaccine. Of these patients, 57 were female, whereas 67 were male (male to female ratio of 67 to 57). The sex was not reported for the remaining case. Of these patients, 85.6 % were over 60 years old. The reported onset of thrombocytopenia after COVID-19 vaccination ranged greatly after vaccination, although some onset time relative to vaccination was unreported. Seven individuals also developed thrombocytopenia after the third dose. Most reports described patients who presented for medical evaluation due to signs and symptoms of bleeding, such as petechiae or bruising. Few reports have described an asymptomatic patient with thrombocytopenia discovered by laboratory work performed for a routine physical examination. In approximately half of the cases (n = 46), ITP occurred following the second COVID-19 vaccine, and a comparable rate was noted after the first dose. The remaining cases occurred after dose one, or the dose number was not specified in the report. Most patients were previously found to have an underlying inflammatory state that may have contributed to ITP development, such as vasculitis, SLE, hyperthyroidism, Crohn's disease, drug allergy, and pregnancy. Major cases reported a prior history of ITP and were likely to develop a relatively increasing decline in platelet counts and severe hemorrhage after vaccination. Other conditions that predispose an individual to thrombocytopenia, such as recent viral infection, other autoimmune disorders, or a family history of thrombocytopenia, were not reported in the remaining cases.
      Table 1Summary of reports of thrombocytopenia after COVID-19 vaccination up to February 11th, 2022.
      Total125
      Vaccine type
       Janssen9 (7.2 %)
       Moderna29 (23.2 %)
       Pfizer-Biontech87 (69.6 %)
      Dose
       154 (43.2 %)
       246 (36.8 %)
       37 (56.0 %)
       Unknown18 (14.4 %)
      Sex
       Female57 (45.6 %)
       Male67 (53.6 %)
       Unknown1 (0.8 %)
      Age
       30-49Y13 (10.4 %)
       50-59Y5 (4.0 %)
       60-79Y37 (29.3 %)
       >80Y23 (18.4 %)
       Unknown47 (37.6 %)
      Onset interval
       1-7d41 (32.8 %)
       8-14d29 (23.2 %)
       15-30d34 (27.2 %)
       31-60d21 (16.8 %)
      The overview on surveillance of adverse reactions to COVID-19 vaccines suggests that the common adverse reactions of Vero inactivated vaccine are similar to other vaccines. To date, no similar case manifesting as thrombocytopenia or hemorrhage has been reported with inactivated COVID-19 vaccines.

      4. Treatment principles of vaccine-associated thrombocytopenia

      The current first-line treatments for vaccine-associated thrombocytopenia are glucocorticoids and IVIg. However, clear guidelines are not available, and most treatments are guided by the clinical experience of doctors. Treatment effects were observed in >90 % of patients. Glucocorticoids act mainly by promoting apoptosis of autoimmune cells and suppressing the production of autoantibodies, whereas IVIg acts mainly by competitively binding to platelet receptors, impeding platelet and megakaryocyte destruction and phagocytosis by macrophages. Similar to primary ITP, TPO-RAs are used as a second-line alternative to promote platelet production. The minority group of patients who respond poorly to glucocorticoids and IVIg could have a therapeutic effect. A very small proportion of the population does not respond well to glucocorticoids, IVIg and even TPO-RAs. Drugs, such as decitabine and vincristine, are also available as alternatives.
      In contrast, when in a life-threatening situation or when emergency surgery is needed, IVIg, adequate glucocorticoids, recombinant human thrombopoietin (rh-TPO) and platelet transfusions should be administered promptly to rapidly increase platelet counts.
      However, unlike treatment of primary ITP, CD20+ monoclonal antibodies, such as rituximab, should be used with caution in vaccine-associated thrombocytopenia not only due to their slow onset of action but also because the long-term effects may compromise the protective effect of the vaccine [
      • Finn-Ole Paulsen
      • Christoph Schaefers
      • Florian Langer
      • et al.
      Immune thrombocytopenic purpura after vaccination with COVID-19 vaccine (ChAdOx1 nCov-19).
      ].

      5. Conclusion

      Vaccine-associated ITP is characterized by isolated peripheral thrombocytopenia with a highly variable clinical presentation ranging from asymptomatic to variable hemorrhagic manifestations. Its distribution is similar to that of primary ITP. However, MMR vaccine-associated ITP is more common in children. Current data suggest that COVID-19 vaccines are also associated with thrombocytopenia mostly in middle-aged and elderly individuals and especially in those under chronic inflammatory status. ITP might worsen in some patients with preexisting ITP or may occur de novo post-COVID-19 vaccination. Therefore, vaccine-associated thrombocytopenia requires careful weighing of the risks and benefits of vaccination to make decisions based on the clinical situations of the subjects.
      The frequency of autoimmunity associated with vaccines is far lower than the frequency of autoimmunity associated with actual naturally occurring infections. Salemi and D'Amelio [
      • Yuh-Lin Hsieh
      • Lung-Huang Lin
      Thrombocytopenic purpura following vaccination in early childhood: experience of a medical center in the past 2 decades.
      ] concluded that because of the cost effectiveness of vaccines and the fact that the benefits of vaccines outweigh the risk of inducing autoimmunity, it is important to aggressively develop and promote vaccination programs.

      Funding

      This work was supported by Science and Technology Program of Guangzhou (grant number 201803010012 ).

      Declaration of competing interest

      The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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