ITP following vaccination

Abstract

Immune thrombocytopenia (ITP) is an autoimmune disorder in which autoantibodies inhibit platelet production and impair the circulating ones, leading to thrombocytopenia and, consequently, mucocutaneous and even major bleeding. It is most commonly idiopathic, but it can also be found secondary to other conditions, such as infections (Cines et al., 2009Cines D.B. Bussel J.B. Liebman H.A. Luning Prak E.T. The ITP syndrome: pathogenic and clinical diversity.Blood. 2009; 113: 6511-6521Crossref PubMed Scopus (566) Google Scholar). Most recently it has also been described following different types of vaccination. Considering the pathogenesis of autoimmune disorders following infections, vaccines could lead to ITP by molecular mimicry, epitope spreading, and polyclonal activation, especially in cases of attenuated virus stimulation (Guimarães et al., 2015Guimarães L.E. Baker B. Perricone C. Shoenfeld Y. Vaccines, adjuvants and autoimmunity.Pharmacol Res. 2015; 100: 190-209Crossref PubMed Scopus (115) Google Scholar, Kivity et al., 2009Kivity S. Agmon-Levin N. Blank M. Shoenfeld Y. Infections and autoimmunity —friends or foes?.Trends Immunol. 2009; 30: 409-414Abstract Full Text Full Text PDF PubMed Scopus (308) Google Scholar, Pordeus et al., 2008Pordeus V. Szyper-Kravitz M. Levy R.A. Vaz N.M. Shoenfeld Y. Infections and autoimmunity: a panorama.Clin Rev Allergy Immunol. 2008; 34: 283-299Crossref PubMed Scopus (46) Google Scholar). The term ‘mosaic of autoimmunity’ indicates that immune-mediated disorders can involve different sources, including genetics, environmental factors, and hormonal or immune defects (Shoenfeld and Isenberg, 1989Shoenfeld Y. Isenberg D.A. The mosaic of autoimmunity.Immunol Today. 1989; 10: 123-126Abstract Full Text PDF PubMed Scopus (166) Google Scholar). One of the environmental triggers that have been described is the use of vaccine adjuvants, with aluminum hydroxide and phosphate being the most studied and commonly used. Adjuvants are included in vaccine preparations to potentiate the adaptive and innate immune response by facilitating the recognition of non-self molecules (Perricone et al., 2013Perricone C. Colafrancesco S. Mazor R.D. Soriano A. Agmon-Levin N. Shoenfeld Y. Autoimmune/inflammatory syndrome induced by adjuvants (ASIA) 2013: Unveiling the pathogenic, clinical and diagnostic aspects.J Autoimmun. 2013; 47: 1-16Crossref PubMed Scopus (173) Google Scholar). Together with other environmental factors, such as chronic silicone exposure (Watad et al., 2018Watad A. Rosenberg V. Tiosano S. Cohen Tervaert J.W. Yavne Y. Shoenfeld Y. et al.Silicone breast implants and the risk of autoimmune/rheumatic disorders: a real-world analysis.Int J Epidemiol. 2018; 47: 1846-1854Crossref PubMed Scopus (93) Google Scholar, Watad et al., 2019Watad A. Bragazzi N.L. Amital H. Shoenfeld Y. Hyperstimulation of Adaptive Immunity as the Common Pathway for Silicone Breast Implants, Autoimmunity, and Lymphoma of the Breast.Isr Med Assoc J. 2019; 21: 517-519PubMed Google Scholar), aluminum is one of the triggers for the recently described ‘autoimmune/inflammatory syndrome induced by adjuvants’ (ASIA), which involves mild-to-severe reactions following exposure to different adjuvants (Perricone et al., 2013Perricone C. Colafrancesco S. Mazor R.D. Soriano A. Agmon-Levin N. Shoenfeld Y. Autoimmune/inflammatory syndrome induced by adjuvants (ASIA) 2013: Unveiling the pathogenic, clinical and diagnostic aspects.J Autoimmun. 2013; 47: 1-16Crossref PubMed Scopus (173) Google Scholar, Watad et al., 2017Watad A. Quaresma M. Brown S. Cohen Tervaert J.W. Rodríguez-Pint I. Cervera R. et al.Autoimmune/inflammatory syndrome induced by adjuvants (Shoenfeld’s syndrome) — an update.Lupus. 2017; 26: 675-681Crossref PubMed Scopus (92) Google Scholar). ITP has been described as one of these reactions (Tomljenovic and Shaw, 2015Tomljenovic L. Shaw C.A. Adverse reactions to human papillomavirus vaccines [Internet].Vaccines and autoimmunity. 2015; (Wiley Online Books). Available from: https://doi.org/10.1002/9781118663721.ch17): 163-174Crossref Scopus (2) Google Scholar). Regardless of the mechanism through which artificial immunization causes ITP, it has been reported following vaccinations against various infectious agents, especially measles-mumps-rubella (MMR), but also Haemophilus influenza, hepatitis B virus (HBV), human papilloma virus (HPV), varicella-zoster, diphteria-tetanus-acellular pertussis (DTap), polio, and pneumococcus (Cines et al., 2009Cines D.B. Bussel J.B. Liebman H.A. Luning Prak E.T. The ITP syndrome: pathogenic and clinical diversity.Blood. 2009; 113: 6511-6521Crossref PubMed Scopus (566) Google Scholar, Perricone et al., 2014Perricone C. Ceccarelli F. Nesher G. Borella E. Odeh Q. Conti F. et al.Immune thrombocytopenic purpura (ITP) associated with vaccinations: a review of reported cases.Immunol Res. 2014; 60: 226-235Crossref PubMed Scopus (82) Google Scholar, Garbe et al., 2012Garbe E. Andersohn F. Bronder E. Salama A. Klimpel A. Thomae M. et al.Drug-induced immune thrombocytopaenia: results from the Berlin Case-Control Surveillance Study.Eur J Clin Pharmacol. 2012; 68: 821-832Crossref PubMed Scopus (51) Google Scholar, Jin et al., 2013Jin C. Dong H. Sun Z. Zhou J. Dou C. Lu S. et al.Acute immune thrombocytopenic purpura as adverse reaction to oral polio vaccine (OPV).Hum Vaccin Immunother. 2013; 9: 1739-1740Crossref PubMed Scopus (6) Google Scholar, Genovese et al., 2018Genovese C. LA Fauci V. Squeri A. Trimarchi G. Squeri R. HPV vaccine and autoimmune diseases: systematic review and meta-analysis of the literature.J Prev Med Hyg. 2018; 59 (E194–9)Google Scholar). A French study that evaluated drug-induced ITP found that around 45% of the cases were post-vaccinal (Moulis et al., 2012Moulis G. Sommet A. Sailler L. Lapeyre-Mestre M. Montastruc J.-L. Drug-induced immune thrombocytopenia: a descriptive survey in the French PharmacoVigilance database.Platelets. 2012; 23: 490-494Crossref PubMed Scopus (20) Google Scholar). A retrospective cohort of more than a million children aged 0–18 years found that 60% of the cases of ITP in children from 12 to 23 months were associated with MMR vaccination, suggesting a higher risk of developing ITP when receiving this vaccine in the second year of life (France et al., 2008France E.K. Glanz J. Xu S. Hambidge S. Yamasaki K. Black S.B. et al.Risk of immune thrombocytopenic purpura after measles-mumps-rubella immunization in children.Pediatrics. 2008; 121 (e687-92)Google Scholar). In a case-controlled study, it was shown that, although the attributable risk was low, children had a higher risk of developing ITP 6 weeks after being vaccinated against MMR when compared with a control group (Black et al., 2003Black C. Kaye J.A. Jick H. MMR vaccine and idiopathic thrombocytopaenic purpura.Br J Clin Pharmacol. 2003; 55: 107-111Crossref PubMed Scopus (103) Google Scholar). A study comparing adverse effects following influenza vaccination with and without adjuvants found that ITP was the third most common autoimmune condition (after Guillain Barret and rheumatoid arthritis), but also found no differences in autoimmune disease incidence between non-adjuvanted and adjuvanted groups (Isai et al., 2012Isai A. Durand J. Le Meur S. Hidalgo-Simon A. Kurz X. Autoimmune disorders after immunisation with Influenza A/H1N1 vaccines with and without adjuvant: EudraVigilance data and literature review.Vaccine. 2012; 30: 7123-7129Crossref PubMed Scopus (39) Google Scholar). This could support the theory of influenza immunization causing ITP by molecular mimicry. The main antigen in the influenza vaccine, hemagglutinin (HA), is believed to be one of the possible molecules involved in the process. The antibodies against HA inhibit the virus entrance to human cells, since one of its roles is to bind to specific receptors in the target cells, permitting the infection (Markovic-Plese et al., 2005Markovic-Plese S. Hemmer B. Zhao Y. Simon R. Pinilla C. Martin R. High level of cross-reactivity in influenza virus hemagglutinin-specific CD4+ T-cell response: implications for the initiation of autoimmune response in multiple sclerosis.J Neuroimmunol. 2005; 169: 31-38Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar). HA can also bind to receptors on the surface of platelets. Hence, the antibodies against it could lead to platelet destruction and ITP (Tsang et al., 2014Tsang P. Gorse G.J. Strout C.B. Sperling M. Greenberg D.P. Ozol-Godfrey A. et al.Immunogenicity and safety of Fluzone(®) intradermal and high-dose influenza vaccines in older adults ≥65 years of age: a randomized, controlled, phase II trial.Vaccine. 2014; 32: 2507-2517Crossref PubMed Scopus (59) Google Scholar). The HBsAg vaccination has also been shown to display peptide sharing and cross-reactivity with the human proteome (Kanduc and Shoenfeld, 2016Kanduc D. Shoenfeld Y. From HBV to HPV: Designing vaccines for extensive and intensive vaccination campaigns worldwide.Autoimmun Rev. 2016; 15: 1054-1061Crossref PubMed Scopus (34) Google Scholar). Likewise, the HPV L1 epitopes used in HPV vaccine have demonstrated peptide sharing with human proteins (Kanduc and Shoenfeld, 2019Kanduc D. Shoenfeld Y. Human Papillomavirus Epitope Mimicry and Autoimmunity: The Molecular Truth of Peptide Sharing.Pathobiology. 2019; 86: 285-295Crossref PubMed Scopus (19) Google Scholar), possibly explaining the induction of ITP following HPV vaccination in terms of molecular mimicry. ITP secondary to vaccination can be mild to severe, but even in severe cases there is a high responsiveness to intravenous immunoglobulin (IVIg) treatment (Black et al., 2003Black C. Kaye J.A. Jick H. MMR vaccine and idiopathic thrombocytopaenic purpura.Br J Clin Pharmacol. 2003; 55: 107-111Crossref PubMed Scopus (103) Google Scholar). Regarding the safety of vaccinating ITP patients, there are insufficient data to consider it a contraindication. The literature includes both studies suggesting that vaccination increases the risk of ITP reactivation (Bibby et al., 2008Bibby A. Farrell A. Cummins M. Erlewyn-Lajeunesse M. Is MMR immunisation safe in chronic idiopathic thrombocytopenic purpura?.Arch Dis Child. 2008; 93: 354-355Crossref PubMed Scopus (9) Google Scholar, Beeler et al., 1996Beeler J. Varricchio F. Wise R. Thrombocytopenia after immunization with measles vaccines: review of the vaccine adverse events reporting system (1990 to 1994).Pediatr Infect Dis J. 1996; 15: 88-90Crossref PubMed Scopus (66) Google Scholar, Vlacha et al., 1996Vlacha V. Forman E.N. Miron D. Peter G. Recurrent thrombocytopenic purpura after repeated measles-mumps-rubella vaccination.Pediatrics. 1996; 97: 738-739PubMed Google Scholar, Molina and Shoenfeld, 2005Molina V. Shoenfeld Y. Infection, vaccines and other environmental triggers of autoimmunity.Autoimmunity [Internet]. 2005; 38 (Available from:): 235-245https://pubmed.ncbi.nlm.nih.gov/16126512Crossref PubMed Scopus (191) Google Scholar, Hamiel et al., 2016Hamiel U. Kventsel I. Youngster I. Recurrent Immune Thrombocytopenia After Influenza Vaccination: a Case Report.Pediatrics. 2016; 138PubMed Google Scholar) and those demonstrating no relation to recurrent flares of disease (Black et al., 2003Black C. Kaye J.A. Jick H. MMR vaccine and idiopathic thrombocytopaenic purpura.Br J Clin Pharmacol. 2003; 55: 107-111Crossref PubMed Scopus (103) Google Scholar, Miller et al., 2001Miller E. Waight P. Farrington C.P. Andrews N. Stowe J. Taylor B. Idiopathic thrombocytopenic purpura and MMR vaccine.Arch Dis Child. 2001; 84: 227-229Crossref PubMed Scopus (182) Google Scholar). However, during acute ITP, programmed vaccination should be delayed (Guimarães et al., 2015Guimarães L.E. Baker B. Perricone C. Shoenfeld Y. Vaccines, adjuvants and autoimmunity.Pharmacol Res. 2015; 100: 190-209Crossref PubMed Scopus (115) Google Scholar). In conclusion, ITP is an autoimmune disorder that is commonly secondary to various infectious conditions, and which has been reported after vaccination for different agents. In some cases it can be explained by molecular mimicry, while in others it can be induced by adjuvants. Further studies on this topic should be carried out to evaluate the exact relationship between these two entities, and possibly to guide new contraindications or new formulations for specific vaccines, including a reduction in levels of adjuvants. Safety of pentavalent DTaP-IPV/Hib combination vaccine in post-marketing surveillance in Guangzhou, China, from 2011 to 2017International Journal of Infectious DiseasesVol. 99PreviewInfectious diseases, such as diphtheria, pertussis, tetanus, Haemophilus influenzae type B, and poliomyelitis (polio), are seriously harmful to children's health. Vaccination is the most effective way to control these diseases. In 2010, the State Food and Drug Administration approved the DTaP-IPV/Hib combination vaccine (from now on referred to as the pentavalent vaccine) for cell-free pertussis (DTaP), inactivated poliomyelitis and Haemophilus influenzae type B (combination), and children started to be vaccinated with this pentavalent vaccine on May 11, 2011, in China. Full-Text PDF Open Access

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