Immune Thrombocytopenia Onset and Relapse During the COVID-19 Pandemic. A Monocenter Study 

Giuseppe Auteri1,2, Simona Paglia1,2, Camilla Mazzoni1,2, Mattia Biondo1,2, Marta Venturi1,2, Andrea Davide Romagnoli1,2, Daniela Bartoletti1, Michele Cavo1,2, Nicola Vianelli1 and Francesca Palandri1

1 IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia "Seràgnoli", Bologna, Italy
2 Dipartimento di Scienze Mediche e Chirurgiche, Università di Bologna, Italy.


Correspondence to: Francesca Palandri, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia “Seràgnoli”, Bologna, Italy. Tel +39 051 214 3834 Fax +39 051 636 4037. E-mail: francesca.palandri@unibo.it
Published: May 1, 2023
Received: February 1, 2023
Accepted: April 18, 2023
Mediterr J Hematol Infect Dis 2023, 15(1): e2023029 DOI 10.4084/MJHID.2023.029

This is an Open Access article distributed under the terms of the Creative Commons Attribution License
(https://creativecommons.org/licenses/by-nc/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Background and objectives: Several infections and vaccinations can provoke immune thrombocytopenia (ITP) onset or relapse. Information on ITP epidemiology and management during the Covid-19 pandemic is scarce.
In a large monocenter ITP cohort, we assessed incidence of and risk factors for: 1) ITP onset/relapse after Covid-19 vaccination/ infection; 2) Covid-19 infection.
Methods: Information on date/type of anti-Covid-19 vaccine, platelet count before and within 30 days from vaccine and date/grade of Covid-19, was collected via phone call or during hematological visits.
ITP relapse was defined as a drop in PLT count within 30 days from vaccination, compared to PLT count before vaccination that required a rescue therapy OR a dose increase of an ongoing therapy OR a PLT count <30 x109/L with ≥20% decrease from baseline.

Results: Between February 2020 and January 2022, 60 new ITP diagnosis were observed (30% related to Covid-19 infection or vaccination). Younger and older age were associated to higher probability of ITP related to Covid-19 infection (p=0.02) and vaccination (p=0.04), respectively. Compared to Covid-19-unrelated ITP, Infection- and vaccine-related ITP had lower response rates (p=0.03) and required more prolonged therapy (p=0.04), respectively. Among the 382 patients with known ITP at pandemic start, 18.1% relapsed; relapse was attributed to Covid-19 infection/vaccine in 52.2% of the cases. The risk of relapse was higher in patients with active disease (p<0.001) and previous vaccine-related relapse (p=0.006). Overall, 18.3% of ITP patients acquired Covid-19 (severe in 9.9%); risk was higher in unvaccinated patients (p<0.001).
Conclusions: All ITP patients should receive ≥1 vaccine dose and laboratory follow-up after vaccination, with case-by-case evaluation of completion of vaccine program if vaccine-related ITP onset/relapse, and with tempestive initiation of antiviral therapy in unvaccinated patients.

Introduction

In December 2019, the first case of severe acute respiratory syndrome (SARS) related to a new virus was described in Wuhan, China.[1] The SARS-CoronaVirus-2 (SARS-CoV-2) virus that causes this infection was quickly isolated in Italy.[2] The Coronavirus-2019 disease (COVID-19) is characterized by a plethora of symptoms, ranging from asymptomatic forms to flu-like syndromes, severe pneumonia, or intensive care unit (ICU) hospitalizations.[3]
Soon during the first months of the pandemic, an association between SARS-CoV-2 infection and thrombocytopenia was observed.[4] The mechanisms by which SARS-CoV-2 induces thrombocytopenia include direct virus damage to bone marrow hematopoietic cells, drug-induced hematological toxicity, and autoimmune mechanism.[5,6] Notably, the drop of platelet count at the time of SARS-CoV-2 infection was associated with a worse outcome in terms of 28-day, 90-day and 180-day survival in hospitalized patients.[7]
Immune thrombocytopenia (ITP) is an autoimmune disease characterized by an isolated low platelet count (below 100x109/L).[8] It can be triggered by any immunologic stimulus, including infections, drugs, and vaccinations.[9] ITP therapy is required when the platelet count drops below 20-30x109/L, or in any case of increased risk of bleeding. High-dose corticosteroids are the recommended first-line therapy in virtually all patients. Second-line, multiple options are available but require individual evaluation.[10,11]
The SARS-CoV-2 pandemic has represented an additional challenge for the management of ITP patients.
To decrease immunosuppression, potentially favoring SARS-CoV-2 infection, the American Society of Hematology panel of experts recommended using front-line corticosteroids at the lowest effective dose to achieve a safe platelet count, with early use of thrombopoietin receptor agonists (TPO-RAs).[12] These indications were accepted also in Italy.[13]
In January 2021, the worldwide vaccination campaign began. In Italy, four vaccine sera were administered to ITP patients. The mRNA-BNT162b2 (Comirnaty, Pfizer/BioNTech) and mRNA-1273 (Spikevax, Moderna) vaccines are lipid nanoparticle-encapsulated, nucleoside-modified mRNA-based vaccines that encodes the full-length Spike protein and the SARS-CoV-2 S-2P antigen, respectively.[14,15] ChAdOx1 nCoV-19 (Vaxzeria, AstraZeneca) and the Ad26.COV2.S (Jcovden, Janssen/Johnson & Johnson) are viral vector vaccines.[16,17]
It is acknowledged that several vaccines can rarely induce ITP.[18] SARS-CoV-2 vaccines have been associated with the onset or relapse of ITP.[19] In addition, Lee et al. reported that ITP patients treated with >5 lines and/or splenectomy were more prone to relapse after SARS-CoV-2 vaccination.[20] Also Visser et al. reported a higher risk of ITP relapse in patients with a platelet count <50x109/L and an ongoing therapy during the vaccination.[21]
During the last years, many cases of ITP onset and relapse after SARS-CoV-2 infection or vaccination have been described.[22-33] However, study cohorts on ITP management during the pandemic, both in terms of treatment optimization and risk of ITP occurrence/relapse following SARS-CoV-2 infection/vaccination, are scarce. In a large monocenter cohort of ITP patients, we aimed to assess: 1) incidence of new cases of ITP following anti-SARS-CoV-2 vaccination and infection, risk factors and outcomes; 2) incidence of ITP relapses following anti-SARS-CoV-2 infection/vaccination and risk factors; 3) incidence and risk factors for Covid-19.

Materials and Methods

Patients and study design. This observational retrospective cohort study (ITP-2011-02) was promoted by the IRCCS Azienda Ospedaliero-Universitaria S. Orsola-Malpighi, Bologna, Italy. The ITP-2011-02 study involves 1142 ITP patients diagnosed between January 1982 and January 2022 at our Hematology Center. After IRB approval, diagnostic and follow-up information about adult ITP patients was derived from medical files and reported by data input into an electronic database developed to record all study data after de-identification of the patients with an alphanumeric code to protect personal privacy.
Data collected included patient demographics, medications, clinical/laboratory tests at diagnosis and during follow-up, type of ITP therapies and responses, hemorrhagic and thrombotic complications, death and causes of death. All information about concomitant diseases, and drugs usage were recorded in each case history, and thereafter used for this retrospective evaluation. Any treatment decision was at the physician’s discretion independent from participation to this study.
All patients were followed until death or to data cut-off date (July 2022).
For this analysis, specific information about SARS-CoV-2 vaccinations (i.e., date of vaccination, type of vaccine, any adverse events, platelet counts prior to and within 30 days after vaccination) and SARS-CoV-2 infection occurring between February 2020 and July 2022 (date, severity, platelet count during and within 30 days after infection resolution) were collected. The causal link between infection/vaccine and the onset of ITP was based on the time-interval between these Covid-19-related events and the occurrence/recurrence of ITP. A maximum time-interval of 30 days was chosen according to previously published papers showing that the onset of ITP generally occurs after 1-2 weeks after infections/vaccinations, with some cases arising up to 4 weeks after SARS-CoV-2 vaccine administration.[21,34]
Waves of the COVID-19 pandemic were divided into four periods, according to the type of predominant circulating variants in Europe: first (wild-type variant, February-June 2020); second (alpha/beta/gamma variants, July 2020-June 2021); third (delta variant, July 2021-January 2022); fourth (omega variant, since January 2022).[35]
Definitions. ITP  diagnosis and response to treatments were defined according to  International Working Group (IWG)-ITP criteria.[8]
New diagnoses of ITP were defined as inf-ITP or vax-ITP when they occurred within 30 days of SARS-CoV-2 infection or vaccination, respectively. Relapses from ITP were deemed associated with infection or vaccination if they occurred within 30 days after these events. ITP relapse was defined as a platelet count drop that required the start of new ITP therapy or a dose increase of the ongoing therapy, or any platelet count drop below 30x109/L and ≥20% from baseline even in absence of treatment start/modification. Charlson Comorbidity Index (CCI) was calculated at the start of the pandemic.[36] Active ITP was defined as the presence of a platelet count <100x109/L and/or an ongoing therapy for ITP.
Ethical aspects. The ITP-2011-02 study was performed in accordance with the guidelines of the IRB of our Institution and the standards of the Helsinki Declaration. All patients provided written informed consent. The promoter of this study was the IRCCS Azienda Ospedaliero-Universitaria S. Orsola-Malpighi, Bologna, that obtained the approval by the Area Vasta Emilia Centro (AVEC) Ethics Committee (Approval file number: 032/2012/O/Oss). The study has no commercial support.
Statistical analyses. Statistical analysis was carried out at the biostatistics laboratory of the MPN/ITP Unit, IRCCS Azienda Ospedaliero-Universitaria S. Orsola-Malpighi, Bologna.
Comparisons of quantitative variables between groups of patients were carried out by Wilcoxon-Mann-Whitney rank-sum test and association between categorical variables was tested by the χ2 test. The following risk factors related to relapse were investigated: male sex, age, CCI ≥1, autoimmune diseases, active ITP (platelet count <100x109/L and/or ongoing therapy), previous splenectomy, and relapse after previous SARS-CoV-2 vaccination.
The following risk factors associated with the occurrence of Covid-19 were studied: male sex, age, CCI ≥1, autoimmune disease, completion of the vaccine course with two doses, previous splenectomy.
Cumulative incidence of Covid-19 was identified, considering death as a competing risk, from pandemic start to the first infection/last contact (Fine and Gray model).

Results

Study cohort. Among the 1142 ITP patients included in the ITP-2011-02 database, 297 patients were excluded because they died before the pandemic start (February 2020). Of the remaining 845 patients, the diagnosis of ITP occurred before February 2020 in 785 patients; 403 (51.3%) were untraceable or refused to answer our questions. Therefore, 382 patients with ITP diagnosis before the pandemic start remained evaluable for the present analysis. Sixty additional patients were diagnosed with ITP during the pandemic (between February 2020 and January 2022) (Figure 1).
Figure 1
Figure 1. Study cohort and aims.
Incidence and risk factors of newly diagnosed ITP during the SARS-CoV-2 pandemic. From February 2020 to January 2022, 60 patients received a diagnosis of ITP (28, 46.7%, during the first year of the pandemic). All these 60 patients were followed for at least 6 months after ITP diagnosis.
Five of these diagnoses (8.3%) were attributed to SARS-CoV-2 infection (inf-ITP) and 13 (21.7%) to vaccination (vax-ITP): 7 after mRNA-BNT162b2, 3 after mRNA-1273 and 3 after ChAdOx1-S. Four patients were diagnosed with vax-ITP after their first dose of vaccine, 4 after the second and 5 after the first booster dose.
In univariate analysis, only a younger age was associated with a higher risk of inf-ITP, with a median age of 41.9 years versus 70.2 years in patients with ITP unrelated to Sars-CoV-2 infection (p=0.02). The remaining risk factors were not associated to inf-ITP, including male sex (40% of inf-ITP patients versus 45.5%, p=0.6), CCI ≥1 (20% of inf-ITP patients versus 25.5%, p=0.63), other autoimmune diseases (0% of inf-ITP patients versus 12.7%, p=0.52).
Conversely, only an older age was associated with a higher risk of vax-ITP (median age 74 versus 55.9, p=0.04). Male sex (OR: 3.48 [0. 85-14.27], p=0.08), CCI ≥1 (OR: 2.3 [0.62-8.64], p=0.21), and presence of additional autoimmune diseases (OR: 3.2 [0.62-16.75], p=0.16) were not associated to vax-ITP.
Response to therapy of newly diagnosed ITP according to relation to SARS-CoV-2 infection/vaccination. Among the 60 newly diagnoses ITP patients, 54 (90%) received ITP therapy in the first 6 months from diagnosis. First-line therapy was prednisone in all patients (dosage of 0.5-1 mg/kg for 21 days, with tapering and discontinuation in about 2-4 weeks).
Overall, 36 patients (66.7%) had a complete response, 12 patients (22.2%) a response, and 6 patients (11.1%) had no response.
A second-line therapy was required in 24 (66.6%) patients, namely TPO-RAs (79.2%) and corticosteroids (20.8%). Seven patients (29.1%) required a third line therapy (71.4% TPO-RAs and 28.6% corticosteroids). A fourth line therapy was administered to 3 patients (42.8%). The median duration of days spent on therapy was 55.5 days (range 0-180). Six months after diagnosis, 18 patients were still on therapy.
All five inf-ITP patients received first line therapy with steroids. Compared with other patients diagnosed during the pandemic, inf-ITP patient achieved less frequently a platelet response to the first line (p= 0.03), with comparable rates of complete responses (p=0.74), median number of lines of therapy (p=0.75), duration of therapy (p=0.42), patients on therapy after 6 months of disease (p = 0.51).
Out of 13 vax-ITP patients, 11 (84.6%) required corticosteroids. Compared with other patients diagnosed during the pandemic, no differences in terms of response to the first line (p= 0.19), complete response to the first line (p= 0.81), and number of lines of therapy (p=0.06) were observed. However, vax-ITP patients required more prolonged therapy (p= 0.04). Also, 63.6% of vax-ITP patients were still on therapy at 6 months after diagnosis (p= 0.02) (Table 1).
Table 1
Table 1. Responses to front-line corticosteroids and number/duration of treatments during the first 6 months after diagnosis in newly diagnosed ITP patients, according to relation to SARS-CoV-2 infection (upper table) and vaccination (lower table). In all patients who required therapy, corticosteroids were used first-line and started at the same time as the diagnosis of ITP.
Incidence of relapsed ITP and correlation with SARS-CoV-2 infection and vaccine. Overall, 382 patients with an ITP diagnosed before the pandemic start were evaluable for this analysis and 69 (18.1%) had at least one relapse between February 2020 and January 2022.
A total of 360 (94.2%), 342 and 313 patients received the first, second and the booster dose of the vaccine, respectively. The distribution of vaccine types and tolerability is described in Table 2.
Table 2
Table 2. Distribution of vaccine types and them adverse events presented in at least 1% of ITP patients diagnosed before pandemic.    
Relapse was attributed to SARS-CoV-2 vaccine in 35 patients (50.7%) and to SARS-CoV-2 infection in 1 patient (1.5%). In 33 patients (47.8%), ITP relapse was independent from both conditions.
Out of 35 patients with a vaccine-related relapse, 10 had a second ITP relapse attributed to the vaccine, for a total of 45 observed relapses. Relapses were defined as reduced platelet count requiring the start of a new therapy (n. 23) or a dose increase of an ongoing therapy (n. 7), or platelet count drop below 30x109/L and ≥20% from baseline in absence of treatment start/modification (n. 15). Only one patient experienced a grade 3 bleeding requiring hospitalization.
Vaccine-related relapses occurred in 12 (3.3%) cases after the first dose, in 16 cases (4.7%) after the second dose and in 17 cases (5.4%) after the booster (p=0.3) (Figure 2).
Figure 2
Figure 2. Patients with ITP who experienced a relapse after < 30 days from Sars-CoV-2 vaccination.
After the first and the second dose, the only risk factor associated with relapse was an active disease (first dose: OR 10.81, CI 2.33-16.13, p 0.002; second dose: OR 6.99, CI 2.16-12.85, p=0.001). After the booster dose, the risk factors associated with relapse were active disease (OR 9.9, CI 2.90-16.88, p< 0.001) and ITP relapse after a previous dose (OR 5.33, CI 1.84-17.87, p=0.007). These two factors remained associated with relapse in multivariable analysis (OR 17.42, CI 3.8-39.2, p<0.001 and OR 5.9, CI 1.7-21.3, p=0.006).
Incidence and risk factor for COVID-19 in ITP patients. Between February 2020 and July 2022, 81 out of the total cohort of 442 (18.3%) patients contracted the SARS-CoV-2 infection (asymptomatic in 16, 19.8%: mild in 47 patients, 58.0%; moderate in 10 patients, 12.3%; severe in 8 patients, 9.9%; no fatal cases).
Infections occurred during the first wave (3 patients, 3.7%; severe in one case), second wave (25 patients, 30.9%; sever in 5 patients) and third wave (37 patients, 45.7%; severe in two patients) and fourth wave (16 patients, 19.7%; no severe cases).
Among the patients who received at least one dose of vaccine, none had a severe infection. Moreover, as the number of doses received increased, the frequency of infections decreased, with an incidence rate of infection of 0.55 per 100 patient-years in patients who did not receive any vaccine dose, 0.25 per 100 patient-years in patients who completed the first vaccine cycle, 0.04 per 100 patient-years in patients who received the booster dose (p<0.001).
In univariate analysis, age ≥60 years and the completion of the vaccine cycle were protective factors against the SARS-CoV-2 infection (SHR 0.4, p=0.03 and SHR 0.08, p<0.001, respectively). In multivariate analysis, only vaccine cycle completion was confirmed as a protective factor (SHR 0.1, p< 0.001) (Figure 3).
Figure 3
Figure 3. Risk factor for COVID19 in ITP patients. 

Discussion

Here we observed that almost 30% of newly diagnosed ITP were related to SARS-CoV-2 infection (8.3%) or vaccination (21.3%). These data confirm that Covid-19 may play a role in the development of ITP in a significant, albeit minority, fraction of patients.
Among the risk factors for ITP onset evaluated, only age (younger if post-infection, older if post-vaccine) was shown to be significantly associated with the development of Covid-19-related ITP. In the absence of strong individual predictive factors (e.g., presence of immune disorders, comorbidities, gender), the recommendation to monitor platelet count in the general population only when signs or symptoms attributable to thrombocytopenia appear, remains valid.[37,38]
Notably, during the first 6 months, vaccine-related ITP required a median of 150 days of therapy compared to Covid-19-unrelated ITP diagnosed in the same period that were treated for a median time of 54 days, with equal treatment choices. This represents an important caveat about the possible greater management difficulties of such ITPs, which would therefore merit closer hematological monitoring and detailed patient information. Notably, Spike protein serology is often higher after the vaccine than in those who are infected and not vaccinated.[39] Greater stimulation by vaccination, compared with infection, might explain why patients with vax-ITP, but not those with inf-ITP, showed a shorter duration of response.
Second, we observed that SARS-CoV-2 vaccination was a significant trigger of ITP relapse in patients with persistent or chronic ITP, being associated to over 50% of ITP relapses observed between February 2020 and January 2022. This association may be due to the activation, mediated by the components of the vaccine, of the immune system. Indeed, the spike protein that is produced by signal translation, mRNA, excipients, lipid component, or viral capsid are capable of stimulating B lymphocytes, T lymphocytes, or complement,[40-44] and could configure an adjuvant-induced autoimmune syndrome.[45,46] Among patients with pre-existing ITP, active disease and previous vaccine-related relapse were significantly associated with ITP relapse following vaccination. In these patients, weekly platelet monitoring for 3-6 weeks is recommended after every single vaccine dose.[37] Overall, these results suggest that Covid-19 testing may be relevant in ITP diagnostic workup both for new and relapse.
Finally, we observed that 81 ITP patients acquired SARS-CoV-2 infection. Of these, about 10% required hospitalization, with two patients admitted to an ICU. As demonstrated in other hematological,[47,48] or rheumatological diseases,[49,50] although the incidence Covid-19 in ITP patients is not significantly increased compared with the general population,[35] severe infection seems to be more frequent.
This observation reinforces the indication to include patients with ITP among those at risk for Covid-19 infection, giving vaccination priority and suggesting careful adherence to hygiene norms and timely swab screening if symptoms appear.
Notably, severe/critical Covid-19 infections occurred only in patients who had not yet received even one dose of vaccine. Therefore, these patients should receive immediate antiviral therapy in case of infection.
Limitations of this study are the retrospective nature of the data collection, with possible reduced accuracy of the data entered, the omission of relevant events and the small cohort. Our results should be validated in larger cohorts.
In fact, some ITP diagnoses and relapses may have escaped our Hematology Center, because they were followed up in another center or by the general practitioner. Also, many patients were excluded from this cohort because untraceable.
Overall, the pandemic has complicated the management of ITP, both the vaccine and the infection being associated with a more aggressive disease onset but also with an increased risk of relapse, compared with a clear protective effect of the vaccine against severe infections.
While the completion of the vaccine program in case of previous ITP relapse requires case-by-case evaluation, all ITP patients should be encouraged to receive at least the first vaccine dose and appropriate laboratory follow-up after vaccination, with tempestive initiation of antiviral therapy in unvaccinated patients.


References   

  1. Cyranoski D. New virus identified as likely cause of mystery illness in China. Nature. 2020. doi:10.1038/d41586-020-00020-9. https://doi.org/10.1038/d41586-020-00020-9
  2. Capobianchi MR, Rueca M, Messina F, Giombini E, Carletti F, Colavita F, Castilletti C, Lalle E, Bordi L, Vairo F, Nicastri E, Ippolito G, Gruber CEM, Bartolini B. Molecular characterization of SARS-CoV-2 from the first case of COVID-19 in Italy. Clin Microbiol Infect. 2020;26:954-56. https://doi.org/10.1016/j.cmi.2020.03.025 PMid:32229288 PMCid:PMC7118617  
  3.  Hu B, Guo H, Zhou P, Shi Z-L. Characteristics of SARS-CoV-2 and COVID-19. Nat Rev Microbiol. 2021;19:141-54. https://doi.org/10.1038/s41579-020-00459-7 PMid:33024307 PMCid:PMC7537588
  4.  Rahman A, Niloofa R, Jayarajah U, De Mel S, Abeysuriya V, Seneviratne SL. Hematological Abnormalities in COVID-19: A Narrative Review. Am J Trop Med Hyg. 2021;104:1188-1201. https://doi.org/10.4269/ajtmh.20-1536 PMid:33606667 PMCid:PMC8045618
  5.  Wool GD, Miller JL. The Impact of COVID-19 Disease on Platelets and Coagulation. Pathobiology. 2021;88:15-27. https://doi.org/10.1159/000512007 PMid:33049751 PMCid:PMC7649697
  6.  Xu P, Zhou Q, Xu J. Mechanism of thrombocytopenia in COVID-19 patients. Ann Hematol. 2020;99:1205-8. https://doi.org/10.1007/s00277-020-04019-0 PMid:32296910 PMCid:PMC7156897
  7.  Zhu Y, Zhang J, Li Y, Liu F, Zhou Q, Peng Z. Association between thrombocytopenia and 180-day prognosis of COVID-19 patients in intensive care units: A two-center observational study. PLoS One. 2021;16:e0248671. https://doi.org/10.1371/journal.pone.0248671 PMid:33735911 PMCid:PMC7972743  
  8.  Rodeghiero F, Stasi R, Gernsheimer T, Michel M, Provan D, Arnold DM, Bussel JB, Cines DB, Chong BH, Cooper N, Godeau B, Lechner K, Mazzucconi MG, McMillan R, Sanz MA, Imbach P, Blanchette V, Kühne T, Ruggeri M, George JN. Standardization of terminology, definitions and outcome criteria in immune thrombocytopenic purpura of adults and children: report from an international working group. Blood. 2009;113:2386-93. https://doi.org/10.1182/blood-2008-07-162503 PMid:19005182
  9. Perricone C, Ceccarelli F, Nesher G, Borella E, Odeh Q, Conti F, Shoenfeld Y, Valesini G. Immune thrombocytopenic purpura (ITP) associated with vaccinations: a review of reported cases. Immunol Res. 2014;60:226-35. https://doi.org/10.1007/s12026-014-8597-x PMid:25427992  
  10.  Provan D, Arnold DM, Bussel JB, Chong BH, Cooper N, Gernsheimer T, Ghanima W, Godeau B, González-López TJ, Grainger J, Hou M, Kruse C, McDonald V, Michel M, Newland AC, Pavord S, Rodeghiero F, Scully M, Tomiyama Y, Wong RS, Zaja F, Kuter DJ. Updated international consensus report on the investigation and management of primary immune thrombocytopenia. Blood Adv. 2019;3:3780-3817. https://doi.org/10.1182/bloodadvances.2019000812 PMid:31770441 PMCid:PMC6880896
  11.  Neunert C, Terrell DR, Arnold DM, Buchanan G, Cines DB, Cooper N, Cuker A, Despotovic JM, George JN, Grace RF, Kühne T, Kuter DJ, Lim W, McCrae KR, Pruitt B, Shimanek H, Vesely SK. American Society of Hematology 2019 guidelines for immune thrombocytopenia. Blood Adv. 2019;3:3829-66. https://doi.org/10.1182/bloodadvances.2019000966 PMid:31794604 PMCid:PMC6963252
  12.  COVID-19 and ITP - Hematology.org [Internet]. Last accessed date: 2022 Nov 11. Available from: https://www.hematology.org:443/covid-19/covid-19-and-itp.  
  13.  Rodeghiero F, Cantoni S, Carli G, Carpenedo M, Carrai V, Chiurazzi F, De Stefano V, Santoro C, Siragusa S, Zaja F, Vianelli N. Practical Recommendations for the Management of Patients with ITP During the COVID-19 Pandemic. Mediterr J Hematol Infect Dis. 2021;13:e2021032. https://doi.org/10.4084/MJHID.2021.032 PMid:34007420 PMCid:PMC8114883  
  14.  Polack FP, Thomas SJ, Kitchin N, Absalon J, Gurtman A, Lockhart S, Perez JL, Pérez Marc G, Moreira ED, Zerbini C, Bailey R, Swanson KA, Roychoudhury S, Koury K, Li P, Kalina WV, Cooper D, Frenck RW, Hammitt LL, Türeci Ö, Nell H, Schaefer A, Ünal S, Tresnan DB, Mather S, Dormitzer PR, Şahin U, Jansen KU, Gruber WC, C4591001 Clinical Trial Group. Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine. N Engl J Med. 2020;383:2603-15. https://doi.org/10.1056/NEJMoa2034577 PMid:33301246 PMCid:PMC7745181
  15. Baden LR, El Sahly HM, Essink B, Kotloff K, Frey S, Novak R, Diemert D, Spector SA, Rouphael N, Creech CB, McGettigan J, Khetan S, Segall N, Solis J, Brosz A, Fierro C, Schwartz H, Neuzil K, Corey L, Gilbert P, Janes H, Follmann D, Marovich M, Mascola J, Polakowski L, Ledgerwood J, Graham BS, Bennett H, Pajon R, Knightly C, Leav B, Deng W, Zhou H, Han S, Ivarsson M, Miller J, Zaks T, COVE Study Group. Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine. N Engl J Med. 2021;384:403-16. https://doi.org/10.1056/NEJMoa2035389 PMid:33378609 PMCid:PMC7787219  
  16.  Emary KRW, Golubchik T, Aley PK, Ariani CV, Angus B, Bibi S, Blane B, Bonsall D, Cicconi P, Charlton S, Clutterbuck EA, Collins AM, Cox T, Darton TC, Dold C, Douglas AD, Duncan CJA, Ewer KJ, Flaxman AL, Faust SN, Ferreira DM, Feng S, Finn A, Folegatti PM, Fuskova M, Galiza E, Goodman AL, Green CM, Green CA, Greenland M, Hallis B, Heath PT, Hay J, Hill HC, Jenkin D, Kerridge S, Lazarus R, Libri V, Lillie PJ, Ludden C, Marchevsky NG, Minassian AM, McGregor AC, Mujadidi YF, Phillips DJ, Plested E, Pollock KM, Robinson H, Smith A, Song R, Snape MD, Sutherland RK, Thomson EC, Toshner M, Turner DPJ, Vekemans J, Villafana TL, Williams CJ, Hill AVS, Lambe T, Gilbert SC, Voysey M, Ramasamy MN, Pollard AJ, COVID-19 Genomics UK consortium, AMPHEUS Project, Oxford COVID-19 Vaccine Trial Group. Efficacy of ChAdOx1 nCoV-19 (AZD1222) vaccine against SARS-CoV-2 variant of concern 202012/01 (B.1.1.7): an exploratory analysis of a randomised controlled trial. Lancet. 2021;397:1351-62. https://doi.org/10.1016/S0140-6736(21)00628-0 PMid:33798499  
  17.  Sadoff J, Gray G, Vandebosch A, Cárdenas V, Shukarev G, Grinsztejn B, Goepfert PA, Truyers C, Fennema H, Spiessens B, Offergeld K, Scheper G, Taylor KL, Robb ML, Treanor J, Barouch DH, Stoddard J, Ryser MF, Marovich MA, Neuzil KM, Corey L, Cauwenberghs N, Tanner T, Hardt K, Ruiz-Guiñazú J, Le Gars M, Schuitemaker H, Van Hoof J, Struyf F, Douoguih M, ENSEMBLE Study Group. Safety and Efficacy of Single-Dose Ad26.COV2.S Vaccine against Covid-19. N Engl J Med. 2021;384:2187-2201. https://doi.org/10.1056/NEJMoa2101544 PMid:33882225 PMCid:PMC8220996
  18.  Miller E, Waight P, Farrington CP, Andrews N, Stowe J, Taylor B. Idiopathic thrombocytopenic purpura and MMR vaccine. Arch Dis Child. 2001;84:227-29. https://doi.org/10.1136/adc.84.3.227 PMid:11207170 PMCid:PMC1718684
  19.  Moulis G, Crickx E, Thomas L, Massy N, Mahévas M, Valnet-Rabier M-B, Atzenhoffer M, Michel M, Godeau B, Bagheri H, Salvo F. De novo and relapsed immune thrombocytopenia after COVID-19 vaccines: results of French safety monitoring. Blood. 2022;139:2561-65. https://doi.org/10.1182/blood.2022015470 PMid:35446373 PMCid:PMC8926428  
  20.  Lee E-J, Beltrami-Moreira M, Al-Samkari H, Cuker A, DiRaimo J, Gernsheimer T, Kruse A, Kessler C, Kruse C, Leavitt AD, Lee AI, Liebman HA, Newland AC, Ray AE, Tarantino MD, Thachil J, Kuter DJ, Cines DB, Bussel JB. SARS-CoV-2 vaccination and ITP in patients with de novo or preexisting ITP. Blood. 2022;139:1564-74. https://doi.org/10.1182/blood.2021013411 PMid:34587251 PMCid:PMC8483984
  21.  Visser C, Swinkels M, van Werkhoven ED, Croles FN, Noordzij-Nooteboom HS, Eefting M, Last-Koopmans SM, Idink C, Westerweel PE, Santbergen B, Jobse PA, Baboe F, RECOVAC-IR Consortium, Te Boekhorst PAW, Leebeek FWG, Levin M-D, Kruip MJHA, Jansen AJG. COVID-19 vaccination in patients with immune thrombocytopenia. Blood Adv. 2022;6:1637-44. https://doi.org/10.1182/bloodadvances.2021006379 PMid:34941989 PMCid:PMC8709724
  22.  Kuter DJ. Exacerbation of immune thrombocytopenia following COVID-19 vaccination. Br J Haematol. 2021;195:365-70. https://doi.org/10.1111/bjh.17645 PMid:34075578 PMCid:PMC8239625  
  23.  Shah SRA, Dolkar S, Mathew J, Vishnu P. COVID-19 vaccination associated severe immune thrombocytopenia. Exp Hematol Oncol. 2021;10:42. https://doi.org/10.1186/s40164-021-00235-0 PMid:34266487 PMCid:PMC8280588
  24.  Tsao HS, Chason HM, Fearon DM. Immune Thrombocytopenia (ITP) in a Pediatric Patient Positive for SARS-CoV-2. Pediatrics. 2020;146:e20201419. https://doi.org/10.1542/peds.2020-1419 PMid:32439817
  25.  Jawed M, Khalid A, Rubin M, Shafiq R, Cemalovic N. Acute Immune Thrombocytopenia (ITP) Following COVID-19 Vaccination in a Patient With Previously Stable ITP. Open Forum Infect Dis. 2021;8:ofab343. https://doi.org/10.1093/ofid/ofab343 PMid:34307734 PMCid:PMC8294682
  26.  Santhosh S, Malik B, Kalantary A, Kunadi A. Immune Thrombocytopenic Purpura (ITP) Following Natural COVID-19 Infection. Cureus. 2022;14:e26582. https://doi.org/10.7759/cureus.26582  
  27.  Koch M, Fuld S, Middeke JM, Fantana J, von Bonin S, Beyer-Westendorf J. Secondary Immune Thrombocytopenia (ITP) Associated with ChAdOx1 Covid-19 Vaccination - A Case Report. TH Open. 2021;5:e315-18. https://doi.org/10.1055/s-0041-1731774 PMid:34377889 PMCid:PMC8324423
  28. Al-Ahmad M, Al Rasheed M, Shalaby N, Rodriguez-Bouza T, Altourah L. Immune Thrombocytopenia (ITP): Relapse Versus de novo After COVID-19 Vaccination. Clin Appl Thromb Hemost. 2022;28:10760296211073920. https://doi.org/10.1177/10760296211073920 PMid:35108113 PMCid:PMC8814962  
  29.  Alonso-Beato R, Morales-Ortega A, Fernández FJD la H, Morón AIP, Ríos-Fernández R, Rubio JLC, Centeno NO. Immune thrombocytopenia and COVID-19: Case report and review of literature. Lupus. 2021;30:1515-21. https://doi.org/10.1177/09612033211021161 PMid:34053365
  30.  Matsumura A, Katsuki K, Akimoto M, Sakuma T, Nakajima Y, Miyazaki T, Fujisawa S, Nakajima H. [Immune thrombocytopenia after BNT162b2 mRNA COVID-19 vaccination]. Rinsho Ketsueki. 2021;62:1639-42.  
  31.  Serrano C, Español I, Cascales A, Moraleda JM. Frequently Relapsing Post-COVID-19 Immune Thrombocytopenia. SN Compr Clin Med. 2021;3:2389-92. https://doi.org/10.1007/s42399-021-01019-7 PMid:34308259 PMCid:PMC8294309
  32.  Ashraf S, Alsharedi M. COVID-19 induced immune thrombocytopenic purpura: case report. Stem Cell Investig. 2021;8:14. https://doi.org/10.21037/sci-2020-060 PMid:34386543 PMCid:PMC8327190
  33.  Fujita M, Ureshino H, Sugihara A, Nishioka A, Kimura S. Immune Thrombocytopenia Exacerbation After COVID-19 Vaccination in a Young Woman. Cureus. 2021;13:e17942. https://doi.org/10.7759/cureus.17942  
  34.  Chen Y, Xu Z, Wang P, Li X-M, Shuai Z-W, Ye D-Q, Pan H-F. New-onset autoimmune phenomena post-COVID-19 vaccination. Immunology. 2022;165:386-401. https://doi.org/10.1111/imm.13443 PMid:34957554
  35. Infografica web - Dati della Sorveglianza integrata COVID-19 in Italia [Internet]. Last accessed date: 2022 Dec 5. Available from: https://www.epicentro.iss.it/coronavirus/sars-cov-2-dashboard.  
  36.  Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis. 1987;40:373-83. https://doi.org/10.1016/0021-9681(87)90171-8 PMid:3558716
  37.  De Stefano V, Marchetti M, Rossi E, Ruggeri M, Zaja F, Santoro C, Barcellini W, Carpenedo M, Palandri F, Risitano A, Vianelli N. Piastrinopenia Immune e vaccinazione anti-SARS-CoV-2: raccomandazioni GIMEMA - SIE - SISET. 2021.Available from: https://www.gimema.it/wp-content/uploads/2015/04/Piastropenia-immune-e-vaccinazione-anti-COVID-19-Raccomandazioni-GIMEMA-SIE-SISET-22-dec-21.pdf.  
  38.  Welsh KJ, Baumblatt J, Chege W, Goud R, Nair N. Thrombocytopenia including immune thrombocytopenia after receipt of mRNA COVID-19 vaccines reported to the Vaccine Adverse Event Reporting System (VAERS). Vaccine. 2021;39:3329-32. https://doi.org/10.1016/j.vaccine.2021.04.054 PMid:34006408 PMCid:PMC8086806  
  39.  Tobolowsky FA, Waltenburg MA, Moritz ED, Haile M, DaSilva JC, Schuh AJ, Thornburg NJ, Westbrook A, McKay SL, LaVoie SP, Folster JM, Harcourt JL, Tamin A, Stumpf MM, Mills L, Freeman B, Lester S, Beshearse E, Lecy KD, Brown LG, Fajardo G, Negley J, McDonald LC, Kutty PK, Brown AC, CDC Infection Prevention and Control Team. Longitudinal serologic and viral testing post-SARS-CoV-2 infection and post-receipt of mRNA COVID-19 vaccine in a nursing home cohort-Georgia, October 2020-April 2021. PLoS One. 2022;17:e0275718. https://doi.org/10.1371/journal.pone.0275718 PMid:36301805 PMCid:PMC9612440
  40.  Portuguese AJ, Sunga C, Kruse-Jarres R, Gernsheimer T, Abkowitz J. Autoimmune- and complement-mediated hematologic condition recrudescence following SARS-CoV-2 vaccination. Blood Adv. 2021;5:2794-98. https://doi.org/10.1182/bloodadvances.2021004957 PMid:34255033 PMCid:PMC8276576  
  41.  Boettler T, Csernalabics B, Salié H, Luxenburger H, Wischer L, Salimi Alizei E, Zoldan K, Krimmel L, Bronsert P, Schwabenland M, Prinz M, Mogler C, Neumann-Haefelin C, Thimme R, Hofmann M, Bengsch B. SARS-CoV-2 vaccination can elicit a CD8 T-cell dominant hepatitis. J Hepatol. 2022;77:653-59. https://doi.org/10.1016/j.jhep.2022.03.040 PMid:35461912 PMCid:PMC9021033  
  42.  Chee YJ, Liew H, Hoi WH, Lee Y, Lim B, Chin HX, Lai RTR, Koh Y, Tham M, Seow CJ, Quek ZH, Chen AW, Quek TPL, Tan AWK, Dalan R. SARS-CoV-2 mRNA Vaccination and Graves' Disease: A Report of 12 Cases and Review of the Literature. J Clin Endocrinol Metab. 2022;107:e2324-30. https://doi.org/10.1210/clinem/dgac119 PMid:35235663 PMCid:PMC8903505
  43.  Klomjit N, Alexander MP, Fervenza FC, Zoghby Z, Garg A, Hogan MC, Nasr SH, Minshar MA, Zand L. COVID-19 Vaccination and Glomerulonephritis. Kidney Int Rep. 2021;6:2969-78. https://doi.org/10.1016/j.ekir.2021.09.008 PMid:34632166 PMCid:PMC8493782  
  44.  Sattui SE, Liew JW, Kennedy K, Sirotich E, Putman M, Moni TT, Akpabio A, Alpízar-Rodríguez D, Berenbaum F, Bulina I, Conway R, Singh AD, Duff E, Durrant KL, Gheita TA, Hill CL, Howard RA, Hoyer BF, Hsieh E, El Kibbi L, Kilian A, Kim AH, Liew DFL, Lo C, Miller B, Mingolla S, Nudel M, Palmerlee CA, Singh JA, Singh N, Ugarte-Gil MF, Wallace J, Young KJ, Bhana S, Costello W, Grainger R, Machado PM, Robinson PC, Sufka P, Wallace ZS, Yazdany J, Harrison C, Larché M, Levine M, Foster G, Thabane L, Rider LG, Hausmann JS, Simard JF, Sparks JA. Early experience of COVID-19 vaccination in adults with systemic rheumatic diseases: results from the COVID-19 Global Rheumatology Alliance Vaccine Survey. RMD Open. 2021;7:e001814. https://doi.org/10.1136/rmdopen-2021-001814 PMid:34493645 PMCid:PMC8424419
  45.  Shoenfeld Y, Agmon-Levin N. "ASIA" - autoimmune/inflammatory syndrome induced by adjuvants. J Autoimmun. 2011;36:4-8. https://doi.org/10.1016/j.jaut.2010.07.003 PMid:20708902
  46.  Jara LJ, Vera-Lastra O, Mahroum N, Pineda C, Shoenfeld Y. Autoimmune post-COVID vaccine syndromes: does the spectrum of autoimmune/inflammatory syndrome expand? Clin Rheumatol. 2022;41:1603-9. https://doi.org/10.1007/s10067-022-06149-4 PMid:35378658 PMCid:PMC8979721
  47.  Breccia M, Piciocchi A, Messina M, Soddu S, De Stefano V, Bellini M, Iurlo A, Martino B, Siragusa S, Albano F, Mora B, Fazi P, Vignetti M, Guglielmelli P, Palandri F. Covid-19 in Philadelphia-negative myeloproliferative neoplasms: a GIMEMA survey on incidence, clinical management and vaccine. Leukemia. 2022;36:2548-50. https://doi.org/10.1038/s41375-022-01675-1 PMid:35963940 PMCid:PMC9375079
  48.  Pagano L, Salmanton-García J, Marchesi F, Busca A, Corradini P, Hoenigl M, Klimko N, Koehler P, Pagliuca A, Passamonti F, Verga L, Víšek B, Ilhan O, Nadali G, Weinbergerová B, Córdoba-Mascuñano R, Marchetti M, Collins GP, Farina F, Cattaneo C, Cabirta A, Gomes-Silva M, Itri F, van Doesum J, Ledoux M-P, Čerňan M, Jakšić O, Duarte RF, Magliano G, Omrani AS, Fracchiolla NS, Kulasekararaj A, Valković T, Poulsen CB, Machado M, Glenthøj A, Stoma I, Ráčil Z, Piukovics K, Navrátil M, Emarah Z, Sili U, Maertens J, Blennow O, Bergantim R, García-Vidal C, Prezioso L, Guidetti A, Del Principe MI, Popova M, de Jonge N, Ormazabal-Vélez I, Fernández N, Falces-Romero I, Cuccaro A, Meers S, Buquicchio C, Antić D, Al-Khabori M, García-Sanz R, Biernat MM, Tisi MC, Sal E, Rahimli L, Čolović N, Schönlein M, Calbacho M, Tascini C, Miranda-Castillo C, Khanna N, Méndez G-A, Petzer V, Novák J, Besson C, Duléry R, Lamure S, Nucci M, Zambrotta G, Žák P, Seval GC, Bonuomo V, Mayer J, López-García A, Sacchi MV, Booth S, Ciceri F, Oberti M, Salvini M, Izuzquiza M, Nunes-Rodrigues R, Ammatuna E, Obr A, Herbrecht R, Núñez-Martín-Buitrago L, Mancini V, Shwaylia H, Sciumè M, Essame J, Nygaard M, Batinić J, Gonzaga Y, Regalado-Artamendi I, Karlsson LK, Shapetska M, Hanakova M, El-Ashwah S, Borbényi Z, Çolak GM, Nordlander A, Dragonetti G, Maraglino AME, Rinaldi A, De Ramón-Sánchez C, Cornely OA, EPICOVIDEHA working group. COVID-19 infection in adult patients with hematological malignancies: a European Hematology Association Survey (EPICOVIDEHA). J Hematol Oncol. 2021;14:168. https://doi.org/10.1186/s13045-021-01177-0 PMid:34649563 PMCid:PMC8515781
  49.  Hyrich KL, Machado PM. Rheumatic disease and COVID-19: epidemiology and outcomes. Nat Rev Rheumatol. 2021;17:71-72. https://doi.org/10.1038/s41584-020-00562-2 PMid:33339986 PMCid:PMC7747184
  50.  Cordtz R, Lindhardsen J, Soussi BG, Vela J, Uhrenholt L, Westermann R, Kristensen S, Nielsen H, Torp-Pedersen C, Dreyer L. Incidence and severeness of COVID-19 hospitalization in patients with inflammatory rheumatic disease: a nationwide cohort study from Denmark. Rheumatology (Oxford). 2021;60:SI59-67. https://doi.org/10.1093/rheumatology/keaa897 PMid:33369663 PMCid:PMC7798558

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