Immune thrombocytopenia exacerbation post COVID-19 vaccination: a systematic review and meta-analysis

Introduction

Since 2019, coronavirus disease 2019 (COVID-19) has remained an ongoing pandemic which has significantly affected patients on an individual level as well as healthcare on a global scale, with unprecedented international endeavours to curb spread of disease and minimize mortality and morbidity.

With the advent of COVID-19 vaccination, the mortality and morbidity from COVID-19 infection has decreased in recent years. Side effects and complications of these vaccinations have been studied in detail, with good safety profiles and efficacy (1,2). With the widespread introduction of COVID-19 vaccination, there needs to be a continuous effort in identifying safety concerns and potential risks and adverse effects of these vaccinations. Patients with immune thrombocytopenia or immune thrombocytopenic purpura (ITP) who are already predisposed to bleeding, are particularly at risk. As such, concerns have been raised regarding the safety of COVID-19 vaccination in this population. There are reports of thrombocytopenia post vaccination in both healthy patients and those with pre-existing thrombocytopenia (2-6). Though many reported cases were asymptomatic, there have been cases of severe thrombocytopenia with life-threatening bleeding manifestations and even fatalities (3).

Factors such as prior splenectomy (3) or active treatment at the time of vaccination (2) have been potentially associated with relapses. A majority of these relapses are mild, with platelet counts and symptoms improving with rescue treatment (4-7).

In order to provide a systematic perspective on the risk of ITP exacerbation post-COVID-19 vaccination, we performed a systematic review and meta-analysis to identify potential factors associated with ITP exacerbation post-COVID-19 vaccination in order to determine high-risk patients who could potentially benefit from increased clinical surveillance or intensification of chronic ITP treatment. We combined results from identified studies with a pre-existing database from our centre, which is a tertiary paediatric hospital in Singapore. We present this article in accordance with the PRISMA reporting checklist (available at https://aob.amegroups.com/article/view/10.21037/aob-24-15/rc).

Methods

The systematic review was registered with PROSPERO (The International Prospective Register of Systematic Reviews) (CRD42023433750). This study was conducted in accordance with the Declaration of Helsinki (as revised in 2013) and approved by the Institutional Review Board of Singapore Health Services (CIRB 2018/2374). Consent was obtained from individual participants included as part of the approved study.

Search strategy and selection of studies

A systematic review of literature was performed across multiple electronic databases: PubMed, Google Scholar, Cochrane, VHL, WOS, Embase and Scopus. PROSPERO and ClinicalTrials.Gov were searched for concurrent similar reviews. The search was performed in March 2023 and updated in April 2023 after refinement of search terms (provided in Table S1). A hand-search of bibliography of our included publications was conducted to improve our search.

We included all studies with ITP patients who received at least 1 dose of COVID-19 vaccination, at all levels of care. We excluded patients with de novo ITP post-vaccination, other types of thrombocytopenia, isolated case reports or case series with less than 10 patients, commentaries, duplicates and those without full text or in a language other than English. We compared patient populations who developed ITP exacerbations with those who did not.

Identified studies were uploaded into Covidence (8)—a software which aids in screening and data extraction for systematic reviews. In the initial phase, titles and abstracts were screened according to relevance and eligibility criteria, as defined above. Each article was reviewed by at least two independent reviewers; any conflicts were resolved by a third. The team was not blinded to study authors nor institutions. In the second phase, full-text screening was conducted by three reviewers independently. To appraise the risk of bias, checklists from the Scottish Intercollegiate Guidelines Network (SIGN) (9) were used. Studies with an unacceptable risk of bias were excluded.

Data collection

Three independent reviewers extracted the data using Excel Sheets, with predetermined variables. The following data were extracted: study title, first author, year of publication, country, number of study sites involved, study design, study population and sample size. For outcomes, data was collected regarding definition of exacerbation, age, gender, baseline platelet level as well as treatment history and active treatment at index date. Active treatment was defined as ongoing treatment or treatment that was expected to continue beyond the date of vaccination (for example, rituximab infusions); all treatment modalities except for platelet transfusions were included. Index date was defined as the date of the first dose of COVID-19 vaccination. If there was insufficient information, the original study investigators were contacted for required data and given a timeframe of 2 weeks for response. If there was no response, they were considered uncontactable. Within each report, not all patients received the same treatment modalities. Only patients whose data were available were included in the analysis.

Statistical analysis

For the purpose of analysis, exacerbation of ITP was defined as: >50% decline in platelet counts from baseline, or nadir platelet count <30×10⁹/L with >20% decrease from baseline, or requirement of rescue therapy, in line with previous reports (4,5,10). Rescue therapy was defined as intensification of ongoing treatment, a change in treatment modality or the addition of alternative treatment modalities (2). Baseline platelet level was defined as the last platelet count before vaccination.

We included our single-centre database in the analysis, which involved retrospective record reviews of 43 patients with current or pre-existing ITP diagnosed from 2002 to 2022 on active follow-up, who received at least 1 COVID-19 vaccination. Data was extracted using the same parameters as described above. Data regarding paediatric patients (age <18 years at time of vaccination, first dose) were collected and analysed separately from adult patients.

Extracted data was analysed using restricted maximum likelihood (REML) random effects models. Results from continuous variables were reported as Hedges’ g with a 95% confidence interval (CI). Results from categorical variables were reported as odds ratio with a 95% CI. Heterogeneity was quantified with Q-statistic and I² statistics, with an I² value of >50% considered as moderate heterogeneity (11). A sensitivity analysis was conducted, excluding the study with the largest population size (n=218) (4) (Figure S1). Meta-analysis results were presented via forest plots. Publication bias was explored using visual inspection of Doi Plots and Luis-Furuya-Kanamori Indexes (12) (Figure S2A-S2G). All analyses were conducted using STATA v18 software (13).

Certainty of assessment was conducted using GRADE (14)—based on study design, risk of bias and other factors.

Results

A total of 811 articles were screened. Fifty-two were assessed for eligibility and 9 were initially included for descriptive analysis (3,4,6,10,15-19). Three of the articles had insufficient data for analysis and their authors were uncontactable, leading to their exclusion (Figure 1). A pre-existing database from a local tertiary paediatric hospital was included as well. All but one of the studies were cohort studies, with 2 prospective studies. The majority of studies involved adult patients, with 1 focusing mainly on children and young adults (Table 1). Only data from young adults aged >18 years from this study and our local study were extracted for the meta-analysis. Baseline characteristics of these patients were examined (Table 2). Of the studies included, they were assessed to have an acceptable risk of bias.

Figure 1 Flowchart of studies.

Synthesis of results

Factors associated with ITP exacerbation included: ongoing active treatment at index date (excluding platelet transfusions) [pooled odds ratio (OR) 3.43, 95% CI: 1.87–6.29, P<0.001], treatment with rituximab at index date or at any time during the disease course prior to vaccination (pooled OR 3.06, 95% CI: 1.68–5.58, P<0.001) and treatment with thrombopoietin agonists at index date or at any time during the disease course prior to vaccination (pooled OR 4.32, 95% CI: 2.20 to 8.49, P<0.001) (Figure 2A-2C). Notably, no evidence of heterogeneity was noted for all 3 factors [Q(5)=5.30, Q(4)=2.18, Q(4)=1.86 respectively, with P values >0.05]. The sensitivity analysis after removing the case-control study with the largest sample size still showed significance for all 3 factors (Figure S1).

Figure 2 Forest plots of factors assessed for association with ITP exacerbation after COVID-19 vaccination. (A) Active treatment. (B) Rituximab use. (C) TPO-agonist use. (D) Age. (E) Female gender. (F) Splenectomy. (G) Baseline platelet level.

Factors that had no evidence of association with ITP exacerbation included baseline age at index date, female gender, splenectomy and baseline platelet count (Figures 2D-2G). A moderate heterogeneity score was noted for splenectomy, baseline platelet count and baseline age at index date [Q(2)=6.35, Q(3)=10.18, Q(3)=12.42, respectively]. This is in contrast to an included study (3), which reported a significant association between splenectomy and risk of ITP exacerbation after an initial dose of COVID-19 vaccination, with a relative risk (RR) of 1.8 and a 95% CI of 1.3 to 2.8.

Risk of bias within studies

We recognize the innate bias present in retrospective cohort studies. Notably, not all factors of concern were available for analysis within each study—leading to different sample sizes for analysis of different factors. Potential selection bias could have arisen from the inclusion of one study (19) which focused on hospitalized ITP patients, with a high proportion of patients with exacerbations (53.6% of the cohort). This was in contrast to other studies which included patients in the outpatient setting.

Studies utilized almost identical definitions of ITP exacerbation, with only one study (6) defining a secondary outcome as nadir platelet count <30×10⁹/L, without the definition of a decrease from baseline platelet level by >20%. All patients that fulfilled the criteria of nadir platelet count <30×10⁹/L also had a decrease from baseline platelet level by >20% and were thus included in the analysis.

Doi plots for each of the factors showed asymmetry in the specific factors of: baseline age at index date, female gender and use of TPO-agonist (Figure S2A,S2B,S2G). This was corroborated by the high LFK indexes of 3.41, −2.06 and 2.72, respectively—possibly indicative of bias.

Certainty of evidence

We found the certainty of evidence to be low for the outcome of ITP exacerbation, given the potential risk of bias and limited number of studies available for analysis.

Extension to paediatric ITP patients

Our initial meta-analysis focused mainly on adult patients with ITP as there has been a dearth of studies looking at the effect of COVID-19 vaccination on paediatric patients. Nevertheless, it is still important to examine if similar risk factors for ITP exacerbation with COVID-19 vaccination are also present in the paediatric population.

Our local database involved a retrospective records review of 33 paediatric patients, with current or previous ITP diagnosed from 2004, who received at least one dose of COVID-19 vaccination. All of our paediatric patients received mRNA vaccines. Nadir platelet counts were not routinely measured in patients post-vaccination.

Four patients (12.1%) developed ITP exacerbation, with a mean baseline platelet count of 35×10⁹/L, compared to 153×10⁹/L for those who had no exacerbation. The mean age of diagnosis was younger in patients with post-vaccine exacerbation (4 years, 8 months) versus those who did not (6 years, 1 month). None of the patients with exacerbation required rescue treatment. One patient experienced post-booster exacerbation—their platelet counts dropped from 58×10⁹/L to 20×10⁹/L. Three exacerbations occurred after the first vaccination dose, with 1 patient receiving the second dose 1 month later without exacerbation.

Discussion

Our systematic review and meta-analysis highlights factors that are potentially associated with ITP exacerbation in adults—ongoing active treatment, use of rituximab or TPO agonists. In accordance with established guidelines, rituximab and TPO agonists are offered to patients with ITP duration of at least 3 months, who are dependent or unresponsive to corticosteroids (20). Of note, the doses of rituximab and TPO-RA were not specified for these patients. Further subgroup analysis of outcomes and rescue treatment response could shed further insight into the progress of these potentially higher-risk patients.

Out of 38 patients with exacerbation who had pre- and post-vaccination platelet levels, 10 patients (26.3%) had exposure to TPO-agonists, with mean platelet count drops of 72×10⁹/L and nadir platelet counts of 25×10⁹/L (Figure S3). Five of these 10 patients received a booster dose with subsequent exacerbation (6,10,19). Within those who had exacerbations, treatment type was not associated with a significant drop in platelet counts—statistical analysis revealed no significant difference in both pre- and post-vaccination platelet counts as well as mean drop in platelet counts, when comparing between treatment groups (not on active treatment, any treatment or TPO-agonists alone). Eight of the above patients required rescue therapy, with 4 of them being on active treatment and 2 of them on TPO-agonist.

Not all studies subdivided patients into vaccine dose or booster dose, possibly due to the introduction of booster vaccines only in late 2021. One small-scale study noted that patients with significant platelet level decreases after initial vaccination doses also had significant drop in platelet counts after their boosters (6). The majority of patients included in our study also received Pfizer and Moderna COVID-19 vaccinations, in line with global trends (21).

Multiple reports noted severe thrombocytopenia in patients who developed exacerbations (6,10,18). Seventeen ITP patients (3.3%, pooled) included in this study developed minor bleeding manifestations (modified WHO bleeding scale Grade 1 or Grade 2) (22). The majority of these patients responded well to rescue therapy. In contrast, 0.8% of ITP patients (n=4, pooled) developed major bleeding manifestations (modified WHO bleeding scale Grade 3 or 4), with 1 death from oesophageal varices. Overall, the safety of COVID-19 vaccinations even in patients with ITP exacerbation is highlighted through the low number of cases of severe bleeding. This was corroborated by other studies not included in our meta-analysis (7,23).

With regards to the analysis for paediatric patients, there was a limited number of articles for analysis, resulting in a small sample size. Of note, the number of patients on active treatment at the time of vaccination in the cohort study was much higher than in our database (69% vs. 6.1%) whilst the mean platelet levels were comparable (142×10⁹/L vs. 139×10⁹/L). This may reflect different institutional-dependent treatment approaches to patients with ITP. Paediatric ITP has a generally more benign course as compared to adult ITP, with a higher rate of spontaneous remission and a higher amenability to treatment, as well as less comorbidities (24). Factors that are associated with post-vaccination ITP exacerbation in paediatric patients may hence also differ from those in adult ITP patients. Initial analysis of the available paediatric data revealed that the same factors associated with adult ITP exacerbation were not significant in children. However, we emphasize the limited sample size available for paediatric patients, which affects the generalizability of these results. Current recommendations for paediatric ITP patients are based off pre-existing studies in adults, but the general consensus remains that COVID-19 vaccination appears to be safe in children (25,26). Larger-scale studies may help identify factors associated with paediatric ITP exacerbations post-COVID-19 vaccination.

Caution should be taken with generalization of these findings due to the limited number of articles, moderate heterogeneity for certain factors and use of the fixed effects model for specific factors. Multiple logistic regression can also be considered to identify the overall risk of ITP exacerbation given a combination of factors—an approach that can help stratify risk of exacerbation given that chronic ITP patients may be exposed to multiple treatment modalities throughout their course of illness, which has been shown to be associated with relapses (3). Due to the lack of available data, this was not pursued in our study.

Currently, the pathophysiology and development of ITP following vaccination is not completely understood, but has been postulated to involve mechanisms such as molecular mimicry and epitope spreading (27). Rituximab has been known to negatively affect antibody responses to COVID-19 vaccination and should, in theory, modulate some of the above mechanisms. However, patients who are on rituximab or TPO-agonists likely are experiencing more severe or active autoimmune processes, necessitating the use of these second or third line treatments. Severe thrombocytopenia may also be triggered by a reduction in platelet production or increased destruction of platelets and megakaryocytes by multiple different mechanisms (28,29).

Strengths and limitations

Our meta-analysis is the first of its kind in summarizing different factors possibly associated with ITP exacerbation post-COVID-19 vaccination. Our study encompassed patients of different races, and varying ages as well as different treatment modalities.

We noted specific limitations in our study. There was an inherent possibility of bias in selectively reporting cases with ITP exacerbation. Additionally, specific timepoints for platelet levels were not routinely established post-vaccination, with the possibility of missing out asymptomatic patients with significant thrombocytopenia (fulfilling criteria of relapse). The natural course of ITP is also fluctuating, with interindividual variability in platelet levels (30)—it would be difficult to ascertain whether relapses are directly due to vaccination or part of a natural disease course.

Few reports examined the type of COVID-19 vaccine as a possible factor for ITP exacerbation. Although mRNA vaccines remain the most commonly used worldwide, cases of ITP exacerbation have been seen with both mRNA and adenovirus vector vaccines (31). Further analysis can be conducted to examine if there is an increased risk of ITP exacerbation with specific vaccine types. Both of these vaccinations have been associated with thrombocytopenia with similar frequency as well as severity (32), with single-digit platelet levels and bleeding manifestations. Cases of immune thrombotic thrombocytopenia have been observed following patients who received AstraZeneca vaccinations as well (33).

Conclusions

Through this study, we identified factors associated with ITP exacerbation following COVID-19 vaccination and highlighted the safety profile of COVID-19 vaccines even in patients with pre-existing ITP. An increased frequency of clinical and biochemical monitoring of high-risk patients can be considered in the immediate post-vaccination period to identify potential exacerbations. We recommend that COVID-19 vaccination should be considered for all patients with ITP to reduce the risk of severe COVID-19 infection; however, in certain high-risk groups as identified from our analysis, a more judicious approach to vaccination may be more appropriate, where the benefits of vaccination should be weighed against the risks and dangers of ITP exacerbation. Further studies can be undertaken to analyse the long-term effects of COVID-19 vaccinations on patients with ITP.

Acknowledgments

Funding: None.

Footnote

Reporting Checklist: The authors have completed the PRISMA reporting checklist. Available at https://aob.amegroups.com/article/view/10.21037/aob-24-15/rc

Peer Review File: Available at https://aob.amegroups.com/article/view/10.21037/aob-24-15/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://aob.amegroups.com/article/view/10.21037/aob-24-15/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was conducted in accordance with the Declaration of Helsinki (as revised in 2013) and approved by the Institutional Review board of Singapore Health Services (CIRB 2018/2374). Consent was obtained from individual participants included as part of the approved study.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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