The systematic database search yielded a total of 113 and 135 records from the MEDLINE and SCOPUS databases, respectively (Supplementary Figure-S1). After excluding duplicates and initial screening, we retrieved the full text of 8 records that were considered potentially eligible for inclusion. Six studies were further excluded [3,4,5, 11,12,13] (Supplementary Table-S1). Finally, we identified two eligible studies for inclusion in the meta-analysis [14, 15], comprising a total of 211 patients with CVST associated with COVID-19 vaccination (Table 1). The quality control and risk of bias of the included studies, as assessed by the Newcastle–Ottawa scale, is presented in Supplementary Table-S2. The overall score was 18 of 18 (100%), indicating high quality and low risk of bias of the included studies.
TTS was diagnosed in included studies in accordance with the Brighton Collaboration criteria . In particular, in the study of van Kammen et al., patients with CVST following COVID-19 vaccination were diagnosed with TTS if they fulfilled all of the following criteria : (1) confirmed thrombosis, (2) new-onset thrombocytopenia, and (3) no known recent exposure to heparin. In the study of Perry et al., TTS–CVST was diagnosed in accordance with the previous criteria, and additionally, in patients in whom D-dimer was measured, the highest value recorded had to be greater than 2000 μg/L .
More than 70% of the CVST cases post COVID-19 vaccination were associated with TTS (95% CI 64–76%; I2 = 4%; p for Cochran Q = 0.31; Supplementary Figure-S2). Following vector-based vaccination, a higher likelihood of presenting TTS–CVST compared to non-TTS-CVST was noted (OR: 52.34; 95% CI 9.58–285.98; I2 = 0%; p for Cochran Q = 0. 0.64; Fig. 1A). On the contrary, non-vector-based vaccination was associated predominantly with non-TTS-CVST (OR:0.02; 95% CI0.00–0.1; I2 = 0%; p for Cochran Q = 0.64; Fig. 1B).
TTS–CVST was recorded with a shorter interval between vaccination and symptom onset (MD:-6.54 days; 95% CI − 12.64 to − 0.45; I2 = 0%; p for Cochran Q = 0.87; Supplementary Figure-S3), affecting younger patients (MD:-9.00 years; 95% CI − 14.02 to − 3.99; I2 = 0%; p for Cochran Q = 0.70; Supplementary Figure-S4), without risk factors for thromboses (OR: 2.34; 95% CI 1.26–4.33; I2 = 0%; p for Cochran Q = 0.90; Supplementary Figure-S5), and was complicated more frequently with intracerebral hemorrhage (OR: 3.60; 95% CI 1.31–9.87; I2 = 60%; p for Cochran Q = 0.11; Supplementary Figure-S6) and concomitant thromboses in other sites (OR:11.85; 95% CI 3.51–39.98; I2 = 0%; p for Cochran Q = 0.57; Supplementary Figure-S7) compared to non-TTS–CVST cases. Female proportion was comparable between the two groups (OR:1.35; 95% CI 0.69–2.62; I2 = 0%; p for Cochran Q = 0.60; Supplementary Figure-S8).
In-hospital mortality of TTS–CVST cases was significantly higher compared to non-TTS–CVST (OR: 13.29; 95% CI 3.96–44.60; I2 = 0%; p for Cochran Q = 0.70; Fig. 2A). Death or dependency at discharge was also found significantly higher in patients with TTS–CVST (OR: 6.70; 95% CI 3.15–14.26; I2 = 0%; p for Cochran Q = 0.43; Fig. 2B).
With respect to TTS–CVST treatments, the pooled proportion of patients treated with non-heparin parenteral anticoagulants was 57% (95% CI 27–84%; 2 studies; I2 = 93%; p for Cochran Q < 0.01; Supplementary Table-S3), followed by heparin-anticoagulants in 31% (95% CI 17–47%; 2 studies; I2 = 77%; p for Cochran Q = 0.04; Supplementary Table-S3) and direct oral anticoagulants in 16% of cases (95% CI 0–49%; 2 studies; I2 = 95%; p for Cochran Q < 0.01; Supplementary Table-S3). Data regarding in-hospital mortality among patients treated with non-heparin-derived anticoagulants versus those administered heparin-derived anticoagulants could not be extracted in the study of van Kammen et al. and, thus, a comparative meta-analysis was not performed. As part of the single-arm meta-analysis, the pooled in-hospital mortality among patients with TTS–CVST treated with heparin-anticoagulants was calculated at 31% (95% CI 11–55%; 2 studies; I2 = 61%; p for Cochran Q = 0.11; Supplementary Figure-S9). It should be noted, however, that heparin-anticoagulants were mostly administered until March 2021, when TTS was first brought to wide attention and clinical practice guidelines were issued advising against heparin use in TTS.
With respect to immunomodulation, the majority of TTS–CVST patients received IVIG (pooled rate: 70%; 95% CI 51–86%; 2 studies; I2 = 83%; p for Cochran Q = 0.02; Supplementary Table-S3), followed by corticosteroids (pooled rate: 53%; 95% CI 15–89%; 2 studies; I2 = 96%; p for Cochran Q < 0.01; Supplementary Table-S3) and plasmapheresis (pooled rate: 14%; 95% CI 0–32%; 2 studies; I2 = 86%; p for Cochran Q = 0.01; Supplementary Table-S3). Treatment of TTS–CVST patients with IVIG was associated with a significant reduction of in-hospital mortality compared to those not receiving IVIG (OR: 0.20; 95% CI 0.07–0.57; I2 = 43%; p for Cochran Q = 0.18; Fig. 3).