An updated systematic review and meta-analysis of caplacizumab for immune thromboticthrombocytopenic purpura: Insights into efficacy and safety

Abstract Background: Immune thromboticthrombocytopenic purpura (iTTP) is a rare but life-threatening hematologic condition associated with thrombocytopenia and hemolytic anemia. Caplacizumab has been shown to improve clinical outcomes in iTTP when combined with therapeutic plasma exchange (TPE) and immunosuppression, with recent studies showing significant clinical benefits. This systematic review and meta-analysis summarizes the current evidence to assess the efficacy and safety of caplacizumab in the treatment of iTTP, focusing on its impact on TPE requirements, time to platelet normalization, relapse prevention, and treatment-related adverse events. Methods: A comprehensive search of PubMed, Scopus, Web of Science, andCochrane Library was carried out up to May 2025. Randomized controlled trials (RCTs) and observational studies comparing caplacizumab to standard care alone or placebo in the management of iTTP were included. Two blinded reviewers independently screened the titles, extracted the data, and assessed the risk of bias using the Cochrane Risk of Bias tool (ROB2) for RCTs and the Newcastle-Ottawa scale (NOS) for the observational studies. The primary endpoints were the number of daily TPE sessions, time to platelet count normalization, mortality, and iTTP-related exacerbations. Secondary outcomes included ADAMTS13 recovery, hospital stay duration, refractoriness, relapse, major bleeding, and major thrombosis. Mean difference (MD) and risk ratio (RR), along with 95% confidence intervals (CI), were used for analyzing continuous and dichotomous outcomes, respectively. Chi-square tests and I2 statistics were used to evaluate the heterogeneity across the studies. Statistical analysis was conducted using R software (version 4.5), and the data were combined using a random effects model. The protocol of this study was registered in PROSPERO (CRD420251085326). Results: Thirteen studies (eleven observational studies and two RCTs), involving 2,956 patients with iTTP, were included in this review. Most studies were of high methodological quality, indicating a low risk of bias based on the assessment tools. Caplacizumab was associated with a significant reduction in daily TPE sessions (MD= -3.92; 95% CI:[-4.86, -2.99], p < 0.001), time to platelet count normalization (MD= -2.44; 95% CI: [-4.70, -0.17], p= 0.03), mortality (RR = 0.29; 95% CI: [0.19, 0.46], p < 0.001), and iTTP exacerbations (RR = 0.27; 95% CI: [0.13, 0.58], p < 0.001). Additional benefits included faster ADAMTS13 recovery (MD = -9.68; 95% CI: [-19.16, -0.21], p= 0.05), shorter hospital stays (MD = -5.13; 95% CI: [-8.21, -2.06], p = 0.001), and reduced refractoriness rates (RR= 0.36; 95% CI: [0.15, 0.84], p= 0.02). The analysis further indicated no significant difference across the groups in terms of relapse (RR= 1.21; 95% CI: [0.42, 3.47], p = 0.72), major bleeding (RR = 2.09; 95% CI: [0.61, 7.14], p = 0.24), and major thrombosis (RR = 1.06; 95% CI: [0.62, 1.79], p= 0.83). Importantly, early initiation of caplacizumab (within 3 days after starting TPE or diagnosis) was associated with a significantly shorter hospital stay (MD = -8.6; 95% CI: [-12.4, -4.8], p < 0.001) compared to delayed initiation. Conclusion: This updated meta-analysis, incorporating both RCTs and real-world studies, provides the most comprehensive evidence to date on the efficacy and safety of caplacizumab in iTTP. The results confirm significant clinical benefits, including reduced TPE requirements, faster platelet recovery, lower mortality, and shorter hospital stays. Moreover, early initiation was associated with more favorable outcomes compared to delayed use. Importantly, the comparable rates of relapse, major bleeding, and thrombosis between groups highlight its favorable safety profile. These findings support the early integration of caplacizumab into frontline iTTP treatment strategies, while also emphasizing the need for further high-quality studies to confirm its long-term effectiveness.