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Presentation Details
| Efficacy and Safety of Caplacizumab in Thrombotic Thrombocytopenic Purpura: A Systematic Review and Meta-Analysis Ursula Medeiros Araujo de Matos1, Pedro Luiz Lage Bodour Danielian2, Ritika Vankina3. 1Internal Medicine Department, University of Connecticut, Farmington, CT, USA.2Harvard T.H.Chan School of Public Health, Boston, MA, USA.3Hematology Oncology Department, University of Connecticut, Farmington, CT, USA |
Abstract
Background:
Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a rare but life-threatening thrombotic microangiopathy characterized by severe ADAMTS13 deficiency, widespread microvascular thrombosis, and multiorgan ischemia. Despite standard therapy with plasma exchange (PEX) and immunosuppression, mortality, refractoriness, and exacerbations remain clinically significant. Caplacizumab, a bivalent nanobody targeting von Willebrand factor, prevents platelet adhesion and has emerged as a novel adjunctive therapy. Randomized controlled trials (RCTs) as TITAN and HERCULES demonstrated faster platelet recovery and reduced composite endpoints with caplacizumab, but earlier reviews were limited by small sample sizes and lack of statistical power.
Objective:
To perform an updated and comprehensive meta-analysis of randomized and observational studies to evaluate the efficacy and safety of caplacizumab in the management of iTTP.
Methods:
We systematically searched PubMed, EMBASE, and the Cochrane Library through September 2025 for RCTs and observational cohorts comparing caplacizumab plus standard of care (PEX and immunosuppression) versus standard of care alone in iTTP. Outcomes included all-cause mortality, refractoriness, exacerbation, relapse, bleeding (overall and clinically relevant), hospital and ICU length of stay, PEX sessions, and time to platelet normalization. Data extraction was performed independently by two investigators. Random-effects models were used to calculate pooled odds ratios (ORs) or mean differences (MDs) with 95% confidence intervals (CIs). Subgroup analyses stratified results by study design to examine consistency of treatment effects.
Results:
Six studies encompassing 2,054 patients (1,295 receiving caplacizumab, 759 controls) met inclusion criteria: two pivotal RCTs (TITAN and HERCULES) and four large multicenter cohorts, including Coppo 2025, a recent study that significantly expanded available evidence. We found that caplacizumab significantly reduced all-cause mortality (OR 0.29, 95% CI 0.16–0.55), refractoriness (OR 0.17, 95% CI 0.06–0.47), and exacerbation (OR 0.27, 95% CI 0.12–0.60). Table 1 summarizes findings for efficacy and safety outcomes. Most bleeding events were mucocutaneous and manageable with drug interruption, though rare severe bleeds were reported. Caplacizumab was associated with fewer PEX sessions (MD -3.05 sessions, 95% CI -5.62 to -0.48), shorter hospital stays (MD -4.52 days, 95% CI -8.81 to -0.22), and faster time to platelet count normalization (MD -1.68 days, 95% CI -2.95 to -0.40). Trends toward shorter ICU stays were observed, but lacked statistical significance (MD -2.89 days, 95% CI -6.46 to 0.69). The magnitude and direction of treatment effects were consistent across RCTs and observational studies, with no evidence of subgroup interaction, underscoring the robustness and external validity of these findings.
Conclusion:
This meta-analysis provides the strongest evidence to date for caplacizumab in iTTP. Beyond faster platelet recovery and reduced PEX requirements, caplacizumab confers a clear mortality benefit - an endpoint underpowered in prior studies. The consistent reduction in refractoriness, exacerbation, and hospitalization highlights both clinical and healthcare utilization advantages, establishing it as a key adjunct to standard therapy with the trade-off of increased bleeding. Relapse prevention remains dependent on durable immunosuppression. Future research should aim to optimize bleeding risk management, clarify the role of concomitant therapies such as rituximab in the era of caplacizumab, evaluate cost-effectiveness, and determine the optimal timing of caplacizumab administration.
No part of this publication may be reproduced, distributed, or transmitted in any form or by any means, including photocopying, recording, or other electronic or mechanical methods, without the prior written permission of the author.
Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a rare but life-threatening thrombotic microangiopathy characterized by severe ADAMTS13 deficiency, widespread microvascular thrombosis, and multiorgan ischemia. Despite standard therapy with plasma exchange (PEX) and immunosuppression, mortality, refractoriness, and exacerbations remain clinically significant. Caplacizumab, a bivalent nanobody targeting von Willebrand factor, prevents platelet adhesion and has emerged as a novel adjunctive therapy. Randomized controlled trials (RCTs) as TITAN and HERCULES demonstrated faster platelet recovery and reduced composite endpoints with caplacizumab, but earlier reviews were limited by small sample sizes and lack of statistical power.
Objective:
To perform an updated and comprehensive meta-analysis of randomized and observational studies to evaluate the efficacy and safety of caplacizumab in the management of iTTP.
Methods:
We systematically searched PubMed, EMBASE, and the Cochrane Library through September 2025 for RCTs and observational cohorts comparing caplacizumab plus standard of care (PEX and immunosuppression) versus standard of care alone in iTTP. Outcomes included all-cause mortality, refractoriness, exacerbation, relapse, bleeding (overall and clinically relevant), hospital and ICU length of stay, PEX sessions, and time to platelet normalization. Data extraction was performed independently by two investigators. Random-effects models were used to calculate pooled odds ratios (ORs) or mean differences (MDs) with 95% confidence intervals (CIs). Subgroup analyses stratified results by study design to examine consistency of treatment effects.
Results:
Six studies encompassing 2,054 patients (1,295 receiving caplacizumab, 759 controls) met inclusion criteria: two pivotal RCTs (TITAN and HERCULES) and four large multicenter cohorts, including Coppo 2025, a recent study that significantly expanded available evidence. We found that caplacizumab significantly reduced all-cause mortality (OR 0.29, 95% CI 0.16–0.55), refractoriness (OR 0.17, 95% CI 0.06–0.47), and exacerbation (OR 0.27, 95% CI 0.12–0.60). Table 1 summarizes findings for efficacy and safety outcomes. Most bleeding events were mucocutaneous and manageable with drug interruption, though rare severe bleeds were reported. Caplacizumab was associated with fewer PEX sessions (MD -3.05 sessions, 95% CI -5.62 to -0.48), shorter hospital stays (MD -4.52 days, 95% CI -8.81 to -0.22), and faster time to platelet count normalization (MD -1.68 days, 95% CI -2.95 to -0.40). Trends toward shorter ICU stays were observed, but lacked statistical significance (MD -2.89 days, 95% CI -6.46 to 0.69). The magnitude and direction of treatment effects were consistent across RCTs and observational studies, with no evidence of subgroup interaction, underscoring the robustness and external validity of these findings.
Conclusion:
This meta-analysis provides the strongest evidence to date for caplacizumab in iTTP. Beyond faster platelet recovery and reduced PEX requirements, caplacizumab confers a clear mortality benefit - an endpoint underpowered in prior studies. The consistent reduction in refractoriness, exacerbation, and hospitalization highlights both clinical and healthcare utilization advantages, establishing it as a key adjunct to standard therapy with the trade-off of increased bleeding. Relapse prevention remains dependent on durable immunosuppression. Future research should aim to optimize bleeding risk management, clarify the role of concomitant therapies such as rituximab in the era of caplacizumab, evaluate cost-effectiveness, and determine the optimal timing of caplacizumab administration.
No part of this publication may be reproduced, distributed, or transmitted in any form or by any means, including photocopying, recording, or other electronic or mechanical methods, without the prior written permission of the author.