Thrombotic thrombocytopenic purpura (TTP) is a rare but life-threatening thrombotic microangiopathy caused by severe ADAMTS-13 deficiency due to either autoantibodies (immune TTP, iTTP) or biallelic mutations (congenital TTP, cTTP). The first International Society on Thrombosis and Haemostasis (ISTH) guidelines were issued in 2020. Since then, substantial advances in therapeutic strategies and real-world evidence have prompted an ISTH 2025 focused update.

The most significant change relates to cTTP prophylaxis. A new strong recommendation was issued in favor of recombinant ADAMTS-13 (rADAMTS-13) over fresh frozen plasma (FFP) in patients in remission. This decision, supported by a phase 3 randomized crossover trial, demonstrated that rADAMTS-13 provides higher and sustained ADAMTS-13 activity and fewer TTP-related manifestations, with a favorable safety profile [1]. Where rADAMTS-13 is unavailable, the panel conditionally recommends FFP over a watch-and-wait strategy, shifting from the neutral stance in 2020 [1,2]. Pregnancy-related cTTP remains a high-risk setting, and prophylactic therapy—preferably rADAMTS-13, or intensified FFP when rADAMTS-13 is not accessible—is emphasized due to high maternal and fetal morbidity and mortality [1].

For iTTP, no major directional changes were made. Therapeutic plasma exchange (TPE) with corticosteroids remains standard of care. The addition of rituximab is conditionally suggested for both initial and relapsed events. Caplacizumab continues to be conditionally recommended, supported by real-world registry and cohort data showing faster platelet recovery, fewer exacerbations, reduced TPE sessions, shorter hospitalization, and mortality consistently below 5% [3,4]. Evidence highlights that early initiation, ideally within three days of diagnosis, maximizes benefit [4].

The update also provides revised good practice statements on antithrombotic therapy. Prophylactic anticoagulation (most often low-molecular-weight heparin) may be considered once platelet counts recover above 50 × 10⁹/L in patients at elevated thromboembolic risk, while antiplatelet agents remain discouraged during the acute phase [1].

Importantly, registry data highlight the long-term morbidity of cTTP, including ischemic stroke, end-stage renal disease, and cardiac dysfunction, as well as pregnancy complications. These findings strengthen the rationale for early and consistent prophylaxis. Regulatory approval of rADAMTS-13 in the United States, Europe, and Japan for both prophylaxis and acute treatment represents a transformative milestone in cTTP management [5].

Conclusion: The ISTH 2025 focused update establishes rADAMTS-13 as the new standard for prophylaxis in cTTP and reaffirms the existing evidence-based triple therapy (TPE, corticosteroids, and caplacizumab ± rituximab) in iTTP. These recommendations, integrating randomized trial results, real-world data, and international consensus, provide globally harmonized, evidence-based guidance to improve outcomes and quality of life for patients with TTP.