Optimizing ADAMTS13 prophylaxis to reduce relapse and organ failure in congenital thrombotic thrombocytopenic purpura Open Access

• Long-term organ complications are prevalent in cTTP and highlight the need for personalized follow-up and tailored prophylactic strategies.

• rhADAMTS13 shows promising safety and efficacy in cTTP, potentially improving relapse-free survival and reducing treatment burden.

Congenital thrombotic thrombocytopenic purpura (cTTP) is caused by a severe inherited ADAMTS13 deficiency. While acute episodes are life-threatening, long-term burden of ischemic complications and effectiveness of prophylactic strategies remain underexplored. We conducted a 25-year national, multicenter study of 88 cTTP patients enrolled in the French Thrombotic Microangiopathy (TMA) registry. Patients were stratified by age and clinical context at disease onset: pediatric-onset (n=42), pregnancy-onset (n=33), adult-onset (n=13). Clinical features, genotypes, treatment regimens, and long-term ischemic outcomes were analyzed. Pediatric patients exhibited early-onset disease (median age at diagnosis: 2 years [IQR: 0;13]) with recurrent episodes and a high burden of neurological complications. In patients with pregnancy-onset disease, no relapses were observed outside pregnancy. Adult-onset patients, typically diagnosed >50-year-old, showed prevalent cardiovascular disease, stroke, and kidney injury. Mental health disorders were common across all groups. Despite long-term plasma prophylaxis, organ dysfunction persisted, particularly in pediatric- and adult-onset groups. In pregnancy-onset cTTP, tailored mid-term prophylaxis during pregnancy reduced maternal and fetal complications. Thirty-nine patients received recombinant human ADAMTS13 (rhADAMTS13) prophylaxis (median follow-up: 5 [6-17] months). Prophylactic treatment significantly improved relapse-free survival, with a comparable outcome using intensive plasma-derived products and rhADAMTS13 in pediatric-onset cases, although adverse events were more prevalent using plasmatherapy. Our findings highlight the clinical and genetic heterogeneity of cTTP and the burden of organ dysfunction. Intensive prophylaxis improves relapse-free survival. rhADAMTS13, by reducing the burden of care, represents a safe and promising first-line option that should help reducing long-term organ damage and improving quality of life.