Apadamtase alfa /Cinaxadamtase alfa

Congenital thrombotic thrombocytopenic purpura (cTTP) is caused by a severe inherited ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 motif, member 13) deficiency. Although 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 patients with cTTP enrolled in the French Thrombotic Microangiopathy registry. Patients were stratified by age and clinical context at disease onset: pediatric (n = 42), pregnancy (n = 33), and 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 [interquartile range, 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 aged >50 years, 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 midterm prophylaxis during pregnancy reduced maternal and fetal complications. Thirty-nine patients received recombinant human ADAMTS13 (rhADAMTS13) prophylaxis (median follow-up, 5 months [interquartile range, 6-17]). 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 plasma therapy. Our findings highlight the clinical and genetic heterogeneity of cTTP and the burden of organ dysfunction. Intensive prophylaxis improves relapse-free survival. rhADAMTS13 represents a safe and promising first-line option that should help reduce long-term organ damage and improve quality of life.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by mucosal inflammation and ulceration. While von Willebrand factor, typically cleaved by ADAMTS13 from ultralarge multimers into smaller fragments, has been found to accumulate in the inflamed lesions of the ADAMTS13-deficient colitis model, the association between aberrant thrombus formation in lesional microvessels and colitis exacerbation remains unclear.

We investigated potential linkages between microthrombus formation and colitis progression.

Plasma and inflamed colonic tissues from patients with UC were analyzed. We employed intravital multiphoton microscopy to reveal the real-time structural dynamics of the mucus layer and mucosal vasculature at single-cell spatial resolution in a dextran sulfate sodium-induced colitis model of wild-type and ADAMTS13-deficient green fluorescent protein-expressing mice.

Patients with UC exhibited significantly reduced plasma ADAMTS13 activity and excessive von Willebrand factor deposition in inflamed colonic tissues. In dextran sulfate sodium-induced colitis mice, ADAMTS13 deficiency showed heightened disease activity and increased mucosal erosion in histochemical analysis compared with wild-type mice. A novel methodology appraised colonic mucus barrier integrity by visualizing fluorescent dextran penetration from the colonic lumen to crypts. ADAMTS13 deficiency accelerated mucus layer disruption, leukocyte recruitment, and microthrombus formation, particularly in periepithelium regions. Vessel-specific analyses demonstrated that obstructive microthrombi were most prominent in the mucosal layer, contributing to local ischemia and mucosal erosion. Recombinant human ADAMTS13 alleviated microthrombus formation, improved mucosal integrity, and mitigated colitis severity in both wild-type and ADAMTS13-deficient mice.

Advanced intravital imaging analysis revealed that obstructive thrombi formed in mucosal vessels due to impaired ADAMTS13 activity were essential for colitis severity.