ADAMTS13 – Congenital Thrombotic Thrombocytopenic Purpura

Autosomal recessive congenital thrombotic thrombocytopenic purpura (cTTP; Upshaw-Schulman syndrome) is caused by biallelic loss-of-function variants in the ADAMTS13 gene, encoding the von Willebrand factor (VWF)-cleaving protease. Patients present in the neonatal period or early childhood with microangiopathic hemolytic anemia and thrombocytopenia, often complicated by hyperbilirubinemia and organ ischemia. Early recognition via ADAMTS13 activity assay and molecular testing is critical for timely plasma therapy and genetic counseling.

Initial case reports described neonates with profound ADAMTS13 deficiency confirmed in affected siblings and mild carrier activity in parents, establishing an autosomal recessive inheritance (PMID:12556937). Subsequent multi-family studies identified over a dozen pathogenic variants distributed throughout ADAMTS13, with severe deficiency (<5% activity) in probands and heterozygous carriers asymptomatic (PMID:12181489). One recurrent population polymorphism (p.Pro475Ser) was shown to reduce protease activity yet retain low-level secretion.

More than 100 individuals from diverse ethnicities have been diagnosed with cTTP, each harboring compound heterozygous or homozygous ADAMTS13 mutations. A representative variant, c.788C>T (p.Ser263Phe), was identified in a child with relapsing TTP; segregation in the family confirmed recessive inheritance and plasma infusions prevented recurrences (PMID:23058857). Founder alleles such as p.Cys908Tyr in Japan further underscore ethnic-specific mutation spectra.

Functional studies demonstrate that missense and splice-site mutations impair ADAMTS13 secretion or catalytic activity, resulting in accumulation of ultra-large VWF multimers. In vitro expression and mouse models of the p.Asp187His variant recapitulate the TTP phenotype, confirming a loss-of-function mechanism (PMID:25442981).

No credible conflicting evidence disputing the causative role of ADAMTS13 deficiency in cTTP has emerged. Integration of genetic and experimental data firmly establishes ADAMTS13 as the disease gene for cTTP. Routine ADAMTS13 activity testing and gene sequencing enable definitive diagnosis, guide plasma-based therapy, and inform family planning.

Key Take-home: Biallelic ADAMTS13 mutations cause autosomal recessive congenital TTP; molecular diagnosis and early plasma replacement are essential for optimal outcomes.

References

• Journal of perinatology • 2003 • Thrombotic thrombocytopenic purpura in a newborn. PMID:12556937
• Proceedings of the National Academy of Sciences of the United States of America • 2002 • Mutations and common polymorphisms in ADAMTS13 gene responsible for von Willebrand factor-cleaving protease activity. PMID:12181489
• Blood Transfusion = Trasfusione del sangue • 2013 • Two novel heterozygote missense mutations of the ADAMTS13 gene in a child with recurrent thrombotic thrombocytopenic purpura. PMID:23058857
• Journal of thrombosis and haemostasis : JTH • 2015 • The novel ADAMTS13-p.D187H mutation impairs ADAMTS13 activity and secretion and contributes to thrombotic thrombocytopenic purpura in mice. PMID:25442981

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