Procedure-triggered late-onset congenital thrombotic thrombocytopenic purpura: Unmasking functional impact of a heterozygous synonymous ADAMTS13 variant (c.1716G>A) associated with reduced enzyme expression Free

Background:

Congenital thrombotic thrombocytopenic purpura (cTTP), also known as Upshaw–Schulman syndrome, is a rare autosomal recessive disorder with an estimated prevalence of approximately 1 per million per year (Sakai, 2023). It is caused by biallelic mutations in the ADAMTS13 gene. The synonymous variation of the ADAMTS13 gene, previously considered benign, may alter the intracellular protein expression and contribute to a “haploinsufficient” state, particularly in the setting of procedural-related stress (Edwards, 2012). This marks a novel mechanism in late-onset cTTP, distinguishing it from the typical biallelic pathogenic mutation. One of the potential consequences of this underrecognized variation is delayed diagnosis in adulthood, which may result in inappropriate treatment with plasma exchange (PLEX) and corticosteroids if mistaken for acquired TTP.

Aims:

To report a rare, late-onset case of cTTP due to a synonymous ADAMTS13 variant in a 55-year-old male, highlighting the clinical challenges, diagnostic delay, and treatment implications.

Methods:

A 55-year-old African American male with a history of diabetes, hypertension, stroke, and myocardial infarction presented with recurrent thrombocytopenia and microangiopathic hemolytic anemia (MAHA) associated with vascular procedures. His initial episode occurred post-myocardial infarction after percutaneous coronary intervention, revealing a platelet count of 12×10³/μL and ADAMTS13 activity of 14%, with a transiently positive inhibitor screen. He was treated as immune thrombocytopenic purpura (ITP) with steroids and discharged. Subsequent procedures, including umbilical hernia repair, peripheral arterial stenting, and femoral endarterectomy, each triggered new episodes of thrombocytopenia (nadir platelets: 21–29×10³/μL), MAHA, and low ADAMTS13 activity (ranging from <5% to 16%), but with absent inhibitor. Despite receiving over 30 sessions of plasma exchange, IVIG, and corticosteroids, the episodes recurred. Genetic sequencing was eventually performed after these repeated episodes.

Results:

Genetic testing revealed a heterozygous synonymous variant in the ADAMTS13 gene: (c.1716G>A, p.Thr572=). The patient demonstrated severe enzyme deficiency and recurrent thrombotic microangiopathy despite the “generally benign” classification of the variant. Plasma infusions and high-dose corticosteroids led to hematologic improvement. The absence of an ADAMTS13 inhibitor and inconsistent response to immune-directed therapies supported the diagnosis of cTTP. The delayed diagnosis led to potentially avoidable neurologic damage and treatment-related complications.

Conclusion:

Congenital TTP should be considered in adult patients with recurrent thrombotic microangiopathy, especially when triggered by surgery or physiologic stress, and in the absence of a sustained inhibitor response. This case underscores the importance of recognizing the pathogenic potential of synonymous variants and the need for expanded interpretation of ADAMTS13 genetic testing. Early recognition can prevent unnecessary PLEX and enable targeted therapy with plasma infusion or recombinant ADAMTS13. This case highlights a novel mechanism for late-onset cTTP and illustrates the serious implications of delayed diagnosis in adult patients.