Adult-Onset Hereditary Thrombotic Thrombocytopenic Purpura Presenting as Kidney Failure: A Heterozygous ADAMTS13...

Hereditary thrombotic thrombocytopenic purpura (TTP) is a rare autosomal recessive disorder caused by ADAMTS13 deficiency, typically presenting in childhood or early adulthood. We describe an atypical presentation of hereditary TTP in a 55-year-old man presenting with AKI on a background of diabetic kidney disease, without suggestive history or identifiable triggers. Initial evaluation revealed features of thrombotic microangiopathy (TMA), including hemolysis, thrombocytopenia, with preserved coagulation parameters. Presumptive complement-mediated TMA was treated with eculizumab; however, the patient progressed to dialysis dependence and developed transient neurologic symptoms. ADAMTS13 activity was reduced (8 U/dl) without a detectable inhibitor, prompting treatment with fresh frozen plasma (FFP), which resulted in hematologic and neurologic improvement. Kidney biopsy demonstrated acute TMA superimposed on advanced diabetic and vascular disease. Genetic testing identified a heterozygous pathogenic ADAMTS13 variant (c.587C>T; p.Thr196Ile) without a second pathogenic allele. Additional long-read sequencing detected polymorphisms that may be associated with reduced ADAMTS13 activity; however, current evidence suggests that these are variants of unknown significance. Although these variants have been associated with variation in ADAMTS13 levels in population or functional studies, the contribution of the additional variants remains uncertain. Functional response to FFP with transient correction of ADAMTS13 levels supported a diagnosis of hereditary TTP. The patient was commenced on regular FFP infusions and has been stable without further hematologic or neurologic events. He remains dialysis dependent, awaiting kidney transplantation. This case highlights a late-onset, atypical presentation of hereditary TTP and raises important questions regarding the pathogenicity of heterozygous variants and modifying polymorphisms. It underscores the need to consider ADAMTS13 deficiency in unexplained TMA and kidney failure, even in the absence of classic features or biallelic mutations.