Thrombomodulin – Atypical Hemolytic Uremic Syndrome

Atypical hemolytic uremic syndrome (aHUS) is a rare, life-threatening thrombotic microangiopathy characterized by microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. Dysregulation of the alternative complement pathway underlies most cases, with mutations in complement regulators predisposing to endothelial injury. Thrombomodulin (THBD) has been identified as a novel membrane-bound cofactor for complement regulation, acting through C3b and anaphylatoxin inactivation to protect microvascular endothelium. Loss-of-function THBD variants impair this complement-regulatory role and contribute to aHUS pathogenesis.

Genetic evidence supports an autosomal dominant mode of inheritance for THBD-related aHUS. Six different heterozygous missense mutations were found in 7/152 unrelated aHUS patients (approximately 5%) (PMID:19625716), and additional single-case reports in both pediatric and adult cohorts have confirmed THBD variants in independent families (PMID:27904864; PMID:37120715). No large multiplex pedigrees have been published, but segregation in small kindreds and de novo absence in controls reinforce pathogenicity.

The variant spectrum in THBD includes missense substitutions clustering in the epidermal growth factor-like domains and rare truncating alleles. A representative example is c.241G>A (p.Val81Ile), identified in an aHUS patient cohort (PMID:20595690). Other reported changes include p.Pro501Leu, p.Arg403Lys, and p.Asp486Tyr. No clear founder effects have been described, and overall carrier frequency in healthy populations is <0.01%.

Functional studies demonstrate that THBD binds to C3b and factor H, accelerating factor I–mediated C3b cleavage and procarboxypeptidase B activation for anaphylatoxin degradation. THBD missense variants show diminished C3b cofactor activity and reduced anaphylatoxin inactivation, leading to unchecked complement activation on endothelial surfaces (PMID:19625716; PMID:39841007). Cell-based assays confirm impaired protein C and TAFI activation for selected mutants, consistent with dual defects in coagulation and complement regulation.

No studies to date have refuted the THBD–aHUS association. Variants of uncertain significance in THBD have been reported in other thrombotic or bleeding contexts, but only the complement-regulatory defects align with the aHUS phenotype. Large exome-wide screens confirm enrichment of rare THBD alleles in aHUS compared to controls.

Integrating genetic and functional data, THBD mutations meet criteria for a definitive gene–disease relationship with aHUS. THBD-related aHUS cases benefit from early complement-targeted therapy, including eculizumab. Key take-home: Genetic testing of THBD should be included in aHUS panels to guide timely diagnosis and personalized complement inhibition.

References

• The New England Journal of Medicine • 2009 • Thrombomodulin mutations in atypical hemolytic-uremic syndrome. PMID:19625716
• Clinical journal of the American Society of Nephrology • 2010 • Relative role of genetic complement abnormalities in sporadic and familial aHUS and their impact on clinical phenotype. PMID:20595690
• Case reports in nephrology and dialysis • 2016 • Nephrotic-Range Proteinuria and Peripheral Edema in a Child: Not Only Idiopathic Nephrotic Syndrome. PMID:27904864
• The American Journal of Case Reports • 2023 • Atypical Hemolytic Uremic Syndrome in a Pregnant Patient with a Thrombomodulin Gene Variant Treated with Plasma Exchange and Eculizumab. PMID:37120715
• Blood • 2025 • Functional assessment of genetic variants in thrombomodulin detected in patients with bleeding and thrombosis. PMID:39841007

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