Thrombotic microangiopathy without renal involvement: two novel mutations in complement-regulator genes.

Area of Science:

• Hematology
• Genetics
• Immunology

Background:

• Thrombotic microangiopathies (TMAs) present diagnostic challenges due to overlapping clinical, laboratory, and genetic features.
• Differentiating between TMAs like thrombotic thrombocytopenic purpura (TTP) and atypical hemolytic uremic syndrome (aHUS) can be difficult.

Observation:

• A 49-year-old woman presented with acute TMA, neurological symptoms, and no renal impairment.
• Initial assessment showed normal ADAMTS-13 levels, a key differentiator for TTP, but elevated von Willebrand factor (VWF) antigen and ultra-large VWF multimers.

Findings:

• Genetic analysis revealed two novel heterozygous mutations: one in the complement factor I (CFI) gene (c.805G>A, p.G269S) and another in the thrombomodulin (THBD) gene (c.1103C>T, p.P368L).
• In vitro studies demonstrated that the THBD mutation reduced the generation of activated thrombin-activatable fibrinolysis inhibitor (TAFIa), contributing to a prothrombotic state.
• The CFI mutation likely promotes complement-mediated endothelial activation, indicating a role for the complement system in TMA pathogenesis.

Implications:

• This case highlights the complement system's potential role in TMAs, even in the absence of renal involvement and with normal ADAMTS-13 levels.
• Identifying novel mutations in complement-regulator genes like CFI and THBD expands our understanding of TMA pathophysiology.
• These findings may lead to improved diagnostic strategies and targeted therapies for TMAs.