Beyond complement: comprehensive assessment of factor XIII plasma dynamics and genetics in atypical hemolytic uremic syndrome.

BACKGROUND: Atypical hemolytic uremic syndrome (aHUS) is a distinct form of thrombotic microangiopathy characterized by formation of fibrin-rich thrombi. Factor XIII (FXIII), a key fibrin-stabilizing enzyme, may therefore represent an unexplored contributor to the pathophysiology of aHUS, and a comprehensive evaluation of its plasma dynamics and genetic background is lacking. OBJECTIVES: This study aimed to evaluate plasma FXIII levels and F13A1/F13B genetic variants in patients with aHUS. METHODS: The cohort comprised 102 patients with aHUS and 73 healthy controls. FXIII activity was measured by ammonia release assay, FXIII antigen levels by ELISA, and F13A1/F13B variants by high-resolution melting analysis with confirmatory Sanger sequencing. RESULTS: FXIII activity was decreased in aHUS patients during the acute phase (median 72.8%; IQR, 52.8%-121.0%) versus those in remission (123.1%; IQR, 97.9%-156.3%; P < .0001) and healthy controls (136.4%; IQR, 108.5%-151.5%; P < .0001). FXIII-A2B2 levels paralleled FXIII activity. Free FXIII-B level was elevated in patients in remission (14.7 mg/L; IQR, 11.9-21.2) versus those in acute phase (12.7 mg/L; IQR, 10.1-16.6; P = .02) and healthy controls (9.4 mg/L; IQR, 8.7-10.9; P < .0001). Genetic analysis identified 6 common and 4 rare nonsynonymous F13A1/F13B variants, with allele and genotype frequencies comparable to European individuals in the 1000Genomes Project. Apart from F13B variant Tyr100Ter, which was associated with reduced FXIII-B, the rare variants did not show a clear impact on FXIII plasma levels. CONCLUSION: This comprehensive genetic and plasma study of FXIII in aHUS argues against it having a causal role, while the remission-associated increase in free FXIII-B supports it as a promising biomarker candidate for this rare but severe disease.