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

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.

This study aimed to evaluate plasma FXIII levels and F13A1/F13B genetic variants in patients with aHUS.

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.

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.

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.