Blood protein may help track disease activity in people with aHUS
Study finds distinct factor XIII patterns during acute episodes and remission
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Factor XIII (FXIII) activity was lower in samples collected during acute episodes of atypical hemolytic uremic syndrome (aHUS), while levels of one of its subunits, FXIII-B, were higher in samples collected during remission, suggesting FXIII-B may serve as a marker of disease activity.
“Free FXIII-B emerges as a promising biomarker candidate in this rare but severe disease,” researchers wrote in “Beyond Complement: Comprehensive Assessment of Factor XIII Plasma Dynamics and Genetics in Atypical Haemolytic Uraemic Syndrome,” which was published in Research and Practice in Thrombosis and Haemostasis.
Factor XIII patterns differ between active aHUS and remission
In thrombotic microangiopathy, blood clots form in small blood vessels. This can damage organs, especially the kidneys. In aHUS, these blood clots are rich in fibrin, a protein that helps blood clots form and become stable. Because FXIII is an enzyme that helps stabilize fibrin clots, the researchers wanted to find out whether FXIII plays a role in aHUS.
FXIII circulates in the blood as a complex made of two types of subunits, called FXIII-A and FXIII-B. Two copies of each subunit join to form the FXIII-A2B2 complex. Two genes, F13A1 and F13B, provide the instructions for producing the FXIII-A and FXIII-B subunits. Once FXIII is activated, it strengthens connections between strands of fibrin, making blood clots more resistant to breakdown.
The main goal of this study was to measure FXIII and determine whether variants in the genes that encode its subunits could explain any changes. The researchers included 102 patients with a diagnosis of aHUS and compared them with 73 healthy individuals. They compared samples collected during acute aHUS, when the disease is active and symptoms can occur, with samples collected during hematologic remission. The two groups consisted mostly of different patients; only four patients had samples available from both phases.
The median FXIII activity was significantly lower during acute episodes of aHUS (72.8%) compared with 123.1% during remission and 136.4% in healthy individuals. Levels of the complete FXIII-A2B2 complex showed a similar pattern, with lower levels during acute aHUS than during remission or in healthy controls.
The pattern was different for FXIII-B. During remission, levels of both total FXIII-B and free FXIII-B were higher than during acute episodes. Free FXIII-B means the B subunit was circulating separately from the FXIII-A2B2 complex. Free FXIII-B was 14.7 mg/L during remission, compared with 12.7 mg/L during acute episodes and 9.4 mg/L in healthy controls.
Fibrinogen, a protein that the body uses to produce fibrin, remained within the normal reference range and did not differ significantly between the groups. However, its levels were positively related to several FXIII measurements. This means that patients with higher fibrinogen tended, overall, to have higher FXIII measurements as well.
D-dimer and gene variants add context to FXIII findings
The researchers also measured D-dimer, which is produced when blood clots are broken down. D-dimer was higher in patients than in healthy individuals, both during acute aHUS and during remission. It was particularly high during acute aHUS, consistent with increased breakdown of fibrin-rich blood clots.
Six relatively common variants, meaning naturally occurring differences in the DNA sequence, were identified in the F13A1 and F13B genes. Their frequencies were similar to those seen in healthy European populations included in the 1000 Genomes Project. This made it unlikely that these common variants were specifically linked to aHUS.
Four rare variants were identified — two in F13A1 and two in F13B. However, there was no evidence that they were more common in aHUS or that they changed FXIII levels. One exception was Tyr100Ter, which introduces a premature stop signal in the F13B gene, potentially disrupting production of the full-length FXIII-B protein. It was found in one adolescent girl with aHUS, her affected brother, and their healthy father, all in one copy of the gene.
Tyr100Ter was linked with lower FXIII-B levels, suggesting that this particular variant can affect production of this subunit. However, the fact that the healthy father also carried the variant is important. It shows that carrying it alone does not necessarily cause aHUS.
The study provides a clearer picture of how FXIII measurements differ between acute aHUS and remission. Compared with healthy controls, acute aHUS samples had lower FXIII activity and FXIII-A2B2 levels, while free FXIII-B levels were higher. In remission samples, FXIII activity and FXIII-A2B2 levels were higher than in acute aHUS, and free FXIII-B levels were higher still.
“The remission-associated increase in FXIII-B, whether reflecting an underlying predisposing factor or a consequence of the preceding microangiopathic event, highlights this protein as a promising biomarker candidate and opens a clinically meaningful direction for future research, requiring further validation,” the researchers concluded.
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