Proteinase 3 (PR3) specific fibrinopeptide Aα-Val541 in alpha-1 antitrypsin deficiency (AATD) patients receiving a liver transplantation

AAT is an important inhibitor of neutrophil elastase, but also of PR3. AATD is a hereditary condition that makes patients susceptible to early onset emphysema and liver cirrhosis. Homozygous carriage of the Z allele (PI ZZ) results in severe AAT deficiency, leading to unopposed activity of PR3 (Strnad et al. NEJM. 2020;382:1443-1455). Aα-Val⁵⁴¹, a biomarker of PR3 activity and indirect marker of AAT activity, is a neoepitope generated by the cleavage of fibrinogen by PR3. It’s levels are higher in AATD disease, and reduced following suppletion by intravenous AAT augmentation therapy (Schouten I.G.M. et al. Int J Mol Sci. 2021;22). In AATD patients, AAT plasma levels normalize after liver transplantation (LT), assuming that the donor has a wild-type genotype. It is unknown whether Aα-Val⁵⁴¹ levels decrease after LT in these patients. Here, we hypothesized that LT in Pi ZZ AATD patients reduces plasma AαVal⁵⁴¹ levels. A specific Europium-based immunoassay was used to measure AαVal541 in plasma. Figure 1 shows the plasma fibrinopeptide Aα-Val⁵⁴¹ levels for five Pi ZZ patients before and after transplantation. The median level was 344.9 nM before LT and 50.6 nM after LT. Aα-Val⁵⁴¹ levels were substantially reduced after LT in each patient. These results further support the specificity and relevance of Aα-Val541 as a biomarker of PR3 activity and an indirect marker of AAT activity.