Increased N ‐terminal cleavage of alpha‐2‐antiplasmin in patients with liver cirrhosis

Summary Background The activity of alpha‐2‐antiplasmin (α2 AP ), the main fibrinolytic inhibitor, is modified by N ‐ and C ‐terminal proteolytic cleavages. C ‐terminal cleavage converts plasminogen‐binding α2 AP ( PB ‐α2 AP ) into a non‐plasminogen‐binding derivative. N ‐terminal cleavage by antiplasmin‐cleaving enzyme ( APCE ), a soluble, circulating derivative of fibroblast activation protein ( FAP ), turns native Met‐α2 AP into Asn‐α2 AP , which is more quickly crosslinked into fibrin. Objectives We developed two novel enzyme‐linked immunosorbent assays ( ELISA s) to determine the N ‐terminal variation of α2 AP to test the hypothesis that liver cirrhosis, characterized by increased expression of FAP / APCE , results in increased N ‐terminal cleavage of α2 AP . Patients/Methods α2 AP and FAP / APCE antigen levels were measured in the plasma samples of 75 patients with cirrhosis with different severities and 30 healthy control individuals. The percentage of N ‐terminal cleavage of α2 AP was calculated. Results Compared with levels (median [interquartile range]) in control individuals, total PB ‐α2 AP levels and Met‐ PB ‐α2 AP levels were reduced in cirrhosis patients (27.3 [21.4–41.3] μg mL −1 vs. 56.2 [49.6–62.8] μg mL −1 , P  <   0.001, and 2.7 [1.7–5.5] μg mL −1 vs. 12.1 [11.0–15.3] μg mL −1 , P  <   0.001, respectively). Interestingly, the percentage of N ‐terminal cleavage was increased in the patients (87.8 [85.0–91.6]% vs. 77.2 [72.2–79.8]% in controls, P  <   0.001), as well as the plasma FAP / APCE levels (166 [60–550] ng mL −1 in patients vs. 107 [67–157] ng mL −1 in controls, P  <   0.001). Additionally, all variables significantly correlated with the severity of disease. Conclusions Using our novel ELISA s we found increased N ‐terminal cleavage of α2 AP in liver cirrhosis patients, which correlated with the severity of disease and is likely to have reflected the increased FAP / APCE levels in these patients.