The level of circulating fibroblast activation protein correlates with incorporation of alpha-2-antiplasmin into the fibrin clot

Introduction: Circulating fibroblast activation protein (cFAP) cleaves alpha-2-antiplasmin (α2AP) N-terminally, converting native Met-α2AP into Asn-α2AP. Previous studies in purified model systems showed that Asn-α2AP is faster incorporated into a fibrin clot by activated factor XIII than Met-α2AP, making the fibrin clot more resistant to fibrinolysis. The objective was to investigate whether cFAP level in plasma associated with the amount of α2AP incorporation into fibrin in a new plasma-based clotting assay. Materials and methods: We included 118 arterial thrombotic patients of the ATTAC study; 59 patients with diabetes mellitus (DM) and 59 age- and sex-matched patients without DM, additionally matched for type of arterial thrombosis (myocardial infarction or ischemic stroke). The percentage of α2AP incorporation was assessed with an α2AP incorporation assay mimicking physiological conditions with endogenous α2AP and physiological cFAP variation. cFAP levels were measured previously by ELISA. Results: We found that on average 32.3 ± 5.1% of α2AP was incorporated into fibrin, with slightly more α2AP incorporation in individuals with DM (33.3 ± 4.9%) compared to individuals without DM (31.4 ± 5.2%, p = 0.047), which validates our assay according to literature. The main finding of this study was that cFAP level positively correlated with α2AP incorporation into the fibrin clot (r = 0.296, p = 0.001). Conclusion: The findings of a positive association between cFAP level and α2AP incorporation in a plasma-based system under physiological conditions support the hypothesis that N-terminal cleavage of α2AP leads to faster and more incorporation of α2AP into the fibrin clot, which may be clinically relevant.

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