Background: Citrullination is the post-translational conversion of arginine into citrulline in proteins. The reaction is catalyzed by peptidylarginine deiminase (PAD), of which five isoforms exist. Fibrinogen is a substrate for PAD2 and PAD4, and citrullinated fibrinogen (cFBG) has been detected in patients with inflammatory diseases. In purified systems, cFBG is known to inhibit the release of fibrinopeptide A (FPA) and B (FPB) and impairs fibrin polymerization. However, the effect of cFBG on fibrin structure and fibrinolysis in a plasma environment remains unclear. We hypothesized that citrullination of fibrinogen impairs fibrin properties. Methods: Fibrinogen was citrullinated by recombinant PAD2 and PAD4. The impact of cFBG on fibrin structure was investigated by turbidity measurements in fibrinogen-deficient plasma spiked with cFBG or native fibrinogen. Results: Citrullination of fibrinogen by PAD2 dose-dependently reduced the rate of fibrin polymerization, as well as the overall hemostasis potential of fibrin, the maximum velocity of fibrin formation, the fibrin mass/length ratio, and the lysis of fibrin clots. Conclusion: Citrullination of fibrinogen by PAD2 affects not only fibrin polymerization but also fibrin fiber properties, indicating that the fibrin network formed in the presence of cFBG may influence hemostasis. Our results suggest that citrullination of fibrinogen alters the composition of fibrin fibers which may lead to a looser fibrin network that is more susceptible to fibrinolysis and thereby affecting the hemostatic balance.

Additional Metadata
Keywords Citrullination, Fibrin fibers properties, Fibrin structure, Fibrinogen, Peptidylarginine deiminase
Persistent URL dx.doi.org/10.1016/j.cca.2019.10.033, hdl.handle.net/1765/122464
Journal Clinica Chimica Acta
Citation
Damiana, T. (Tyrillshall), Damgaard, D. (Dres), Sidelmann, J.J. (Johannes J.), Nielsen, C.H. (Claus H.), de Maat, M.P.M, Münster, A.-M.B. (Anna-Marie B.), & Palarasah, Y. (Yaseelan). (2020). Citrullination of fibrinogen by peptidylarginine deiminase 2 impairs fibrin clot structure. Clinica Chimica Acta, 501, 6–11. doi:10.1016/j.cca.2019.10.033