Abstract
Coagulation factor XIII (FXIII) is a plasma-circulating heterotetrameric pro-transglutaminase complex that is composed of two catalytic FXIII-A and two protective/regulatory FXIII-B subunits. FXIII acts by forming covalent cross-links within a preformed fibrin clots to prevent its premature fibrinolysis. The FXIII-A subunit is known to have pleiotropic roles outside coagulation, but the FXIII-B subunit is a relatively unexplored entity, both structurally as well as functionally. Its discovered roles so far are limited to that of the carrier/regulatory protein of its partner FXIII-A subunit. In the present study, we have explored the co-presence of protein excipients in commercial FXIII plasma concentrate FibrogamminP by combination of protein purification and mass spectrometry-based verification. Complement factor H was one of the co-excipients observed in this analysis. This was followed by performing pull down assays from plasma in order to detect the putative novel interacting partners for the FXIII-B subunit. Complement system proteins, like complement C3 and complement C1q, were amongst the proteins that were pulled down. The only protein that was observed in both experimental set ups was alpha-2-macroglobulin, which might therefore be a putative interacting partner of the FXIII/FXIII-B subunit. Future functional investigations will be needed to understand the physiological significance of this association.
Highlights
Coagulation Factor XIII (FXIII) is plasma-circulating pro-transglutaminase acting at the terminal phase of the coagulation pathway, which is responsible for cross-linking pre-formed fibrin polymers within it and to anti-fibrinolytic inhibitors to prevent its premature fibrinolysis
Amongst the two FXIII subunits, the FXIII-B2 dimeric subunit has a unique filamentous structure, with each of its monomers consisting of 10 sushi domains ( known as complement control protein (CCP) modules) that are rich in cysteine bonds and bear specific structure with beta-sandwich arrangement [6,14,15,16]
While we found that fibrinogen-α, -β, -γ chains, complement C1q, and complement C3 in the pull downs for both FXIII-B, as well as FXIII-B exposed to FXIII-A, none of the pull downs detected complement factor H (CFH)
Summary
Coagulation Factor XIII (FXIII) is plasma-circulating pro-transglutaminase acting at the terminal phase of the coagulation pathway, which is responsible for cross-linking pre-formed fibrin polymers within it and to anti-fibrinolytic inhibitors to prevent its premature fibrinolysis. The two major types of FXIII concentrates that are administered to the patients include virus inactivated fresh frozen plasma (FFP) derived from healthy donors; or the commercially available drug Cortifact (US)/FibrogamminP (Europe & Asia), marketed by CSL Behring [9,11]. These plasma concentrates are suitable for both FXIII-A and FXIII-B subunit deficient states. When compared to all the detected proteins, only alpha-2-macroglobulin was a common denominator detected in the pull-down assay as well as an excipient in FibrogamminP, which indicates that it might be the true interacting partner of the FXIII/FXIII-B subunit
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