Impact of fibrinogen carbamylation on fibrin clot formation and stability

• DOI: 10.1160/th16-09-0704
• Publication Date: 2017-04-06T07:12:42Z
• Authors: Stéphane Jaisson; Philippe Gillery; Carsten Scavenius; Endy Spriet; Anne Nyhaug; Helen Roberts; Iain Chapple; Annelie Hellvard; Nicolas Delaleu; Piotr Mydel; Veronika Binder; Brith Bergum
• Keywords: 0301 basic medicine; CROSS-LINKING; LYSINE DONOR; Neutrophils; Protein Conformation; Polymerization; Structure-Activity Relationship; 03 medical and health sciences; Renal Dialysis; PROTEIN CARBAMYLATION; Humans; Renal Insufficiency; Blood Coagulation; Cyanates; Fibrinopeptide A; Fibrin; MOLECULAR-MECHANISMS; Protein Stability; Fibrinolysis; Thrombin; Fibrinogen; KIDNEY-DISEASE; CYANATE; RHEUMATOID-ARTHRITIS; 3. Good health; Chemotaxis, Leukocyte; Kinetics; fibrin structure; ANTIBODIES; carbamylation; Citrulline; CLINICAL-IMPLICATIONS; AUTOANTIBODIES; fibrinogen; Factor XIIIa; Protein Processing, Post-Translational; Coagulation and Fibrinolysis

Summary Carbamylation is a non-enzymatic post-translational modification induced upon exposure of free amino groups to urea-derived cyanate leading irreversible changes protein charge, structure and function. Levels carbamylated proteins increase significantly in chronic kidney disease albumin considered as an important biomarker indicating mortality risk. High plasma concentrations long half-life make fibrinogen prime target for carbamylation. As aggregation cross-linking fibrin monomers rely on lysine residues, it likely that carbamylation impacts processing. In this study we investigated levels from patients well the impact cleavage by thrombin, polymerisation vitro. conjunction, all these factors determine clot stability thus control biochemical mechanical properties. LC-MS/MS analyses revealed higher homocitrulline patient than isolated plasma. our vitro studies found although does not affect thrombin per se, alters kinetics impairs degradation. addition, clots had reduced fiber size porosity associated with decreased stability. Using mass spectroscopy, discovered N-terminally fibrinopeptide A was generated process acted strong neutrophil chemoattractant potentially mediating recruitment inflammatory cells sites fibrin(ogen) turnover. Taken together, seems play role aberrant formation might be involved haemostatic disorders diseases.