title: The disulfide isomerase ERp57 is required for fibrin deposition in vivo.
abstract: BACKGROUND
  ERp57 is required for platelet function; however, whether ERp57 contributes to fibrin generation is unknown.
  
  
  RESULTS
  Using an inhibitory anti-ERp57 antibody (mAb1), Pf4-Cre/ERp57(fl/fl) mice, Tie2-Cre/ERp57(fl/fl) mice, and mutants of ERp57, we analyzed the function of ERp57 in laser-induced thrombosis. Fibrin deposition was decreased in Pf4-Cre/ERp57(fl/fl) mice, consistent with a role for platelet ERp57 in fibrin generation. Fibrin deposition was further decreased with infusion of mAb1 and in Tie2-Cre/ERp57(fl/fl) mice, consistent with endothelial cells also contributing to fibrin deposition. Infusion of eptibifatide inhibited platelet and fibrin deposition, confirming a role for platelets in fibrin deposition. Infusion of recombinant ERp57 corrected the defect in fibrin deposition but not platelet accumulation, suggesting a direct effect of ERp57 on coagulation. mAb1 inhibited thrombin generation in vitro, consistent with a requirement for ERp57 in coagulation. Platelet accumulation was decreased to similar extents in Pf4-Cre/ERp57(fl/fl) mice, Tie2-Cre/ERp57(fl/fl) mice and normal mice infused with mAb1. Infusion of completely inactivated ERp57 or ERp57 with a non-functional second active site inhibited fibrin deposition and platelet accumulation, indicating that the isomerase activity of the second active site is required for these processes.
  
  
  CONCLUSIONS
  ERp57 regulates thrombosis via multiple targets.
authors.affiliation: The Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, Jiangsu Institute of Hematology, Soochow University, Suzhou, China.
authors.forename: J
authors.initials: J
authors.lastname: Zhou
authors.forename: Y
authors.initials: Y
authors.lastname: Wu
authors.forename: L
authors.initials: L
authors.lastname: Wang
authors.forename: L
authors.initials: L
authors.lastname: Rauova
authors.forename: V M
authors.initials: VM
authors.lastname: Hayes
authors.forename: M
authors.initials: M
authors.lastname: Poncz
authors.forename: D W
authors.initials: DW
authors.lastname: Essex
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001777:Blood Coagulation; D001792:Blood Platelets / Q000201:enzymology; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000201:enzymology; D005337:Fibrin / Q000378:metabolism*; D005343:Fibrinolytic Agents / Q000494:pharmacology; D053685:Laser Therapy; D018345:Mice, Knockout; D010974:Platelet Aggregation; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D019704:Protein Disulfide-Isomerases / Q000172:deficiency / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction; D013927:Thrombosis / Q000097:blood / Q000201:enzymology* / Q000209:etiology / Q000235:genetics / Q000517:prevention & control; D013997:Time Factors
chemical_list: D000911:Antibodies, Monoclonal; D005343:Fibrinolytic Agents; D010975:Platelet Aggregation Inhibitors; D005337:Fibrin; C513195:Pdia3 protein, mouse; D019704:Protein Disulfide-Isomerases
keywords: blood coagulation; blood platelets; fibrin; platelet aggregation; protein disulfide isomerases