title: Novel heterozygous dysfibrinogenemia, Sumida (AαC472S), showed markedly impaired lateral aggregation of protofibrils and mildly lower functional fibrinogen levels.
abstract: BACKGROUND
  We encountered a 6-year-old girl with systemic lupus erythematosus. Although no bleeding or thrombotic tendency was detected, routine coagulation screening tests revealed slightly lower plasma fibrinogen levels, as determined by functional and antigenic measurements (functional/antigenic ratio=0.857), suggesting hypodysfibrinogenemia.
  
  
  METHODS
  DNA sequence and functional analyses were performed on purified plasma fibrinogen, and recombinant variant fibrinogen was synthesized in Chinese hamster ovary cells based on the results obtained.
  
  
  RESULTS
  DNA sequencing revealed a heterozygous AαC472S substitution (mature protein residue number) in the αC-domain. AαC472S fibrinogen indicated the presence of additional disulfide-bonded molecules, and markedly impaired lateral aggregation of protofibrils in spite of slightly lower functional plasma fibrinogen levels. Scanning electron microscopic observations showed a thin fiber fibrin clot, and t-PA and plasminogen-mediated clot lysis was similar to that of a normal control. Recombinant variant fibrinogen-producing cells demonstrated that destruction of the Aα442C-472C disulfide bond did not prevent the synthesis or secretion of fibrinogen, whereas the variant Aα chain of the secreted protein was degraded faster than that of the normal control.
  
  
  CONCLUSIONS
  Our results suggest that AαC472S fibrinogen may cause dysfibrinogenemia, but not hypofibrinogenemia. The destruction and steric hindrance of the αC-domain of variant fibrinogen led to the impaired lateral aggregation of protofibrils and t-PA and plasminogen-mediated fibrinolysis, as well as several previously reported variants located in the αC-domain, and demonstrated the presence of disulfide-bonded molecules.
authors.affiliation: Department of Clinical Laboratory Investigation, Graduate School of Medicine, Shinshu University, Matsumoto, Japan; Department of Laboratory Medicine, Shinshu University Hospital, Matsumoto, Japan.
authors.forename: Minami
authors.initials: M
authors.lastname: Ikeda
authors.affiliation: Department of Laboratory Medicine, Shinshu University Hospital, Matsumoto, Japan; Department of Laboratory Medicine, Graduate School of Medicine, Shinshu University, Matsumoto, Japan.
authors.forename: Shinpei
authors.initials: S
authors.lastname: Arai
authors.affiliation: Department of Laboratory Medicine, Shinshu University Hospital, Matsumoto, Japan; Department of Health and Medical Sciences, Graduate School of Medicine, Shinshu University, Matsumoto, Japan.
authors.forename: Saki
authors.initials: S
authors.lastname: Mukai
authors.affiliation: Department of Laboratory Medicine, Shinshu University Hospital, Matsumoto, Japan.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Takezawa
authors.affiliation: Department of Clinical Laboratory Investigation, Graduate School of Medicine, Shinshu University, Matsumoto, Japan; Department of Health and Medical Sciences, Graduate School of Medicine, Shinshu University, Matsumoto, Japan.
authors.forename: Fumiko
authors.initials: F
authors.lastname: Terasawa
authors.affiliation: Department of Clinical Laboratory Investigation, Graduate School of Medicine, Shinshu University, Matsumoto, Japan; Department of Health and Medical Sciences, Graduate School of Medicine, Shinshu University, Matsumoto, Japan. Electronic address: nobuoku@shinshu-u.ac.jp.
authors.forename: Nobuo
authors.initials: N
authors.lastname: Okumura
mesh_terms: D000347:Afibrinogenemia / Q000097:blood* / Q000235:genetics* / Q000473:pathology; D002648:Child; D005260:Female; D005340:Fibrinogen / Q000378:metabolism*; D006801:Humans
chemical_list: D005340:Fibrinogen
keywords: Clot lysis; Dysfibrinogenemia; Fibrin fiber; Fibrinogen; Lateral aggregation of protofibrils