title: [Functional study of abnormal fibrinogen caused by Arg275His mutation in fibrinogen γ chain].
abstract: OBJECTIVE
  To investigate the function of abnormal fibrinogen in two inherited dysfibrinogenemia pedigrees.
  
  
  METHODS
  Routine coagulation tests were conducted in the probands and related family members. The antigen and activity levels of fibrinogen were detected by immunoturbidimetry assay and clauss assay, respectively. All the exons and exon-intron boundaries of the three fibrinogen genes and antithrombin gene（AT3）were analyzed by PCR amplification and direct sequencing. Routine thrombelastography (TEG) test and functional fibrinogen TEG test were both used to make a comprehensive evaluation of coagulation status and functional fibrinogen level in patients. The molecular weights of the three peptides from fibrinogen were measured by Western blot. The function of abnormal fibrinogen was assessed by fibrinogen dynamic polymerization and fibrinolysis velocity.
  
  
  RESULTS
  The coagulation routine tests were normal in two probands except for prolonged thrombin time (TT) and reptilase time (RT), as well as reduced activity levels of 0.5 g/L and 0.6 g/L fibrinogen, respectively. The antigen levels of fibrinogen were 2.32 g/L and 2.66 g/L in two probands, which were in the normal reference range. The genotype analysis showed that Arg275His in fibrinogen γ chain (γ Arg275His) existed in both probands and patients in these two pedigrees. Meanwhile, proband B's grandfather and aunt also carried heterozygote g.5876T>C (Ser116Pro) mutation in AT3. The results of routine TEG test demonstrated that the α values of proband B and his father were close to and lower than the lower limit of reference range, respectively, while the MA values were normal in both of them. However, functional fibrinogen TEG test revealed obviously reduced MA value. All the probands and patients demonstrated prolonged lag-off time and reduced peak value in fibrinogen dynamic polymerization tests. Meanwhile, most of fibrin formed from the patients' plasma could not be dissolved completely by plasminogen (PLG) and urokinase-typeplasminogenactivator (u-PA) at a certain time.
  
  
  CONCLUSIONS
  We first reported cases of inherited dysgibrinogenemia associated with inherited AT deficiency. γArg275His mutation caused the abnormal fibrinogen in terms of fibrin mono polymerization and possibly in fibrinolysis. Combined use of routine TEG test and functional fibrinogen TEG test with comprehensive analyses of the parameters in both tests could better evaluate the level of functional fibrinogen and predict the risk of hemorrhage and thrombosis in patients with inherited dysfibrinogenemia.
authors.affiliation: Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Jing-yi
authors.initials: JY
authors.lastname: Zhou
authors.forename: Xue-feng
authors.initials: XF
authors.lastname: Wang
authors.forename: Qiu-lan
authors.initials: QL
authors.lastname: Ding
authors.forename: Guan-qun
authors.initials: GQ
authors.lastname: Xu
authors.forename: Li-wei
authors.initials: LW
authors.lastname: Zhang
authors.forename: Jing
authors.initials: J
authors.lastname: Dai
authors.forename: Ye-ling
authors.initials: YL
authors.lastname: Lu
authors.forename: Xiao-dong
authors.initials: XD
authors.lastname: Xi
authors.forename: Hong-li
authors.initials: HL
authors.lastname: Wang
mesh_terms: D000328:Adult; D000347:Afibrinogenemia / Q000235:genetics*; D002648:Child; D005260:Female; D005340:Fibrinogen / Q000235:genetics*; D015241:Fibrinogens, Abnormal / Q000235:genetics / Q000502:physiology*; D005838:Genotype; D006801:Humans; D008297:Male; D009154:Mutation; D010375:Pedigree; D010641:Phenotype
chemical_list: D015241:Fibrinogens, Abnormal; C027539:fibrinopeptides gamma; D005340:Fibrinogen