No abstract available.
Afibrinogenemia*

OBJECTIVE: To detect and analyze coagulation related indexes and genotypes of a patient with congenital fibrinogen deficiency and his family members, and to investigate the possible molecular pathogenesis. METHODS: Four peripheral blood samples (proband and 3 family members) were collected and the prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT), fibrinogen (Fg), D-Dimer and eight coagulation factor indicators were detected. All exons and flanking sequences of the FGA, FGB, and FGG genes encoding the three peptide chains of fibrinogen were sequenced and analyzed by bioinformatics. RESULTS: Among the eight coagulation factors of the proband and the elder sister, F Ⅴ and F Ⅷ were slightly higher, TT was significantly prolonged, and Fg was significantly reduced. Sequencing results showed that c.901C>T heterozygous mutation existed in the FGG gene. Bioinformatics analysis showed that the mutation changed the original protein structure and reduced the number of hydrogen bonds. CONCLUSION The fibrinogen gamma chain c.901C>T heterozygous mutation is the main cause of congenital fibrinogen deficiency in this family. This mutation is reported for the first time at home and abroad.
Afibrinogenemia/genetics* ; Aged ; Fibrinogen/genetics* ; Heterozygote ; Humans ; Mutation ; Pedigree

As the most abundant component of coagulation system, fibrinogen not only takes part in clotting, but also works as one of acute phase proteins, which participates in many physiological and pathophysiological processes. Studies of fibrinogen abnormalities contribute to understand the molecular basis of disorders of fibrinogen protein function and metabolism, caused mainly by gene mutation, commonly associated with bleeding, thrombophilia, or both. Diseases affecting fibrinogen could be classified to the acquired or inherited disease. In this review, the research progress on the molecular basis, possible action mechanism of the hereditary fibrinogen abnormalities and its clinical research are summarized.
Afibrinogenemia ; genetics ; Blood Coagulation Disorders ; genetics ; Humans ; Mutation

Objective: To analyze the phenotype and genotype of two pedigrees with inherited fibrinogen (Fg) deficiency caused by two heterozygous mutations. We also preliminarily probed the molecular pathogenesis. Methods: The prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT) and plasma fibrinogen activity (Fg∶C) of all family members (nine people across three generations and three people across two generations) were measured by the clotting method. Fibrinogen antigen (Fg:Ag) was measured by immunoturbidimetry. Direct DNA sequencing was performed to analyze all exons, flanking sequences, and mutated sites of FGA, FGB, and FGG for all members. Thrombin-catalyzed fibrinogen polymerization was performed. ClustalX 2.1 software was used to analyze the conservatism of the mutated sites. MutationTaster, PolyPhen-2, PROVEAN, SIFT, and LRT online bioinformatics software were applied to predict pathogenicity. Swiss PDB Viewer 4.0.1 was used to analyze the changes in protein spatial structure and molecular forces before and after mutation. Results: The Fg∶C of two probands decreased (1.28 g/L and 0.98 g/L, respectively). The Fg∶Ag of proband 1 was in the normal range of 2.20 g/L, while it was decreased to 1.01 g/L in proband 2. Through genetic analysis, we identified a heterozygous missense mutation (c.293C>A; p.BβAla98Asp) in exon 2 of proband 1 and a heterozygous nonsense mutation (c.1418C>G; p.BβSer473*) in exon 8 of proband 2. The conservatism analysis revealed that Ala98 and Ser473 presented different conservative states among homologous species. Online bioinformatics software predicted that p.BβAla98Asp and p.BβSer473* were pathogenic. Protein models demonstrated that the p.BβAla98Asp mutation influenced hydrogen bonds between amino acids, and the p.BβSer473* mutation resulted in protein truncation. Conclusion: The dysfibrinogenemia of proband 1 and the hypofibrinogenemia of proband 2 appeared to be related to the p.BβAla98Asp heterozygous missense mutation and the p.BβSer473* heterozygous nonsense mutation, respectively. This is the first ever report of these mutations.
Humans ; Afibrinogenemia/genetics* ; Codon, Nonsense ; Pedigree ; Phenotype ; Fibrinogen/genetics* ; Genotype

Congenital afibrinogenemia is a rare disorder that refers to a congenital lack of production of fibrinogen, a key component of the hemostatic system. Bleeding manifestations of congenital afibrinogenemia vary in severity from mild to catastrophic. This is a case report of splenic rupture occurred in an eight-year-old boy with congenital afibrinogenemia. A conservative treatment was carried out with perfusion of cryoprecipitate and purified virally inactivated fibrinogen concentrates and splenectomy was avoided.
Afibrinogenemia* ; Fibrinogen ; Hemorrhage ; Humans ; Male ; Perfusion ; Rupture* ; Spleen* ; Splenectomy ; Splenic Rupture

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening disease caused by uncontrolled proliferation of activated macrophage, and secreting high amounts of inflammatory cytokines which lead to multi-organ dysfunction syndrome. HLH patients often show different clinical characteristics during the disease was progressed, in which coagulopathy were the most common, including thrombocytopenia and hypofibrinogenemia, those are the major cause of death in patients, and the clinicians should increase awareness of the mechanisms, clinical characteristics, prognosis and treatment. In this review, the above problems are briefly summarized, to deepen understanding of the HLH related coagulation dysfunctions, and early identification and treatment to reduce mortality, so as to provide more opportunities for HLH patients to recieve subsequent treatment.
Afibrinogenemia ; Blood Coagulation Disorders/therapy* ; Humans ; Lymphohistiocytosis, Hemophagocytic/therapy* ; Prognosis ; Thrombocytopenia

OBJECTIVE: To study the clinical phenotype and gene mutation analysis of a hereditary abnormal fibrinogenemia family and explore its molecular pathogenesis. METHODS: The STA-R automatic hemagglutination analyzer to detect the proband and its family members (3 generations of 5 people) of prothrombin time(PT), activated partial thromboplastin time (APTT), thrombin time (TT), fibrinogen activity (Fg: C), D-dimer (D-D), fibrinogen and fibrin degradation products (FDPs), plasminogen activity (PLG: A); The plasma levels of Fg: C and fibrinogen (Fg: Ag) were measured by Clauss method and immunoturbidimetry respectively. All exons and flanking sequences of FGA, FGB and FGG genes of fibrinogen were amplified by PCR, and the PCR products were purified and sequenced for gene analysis. The model was analyzed by Swiss software. RESULTS: The PT and APTT of the proband, her mother and sister were slightly prolonged, TT was significantly extend, Fg: C decreased significantly, Fg: Ag, PLG: A, D-D and FDPs are within the normal range; Her brother and daughter of the results are normal. Genetic analysis showed that g.7476 G>A heterozygous missense mutation in exon 8 of FGG gene resulted in mutations in arginine at position 275 of fibrinogen gamma D domain to histidine (Arg275His). Her mother and sister have the same Arg275His heterozygous mutation, brother and daughter for the normal wild type. CONCLUSION The heterozygous missense mutation of FGG gene Arg275His in patients with hereditary dysfibrinogenemia is associated with a decrease in plasma fibrinogen activity.
Afibrinogenemia ; genetics ; DNA Mutational Analysis ; Female ; Fibrinogen ; genetics ; Fibrinogens, Abnormal ; genetics ; Humans ; Male ; Mutation ; Pedigree

OBJECTIVE: To analyze the phenotype and genotype of a pedigree affected with congenital dysfibrinogenemia. METHODS: Liver and kidney functions of the proband and her relatives were determined. Coagulation tests including prothrombin time (PT), activated partial thromboplastin time (APTT) and thrombin time(TT), fibrin(ogen) degradation products (FDPs), D-dimer(D-D) and the calibration experiment of protamine sulfate of against plasma TT were detected in the proband and her predigree members. The activity and antigen of fibrinogen (Fg) in plasma were measured by Clauss method and immunonephelometry method, respectively. All of the exons and exons-intron boundaries of the three fibrinogen genes (FGA, FGB and FGG) were subjected to PCR amplification and Sanger sequencing. Potential influence of the suspected mutations were analyzed with bioinformatics software including PolyPhen-2, SIFT and Mutation Taster. RESULTS: The proband had normal PT, APTT, FDPs, D-D and prolonged TT (31.8 s). The activity of fibrinogen (Fg) in plasma was significantly decreased but the antigen was normal. Genetic analysis revealed a heterozygous c.92G>A (p.Gly31Glu) mutation in exon 2 of the FGA gene. Family studies revealed that the mother carried the same mutation. Bioinformatic analysis suggested that the mutation may affect the function of Fg Protein. CONCLUSION The dysfibrinogenemia was probably caused by the novel Gly31Glu mutation of the FGA gene.
Afibrinogenemia ; congenital ; genetics ; DNA Mutational Analysis ; Female ; Fibrinogen ; genetics ; Humans ; Mutation ; Pedigree ; Phenotype

OBJECTIVETo explore the genetic basis for a Chinese pedigree affected with congenital hypofibrinogenamia.

METHODSPeripheral blood samples were collected from 9 members from the pedigree. Routine coagulation tests including activated partial thromboplastin time (APTT), thrombin time (TT), the prothrombin time (PT) were carried out. The activity of fibrinogen (Fg: C) was measured using Clauss method, and fibrinogen antigen (Fg: Ag) was measured with immunoturbidimetry. All exons and exon-intron boundaries of the fibrinogen Aα, Bβ and γ chain genes were amplified using PCR, which was followed by direct sequencing. Suspected mutation was confirmed by reverse sequencing. The mutant fibrinogen was analyzed with Swiss-PdbViewer.

RESULTSThe proband showed prolonged APTT, PT and TT. Her functional fibrinogen (Fg: C) and antigen fibrinogen (Fg: Ag) levels were reduced to 0.69 g/L and 0.72 g/L, respectively. Her mother and grandmother also had a low levels of fibrinogen, which were 0.99 g/L and 0.83 g/L for Fg: C, 1.02 g/L and 0.87 g/L for Fg: Ag, respectively. The results of other members from the pedigree were all within the normal range. Genetic analysis reveled a heterozygous G>T mutation at nucleotide 7590 in exon 8 of γ gene in the proband, which was predicted to be a novel Ser313Ile mutation. The mutation was also found in her mother and grandmother. Model analysis showed that the Ser313Ile mutation disturbed the hydrogen bonds between Ser313, Asn319 and Asp320. Moreover, the mutation also altered the mutual electrostatic force and affected the folding and instability of the mutant fibrinogen.

CONCLUSIONThe heterozygous Ser313Ile mutation probably underlies the hypofibrinogenemia in this pedigree.

Adult ; Afibrinogenemia ; genetics ; Female ; Fibrinogen ; chemistry ; genetics ; Heterozygote ; Humans ; Male ; Middle Aged ; Mutation ; Pedigree

OBJECTIVE: To explore the genetic basis for a Chinese pedigree affected with inherited afibrinogenemia. METHODS: For the proband and his family members, prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT), Fibrin(ogen) degradation products (FDPs), D-dimer (D-D), plasminogen activity (PLG:A) and the TT mixed experiment with protamine sulfate were determined with a STAGO-R automatic coagulation analyzer. The activity and antigen of fibrinogen (Fg) in plasma were measured with the Clauss method and immunonephelometry method, respectively. All exons and flanking regions of the fibrinogen genes (FGA, FGB and FGG) were amplified by PCR and directly sequenced. Human Splicing Finder software was used to predict and score the change of splicing site caused by the mutation. RESULTS: The proband showed normal FDPs and D-D but significantly prolonged TT, PT and APTT. The activity and antigen of fibrinogen in plasma were significantly decreased (<0.1 g/L). His young sister and parents showed slightly prolonged TT (18.20-18.50 s) and decreased fibrinogen activity (1.27-1.54 g/L) and fibrinogen antigenic content (1.34-1.56 g/L). Genetic testing revealed that the proband has carried homozygous IVS7-12A>G (g.4147A>G) mutations of the FGG gene, for which his parents and young sister were heterozygous. As predicted by Human Splicing Finder and Mutation Taster software, the variant may generate a new splicing site which can extend the sequence of exon 7 by 11 bp, with alteration of the coding sequence. PROVEAN suggested the variant to be deleterious. CONCLUSION The afibrinogenemia of the proband may be attributed to the FGG IVS7-12A>G variant, which was unreported previously.
Adult ; Afibrinogenemia/genetics* ; Female ; Fibrinogen/genetics* ; Heterozygote ; Humans ; Male ; Mutation ; Pedigree