Dysfibrinogenemia is a coagulation disorder caused by a variety of structural abnormalities in the fibrinogen molecule that result in fibrinogen function. The molecular basis of hypodysfibrinogenemia was investigated in a 66-year-old woman with peripheral artery obstructive disease and in her family members. Plasma level of functional fibrinogen determined using the Clauss method was lower (75 mg/dL; normal, 140–460 mg/dL) than that measured with immunologic nephelometric assay (137 mg/dL; normal, 180–400 mg/dL). Similar results were also observed in two family members through two generations. DNA was extracted from whole blood, and the coding regions and intron/exon boundaries of gamma chain gene (FGG) were amplified. A novel (Fibrinogen Seoul) heterozygous FGG mutation (GCT->GAT, Ala341Asp) was identified in all three affected family members. Thrombin-catalyzed polymerization was found to be defective on the analysis of purified fibinogen from the propositus. Molecular modeling also showed a conformational change of fibrinogen structure.
McDonagh J. Dysfibrinogenemia and other disorders of fibrinogen structure or function. In Colman R, Hirsh J, Marder V, Clowes A, George J, eds. Hemostasis and Thrombosis, 4th ed.Philadelphia: Lippincott Williams & Wilkins; 2001:855-855.
2.
Matsuda M. Structure and function of fibrinogen inferred from hereditary dysfibrinogens. Int J Hematol2000;72: 436-436.
3.
Yamazumi K, Doolittle RF. Photoaffinity labeling of the primary fibrin polymerization site: Localization of the label to gamma-chain Tyr-363. Proc Natl Acad Sci USA1992;89:2893-2893.
4.
Shimizu A, Nagel GM, Doolittle RF. Photoaffinity labeling of the primary fibrin polymerization site: Isolation and characterization of a labeled cyanogens bromide fragment corresponding to γ-cain residues 337-379. Proc Natl Acad Sci USA1992;89:2888-2888.
5.
Hanss M, Biot F. A database for human fibrinogen variants. Ann NY Acad Sci2001;936:89-89.
6.
Haverkate F, Samama M. Familial dysfibrinogenemia and thrombophilia: Report on a study of the SCC Subcommittee on fibrinogen. Thromb Haemost1995;73: 151-151.
7.
Gralnick HR, Givelber HM, Shainoff JR, et al. Fibrinogen Bethesda: A congenital dysfibrinogenemia with delayed fibrinopeptide release. J Clin Invest1971;50:1819-1819.
8.
Mathonnet F, Guillon L, Detruit H, et al. Fibrinogen Poissy II (γN361K): A novel dysfibrinogenemia associated with defective polymerization and peptide B release. Blood Coagul Fibrinol2003;14:293-293.
9.
Lefebvre P, Valasco PT, Dear A, et al. Severe hypodysfibrinogenemia in compund heterozygotes of the fibrinogen A αIVS4+ 1G>T mutation and an AαGln328 truncation (fibrinogen Keokuk). Blood2004;103:2571-2571.
10.
Baker D, Sali A. Protein structure prediction and structural genomics. Science2001;294:93-93.
11.
Cote HCF, Lord ST, Pratt KP. γ chain dysfibrinogenemias: Molecular structure-function relationships of naturally occurring mutations in the γ chain of human fibrinogen. Blood1988;92:2195-2195.
12.
Pratt KP, Cote HCF, Chung DW, et al. The primary fibrin polymerization pocket: Three-dimensional structure of a 30-kDa C-terminal γ chain fragment complexed with the peptide Gly-Pro-Arg-Pro. Proc Natl Acad Aci USA1997;94: 7176-7176.
13.
Reber P, Furlan M, Rupp C, et al. Characterization of fibrinogen Milano I: Amino acid exchange γ330Asp > Val impairs fibrin polymerization. Blood1986;67:1751-1751.
14.
Terukina S, Yamazumi K, Okamoto K, et al. Fibrinogen Kyoto III: A congenital dysfibrinogen with a γ aspartic acid-330 to tyrosine substitution manifesting impaired fibrin monomer polymerization. Blood1989;74:2681-2681.
15.
Steinmann C, Reber P, Jungo M, et al. Fibrinogen Bern I: Substitution γ 337 Asn > Lys is responsible for defective fibrin monomer polymerization. Blood1993;82:2104-2104.
16.
Steinmann BC, Bogil C, Jungo M, et al. A new substitution, γ 358 Ser-> Cys, in Fibrinogen Milano VII causes defective fibrin polymerization. Blood1994;84:1874-1874.
17.
Okumura N, Furihata K, Terasawa F, et al. Fibrinogen Matsumoto I: A γ364Asp-> His (GAT->CAT) substitution associated with defective fibrin polymerization. Thromb Haemost1996;75:887-887.
18.
Bentolila S, Samama MM, Conard J, et al. Association of dysfibrinogenemia and thrombosis: Apropos of a family (Fibrinogen Melun) and review of the literature. Ann Med Interne (Paris)1995;146:575-575.
19.
Yoshida N, Hirata H, Morigami Y, et al. Characterization of an abnormal fibrinogen Osaka V with the replacement of γ-Arginine 375 by Glycine. J Biol Chem1992;267:2753-2753.
20.
Cunningham MT, Brandt JT, Laposata M, et al. Laboratory diagnosis of dysfibrinogenemia. Arch Pathol Lab Med2002;126:499-499.
21.
Hamano A, Mimuro J, Aoshima M, et al. Thrombophilic dysfibrinogen Tokyo V with the amino acid substitution of γAla327Thr: Formation of fragile but fibrinolysis-resistant fibrin clots and its relevance to arterial thromboembolism. Blood2004;103:3045-3045.
22.
Nieuwenhuizen W, Vermond A, Voskuilen M, et al. Identification of a site in fibrin(ogen) which is involved in the acceleration of plasminogen activation by tissue-type plasminogen activator. Biochim Biophys Acta1983;748:86-86.
23.
Yonegawa S, Voskuilen M, Nieuwenhuizen W. Localization in the fibrinogen γ chain of a new site that is involved in the acceleration of by tissue-type plasminogen activator catalyzed activation of plasminogen. Biochem J1992;283: 187-187.
24.
Gabriel DA, Muga K, Boothroyd EM. The effect of fibrin structure on fibrinolysis. J Biol Chem1992;267:24259-24259.
