Download PDF
Thromb Haemost 2000; 84(02): 263-270
DOI: 10.1055/s-0037-1614006
Review Article
Schattauer GmbH

Fibrinogen Caracas V, an Abnormal Fibrinogen with an Aα 532 Ser→Cys Substitution Associated with Thrombosis

Rita Marchi
1   From Centro de Medicina Experimental, Laboratorio de Fisiopatología, Instituto Venezolano de Investigaciones Científicas, IVIC, Caracas, Venezuela, The Netherlands
,
Ulf Lundberg
1   From Centro de Medicina Experimental, Laboratorio de Fisiopatología, Instituto Venezolano de Investigaciones Científicas, IVIC, Caracas, Venezuela, The Netherlands
,
Jos Grimbergen
2   Gaubius Laboratory TNO, Leiden, The Netherlands
,
Jaap Koopman
3   Pharming, Leiden, The Netherlands
,
Argimiro Torres
4   Banco Municipal de Sangre del Distrito Federal, Caracas, Venezuela, The Netherlands
,
Norma B. de Bosch
4   Banco Municipal de Sangre del Distrito Federal, Caracas, Venezuela, The Netherlands
,
Frits Haverkate
1   From Centro de Medicina Experimental, Laboratorio de Fisiopatología, Instituto Venezolano de Investigaciones Científicas, IVIC, Caracas, Venezuela, The Netherlands
2   Gaubius Laboratory TNO, Leiden, The Netherlands
,
Carmen Luisa Arocha Piñango
1   From Centro de Medicina Experimental, Laboratorio de Fisiopatología, Instituto Venezolano de Investigaciones Científicas, IVIC, Caracas, Venezuela, The Netherlands
› Author AffiliationsThis work was supported by Grants provided by the Consejo Nacional de Investigationes Cientificas y Tecnologicas CONICIT numbers S1-2697 and S1-2702. We are deeply indebted to the personnel of the Blood Bank of the Federal District of Caracas for their invaluable help in providing the samples. We would also like to thank the Laboratory of Photography at IVIC for photographic work and the department of Graphic Design at IVIC for artwork. We deeply thank Dr. Francisco Gil and Mrs. M. Romano for their expert advice in electron microscopy specimen handling.
Further Information

Publication History

Received 22 November 1999

Accepted after revision 16 March 2000

Publication Date:
14 December 2017 (online)

    Permissions and Reprints

Summary

A new dysfibrinogenemia associated with thrombophilia has been identified in a Venezuelan kindred. Thrombin and Reptilase times were prolonged and the accelerating capacity of the patient’s fibrin on the t-PA-induced plasminogen activation was decreased. In addition the affinity of fibrinogen for plasminogen was diminished. Permeability and electron microscopy studies revealed that the abnormal clot was made up of thin and densely packed fibres giving rise to a reduced fibrin gel porosity. This was confirmed by turbidity studies showing a decreased fibre mass/length ratio. Affected members were heterozygous for an Aα 532 Ser→ Cys mutation as demonstrated by genetic analyses. This abnormal fibrinogen has been designated as Fibrinogen Caracas V. The family study showed a convincing association between the mutation and thrombotic manifestations. The thrombotic tendency may be ascribed to lack of accelerating capacity of fibrin to induce fibrinolysis caused by an abnormal clot structure with thin fibres and reduced porosity.

Keywords

Dysfibrinogenemia - thrombophilia - thrombosis
 

  • References

  • 1 Everse SJ, Spraggon G, Doolittle RF. A three dimensional consideration of variant human fibrinogens. Thromb Haemost 1998; 80: 1-9.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 2 Haverkate F, Samama MM. Familial Dysfibrinogenemia and Thrombophilia Report on a study of the SSC Subcommittee on fibrinogen. Thromb Haemost 1995; 73: 151-61.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 3 Koopman J, Haverkate F. Hereditary variants of human fibrinogen. In: Haemostasis and Thrombosis. 3rd ed. Bloom AL, Forbes CD, Thomas DP, Tuddenham EGD. eds. Edinburgh: Churchill Livingstone; 1994: 515-29.
    Google Scholar
  • 4 Soria J, Mirshahi MC, Collet JP, Vasse M, Caen JP, Soria C. In: Dysfibrinogénémies, Manuel d´hemostase. Sampol J, Arnoux D, Boutiere B. eds. Amsterdam: Elsevier; 1995: 489-93.
  • 5 Samama MM, Haverkate F. Hereditary dysfibrinogenemia, Afibrinogenemia, Hypofibrinogenemia and Thrombosis. In: Hypercoagulable states. Fundamental aspects, Acquired disorders and Congenital thrombophilia. Segatchian MJ, Samama MM, Hecker SP. eds. Boca de Raton: CRC Press Inc; 1996: 379-83.
    Google Scholar
  • 6 Liu CY, Wallen P, Handley DA. Fibrinogen New York I: the structural, functional, and genetic defects and a hypothesis of the role of fibrin in the regulation of coagulation and fibrinolysis. In: Fibrinogen-Fibrin Formation and Fibrinolysis. Lane DA, Henschen A, Jasani MK. eds. Berlin: Walter de Gruyter; 1986: 79-90.
    Google Scholar
  • 7 Liu CY, Koehn JA, Morgan FJ. Characterization of fibrinogen New York I A dysfunctional fibrinogen with a deletion of Bβ (9-72) corresponding to exon II of the gene. J Biol Chem 1985; 260: 4390-6.
    PubMedGoogle Scholar
  • 8 Koopman J, Haverkate F, Lord ST, Grimbergen J, Mannucci PM. Molecular basis of Fibrinogen Naples associated with defective thrombin binding and thrombophilia Homozygous substitution of Bβ 68 Ala→Thr. J Clin Invest 1992; 90: 238-44.
    CrossrefPubMedGoogle Scholar
  • 9 Soria J, Soria C, Hedner U, Nilsson IM, Bergquist D, Samama M. Episodes of increased fibronectin level observed in a patient suffering from recurrent thrombosis related to congenital hypodysfibrinogenemia (fibrinogen Malmö). Brit J Haematol 1985; 61: 727-38.
    CrossrefPubMedGoogle Scholar
  • 10 Gandrille S, Priollet P, Capron L, Roncato M, Fiessinger JN, Aiach M. Association of inherited dysfibrinogenemia and Protein C deficiency in two unrelated families. Brit J Haematol 1988; 68: 329-37.
    CrossrefPubMedGoogle Scholar
  • 11 Paramo J., Fernandez JA, Cuesta B, Aranda A, Rocha E. Fibrinogen Pamplona II A new congenital dysfibrinogenemia with abnormal fibrin enhanced plasminogen activation and defective binding of thrombin to fibrin. In: Fibrinogen and its Derivatives. Biochemistry, Physiology and Pathophysiology. Müller-Berghaus G, Scheefers-Borchel U, Seylmar E, Henschen A. eds. Amsterdam, New York, Boston: Excerpta Medica, Elsevier Science Publishers; 1986: 25-30.
    Google Scholar
  • 12 Lijnen HR, Soria J, Soria C, Collen D, Caen JP. Dysfibrinogenemia (Fibrinogen Dusard) associated with impaired fibrin-enhanced plasminogen activation. Thromb Haemost 1984; 51: 113-20.
    PubMedGoogle Scholar
  • 13 Koopman J, Haverkate F, Grimbergen J, Lord ST, Mosesson M, Diorio JP, Siebenlist KS, Legrand C, Soria J, Soria C, Caen JP. Molecular basis for fibrinogen Dusart (Aα 554Arg→Cys) and its association with abnor-mal fibrin polymerization and thrombophilia. J Clin Invest 1993; 91: 1637-43.
    CrossrefPubMedGoogle Scholar
  • 14 Engesser L, Koopman J, De Munk G, Haverkate F, Nováková Y, Verheijen JH, Briët E, Brommer EJP. Fibrinogen Nijmegen: congenital dysfibrinogenemia associated with impaired t-PA mediated plasminogen activation and decreased binding of t-PA. Thromb Haemost 1988; 60: 113-20.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 15 Ieko M, Sawada KI, Sakamura S, Yamagishi Y, Isogawa S, Nakagawa S, Satoh M, Yasukuochi T, Matsuda M. Fibrinogen Date: congenital hypodysfibrinogenemia associated with decreased binding of tissue-plasminogen activator. Am J Hematol 1991; 37: 228-33.
    CrossrefPubMedGoogle Scholar
  • 16 Soria J, Soria C, Caen JP. A new type of congentital dysfibrinogenemia with defective fibrin lysis-Dusard syndrome: possible relation to thrombosis. Br J Haematol 1983; 53: 575-86.
    CrossrefPubMedGoogle Scholar
  • 17 Wada Y, Lord ST. A correlation between thrombotic disease and a specific fibrinogen abnormality (Aα 554 Arg→Cys) in two unrelated kindred Dusart and Chapel Hill III. Blood 1994; 84: 3709-14.
    CrossrefPubMedGoogle Scholar
  • 18 Carrell N, Gabriel DA, Blatt PM, Carr ME, Mc JDonagh. Hereditary dysfibrinogenemia in a patient with thrombotic disease. Blood 1983; 62: 439-47.
    PubMedGoogle Scholar
  • 19 Giddings JC. The investigation of hereditary coagulation disorders. In: Blood Coagulation and Haemostasis. A Practical Guide. Thomson JD. eds. Edinburgh: Churchill Livingstone; 1980: 117-57.
    Google Scholar
  • 20 Ingram GIC. The determination of plasma fibrinogen by the clot weight method. Biochem J 1952; 51: 583-5.
    CrossrefPubMedGoogle Scholar
  • 21 Bouvier CA, Gruedlinger J. Etude des phénomènes de coagulation et de fibrinolyse, per une méthode simple d´enregistrement optique. Schweiz Wsch 1963; 93: 1451-5.
    PubMedGoogle Scholar
  • 22 Gralnick HR, Givelber HM, Shainoff JR, Finlayson JS. Fibrinogen Bethesda: a congenital dysfibrinogenemia with delayed fibrinopeptide release. J Clin Invest 1971; 50: 1819-30.
    CrossrefPubMedGoogle Scholar
  • 23 Schwartz ML, Pizzo SV, Hill RL, McKee P. The effect of fibrin stabilizing factor on the subunit structure of human fibrin. J Clin Invest 1971; 50: 1506-13.
    CrossrefPubMedGoogle Scholar
  • 24 Southan C, Henschen A, Lottspeich F. The search for Molecular defects in Abnormal Fibrinogens. In: Fibrinogen, Recent Biochemical and medical Aspects. Henschen A, Graeff H, Lottspeich F. eds. Berlin, Walter de Gruyter: 1982: 153-62.
    Google Scholar
  • 25 Lundberg U, Rodriguez S, Marchi R, Ruíz-Sáez A, Arocha-Piñango CL. Fibrinogen Guarenas I: Partial Characterisation of a New Dysfibrinogenemia with an Altered rate of Fibrinopeptide Release and an Impaired Polymerisation. Thromb Res 78 1995; 95-106.
    CrossrefPubMedGoogle Scholar
  • 26 Matsuda M, Baba M, Moritomo K, Nakamikawa C. Fibrinogen Tokyo II An Abnormal Fibrinogen with an Impaired Polymerisation site on the aligned DD domain of fibrin molecules. J Clin Invest 1983; 72: 1034-41.
    CrossrefPubMedGoogle Scholar
  • 27 Kazal LA, Amsel S, Miller OP, Tocantins LM. Preparation and some properties of fibrinogen precipitated from human plasma by glycine. Proc Soc Exp Biol Med 1963; 113: 989-94.
    CrossrefPubMedGoogle Scholar
  • 28 Schägger H, Von Jagow G. Tricine-sodium dodecyl sulphate-polyacrylamide gel electrophoresis for the separation of proteins in the range from 1 to 100 kD. Anal Biochem 1987; 166: 368-79.
    CrossrefPubMedGoogle Scholar
  • 29 Deutsch GD, Mertz ET. Plasminogen: Purification from Human Plasma by Affinity Chromatography. Science 1970; 170: 1095-6.
    CrossrefPubMedGoogle Scholar
  • 30 Suenson E, Thorsen S. The Course and Prerequisites of Lys-plasminogen Formation during Fibrinolysis. Biochemistry 1988; 27: 2435-43.
    CrossrefPubMedGoogle Scholar
  • 31 Angles-Cano E. A Spectrophotometric Solid-Phase Fibrin-Tissue Plasminogen Activator Activity Assay (SOFIA-tPA) for High-Fibrin-Affinity Tissue Plasminogen Activators. Anal Biochem 1986; 153: 201-10.
    CrossrefPubMedGoogle Scholar
  • 32 Pirie-Shepherd SR, Jett AA, Andon NL, Pizzo SV. Sialic acid Content of Plasminogen 2 Glycoforms as a regulator of fibrinolytic Activity. J Biol Chem 1995; 270: 5877-81.
    CrossrefPubMedGoogle Scholar
  • 33 Branson HE. The structural components of the “Dirty” fiber of fibrinogen Seattle A new model of fibrin assembly. Thromb Haemost 1979; 42: 1378-87.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 34 Blombäck B, Okada M. Fibrin gel structure and clotting time. Thromb Res 1982; 25: 51-70.
    CrossrefPubMedGoogle Scholar
  • 35 Blombäck B, Carlsson K, Hessel B, Liljeborg A, Procyk R, Aslund N. Native fibrin gel networks observed by 3D microscopy, permeability and turbidity. Biochem Biophys Acta 1989; 997: 96-110.
    CrossrefPubMedGoogle Scholar
  • 36 Blombäck B, Blombäck M. Purification of human and bovine fibrinogen. Arkiv för Kemi 10 1956; 415-43.
    PubMedGoogle Scholar
  • 37 Carr ME, Hermans J. Size and density of fibrin fibers from turbidity. Macromolecules 1978; 11: 46-50.
    CrossrefPubMedGoogle Scholar
  • 38 Nair CH, Azhar A, Dhall DP. Studies of Fibrin Network Structure in Human Plasma Part One: methods for Clinical Application. Thromb Res 1991; 64: 455-76.
    CrossrefPubMedGoogle Scholar
  • 39 Gustavson S, Proper JA, Bowie EJW, Sommers SS. Parameters Affecting the Yield of DNA from Human Blood. Anal Biochem 1987; 165: 294-9.
    CrossrefPubMedGoogle Scholar
  • 40 Kirshbaum NE, Foster PA. The polymerase chain reaction with sequencespecific primers for the detection of the Factor V mutation associated with activated Protein C Resistance. Thromb Haemost 1995; 74: 874-8.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 41 Bellisimo B, Kirshbaum N, Foster P. Improved method for Factor V Leiden Typing by PCR-SSP. Thromb Haemost 1996; 75: 520-1.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 42 Poort SR, Rosendaal FR, Reitsma PH, Bertina RM. A Common Genetic Variation in the 3’-Untranslated Region of the Prothrombin Gene is Associated With Elevated Plasma Prothrombin Levels and an Increase in Venous Thrombosis. Blood 1996; 88: 3698-703.
    PubMedGoogle Scholar
  • 43 Veklich YI, Gorkun OV, Medved LV, Nieuwenhuizen W, Weisel JW. Carboxy-terminal portions of the α chains of fibrinogen and fibrin Localisation by electron microscopy and the effects of isolated αC fragments on polymerisation. J Biol Chem 1993; 268: 13577-85.
    PubMedGoogle Scholar
  • 44 Gorkun OV, Veklich YI, Medved LV, Henschen AH, Weisel JW. Role of the αC domains of fibrin in clot formation. Biochemistry 1994; 33: 6986-97.
    CrossrefPubMedGoogle Scholar
  • 45 Blombäck B, Banerjee D, Carlsson K, Hamsten A, Hessel B, Procyk R, Silveira A, Zacharski L. Native fibrin gel networks and factors influencing their formation in health and disease. In: Liu CY, Chien S. (eds) Fibrinogen, Thrombosis, Coagulation, and Fibrinolysis. New York: Plenun Press; 1990: 1.
    Google Scholar
  • 46 Woodhead JL, Nagaswami C, Matsuda M, Arocha-Piñango CL, Weisel W. The ultrastructure of fibrinogen Caracas II molecules, fibres, and clots. J Biol Chem 1996; 271: 4946-53.
    CrossrefPubMedGoogle Scholar
  • 47 Collet JP, Soria J, Mirshahi M, Hirsch M, Dagonnet FB, Caen J, Soria C. Dusart Syndrome: a new concept of the relationship between fibrin clot degradability: hypofibrinolysis related to an abnormal clot structure. Blood 1993; 82: 2462-69.
    CrossrefPubMedGoogle Scholar
  • 48 Collet JP, Woodhead JL, Soria J, Soria C, Mirshahi M, Caen JP, Weisel JW. Fibrinogen Dusart: Electron microscopy of molecules, fibres and clots, and viscoelastic properties of clots. Biophys J 1996; 70: 500-10.
    CrossrefPubMedGoogle Scholar
  • 49 Furlan M, Steinmann C, Jungo M, Bogli C, Baudo F, Redaelli R, Fedeli F, Lämmle B. A frameshift mutation in Exon V of the A alpha-chain gene leading to truncated Aα-chains in the homozygous dysfibrinogen Milano III. J Biol Chem 1994; 269: 33129-34.
    PubMedGoogle Scholar
  • 50 Koopman J, Haverkate F, Grimbergen J, Egbring R, Lord ST. Fibrinogen Marburg: a homozygous case of dysfibrinogenemia, lacking amino acids Aα 461-610 (Lys 461 AAA→stop TAA). Blood 1992; 80: 1972-9.
    PubMedGoogle Scholar
  • 51 Furlan M, Steinmann C, Jungo M, Lämmle B. Binding of calcium ions and their effect on clotting of fibrinogen Milano III, a variant with truncated Aα-chains. Blood Coag Fibrinol 1996; 07: 331-5.
    CrossrefPubMedGoogle Scholar
  • 52 Sugo T, Nakamikawa C, Takebe M, Kohno I, Egbring R, Matsuda M. Factor XIIIa cross-linking of the Marburg fibrin: formation of alpham gamman-heteromultimers and the alpha-chain-linked albumin. gamma complex, and disturbed protofibril assembly resulting in acquisition of plasmin resistance relevant to thrombophila. Blood 1998; 91: 3282-8.
    PubMedGoogle Scholar
  • 53 Maekawa H, Yamazumi K, Muramatsu S, Kaneko M, Hirata H, Takahashi N, Bosch N, Carvajal Z, Ojeda A, Arocha-Piñango CL, Matsuda M. An Aα Ser-434 to N-glycosylated Asn substitution in a dysfibrinogen, Fibrinogen Caracas II, characterised by impaired fibrin gel formation. J Biol Chem 1991; 266: 11575-81.
    PubMedGoogle Scholar
  • 54 Gabriel DA, Muga K, Boothroyd EM. The effect of fibrin structure on fibrinolysis. J Biol Chem 1992; 267: 24259-63.
    PubMedGoogle Scholar
  • 55 Pring JB, Gaffney PJ. Fibrin formationInfluence of various components of coagulation and fibrinolysis on clot structure. Thromb Haemost 1991; 65: 737-45.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 56 Gabriel DA, Muga K, Boothroyd EM. The influence of fibrin mass/length ratio on fibrinolysis. Thromb Haemost 1992; 267: 24259-63.
    PubMedGoogle Scholar
  • 57 Blombäck B. Fibrinogen and fibrin-proteins with complex roles in hemostasis and thrombosis. Thromb Res 1996; 83: 1-75.
    CrossrefPubMedGoogle Scholar
  • 58 Hessel B, Silveira AMV, Carlsson K, Oksa H, Rasi V, Vahtera E, Procyk R, Blombäck B. Fibrinogen TampereA dysfibrinogenemia with defective gelation and thromboembolic disease. Thromb Res 1995; 78: 323-39.
    CrossrefPubMedGoogle Scholar
  • 59 Benson MD, Liepnieks J, Uemichi T, Wheeler G, Correa R. Hereditay Renal amyloidosis Associated with a Mutant Fibrinogen α-chain. Nat Genet 1993; 03: 252-5.
    CrossrefPubMedGoogle Scholar
  • 60 Uemichi T, Liepnieks JJ, Benson MD. Hereditary Renal Amyloidosis with a Novel variant fibrinogen. J Clin Invest 1994; 93: 731-6.
    CrossrefPubMedGoogle Scholar
  • 61 Hamidi AL, Liepnieks JJ, Uemichi T, Rebibou JM, Justrabo E, Droz D, Mousson C, Chalopin JM, Benson MD, Delpech M, Grateau G. Renal Amyloidosis with a Frame Shift Mutation in Fibrinogen Aα-chain gene producing a Novel Amyloid Protein. Blood 1997; 90: 4799-805.
    PubMedGoogle Scholar