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

Rita Marchi; Ulf Lundberg; Jos Grimbergen; Jaap Koopman; Argimiro Torres; Norma B. de Bosch; Frits Haverkate; Carmen Luisa Arocha Piñango

doi:10.1055/s-0037-1614006

Thrombosis and Haemostasis, Table of Contents

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

¹From Centro de Medicina Experimental, Laboratorio de Fisiopatología, Instituto Venezolano de Investigaciones Científicas, IVIC, Caracas, Venezuela, The Netherlands

,

Ulf Lundberg

¹From Centro de Medicina Experimental, Laboratorio de Fisiopatología, Instituto Venezolano de Investigaciones Científicas, IVIC, Caracas, Venezuela, The Netherlands

,

Jos Grimbergen

²Gaubius Laboratory TNO, Leiden, The Netherlands

,

Jaap Koopman

³Pharming, Leiden, The Netherlands

,

Argimiro Torres

⁴Banco Municipal de Sangre del Distrito Federal, Caracas, Venezuela, The Netherlands

,

Norma B. de Bosch

⁴Banco Municipal de Sangre del Distrito Federal, Caracas, Venezuela, The Netherlands

,

Frits Haverkate

¹From Centro de Medicina Experimental, Laboratorio de Fisiopatología, Instituto Venezolano de Investigaciones Científicas, IVIC, Caracas, Venezuela, The Netherlands

²Gaubius Laboratory TNO, Leiden, The Netherlands

,

Carmen Luisa Arocha Piñango

¹From Centro de Medicina Experimental, Laboratorio de Fisiopatología, Instituto Venezolano de Investigaciones Científicas, IVIC, Caracas, Venezuela, The Netherlands

› Author Affiliations

Abstract

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

Full Text

References

References
1 Everse SJ, Spraggon G, Doolittle RF. A three dimensional consideration of variant human fibrinogens. Thromb Haemost 1998; 80: 1-9.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
18 Carrell N, Gabriel DA, Blatt PM, Carr ME, Mc JDonagh. Hereditary dysfibrinogenemia in a patient with thrombotic disease. Blood 1983; 62: 439-47.
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.
20 Ingram GIC. The determination of plasma fibrinogen by the clot weight method. Biochem J 1952; 51: 583-5.
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.
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.
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.
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.
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.
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.
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.
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.
29 Deutsch GD, Mertz ET. Plasminogen: Purification from Human Plasma by Affinity Chromatography. Science 1970; 170: 1095-6.
30 Suenson E, Thorsen S. The Course and Prerequisites of Lys-plasminogen Formation during Fibrinolysis. Biochemistry 1988; 27: 2435-43.
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.
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.
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.
34 Blombäck B, Okada M. Fibrin gel structure and clotting time. Thromb Res 1982; 25: 51-70.
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.
36 Blombäck B, Blombäck M. Purification of human and bovine fibrinogen. Arkiv för Kemi 10 1956; 415-43.
37 Carr ME, Hermans J. Size and density of fibrin fibers from turbidity. Macromolecules 1978; 11: 46-50.
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.
39 Gustavson S, Proper JA, Bowie EJW, Sommers SS. Parameters Affecting the Yield of DNA from Human Blood. Anal Biochem 1987; 165: 294-9.
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.
41 Bellisimo B, Kirshbaum N, Foster P. Improved method for Factor V Leiden Typing by PCR-SSP. Thromb Haemost 1996; 75: 520-1.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
52 Sugo T, Nakamikawa C, Takebe M, Kohno I, Egbring R, Matsuda M. Factor XIIIa cross-linking of the Marburg fibrin: formation of alpha_m gamma_n-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.
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.
54 Gabriel DA, Muga K, Boothroyd EM. The effect of fibrin structure on fibrinolysis. J Biol Chem 1992; 267: 24259-63.
55 Pring JB, Gaffney PJ. Fibrin formationInfluence of various components of coagulation and fibrinolysis on clot structure. Thromb Haemost 1991; 65: 737-45.
56 Gabriel DA, Muga K, Boothroyd EM. The influence of fibrin mass/length ratio on fibrinolysis. Thromb Haemost 1992; 267: 24259-63.
57 Blombäck B. Fibrinogen and fibrin-proteins with complex roles in hemostasis and thrombosis. Thromb Res 1996; 83: 1-75.
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.
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.
60 Uemichi T, Liepnieks JJ, Benson MD. Hereditary Renal Amyloidosis with a Novel variant fibrinogen. J Clin Invest 1994; 93: 731-6.
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.