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Semin Thromb Hemost 2010; 36(1): 007-017
DOI: 10.1055/s-0030-1248720
© Thieme Medical Publishers

Fibrinogen and the Risk of Thrombosis

Philippe de Moerloose1 , Françoise Boehlen1 , Marguerite Neerman-Arbez1 , 2
  • 1Division of Angiology and Haemostasis, University Hospital, Geneva, Switzerland
  • 2Department of Genetic Medicine and Development, University Medical School, Geneva, Switzerland
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Publication History

Publication Date:
13 April 2010 (online)

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ABSTRACT

Fibrinogen contributes to thrombosis risk in different ways. Indeed, various mutations in the fibrinogen genes predispose to thrombosis. At the same time, high levels of fibrinogen are also associated with thrombotic complications. Although the underlying causative mechanisms are not clear, this most likely involves the associated inflammatory and hypercoagulable states. In the last few years, particular attention has focused on the polymorphisms of fibrinogen genes involved in increased fibrinogen levels or fibrinogen qualitative changes. The association between dysfibrinogenemia and risk of thrombosis is well known, and some mechanisms have been clearly identified. Paradoxically, some patients with either hypofibrinogenemia or afibrinogenemia may also suffer from severe thromboembolic complications. The management of these patients is particularly challenging because they are not only at risk of thrombosis but also of bleeding. This review discusses the various quantitative and qualitative defects of fibrinogen associated with thrombosis, the tests that may predict the thrombotic risk, as well as some preventive or therapeutic approaches.

KEYWORDS

Thrombosis - fibrinogen - afibrinogenemia - dysfibrinogenemia - hypofibrinogenemia - hyperfibrinogenemia - polymorphisms

REFERENCES

  • 1 de Moerloose P, Neerman-Arbez M. Congenital fibrinogen disorders.  Semin Thromb Hemost. 2009;  35(4) 356-366
    Article in Thieme ConnectPubMedGoogle Scholar
  • 2 Kant J A, Fornace Jr A J, Saxe D, Simon M I, McBride O W, Crabtree G R. Evolution and organization of the fibrinogen locus on chromosome 4: gene duplication accompanied by transposition and inversion.  Proc Natl Acad Sci U S A. 1985;  82(8) 2344-2348
    CrossrefPubMedGoogle Scholar
  • 3 Danesh J, Collins R, Appleby P, Peto R. Association of fibrinogen, C-reactive protein, albumin, or leukocyte count with coronary heart disease: meta-analyses of prospective studies.  JAMA. 1998;  279(18) 1477-1482
    CrossrefPubMedGoogle Scholar
  • 4 Koenig W. Fibrin(ogen) in cardiovascular disease: an update.  Thromb Haemost. 2003;  89(4) 601-609
    PubMedGoogle Scholar
  • 5 Danesh J, Lewington S, Thompson S G Fibrinogen Studies Collaboration et al. Plasma fibrinogen level and the risk of major cardiovascular diseases and nonvascular mortality: an individual participant meta-analysis.  JAMA. 2005;  294(14) 1799-1809
    CrossrefPubMedGoogle Scholar
  • 6 Kaptoge S, White I R, Thompson S G et al.. Associations of plasma fibrinogen levels with established cardiovascular disease risk factors, inflammatory markers, and other characteristics: individual participant meta-analysis of 154,211 adults in 31 prospective studies: the fibrinogen studies collaboration.  Am J Epidemiol. 2007;  166(8) 867-879
    CrossrefPubMedGoogle Scholar
  • 7 Woodward M, Rumley A, Welsh P, MacMahon S, Lowe G. A comparison of the associations between seven hemostatic or inflammatory variables and coronary heart disease.  J Thromb Haemost. 2007;  5(9) 1795-1800
    CrossrefPubMedGoogle Scholar
  • 8 Welsh P, Woodward M, Rumley A, Lowe G. Associations of plasma pro-inflammatory cytokines, fibrinogen, viscosity and C-reactive protein with cardiovascular risk factors and social deprivation: the fourth Glasgow MONICA study.  Br J Haematol. 2008;  141(6) 852-861
    CrossrefPubMedGoogle Scholar
  • 9 del Zoppo G J, Levy D E, Wasiewski W W et al.. Hyperfibrinogenemia and functional outcome from acute ischemic stroke.  Stroke. 2009;  40(5) 1687-1691
    CrossrefPubMedGoogle Scholar
  • 10 Chuang S Y, Bai C H, Chen W H, Lien L M, Pan W H. Fibrinogen independently predicts the development of ischemic stroke in a Taiwanese population: CVDFACTS study.  Stroke. 2009;  40(5) 1578-1584
    CrossrefPubMedGoogle Scholar
  • 11 Koster T, Rosendaal F R, Reitsma P H, van der Velden P A, Briët E, Vandenbroucke J P. Factor VII and fibrinogen levels as risk factors for venous thrombosis. A case-control study of plasma levels and DNA polymorphisms—the Leiden Thrombophilia Study (LETS).  Thromb Haemost. 1994;  71(6) 719-722
    PubMedGoogle Scholar
  • 12 Kamphuisen P W, Eikenboom J C, Vos H L et al.. Increased levels of factor VIII and fibrinogen in patients with venous thrombosis are not caused by acute phase reactions.  Thromb Haemost. 1999;  81(5) 680-683
    PubMedGoogle Scholar
  • 13 van Hylckama Vlieg A, Rosendaal F R. High levels of fibrinogen are associated with the risk of deep venous thrombosis mainly in the elderly.  J Thromb Haemost. 2003;  1(12) 2677-2678
    CrossrefPubMedGoogle Scholar
  • 14 Daskalopoulou S S, Daskalopoulos M E, Liapis C D, Mikhailidis D P. Peripheral arterial disease: a missed opportunity to administer statins so as to reduce cardiac morbidity and mortality.  Curr Med Chem. 2005;  12(4) 443-452
    PubMedGoogle Scholar
  • 15 Schneider D J, Taatjes D J, Howard D B, Sobel B E. Increased reactivity of platelets induced by fibrinogen independent of its binding to the IIb-IIIa surface glycoprotein: a potential contributor to cardiovascular risk.  J Am Coll Cardiol. 1999;  33(1) 261-266
    CrossrefPubMedGoogle Scholar
  • 16 Falls L A, Farrell D H. Resistance of gammaA/gamma′ fibrin clots to fibrinolysis.  J Biol Chem. 1997;  272(22) 14251-14256
    CrossrefPubMedGoogle Scholar
  • 17 Lepedda A J, Cigliano A, Cherchi G M et al.. A proteomic approach to differentiate histologically classified stable and unstable plaques from human carotid arteries.  Atherosclerosis. 2009;  203(1) 112-118
    CrossrefPubMedGoogle Scholar
  • 18 Hicks R C, Golledge J, Mir-Hasseine R, Powell J T. Vasoactive effects of fibrinogen on saphenous vein.  Nature. 1996;  379(6568) 818-820
    CrossrefPubMedGoogle Scholar
  • 19 Retzinger G S, DeAnglis A P, Patuto S J. Adsorption of fibrinogen to droplets of liquid hydrophobic phases. Functionality of the bound protein and biological implications.  Arterioscler Thromb Vasc Biol. 1998;  18(12) 1948-1957
    PubMedGoogle Scholar
  • 20 Rabbani L E, Loscalzo J. Recent observations on the role of hemostatic determinants in the development of the atherothrombotic plaque.  Atherosclerosis. 1994;  105(1) 1-7
    CrossrefPubMedGoogle Scholar
  • 21 Hamsten A, Mannila M N, Silveira A. Quest for genes regulating plasma fibrinogen concentration: still a long way to go.  Arterioscler Thromb Vasc Biol. 2005;  25(6) 1100-1101
    CrossrefPubMedGoogle Scholar
  • 22 Soria J M, Almasy L, Souto J C et al.. A genome search for genetic determinants that influence plasma fibrinogen levels.  Arterioscler Thromb Vasc Biol. 2005;  25(6) 1287-1292
    CrossrefPubMedGoogle Scholar
  • 23 Yang Q, Tofler G H, Cupples L A et al.. A genome-wide search for genes affecting circulating fibrinogen levels in the Framingham Heart Study.  Thromb Res. 2003;  110(1) 57-64
    CrossrefPubMedGoogle Scholar
  • 24 Dehghan A, Yang Q, Peters A et al.. Association of novel genetic Loci with circulating fibrinogen levels: a genome-wide association study in 6 population-based cohorts.  Circ Cardiovasc Genet.. 2009;  2 125-133
    CrossrefPubMedGoogle Scholar
  • 25 Ridker P M, Chasman D I, Zee R Y Women’s Genome Health Study Working Group et al. Rationale, design, and methodology of the Women’s Genome Health Study: a genome-wide association study of more than 25,000 initially healthy American women.  Clin Chem. 2008;  54(2) 249-255
    CrossrefPubMedGoogle Scholar
  • 26 van der Krabben M D, Rosendaal F R, van der Bom J G, Doggen C J. Polymorphisms in coagulation factors and the risk of recurrent cardiovascular events in men after a first myocardial infarction.  J Thromb Haemost. 2008;  6(5) 720-725
    CrossrefPubMedGoogle Scholar
  • 27 Carty C L, Cushman M, Jones D et al.. Associations between common fibrinogen gene polymorphisms and cardiovascular disease in older adults. The Cardiovascular Health Study.  Thromb Haemost. 2008;  99(2) 388-395
    PubMedGoogle Scholar
  • 28 Reiner A P, Carty C L, Carlson C S et al.. Association between patterns of nucleotide variation across the three fibrinogen genes and plasma fibrinogen levels: the Coronary Artery Risk Development in Young Adults (CARDIA) study.  J Thromb Haemost. 2006;  4(6) 1279-1287
    CrossrefPubMedGoogle Scholar
  • 29 Jood K, Danielson J, Ladenvall C, Blomstrand C, Jern C. Fibrinogen gene variation and ischemic stroke.  J Thromb Haemost. 2008;  6(6) 897-904
    CrossrefPubMedGoogle Scholar
  • 30 Smith G D, Harbord R, Milton J, Ebrahim S, Sterne J A. Does elevated plasma fibrinogen increase the risk of coronary heart disease? Evidence from a meta-analysis of genetic association studies.  Arterioscler Thromb Vasc Biol. 2005;  25(10) 2228-2233
    CrossrefPubMedGoogle Scholar
  • 31 Rallidis L S, Gialeraki A, Fountoulaki K et al.. G-455A polymorphism of beta-fibrinogen gene and the risk of premature myocardial infarction in Greece.  Thromb Res. 2009;  , April 30 (Epub ahead of print)
    PubMedGoogle Scholar
  • 32 Cheung E Y, Bos M J, Leebeek F W et al.. Variation in fibrinogen FGG and FGA genes and risk of stroke: the Rotterdam Study.  Thromb Haemost. 2008;  100(2) 308-313
    PubMedGoogle Scholar
  • 33 van Oijen M, Cheung E Y, Geluk C E et al.. Haplotypes of the fibrinogen gene and cerebral small vessel disease: the Rotterdam scan study.  J Neurol Neurosurg Psychiatry. 2008;  79(7) 799-803
    CrossrefPubMedGoogle Scholar
  • 34 Carter A M, Catto A J, Grant P J. Association of the alpha-fibrinogen Thr312Ala polymorphism with poststroke mortality in subjects with atrial fibrillation.  Circulation. 1999;  99(18) 2423-2426
    PubMedGoogle Scholar
  • 35 Carter A M, Catto A J, Kohler H P, Ariëns R A, Stickland M H, Grant P J. alpha-fibrinogen Thr312Ala polymorphism and venous thromboembolism.  Blood. 2000;  96(3) 1177-1179
    PubMedGoogle Scholar
  • 36 Standeven K F, Grant P J, Carter A M, Scheiner T, Weisel J W, Ariëns R AS. Functional analysis of the fibrinogen Aalpha Thr312Ala polymorphism: effects on fibrin structure and function.  Circulation. 2003;  107(18) 2326-2330
    CrossrefPubMedGoogle Scholar
  • 37 Siegerink B, Rosendaal F R, Algra A. Genetic variation in fibrinogen; its relationship to fibrinogen levels and the risk of myocardial infarction and ischemic stroke.  J Thromb Haemost. 2009;  7(3) 385-390
    CrossrefPubMedGoogle Scholar
  • 38 Behague I, Poirier O, Nicaud V et al.. Beta fibrinogen gene polymorphisms are associated with plasma fibrinogen and coronary artery disease in patients with myocardial infarction. The ECTIM Study. Etude Cas-Témoins sur l’Infarctus du Myocarde.  Circulation. 1996;  93(3) 440-449
    PubMedGoogle Scholar
  • 39 Mosesson M W. Antithrombin I. Inhibition of thrombin generation in plasma by fibrin formation.  Thromb Haemost. 2003;  89(1) 9-12
    PubMedGoogle Scholar
  • 40 Lovely R S, Falls L A, Al-Mondhiry H A et al.. Association of gammaA/gamma′ fibrinogen levels and coronary artery disease.  Thromb Haemost. 2002;  88(1) 26-31
    PubMedGoogle Scholar
  • 41 Uitte de Willige S U, de Visser M C, Houwing-Duistermaat J J, Rosendaal F R, Vos H L, Bertina R M. Genetic variation in the fibrinogen gamma gene increases the risk for deep venous thrombosis by reducing plasma fibrinogen gamma′ levels.  Blood. 2005;  106(13) 4176-4183
    CrossrefPubMedGoogle Scholar
  • 42 Rosendaal F R, Reitsma P H. Genetics of venous thrombosis.  J Thromb Haemost. 2009;  7(suppl 1) 301-304
    CrossrefPubMedGoogle Scholar
  • 43 de Willige S U, Pyle M E, Vos H L et al.. Fibrinogen gamma gene 3′-end polymorphisms and risk of venous thromboembolism in the African-American and Caucasian population.  Thromb Haemost. 2009;  101(6) 1078-1084
    PubMedGoogle Scholar
  • 44 Gohil R, Peck G, Sharma P. The genetics of venous thromboembolism. A meta-analysis involving approximately 120,000 cases and 180,000 controls.  Thromb Haemost. 2009;  102(2) 360-370
    Article in Thieme ConnectPubMedGoogle Scholar
  • 45 Kurnik D, Lubetsky A. Genetic variants and risk for venous thromboembolic events: summing up the evidence.  Thromb Haemost. 2009;  102(2) 183-184
    PubMedGoogle Scholar
  • 46 Haverkate F, Samama M. Familial dysfibrinogenemia and thrombophilia. Report on a study of the SSC Subcommittee on Fibrinogen.  Thromb Haemost. 1995;  73(1) 151-161
    PubMedGoogle Scholar
  • 47 Hayes T. Dysfibrinogenemia and thrombosis.  Arch Pathol Lab Med. 2002;  126(11) 1387-1390
    PubMedGoogle Scholar
  • 48 McDonagh J. Dysfibrinogenemia and other disorders of fibrinogen structure or function. In: Colman R, Hirsh J, Marder V, Clowes A, George J Hemostasis and Thrombosis. Basic Principles and Clinical Practice. Philadelphia, PA; Lippincott Williams & Wilkins 2001: 855-892
    PubMedGoogle Scholar
  • 49 Morris T A, Marsh J J, Chiles P G et al.. High prevalence of dysfibrinogenemia among patients with chronic thromboembolic pulmonary hypertension.  Blood. 2009;  114(9) 1929-1936
    CrossrefPubMedGoogle Scholar
  • 50 Lak M, Keihani M, Elahi F, Peyvandi F, Mannucci P M. Bleeding and thrombosis in 55 patients with inherited afibrinogenaemia.  Br J Haematol. 1999;  107(1) 204-206
    CrossrefPubMedGoogle Scholar
  • 51 Dupuy E, Soria C, Molho P et al.. Embolized ischemic lesions of toes in an afibrinogenemic patient: possible relevance to in vivo circulating thrombin.  Thromb Res. 2001;  102(3) 211-219
    CrossrefPubMedGoogle Scholar
  • 52 Acharya S S, Coughlin A, Dimichele D M. North American Rare Bleeding Disorder Study Group . Rare Bleeding Disorder Registry: deficiencies of factors II, V, VII, X, XIII, fibrinogen and dysfibrinogenemias.  J Thromb Haemost. 2004;  2(2) 248-256
    CrossrefPubMedGoogle Scholar
  • 53 Bolton-Maggs P H, Perry D J, Chalmers E A et al.. The rare coagulation disorders—review with guidelines for management from the United Kingdom Haemophilia Centre Doctors’ Organisation.  Haemophilia. 2004;  10(5) 593-628
    CrossrefPubMedGoogle Scholar
  • 54 Girolami A, Ruzzon E, Tezza F, Scandellari R, Vettore S, Girolami B. Arterial and venous thrombosis in rare congenital bleeding disorders: a critical review.  Haemophilia. 2006;  12(4) 345-351
    CrossrefPubMedGoogle Scholar
  • 55 De Marco L, Girolami A, Zimmerman T S, Ruggeri Z M. von Willebrand factor interaction with the glycoprotein IIb/IIa complex. Its role in platelet function as demonstrated in patients with congenital afibrinogenemia.  J Clin Invest. 1986;  77(4) 1272-1277
    CrossrefPubMedGoogle Scholar
  • 56 Korte W, Feldges A. Increased prothrombin activation in a patient with congenital afibrinogenemia is reversible by fibrinogen substitution.  Clin Investig. 1994;  72(5) 396-398
    CrossrefPubMedGoogle Scholar
  • 57 de Bosch N B, Mosesson M W, Ruiz-Sáez A, Echenagucia M, Rodriguez-Lemoin A. Inhibition of thrombin generation in plasma by fibrin formation (antithrombin I).  Thromb Haemost. 2002;  88(2) 253-258
    PubMedGoogle Scholar
  • 58 Ni H, Denis C V, Subbarao S et al.. Persistence of platelet thrombus formation in arterioles of mice lacking both von Willebrand factor and fibrinogen.  J Clin Invest. 2000;  106(3) 385-392
    CrossrefPubMedGoogle Scholar
  • 59 Remijn J A, Wu Y-P, Ijsseldijk M J, Zwaginga J J, Sixma J J, de Groot P G. Absence of fibrinogen in afibrinogenemia results in large but loosely packed thrombi under flow conditions.  Thromb Haemost. 2001;  85(4) 736-742
    PubMedGoogle Scholar
  • 60 Di Napoli M, Singh P. Is plasma fibrinogen useful in evaluating ischemic stroke patients?: why, how, and when.  Stroke. 2009;  40(5) 1549-1552
    CrossrefPubMedGoogle Scholar
  • 61 Hoegee-de Nobel E, Voskuilen M, Briët E, Brommer E J, Nieuwenhuizen W. A monoclonal antibody-based quantitative enzyme immunoassay for the determination of plasma fibrinogen concentrations.  Thromb Haemost. 1988;  60(3) 415-418
    PubMedGoogle Scholar
  • 62 Gabay C, Roux-Lombard P, de Moerloose P, Dayer J M, Vischer T, Guerne P A. Absence of correlation between interleukin 6 and C-reactive protein blood levels in systemic lupus erythematosus compared with rheumatoid arthritis.  J Rheumatol. 1993;  20(5) 815-821
    PubMedGoogle Scholar
  • 63 Peters A, Greven S, Heid I M AIRGENE Study Group et al. Fibrinogen genes modify the fibrinogen response to ambient particulate matter.  Am J Respir Crit Care Med. 2009;  179(6) 484-491
    CrossrefPubMedGoogle Scholar
  • 64 Jacquemin B, Antoniades C, Nyberg F et al.. Common genetic polymorphisms and haplotypes of fibrinogen alpha, beta, and gamma chains affect fibrinogen levels and the response to proinflammatory stimulation in myocardial infarction survivors: the AIRGENE study.  J Am Coll Cardiol. 2008;  52(11) 941-952
    CrossrefPubMedGoogle Scholar
  • 65 Dargaud Y, Trzeciak M C, Bordet J C, Ninet J, Negrier C. Use of calibrated automated thrombinography + /– thrombomodulin to recognise the prothrombotic phenotype.  Thromb Haemost. 2006;  96(5) 562-567
    Article in Thieme ConnectPubMedGoogle Scholar
  • 66 Ingerslev J, Sørensen B, Castaman G, Lloyd J V, Varon J D, Savion N. New approaches in the measurement of coagulation.  Haemophilia. 2008;  14(suppl 3) 104-112
    CrossrefPubMedGoogle Scholar
  • 67 The Ancrod Stroke Study Investigators . Ancrod for the treatment of acute ischemic brain infarction.  Stroke. 1994;  25(9) 1755-1759
    PubMedGoogle Scholar
  • 68 Sherman D G, Atkinson R P, Chippendale T et al.. Intravenous ancrod for treatment of acute ischemic stroke: the STAT study: a randomized controlled trial. Stroke Treatment with Ancrod Trial.  JAMA. 2000;  283(18) 2395-2403
    CrossrefPubMedGoogle Scholar
  • 69 Hennerici M G, Kay R, Bogousslavsky J et al.. Intravenous ancrod for acute ischaemic stroke in the European Stroke Treatment with Ancrod Trial: a randomised controlled trial.  Lancet. 2006;  368(9550) 1871-1878
    CrossrefPubMedGoogle Scholar
  • 70 Levy D E, Trammel J, Wasiewski W W. Ancrod Stroke Program (ASP) Study Team . Ancrod for acute ischemic stroke: a new dosing regimen derived from analysis of prior ancrod stroke studies.  J Stroke Cerebrovasc Dis. 2009;  18(1) 23-27
    CrossrefPubMedGoogle Scholar
  • 71 Lynch A I, Boerwinkle E, Davis B R et al.. Antihypertensive pharmacogenetic effect of fibrinogen-beta variant -455G> A on cardiovascular disease, end-stage renal disease, and mortality: the GenHAT study.  Pharmacogenet Genomics. 2009;  19(6) 415-421
    CrossrefPubMedGoogle Scholar
  • 72 de Moerloose P, Neerman-Arbez M. Treatment of congenital fibrinogen disorders.  Expert Opin Biol Ther. 2008;  8(7) 979-992
    CrossrefPubMedGoogle Scholar
  • 73 Schuepbach R A, Meili E O, Schneider E, Peter U, Bachli E B. Lepirudin therapy for thrombotic complications in congenital afibrinogenaemia.  Thromb Haemost. 2004;  91(5) 1044-1046
    PubMedGoogle Scholar

Philippe de MoerlooseM.D. 

Haemostasis Unit, University Hospital of Geneva

1211 Geneva 14/Switzerland

Email: Philippe.deMoerloose@hcuge.ch