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
-
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
-
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
-
4
Koenig W.
Fibrin(ogen) in cardiovascular disease: an update.
Thromb Haemost.
2003;
89(4)
601-609
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
16
Falls L A, Farrell D H.
Resistance of gammaA/gamma′ fibrin clots to fibrinolysis.
J Biol Chem.
1997;
272(22)
14251-14256
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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)
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
39
Mosesson M W.
Antithrombin I. Inhibition of thrombin generation in plasma by fibrin formation.
Thromb Haemost.
2003;
89(1)
9-12
-
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
-
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
-
42
Rosendaal F R, Reitsma P H.
Genetics of venous thrombosis.
J Thromb Haemost.
2009;
7(suppl 1)
301-304
-
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
-
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
-
45
Kurnik D, Lubetsky A.
Genetic variants and risk for venous thromboembolic events: summing up the evidence.
Thromb Haemost.
2009;
102(2)
183-184
-
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
-
47
Hayes T.
Dysfibrinogenemia and thrombosis.
Arch Pathol Lab Med.
2002;
126(11)
1387-1390
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
67
The Ancrod Stroke Study Investigators .
Ancrod for the treatment of acute ischemic brain infarction.
Stroke.
1994;
25(9)
1755-1759
-
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
-
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
-
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
-
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
-
72
de Moerloose P, Neerman-Arbez M.
Treatment of congenital fibrinogen disorders.
Expert Opin Biol Ther.
2008;
8(7)
979-992
-
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
Philippe de MoerlooseM.D.
Haemostasis Unit, University Hospital of Geneva
1211 Geneva 14/Switzerland
eMail: Philippe.deMoerloose@hcuge.ch
