Download PDF
Thromb Haemost 1997; 77(01): 075-079
DOI: 10.1055/s-0038-1655910
Clinical Studies
Schattauer GmbH Stuttgart

Modulation of Plasma Fibrinogen Levels by Ciprofibrate and Gemfibrozil in Primary Hyperlipidaemia

M P M de Maat
1   Gaubius Laboratory TNO-PG, Leiden, Academic Medical Centre, Amsterdam, The Netherlands
,
H C Knipscheer
2   Centre for Haemostasis, Thrombosis, Atherosclerosis and Inflammation Research, Academic Medical Centre, Amsterdam, The Netherlands
,
J J P Kastelein
2   Centre for Haemostasis, Thrombosis, Atherosclerosis and Inflammation Research, Academic Medical Centre, Amsterdam, The Netherlands
,
C Kluft
1   Gaubius Laboratory TNO-PG, Leiden, Academic Medical Centre, Amsterdam, The Netherlands
› Author Affiliations
Further Information

Publication History

Received 05 April 1996

Accepted after revision 18 September 1996

Publication Date:
11 July 2018 (online)

  PDF Download  Permissions and Reprints

Summary

An elevated plasma fibrinogen level is increasingly accepted as an independent risk indicator of cardiovascular disease. This has enhanced the interest in identifying agents that can normalize elevated plasma fibrinogen levels. One group of agents with this capacity are the fibric acid derivatives, e.g. ciprofibrate and gemfibrozil.

We studied fibrinogen levels after 12 weeks of treatment with ciprofibrate (n = 48) and gemfibrozil (n = 51) in hypercholesterolemic patients. The correlation of the decrease in fibrinogen with lipid lowering and the contribution of the acute phase and genetic polymorphisms to this decrease were also evaluated.

After 12 weeks of treatment, the fibrinogen levels were significantly decreased (p<0.0005) with both drugs, although the decrease in the ciprofibrate group (mean 3.4 g/1 pre-treatment to 2.4 g/1 after 12 weeks) was larger than in the gemfibrozil group (mean 3.4 g/1 to 3.0 g/1.). The lipid lowering effect was comparable for the two drugs but there was no correlation for either ciprofibrate or gemfibrozil between the lipid lowering and the magnitude or the velocity of the fibrinogen lowering effect. An attenuation of the major regulatory mechanism of plasma fibrinogen levels, the acute phase reaction, was invoked as the underlying mechanism. However, pre-treatment C-reactive protein levels were not increased and did not change after treatment. Moreover, no effects of the polymorphisms of the fibrinogen β-gene on the decrease of the plasma fibrinogen levels were observed. This suggests that a new, as yet unknown, mechanism is involved in fibrinogen lowering by fibrates.

 

  • References

  • 1 Meade TW, Brozovic M, Haines AP, Imenson JD, Mellows S, Miller GJ, North MRS, Stirling Y, Thompson SG. Haemostatic function and ischaemic heart disease: Principal results of the Northwick Park Heart Study. Lancet 1986; 02: 533-538
    PubMedGoogle Scholar
  • 2 Kannel WB, Wolf PA, Castelli WP, D’Agostino RBD. Fibrinogen and risk of cardiovascular disease: The Framingham Study. JAMA 1987; 258: 1183-1186
    CrossrefPubMedGoogle Scholar
  • 3 Heinrich J, Balleisen L, Schulte H, Assmann G, van deLooJ. Fibrinogen and factor VII in the prediction of coronary risk. Results from the PROCAM Study in healthy men. Arterioscl Thromb 1994; 14: 54-59
    CrossrefPubMedGoogle Scholar
  • 4 Stone MC, Thorp JM. Plasma fibrinogen: a major coronary risk factor. JR Coll GenPract 1985; 35: 565-569
    PubMedGoogle Scholar
  • 5 Wilhelmsen L, Svärdsudd K, Korsan-Bengtsen K, Larsson B, Welin L, Tibblin G. Fibrinogen as a risk factor for stroke and myocardial infarction. N Engl J Med 1984; 311: 501-505
    CrossrefPubMedGoogle Scholar
  • 6 Yamell JWG, Baker IA, Sweetnam PM, Bainton D, O’Brien JR, Whitehead PJ, ELwood PC. Fibrinogen, viscosity, and white blood cell count are major risk factors for ischemic heart disease. The Caerphilly and Speedwell Collaborative Heart Disease Studies. Circulation 1991; 83: 836-844
    CrossrefPubMedGoogle Scholar
  • 7 Thompson SG, Kienast J, Pyke S, Haverkate F, van deLooJ. for the EC AT Angina Pectoris Study Group. Haemostatic risk factors and the risk for myocardial infarction or sudden cardiac death in patients with angina pectoris. N Engl J Med 1995; 332: 635-641
    CrossrefPubMedGoogle Scholar
  • 8 Catapano AL. Mode of action of fibrates. Pharmac Res 1992; 26: 331-340
    PubMedGoogle Scholar
  • 9 Koenig W, Sund M, Ernst E, Mraz W, Doring A, Keil U, Hombach V. Blood viscosity and hyperlipoproteinemia. Biorheology 1989; 26: 601
    PubMedGoogle Scholar
  • 10 Lowe GDO, Drummond MN, Third JLH, Bremner WF, Forbes CD, Prentice CR, Lawrie TD. Increased plasma fibrinogen, and platelet aggregates in type II hyperlipoproteinaemia. Thromb Haemost 1979; 42: 1503-1507
    Article in Thieme ConnectPubMedGoogle Scholar
  • 11 Niort G, Bulgarelli A, Cassader M, Pagano G. Effect of short-term treatment with bezafibrate on plasma fibrinogen, fibrinopeptide A, platelet activation and blood filterability in atherosclerotic hyperfibrinogenemic patients. Atherosclerosis 1988; 71: 113
    CrossrefPubMedGoogle Scholar
  • 12 Bo M, Bonino F, Neirotti M, Gottero M, Pemigotti L, Molaschi M, Fabris F. Hemorheologic and coagulative pattern in hypercholesterolemic subjects treated with lipid-lowering drugs. Angiology 1991; 42: 106
    CrossrefPubMedGoogle Scholar
  • 13 Branchi A, Rovellini A, Sommariva D, Gugliandolo AG, Fasoli A. Effect of three fibrate derivatives and of two HMG-CoA reductase inhibitors on plasma fibrinogen level in patients with primary hypercholesterolemia. Thromb Haemost 1993; 70: 241-243
    Article in Thieme ConnectPubMedGoogle Scholar
  • 14 Aimer LO, Kjelström T. The fibrinolytic system and coagulation during bezafibrate treatment of hypertriglyceridemia. Atherosclerosis 1986; 61: 81-85
    CrossrefPubMedGoogle Scholar
  • 15 Caimi G, francavilla g, Romano A, Catania A, Santonocito G, Sarno A. Blood rheology changes during bezafibrate treatment. Br J Clin Practice 1988; 42: 456-458
    PubMedGoogle Scholar
  • 16 Simpson IA, Lorimer AR, Walker ID, Davidson JF. Effect of ciprofibrate on platelet aggregation and fibrinolysis in patients with hypercholesterolaemia. Thromb Haemost 1985; 54: 442-444
    Article in Thieme ConnectPubMedGoogle Scholar
  • 17 Andersen P, Smith P, Seljeflot I, Brataker S, Amesen H. Effects of gemfibrozil on lipids and haemostasis after myocardial infarction. Thromb Haemost 1990; 63: 174-177
    Article in Thieme ConnectPubMedGoogle Scholar
  • 18 O’Brien J, Etherington MD, Shuttleworth R, Adams C, Middleton JE. et al A pilot study of the effect of gemfibrozil on some haematological parameters. Thromb Res 1982; 26: 275-279
    CrossrefPubMedGoogle Scholar
  • 19 Avellone G, Di GarboV, Crodova R, Ranelli G, De SimoneR, Bimppiani G. Effect of gemfibrozil treatment on fibrinolysis system in patients with hypertriglyceridemia. Curr Therapeutic Res 1992; 52: 338-348
    PubMedGoogle Scholar
  • 20 Wilkes HC, Meade TW, Barzegar S, Foley AJ, Hughes LO, Bauer KA, Rosenberg RD, Miller GJ. Gemfibrozil reduces plasma prothrombin fragment F1+2concentration, a marker of coagulability, in patients with coronary heart disease. Thromb Haemost 1992; 67: 503-506
    Article in Thieme ConnectPubMedGoogle Scholar
  • 21 Kushner I. The phenomenon of the acute phase response. Ann N Y Acad Sci 1982; 389: 39-48
    CrossrefPubMedGoogle Scholar
  • 22 Baumann H, Onorato V, Gauldie J, Jahreis GP. Distinct sets of acute phase plasma proteins are stimulated by separate human hepatocyte-stimulating factors in monokines in rat hepatoma cells. J Biol Chem 1987; 262: 9756-9768
    PubMedGoogle Scholar
  • 23 Pickart L. Suppression of acute-phase synthesis of fibrinogen by a hypolipidemic drug (Clofibrate). Int J Tiss Reac 1981; 03: 65-72
    PubMedGoogle Scholar
  • 24 Humphries SE, Cook M, Dubowitz M, Stirling Y, Meade TW. Role of genetic variation at the fibrinogen locus in determination of plasma fibrinogen concentrations. Lancet 1987; 01: 1452-1455
    PubMedGoogle Scholar
  • 25 Thomas A, Lamlum H, Humphries S, Green F. Linkage disequilibrium across the fibrinogen locus as shown by five genetic polymorphisms, G/A-455(HaeIII), C/T-148 (HinIII/VAluI),T/G+1689(AvaII), andBclI(β-fibrinogen) andTaqI(α-fibrinogen), and their detection by PCR. Human Mutation 1994; 03: 79-81
    CrossrefPubMedGoogle Scholar
  • 26 Cook M, Godiner N, Green F, Stirling Y, Meade TW, Humphries SE. Genetic control of plasma fibrinogen levels. In: Fibrinogen 3. Biochemistry, biological functions, gene regulations and expression. Mosseson MW, Amran DL, Siebenlist KR, DiOrio JP. eds Amsterdam: Elsevier Science Publishers BV; 1988: 11-15
    Google Scholar
  • 27 Thomas AE, Green FR, Kelleher CH, Wilkes HC, Brennan PJ, Meade TW, Humphries SE. Variation in the promoter region of the β-fibrinogen gene is associated with plasma fibrinogen levels in smokers and non-smokers. Thromb Haemost 1991; 65: 487-490
    Article in Thieme ConnectPubMedGoogle Scholar
  • 28 Green F, Hamsten A, Blombäck M, Humphries S. The role of β-fibrinogen genotype in determining plasma levels in young survivors of myocardial infarction and healthy controls from Sweden. Thromb Haemost 1993; 70: 915-920
    Article in Thieme ConnectPubMedGoogle Scholar
  • 29 de BartACW, de MaatMPM, Hennis BC, Kluft C. Longitudinal stability of plasma fibrinogen levels in healthy volunteers. In: Fibrinogen: a “new” cardiovascular risk factor. Ernst E, Koenig W, Lowe GDO, Meade TW. eds Vienna: Blackwell-MZV; 1992: 86-90
    Google Scholar
  • 30 Von ClaussA. Gerinnungsphysiologische Schnellmethode zur Bestimmung des Fibrinogens. Acta Haematol 1957; 17: 237-246
    CrossrefPubMedGoogle Scholar
  • 31 Knipscheer HC, de ValoisJC, van denEndeA, ten CateJW, Kastelein JJP. Ciprofibrate versus Gemfibrozil in the treatment of primary hyperlipidemia. Atherosclerosis 1996; 124 Suppl S75-S81
    CrossrefPubMedGoogle Scholar
  • 32 de MaatMPM, Pietersma A, Kofflard M, Sluiter W, Kluft C. The complex association of plasma fibrinogen levels with coronary artery disease, smoking and inflammatory markers. Atherosclerosis 1996; 121: 185-191
    CrossrefPubMedGoogle Scholar
  • 33 Cortellaro M, Boschetti C, Cofrancesco E, Zanussi C, Catalano M, de GaetanoG, Gabrielli L, Lombardi B, Specchia G, Tavazzi L, Tremoli E, Della VolpeA, Polli E. PLAT Study Group The PLAT Study: a multidisciplinary study of hemostatic function and conventional risk factors in vascular disease patients. Atherosclerosis 1991; 90: 109-118
    CrossrefPubMedGoogle Scholar
  • 34 Fowkes FGR, Connor JM, Smith FB, Wood J, Donnan PT, Lowe GDO. Fibrinogen genotype and risk of peripheral atherosclerosis. Lancet 1992; 339: 693-696
    CrossrefPubMedGoogle Scholar
  • 35 Wiseman SA, Jaye PD, Powell JT, Humphries SE, Greenhalgh RM. Frequency of DNA polymorphisms of the apolipoprotein B and fibrinogen genes in young patients with peripheral arterial disease. In: Applied Cardiovascular Biology 1989. Zilla P, Fasol R, Callow A. eds Int Soc Appl Cardiovasc Biol Basel, Karger. 1990. vol 01. pp 118-123
    Google Scholar
  • 36 Scarabin PY, Bara L, Ricard S, Poirier O, Cambou JP, Arveiler D, Luc G, Evans AE, Samama MM, Cambien F. Genetic variation at the β-fibrinogen locus in relation to plasma fibrinogen concentrations and risk of myocardial infarction. The ECTIM study. Arterioscl Thrombos 1993; 13: 886-891
    PubMedGoogle Scholar
  • 37 Koster T, Rosendaal FR, Reitsma PH, Van derVelden PA, Briët E, Vandenbroucke JP. 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: 719-722
    Article in Thieme ConnectPubMedGoogle Scholar