Subscribe to RSS
DOI: 10.1055/s-0038-1657709
Effects of Gemfibrozil and Ciprofibrate on Plasma Levels of Tissue-type Plasminogen Activator, Plasminogen Activator Inhibitor-1 and Fibrinogen in Hyperlipidaemic Patients
Publication History
Received 31 1996
Accepted after resubmission 05 June 1997
Publication Date:
12 July 2018 (online)
![](https://www.thieme-connect.de/media/10.1055-s-00035024/199701/lookinside/thumbnails/10-1055-s-0038-1657709-1.jpg)
Summary
Evaluation of fibrate treatment in humans has focused primarily on its anti-lipidaemic effects. A potentially favourable haemostasis-modulating activity of fibrates has also been recognized but the data are not consistent. We sought to learn more about this variability by examining the effects of gemfibrozil and ciprofibrate on plasma levels of tissue-type plasminogen activator (t-PA), plasminogen activator inhibitor-1 (PAI-1) and fibrinogen in primary hyperlipidaemic patients after six and twelve weeks of treatment using different assay systems for PAI-1 and fibrinogen. Although both fibrates effectively lowered triglyceride and cholesterol levels, no effect on the elevated baseline antigen levels of t-PA and PAI-1 was observed after fibrate treatment. However, both fibrates influenced plasma fibrinogen levels, albeit in a different way. Fibrinogen antigen levels were elevated by 17.6% (p <0.05) and 24.3% (p <0.001) with gemfibrozil after six and twelve weeks, respectively, whereas with ciprofibrate there was no effect. Using a Clauss functional assay with either a mechanical end point or a turbidity-based end point, no significant change in fibrinogen levels was seen after six weeks of gemfibrozil treatment. However, after twelve weeks, gemfibrozil enhanced functional fibrinogen levels by 7.2% (p <0.05) as assessed by the Clauss mechanical assay, but decreased functional fibrinogen levels by 12.5% (p <0.0001) when a Clauss assay based on turbidity was used. After six or twelve weeks of ciprofibrate treatment, functional fibrinogen levels were decreased by 10.1% (p <0.001) and 10.5% (p <0.0001), respectively on the basis of Clauss mechanical and by 14.2% (p <0.001) and 28.2% (p <0.0001), respectively with the Clauss turbidimetric assay. A remarkable and consistent finding with both fibrates was the decrease in functionality of fibrinogen as assessed by the ratio of functional fibrinogen (determined by either of the two Clauss assays) to fibrinogen antigen.
Taken together, our results indicate that at least part of the variability in the effects of fibrates on haemostatic parameters can be explained by intrinsic differences between various fibrates, by differences in treatment period and/or by the different outcomes of various assay systems. Interestingly, the two fibrates tested both reduced the functionality of fibrinogen.
-
References
- 1 Levine GN, Keaney JF, Vita JA. Cholesterol reduction in cardiovascular disease. N Engl J Med 1995; 332: 512-521
- 2 Sirtori CR, Chiesa G. Effects of lipid-lowering agents and other treatment regimens on serum lipoproteins. Curr Opin Lipidol 1990; 1: 262-269
- 3 Schonfeld G. The effects of fibrates on lipoprotein and hemostatic coronary risk factors. Atherosclerosis 1994; 111: 161-174
- 4 Tikkanen MJ. Fibric acid derivatives. Curr Opin Lipidol 1992; 3: 29-33
- 5 Thompson SG, Kienast J, Pyke S, Haverkate F, Van deLoo JCW. Hemostatic factors and the risk of myocardial infarction or sudden death in patients with angina pectoris. N Engl J Med 1995; 332: 635-641
- 6 Meade TW. Haemostatic function and arterial disease. Br Med Bull 1994; 50: 755-775
- 7 Keber I, Lavre J, Sue S, Keber D. The decrease of plasminogen activator inhibitor after normalization of triglycerides during treatment with fibrates. Fibrinolysis 1994; 8: 57-59
- 8 Branchi A, Rovelline A, Sommariva D, Gugliandolo AG, Fasoli A. Effect of three fibrate derivatives and of two HMG-CoA reductase inhibitors on plasma fibrinogen levels in patients with primary hypercholesterolemia. Thromb Haemost 1993; 70: 241-243
- 9 Andersen P, Smith P, Seljeflot I, Brataker S, Amesen H. Effect of gemfibrozil on lipids and haemostasis after myocardial infarction. Thromb Haemost 1990; 63: 174-177
- 10 Haire WD. Gemfibrozil predictably lowers triglycerides but does not significantly change plasminogen activator inhibitor activity in hypertrigly-ceridemic patients with a history of thrombosis. Thromb Res 1991; 64: 493-501
- 11 Brӧijersén A, Eriksson M, Wiman B, Angelin B, Hjemdahl P. Gemfibrozil treatment of combined hyperlipoproteinemia. Arterioscler Thromb Vase Biol 1996; 16: 511-516
- 12 Avellone G, Di GarboV, Cordova R, Panno AV, Ranelli G, De SimoneR, Bompiani GD. Fibrinolytic effect of gemfibrozil versus placebo administration in response to venous occlusion. Fibrinolysis 1993; 7: 416-421
- 13 Wilkes HC, Meade TW, Barzegar S, Foley AJ, Hughes LO, Bauer KA, Rosenberg RD, Miller GJ. Gemfibrozil reduces plasma prothrombin fragment FI+2 concentration, a marker of coagulability, in patients with coronary heart disease. Thromb Haemost 1992; 67: 503-506
- 14 O’Brien JR, Etherington MD, Shuttleworth RD, Adams CM, Middleton JE, Goodland FC. A pilot study of the effect of gemfibrozil on some haemato-logical parameters. Thromb Res 1982; 26: 275-279
- 15 Meijer P, Pollet DE, Wauters J, Kluft C. Specificity of antigen assays of plasminogen activator inhibitor in plasma: Innotest PAI-1 immunoassay evaluated. Clin Chem 1994; 40: 110-115
- 16 Kluft C, Jie AFH. Comparison of specificities of antigen assays for plasminogen activator inhibitor 1 (PAI-1). Fibrinolysis 1990; 4: 136-137
- 17 Halbmayer WM, Haushofer A, Schӧn R, Radek J, Fischer M. Comparison of a new automated kinetically determined fibrinogen assay with the 3 most used fibrinogen assays (functional, derived and nephelometric) in Austrian laboratories in several clinical populations and healthy controls. Haemostasis 1995; 25: 114-123
- 18 De MaatMPM, Kamerling SWA, Kluft C. The sensitivity of some clotting rate and immunological fibrinogen assays for high, low and low’ molecular weight forms of fibrinogen. In: Regulation and modulation of the plasma fibrinogen level. Thesis. University of Rotterdam ISBN ISBN: 90-5412-020-7 1995. pp 29-46
- 19 Simpson IA, Lorimer R, Walker ID, Davidson JF. Effect of ciprofibrate on platelet aggregation and fibrinolysis in patients with hypercholesterolaemia. Thromb Haemost 1985; 54: 442-444
- 20 Declerck PJ, Alessi M-C, Verstreken M, Kruithof EKO, Juhan-Vague I, Collen D. Measurement of plasminogen activator inhibitor 1 in biologic fluids with a murine monoclonal antibody-based enzyme-linked immunosorbent assay. Blood 1987; 71: 220-225
- 21 Knipscheer HC, De ValoisJC, Van denEnde B, Ten CateJ, Kastelein JJP. Ciprofibrate versus gemfibrozil in the treatment of primary hyperlipidaemia. Atherosclerosis 1996; 124: 75-81
- 22 Kluft C, Meijer P. Update 1996: blood collection and handling procedures for assessment of plasminogen activators and inhibitors (Leiden Fibrinolysis Workshop). Fibrinolysis 1996; 10 (Suppl. 02) 171-179
- 23 Hoegee-de NobelE, Voskuilen M, Briët E, Brommer EJP, Nieuwenhuizen W. A monoclonal antibody-based quantitative enzyme immunoassay for the determination of plasma fibrinogen concentrations. Thromb Haemost 1988; 60: 1-4
- 24 Von ClaussA. Gerinnungsphysiologische Schnellmethode zur Bestim-mung des Fibrinogenes. Acta Haematol 1957; 17: 141-153
- 25 Huber K, Beckmann R, Lang I, Schuster E, Binder BR. Circadian fluctuations in plasma levels of tissue plasminogen activator antigen and plasminogen activator inhibitor activity. Fibrinolysis 1989; 3: 41-43
- 26 Nieuwenhuizen W, Laterveer R, Hoegee-de NobelE, Bos R. A one-step enzyme immunoassay for total plasminogen activator inhibitor-1 antigen in human plasma. Blood Coag Fibrinol 1995; 6: 268-272
- 27 Seifried E, Oethinger M, Tanswell P, Hoegee-de NobelE, Nieuwenhuizen W. Influence of acute myocardial infarction and rt-PA therapy on circulating fibrinogen. Thromb Haemost 1993; 69: 321-327
- 28 Hoffmann JJML, Vijgen M, Nieuwenhuizen W. Comparison of the specificity of four fibrinogen assays during thrombolytic therapy. Fibrinolysis 1990; 4: 121-123
- 29 De MaatMPM, Arnold AER, Van BurenS, Wilson JHP, Kluft C. Modulation of plasma fibrinogen levels by ticlopidine in healthy volunteers and patients with stable angina pectoris. Thromb Res 1993; 70: 349-354
- 30 Regañon E, Vila V, Aznar J, Lacueva V, Martinez V, Ruano M. Studies on the functionality of newly synthesized fibrinogen after treatment of acute myocardial infarction with streptokinase, increase in the rate of fibrinopeptide release. Thromb Haemost 1993; 70: 978-983
- 31 Holm B, Nilsen EWT, Kierulf P, Godal HC. Purification and characterization of 3 fibrinogens with different molecular weights obtained from normal human plasma. Thromb Res 1985; 84: 509-516
- 32 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; 2: 533-538
- 33 ECAT Angina Pectoris Study Group. ECAT Angina Pectoris Study: baseline associations of haemostatic factors with extent of coronary arteriosclerosis and other coronary risk factors in 3000 patients with angina pectoris undergoing coronary angiography. Eur Heart J 1993; 14: 08-17
- 34 Blombäck B. Fibrinogen and fibrin-proteins with complex roles in hemostasis and thrombosis. Thromb Res 1996; 83: 01-75
- 35 Collet J, Mishal Z, Vasse M, Mirshahi M, Caen J, Soria C, Soria J. Pharmacological approaches of fibrin gel architecture modulation and thrombus degradation: its implication in atherogenesis and thromboembolism disease. Thromb Res 1994; 75: 353-359
- 36 Koopman J, Haverkate F, Grimbergen J, Egbring R, Lord ST, Mosesson MW, DiOrio JP, Siebenlist K, Legrand C, Soria J, Soria C, Caen JP. The molecular basis for fibrinogen Dusart (Aα 554 Arg → Cys) and its association with abnormal fibrin polymerization and thrombophilia. J Clin Invest 1993; 91: 1637-1642
- 37 Fatah K, Silveira A, Tomvall P, Karpe F, Blombäck M, Hamsten A. Proneness to formation of tight and rigid fibrin gel structures in men with myocardial infarction at a young age. Thromb Haemost 1996; 76: 535-540
- 38 Brӧijersén A, Hamsten A, Silveira A, Fatah K, Goodall AH, Eriksson M, Angelin B, Hjemdahl P. Gemfibrozil reduces thrombin generation in patients with combined hyperlipidaemia, without influencing plasma fibrinogen, fibrin gel structure or coagulation factor VII. Thromb Haemost 1996; 76: 171-176
- 39 Hamsten A, Walldius G, Szamosi A, Blombäck M, De FaireU, Dahlen G, Landou C, Wiman B. Plasminogen activator inhibitor in plasma: risk factor for recurrent myocardial infarction. Lancet 1987; 4: 3-9
- 40 Mussoni L, Mannucci L, Sirtori M, Camera M, Madema P, Sironi L, Tremoli E. Hypertriglyceridemia and regulation of fibrinolytic activity. Arterioscler Thromb 1992; 12: 19-27
- 41 Scarabin P-Y, Plu-Bureau G, Zitoun D, Bara L, Guize L, Meyer SamamaM. Changes in haemostatic variables induced by oral contraceptives containing 50 μg or 30 μg oestrogen: absence of dose-dependent effect on PAI-1 activity. Thromb Haemost 1995; 74: 928-932
- 42 Oosthuizen W, Vorster HH, Jerling JC, Barnard HC, Smuts CM, Silvis N, Druger A, Venter CS. Both fish oil and olive oil lowered plasma fibrinogen in women with high baseline fibrinogen levels. Thromb Haemost 1994; 72: 557-562
- 43 Barriocanal LA, Mishra V, Tarbit M, Kesteven P, Alberti KGMM, Walker M. The effect of triglyceride infusion on the regulators of fibrinolysis. Fibrinolysis 1995; 9: 243-246
- 44 Heller FR, Parfonry A, Descamps O, Desager J, Harvengt C. Effects of gemfibrozil on plasma lipoproteins, plasma activities of hepatic enzymes, and hemostatic variables in hypertriglyceridemic patients. Curr Therap Res 1995; 56: 597-606