Gemfibrozil Reduces Thrombin Generation in Patients with Combined Hyperlipidaemia, without Influencing Plasma Fibrinogen, Fibrin Gel Structure or Coagulation Factor VII

Anders Bröijersén; Anders Hamsten; Angela Silveira; Kamaran Fatah; Alison H Goodall; Sabina Eriksson; Bo Angelin; Paul Hjemdahl

doi:10.1055/s-0038-1650548

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 1996; 76(02): 171-176
DOI: 10.1055/s-0038-1650548

Original Article

Schattauer GmbH Stuttgart

Gemfibrozil Reduces Thrombin Generation in Patients with Combined Hyperlipidaemia, without Influencing Plasma Fibrinogen, Fibrin Gel Structure or Coagulation Factor VII

Authors

Anders Bröijersén

¹The Department of Clinical Pharmacology, Stockholm, Sweden
Anders Hamsten

³The Atherosclerosis Research Unit, King Gustaf V Research Institute, Department of Medicine, Karolinska Hospital, Stockholm, Sweden
Angela Silveira

³The Atherosclerosis Research Unit, King Gustaf V Research Institute, Department of Medicine, Karolinska Hospital, Stockholm, Sweden
Kamaran Fatah

²Clinical Chemistry and Blood Coagulation, Department of Laboratory Medicine, Stockholm, Sweden
Alison H Goodall

⁵The Vascular Cell Biology Laboratory, Department of Chemical Pathology, Royal Free Hospital School of Medicine, London, UK
Sabina Eriksson

⁴The Metabolism Unit, Department of Medicine, Huddinge University Hospital, Karolinska Institute, Stockholm, Sweden
Bo Angelin

⁴The Metabolism Unit, Department of Medicine, Huddinge University Hospital, Karolinska Institute, Stockholm, Sweden
Paul Hjemdahl

¹The Department of Clinical Pharmacology, Stockholm, Sweden

Abstract

PDF Download

Summary

A double-blind, placebo-controlled, cross-over study was conducted in 21 men with combined hyperlipoproteinaemia to examine if lipid-lowering treatment with gemfibrozil (10-12 weeks) affects blood coagulation and fibrin gel structure at rest or during mental stress. Gemfibrozil lowered plasma triglycerides by 57 ± 4%, whereas high density lipoprotein (HDL) cholesterol increased by 22 ± 5%. Gemfibrozil lowered the triglyceride content of low density lipoprotein (LDL). Gemfibrozil reduced the plasma concentrations of thrombin-antithrombin complex (TAT) and prothrombin fragment F₁₊₂ (F₁₊₂), both at rest and during mental stress. However, there were no effects of gemfibrozil treatment on the plasma concentrations of fibrinogen, factor VII antigen, activated factor VII (Vila) or activated factor XII (XIIa), or on fibrin gel structure. Acute mental stress per se did not influence coagulation factors, reaction products or fibrin gel structure, or their responses to the study drug. Thus, gemfibrozil reduces thrombin generation in men with combined hyperlipoproteinaemia, without influencing the plasma levels of fibrinogen, Vila and XIIa, or fibrin gel structure. Attenuation of thrombin generation may contribute to the primary-preventive effects of gemfibrozil on coronary heart disease.

PDF (378 kb)

References

References
1 Salomaa V, Rasi V, Pekkanen J, Jauhiainen M, Vahtera E, Pietinen P, Korhonen H, Kuulasmaa K, Ehnholm C. The effects of saturated fat and n-6 polyunsaturated fat on postprandial lipemia and hemostatic activity. Atherosclerosis 1993; 103: 1-11
2 Silveira A, Karpe F, Blombäck M, Steiner G, Walldius G, Hamsten A. Activation of coagulation factor VII during alimentary lipemia. Arterioscler Thromb 1994; 14: 60-69
3 Scarabin PY, Bara L, Samama M, Orssaud G. Further evidence that activated factor VII is related to plasma lipids. Br J Haematol 1985; 61: 186-187
4 Moor E, Silveira A, van’t Hooft F, Suontaka A-M, Eriksson P, Blombäck M, Hamsten A. Coagulation factor VII mass and activity in young men with myocardial infarction at a young age: role of plasma lipoproteins and factor VII genotype. Arterioscler Thromb Vase Biol 1995; 15: 655-664
5 Miller GJ, Walter SJ, Stirling Y, Thompson SG, Esnouf MP, Meade TW. Assay of factor VII activity by two techniques: evidence for increased conversion of VII to Vila in hyperlipidaemia, with possible implications for ischaemic heart disease. Br J Haematol 1985; 59: 249-258
6 Folsom AR, Wu KK, Davis CE, Conlan MG, Solie PD, Szklo M. Population correlates of plasma fibrinogen and factor VII, putative cardiovascular risk factors. Atherosclerosis 1991; 91: 191-205
7 Lowe GDO, Drummond MM, Third JLHC, Brenner WF, Forbes CD, Prentice CR, Lawrie TD. Increased plasma fibrinogen and platelet-aggre-gates in type II hyperlipoproteinaemia. Thromb Haemost 1980; 42: 1503-1507
8 Manninen V, Malkonen M, Eisalo A, Virtamo J, Tuomilehto J, Kuusisto P. Gemfibrozil in the treatment of dyslipidemia. A five-year follow-up study. Acta Med Scand 1982; 668 (suppl) 82-87
9 Weintraub MS, Eisenberg S, Breslow JL. Different patterns of postprandial lipoprotein metabolism in normal, type Ha, type III, and type IV hyper-lipoproteinemic individuals. Effects of treatment with cholestyramine and gemfibrozil. J Clin Invest 1987; 79: 1110-1119
10 Frick MH, Elo O, Haapa K, Heinonen OP, Heinsalmi P, Helo P, Huttunen JK, Kaitaniemi P, Koskinen P, Manninen V, Maenpaa M, Malkonen M, Manttari M, Norda S, Pastemach A, Pilikarainen J, Romo M, Sjoblom T, Nikkila EA. Helsinki Heart Study: primary prevention trial with gemfibrozil in middle-aged men with dyslipidemia. Safety of treatment, changes in risk factors, and incidence of coronary heart disease. N Engl J Med 1987; 317: 1237-1245
11 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
12 Stringer MD, Steadman CA, Kakkar VV. Gemfibrozil in hyperlipidaemic patients with peripheral arterial disease: some undiscovered actions. Curr Med Res Opin 1990; 12: 207-214
13 Avellone G, Di GarboV, Cordova R, Piliego T, Raneli G, De Simone R, Bompiani GD. Improvement of fibrinolysis and plasma lipoprotein levels induced by gemfibrozil in hypertriglyceridemia. Blood Coag Fibrinol 1995; 6: 543-548
14 Wilkes HC, Meade TW, Barzegar S, Foley AJ, Hughes LO, Bauer KA, Rosenberg RD, Miller GJ. Gemfibrozil reduces plasma prothrombin fragment F1+2 concentration, a marker of coagulability, in patients with coronary heart disease. Thromb Haemost 1992; 67: 503-506
15 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
16 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. Res Clin Forums 1982; 4: 71-76
17 Avellone G, di Garbo V, Panno AV, Cordova R, Lepore R, Strano A. Changes induced by gemfibrozil on lipidic, coagulative and fibrinolytic pattern in patients with type IV hyperlipoproteinemia. Int Angiol 1988; 7: 270-277
18 Mann KG. Factor VII assays, plasma triglyceride levels, and cardiovascular disease risk. Arteriosclerosis 1989; 9: 783-784
19 Broijersen A, Eriksson M, Angelin B, Hjelmdahl P. Gemfibrozil enhances platelet activity in patients with combined hyperlipoproteinemia. Arterio-scler Thromb Vase Biol 1995; 15: 121-127
20 Broijersen A, Eriksson M, Wiman B, Angelin B, Hjelmdahl P. Gemfibrozil treatment of combined hyperlipoproteinemia: no improvement of fibrinolysis despite marked reduction of plasma triglycerides. Arterioscler Thromb Vase Biol 1996; 16: 511-516
21 Frankenhaeuser M, Mellis I, Rissler A, Bjorkvall C, Patkai P. Catecholamine excretion as related to cognitive and emotional reaction patterns. PsychosomMed 1968; 30: 109-120
22 Vermylen C, de Vreker R, Verstraete M. A rapid enzymatic method for assay of fibrinogen fibrin polymerization time (FPT test). Clin Chim Acta 1963; 8: 418-424
23 Wildgoose P, Nemerson Y, Lyng HansenL, Nielsen FE, Glazer S, Hedner U. Measurement of basal levels of factor Vila in hemophilia A and B patients. Blood 1992; 80: 25-28
24 Morrissey JH, Macik BG, Neuenschwander PF, Comp PC. Quantitation of activated factor VII levels in plasma using a tissue factor mutant selectively deficient in promoting factor VII activation. Blood 1993; 81: 734-744
25 Silveira A, Green F, Karpe F, Blomback M, Humphries S, Hamsten A. Elevated levels of factor VII activity in the postprandial state: effect of the factor VII Arg-Gln polymorphism. Thromb Haemost 1994; 72: 734-739
26 Blombäck B, Carlsson K, Hessel B, Liljeborg A, Procyk R, Aslund N. Native fibrin gel networks observed by 3 D microscopy, permeation and turbidity. Biochim Biophys Acta 1989; 997: 96-110
27 Fatah K, Hamsten A, Blombäck B, Blombäck M. Native fibrin gel network properties and coronary heart disease: relations to plasma fibrinogen, acute phase protein, serum lipoproteins and coronary atherosclerosis. Thromb Haemost 1992; 68: 130-135
28 Blombäck B, Carlsson K, Fatah K, Hessel B, Procyk R. Fibrin in human plasma: gel architectures governed by rate and nature of fibrinogen activation. Thromb Res 1994; 75: 521-538
29 Blombäck B, Okada M. Fibrin gel structure and clotting time. Thromb Res 1982; 25: 51-70
30 Blombäck B, Bannerjee 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, and Chien S. (Eds) Fibrinogen, Thrombosis, Coagulation, and Fibrinolysis. Plenum Press; New York: 1991: 1-23
31 Carlson K. Lipoprotein fractionation. J Clin Pathol 1973; 26 (Suppl. 05) 32-37
32 Lopez-Virella MF, Stone P, Ellis S, Colwell JA. Cholesterol determination in high density lipoproteins separated by three different methods. Clin Chem 1977; 23: 882-884
33 Hjelmdahl P. Catecholamine measurements in plasma by high-performance liquid chromatography with electrochemical detection. Methods Enzymol 1987; 142: 521-534
34 Jones B, Kenward MG. Design and analysis of cross-over trials. New York, NY: Chapman and Hall; 1989
35 Bauer KA, Weiss LM, Sparrow D, Vokonas PS, Rosenberg RD. Aging-associated changes in indices of thrombin generation and protein C activation in humans. J Clin Invest 1987; 80: 1527-1534
36 Eichinger S, Wolzt M, Nieszpaur-Los M, Schneider B, Lechner K, Eichler H-G, Kyrle PA. Effects of a low molecular weight heparin (Fragmin) and of unfractionated heparin on coagulation activation at the site of plug formation in vivo. Thromb Haemost 1994; 72: 831-835
37 Eichinger S, Wolzt M, Schneider B, Nieszpaur-Los M, Heinrichs H, Lechner K, Eichler H-G, Kyrle PA. Effects of recombinant hirudin (r-Hirudin, HBW 023) on coagulation and platelet activation in vivo. Comparison with unfractionated heparin and a low-molecular-weight heparin preparation (Fragmin). Arterioscler Thromb Vase Biol 1995; 15: 886-892
38 Merlini PA, Bauer KA, Oltrona L, Ardissino D, Cattaneo M, Belli C, Man-nucci PM, Rosenberg RD. Persistent activtion of cogulation mechanism in unstable angina and myocardial infarction. Circulation 1994; 90: 61-68
39 Szczeklik A, Dropinski J, Radwan J, Krzanowski M. Persistent generation of thrombin after acute myocardial infarction. Arterioscler Thromb 1992; 12: 548-553
40 Bauer KA, Kass BL, ten Cate H, Hawiger JJ, Rosenberg RD. Factor IX is activated in vivo by the tissue factor mechanism. Blood 1990; 76: 731-736
41 Elkeles RS, Chakrabarti R, Vickers M, Stirling Y, Meade TW. Effect of treatment of hyperlipidaemia on haemostatic variables. Br Med J 1980; 281: 973-294
42 Simpson HCR, Meade TW, Stirling Y, Mann JI, Chakrabarti R, Woolf L. Hypertriglyceridaemia and hypercoagulability. Lancet 1983; i: 786-789
43 Mitropoulos KA, Reeves BEA, O’Brien DP, Cooper JA, Martin JC. The relationship between factor VII coagulant activity and factor XII activation induced in plasma by endogenous or exogenously added contact surface. Blood Coag Fibrinol 1993; 4: 223-234