Hypocoagulant and Lipid-Lowering Effects of Dietary n-3 Polyunsaturated Fatty Acids With Unchanged Platelet Activation in Rats

From the Departments of Human Biology (C.M.A.N., R.F.G.O., G.H., J.W.M.H.) and Biochemistry (S.B., J.W.M.H.), University of Maastricht, Maastricht, and the Gaubius Laboratory, TNO-PG (J.J.E.), Leiden, The Netherlands.

Correspondence to Dr C.M.A. Nieuwenhuys, Department of Human Biology, Maastricht University, PO Box 616, 6200 MD Maastricht, The Netherlands. E-mail C.Nieuwenhuys{at}hb.unimaas.nl

Abstract—We investigated the effects of dietary polyunsaturated fatty acids (PUFAs) on blood lipids and processes that determine hemostatic potential: platelet activation, coagulation, and fibrinolysis. For 8 to 10 weeks, Wistar rats were fed a high-fat diet containing various amounts (2% to 16%) of n-3 PUFAs derived from fish oil (FO) or a diet enriched in n-6 PUFAs from sunflower seed oil (SO). Only the FO diets caused a reduction in mean platelet volume, platelet arachidonate level, and formation of thromboxane B₂ by activated platelets, but neither of the diets had a measurable effect on platelet activation. The FO-rich diets decreased the plasma concentrations of triglycerides and cholesterol, whereas the SO diet reduced triglycerides only. Parameters of fibrinolysis and standard coagulation times, ie, activated partial thromboplastin time and prothrombin time, were only marginally influenced by these diets. In contrast, dietary FO, but not SO, led to decreased levels of the vitamin K–dependent coagulation factors prothrombin and factor VII, while the level of antithrombin III was unchanged. The endogenous thrombin potential (ETP) was measured with an assay developed to detect the hypocoagulable state of plasma. After activation with tissue factor and phospholipids, the ETP was reduced by 23% or more in plasma from animals fed a diet with >4% FO. No significant effect of the SO diet on ETP was observed. Control experiments with plasma from warfarin-treated rats indicated that the ETP was more sensitive to changes in prothrombin concentration than in factor VII concentration. Taken together, these results indicate that in rats, prolonged administration of n-3 but not n-6 PUFAs can lead to a hypocoagulable state of plasma through a reduced capacity of vitamin K–dependent thrombin generation, with unchanged thrombin inactivation by antithrombin III.

Key Words: fish oil • coagulation • n-3 polyunsaturated fatty acids • thrombin • platelets

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