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© 2003 The American Society for Nutritional Sciences J. Nutr. 133:2210-2213, July 2003

Human Nutrition and Metabolism
Research Communication

Plant and Marine Derived (n-3) Polyunsaturated Fatty Acids Do Not Affect Blood Coagulation and Fibrinolytic Factors in Moderately Hyperlipidemic Humans

Yvonne E. Finnegan, David Howarth*, Anne M. Minihane, Samantha Kew{dagger}, George J. Miller*, Philip C. Calder{dagger} and Christine M. Williams3

Hugh Sinclair Unit of Human Nutrition, University of Reading, Reading, UK; * Medical Research Council Cardiovascular Research Group, Wolfson Institute of Preventive Medicine, London, UK; and {dagger} Institute of Human Nutrition, University of Southampton, Southampton, UK

3To whom correspondence should be addressed. E-mail: c.m.williams{at}reading.ac.uk.


   ABSTRACT
TOP
 ABSTRACT
SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 LITERATURE CITED
 
Dietary {alpha}-linolenic acid (ALA) can be converted to long-chain (n-3) PUFA in humans and may potentially reproduce the beneficial effects of eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids on risk factors for coronary heart disease (CHD). This study compared the effects of increased intakes of ALA with those of dietary EPA and DHA on blood coagulation and fibrinolytic factors in fasting subjects. A placebo-controlled, parallel study was conducted in 150 moderately hyperlipidemic subjects, age 25–72 y. Subjects were randomly assigned to one of five interventions and consumed a total intake of 0.8 or 1.7g/d EPA+DHA, 4.5 or 9.5g/d ALA or control (linoleic acid; LA) for 6 mo. Fatty acids were incorporated into 25 g of fat spread, which replaced the subject’s normal spread and three capsules. Long-term supplementation with either dietary EPA+DHA or estimated biologically equivalent amounts of ALA did not affect factors VIIa, VIIc, VIIag, XIIa, XIIag, fibrinogen concentrations, plasminogen activator inhibitor-1 or tissue plasminogen activator activity compared with the control. (n-3) PUFA of plant or marine origin do not differ from one another or from LA in their effect on a range of blood coagulation and fibrinolytic factors.

KEY WORDS: • {alpha}-linolenic acid • eicosapentaenoic acid • docosahexaenoic acid • Factor VIIc • Factor XII

Blood coagulation and fibrinolysis play an important role in the development and complications of coronary heart disease (CHD). Fibrinogen concentration (1,2), tissue plasminogen activator (tPA) and plasminogen activator inhibitor-1 (PAI-1) antigen concentrations (3) are positively associated with CHD incidence. High factor VII coagulant activity (FVIIc) has also been reported to increase CHD risk in men in the Northwick Park Heart Study (1), although this finding was not replicated in more recent studies (4,5).

Individual studies have shown that supplementation with fish oils rich in eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) can alter coagulation and fibrinolysis variables, although there is little agreement on the overall effect of (n-3) PUFA on these variables (6). The intakes of EPA+DHA used in these studies (> 3 g/d) (7–11) are generally greater than levels that can be accomplished through dietary means, and there is little information on the effects of more modest increases in intakes.

One of the aims of the present study was therefore to examine the effects of modest increases in EPA+DHA, given long term, on a range of coagulation and fibrinolytic variables. A further aim was to study the effects on these variables of the precursor (n-3) PUFA. {alpha}-Linolenic acid (ALA), a plant-derived (n-3) fatty acid found in a wide variety of foods including commercial vegetable oils, can be converted by alternate desaturation and elongation to EPA and DHA in humans (12,13). Interest in potential cardioprotective effects of ALA was raised by findings from a secondary prevention trial that reported a substantial reduction in coronary events and death in subjects following a Mediterranean style diet that also included an ALA-rich margarine (14). As with reported effects of EPA+DHA in the GISSI (15) secondary prevention trials, the benefits were observed early in the trial, suggesting either an improved hemostatic profile or an antiarrhythmic effect.

Few studies have investigated the effects of ALA and none have noted any significant change in a range of blood coagulation or fibrinolysis factors (11,16,17). However, in all of these studies, supplementation was relatively short term (4–6 wk), which may not have allowed sufficient time for accumulation of long-chain (LC) (n-3) PUFA from the desaturation and elongation of ALA. The present study is the first to undertake a comparison of the effects of low dose EPA+DHA with increased intakes of ALA. The prolonged time period of supplementation and the measurement of FXII activation in response to (n-3) fatty acids are also important features of the study.


   SUBJECTS AND METHODS
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 ABSTRACT
 SUBJECTS AND METHODS
RESULTS
 DISCUSSION
 LITERATURE CITED
 
Subjects and study design.

Moderately hyperlipidemic, but otherwise healthy men and women aged 25–72 y were recruited from the local population and provided a screening blood sample after an overnight fast. Exclusion criteria for participation in the study included: cardiovascular, liver or other endocrine disease; diabetes; pregnancy/lactation; smoking >15 cigarettes/d; BMI < 20 and > 32 kg/m2; regular use of hypolipidemic or anti-inflammatory medication, aspirin, anticoagulants, fatty acid or antioxidant supplements; eating >2 portions of oily fish/wk (~180 g/wk); and vegetarianism. Moderate hyperlipidemia was defined as fasting total cholesterol (TC) 4.6–8.0 mmol/L and fasting triacylglycerol (TAG) 0.8–3.2 mmol/L. The study was approved by the University of Reading Ethics and Research Committee and West Berkshire Health Authority Ethics Committees (UK). Each volunteer gave written consent.

The study was a double-blind, placebo controlled, parallel study (18). Before the 6-mo intervention period with the test margarine/capsules, all participants consumed the control margarine and capsules for 1 mo. Subjects were then assigned to one of the five dietary treatment groups (n = 30 per group) by blocked stratified randomization with the groups matched for fasting TAG, age and sex. Sample size (n = 150) was estimated using power calculations based on the predictive TAG-lowering effect of 1.5g/d EPA+DHA, with 80% power and 5% significance. The study was run in three cohorts of ~50 subjects. Blood samples were taken at 0, 3 and 6 mo, after an overnight fast.

Dietary intervention.

The aim of the dietary intervention was to supplement the diet with modest amounts of EPA+DHA or biologically equivalent levels of the precursor, ALA, based on the existing literature, which suggests that 7 g ALA {cong} 1 g EPA+DHA in raising tissue LC (n-3) PUFA concentrations (12,19,20). The target intakes of EPA+DHA in the two fish oil intervention groups were 0.7 and 1.5 g/d, respectively, whereas target intakes of ALA in the two ALA-supplemented groups were 5.0 and 10.0 g/d, respectively. The target intakes in the (n-3) PUFA-supplemented groups and the control were calculated to include the estimated average contribution from the background UK diet of EPA+DHA (0.2 g/d) and ALA (1.5 g/d) (21).

The intervention was provided as 25 g/d of specially formulated spreads (85% fat) and three capsules. The control margarine was a typical (n-6) PUFA-rich margarine based mainly on sunflower and safflower oil (Table 1). The EPA+DHA enriched margarine was a sunflower- and fish oil-based margarine containing 0.5 g EPA+DHA/25 g portion. For the higher dose EPA+DHA intervention, three fish oil capsules containing a total of 0.8 g EPA+DHA were taken in addition to the fish oil margarine as described above. To maintain the double-blind aspect of the study, all other intervention groups were provided with placebo capsules. The moderate and high ALA interventions were based on rapeseed, linseed and sunflower oils. The amount of vitamin E in the interventions was standardized according to intake of unsaturated bonds, based on the amount and type of PUFA present (22).


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  		TABLE 1 Fatty acid composition of the margarines and capsules1, 2

 
Biochemical measurements.

Fasting venous samples were collected into a 1 x 4.5 mL sodium citrate tube (Becton Dickinson, Plymouth, UK) for analysis of factors VIIa, VIIc, VIIag, XIIa, XIIag and fibrinogen, a 1 x 2 mL sodium citrate tube for analysis of PAI-1 and a 1 x 2 mL acid citrate tube for analysis of tPA. Samples were centrifuged immediately at 1600 x g for 15 min and plasma was stored at -70°C. Samples from each subject were analyzed at the end of each cohort in a single batch to minimize variability, and all analyses of hemostatic factors were carried out at the Wolfson Coagulation Laboratory (MRC). FVIIa was measured by a one-stage clotting assay (23). FVIIc was measured by a one-stage semiautomated bioassay using rabbit brain thromboplastin (Diagen, Thame, Oxon, UK) and a FVII-deficient plasma, described elsewhere (24). FVIIag was determined using an ELISA with specific rabbit antihuman FVII antibody (Asserachrom VII:Ag; Diagnostico Stago, Cedex, France). FXIIa was measured by ELISA (Activated FXII assay kit FAFT200; Axis-Shield, Dundee, UK). FXIIag was measured both by ELISA using paired antibodies (FXII-EIA) and by Laurell "Rocket" electroimmunoassay using goat anti-human FXII IgG (GAFXII-AG; both from Enzyme Research Laboratories, Swansea, UK). Fibrinogen was measured using a thrombin clotting assay, modified from Clauss (25), using standard plasma (Immuno Vienna, Austria). TPA and PAI-1 activities were measured using the Coatest PAI-1 assay kit (Chromogenix Coatest PAI; Quadratech Diagnostics, Epsom, Surrey, UK) using different methodologies and differently anticoagulated samples. All assays were performed in duplicate; all samples from individual subjects were assayed at the same time. The intra-assay CV for FVIIa, FVIIc, FVIIag and FXIIa were 11.1, 2.2 3.5 and 5.4%, respectively. The intra-assay CV for fibrinogen, t-PA and PAI-1 were 4.4, 4.2 and 2.4%, respectively.

Statistics.

Results are expressed as means and SD for all variables unless otherwise indicated. FVIIa and PAI-1 were log-transformed before analysis and results expressed as geometric means with approximate SD. Plasma tPA activity was expressed as median and range. Differences between treatments at each time point were tested by ANOVA. For tPA, the nonparametric Kruskal-Wallis test was used. To take account of any baseline differences, we expressed 3- and 6-mo concentrations as a percentage of the baseline concentration and repeated-measures ANOVA models were used to determine the effect of treatment over time. A diet x time interaction term was fitted in each model to determine whether the diet effect was constant across all time points. Changes from baseline to 6 mo were assessed using paired t tests. All statistical tests were carried out using statistics package STATA version 7.0 (Stata, College Station, TX).


   RESULTS
TOP
 ABSTRACT
 SUBJECTS AND METHODS
 RESULTS
DISCUSSION
 LITERATURE CITED
 
At baseline, the 5 groups did not differ in age (mean 53.3 ± 11.1 y), gender (M:F 18:12) or BMI (mean 26.1 ± 4.5 kg/m2). In summary, total ALA intakes with consumption of the moderate and high ALA diets were 4.5 ± 0.1 and 9.5 ± 0.1 g/d, respectively, with EPA+DHA intakes of 0.35 ± 0.05 g/d as estimated by a food-frequency questionnaire. In subjects who consumed the moderate and high EPA+DHA diets, EPA+DHA intakes were 0.8 ± 0.05 and 1.7 ± 0.05 g/d, respectively, with ALA intakes of 1.4 ± 0.1g/d. The intakes of these fatty acids by the control group were 0.47 ± 0.06 g/d EPA+DHA and 1.5 ± 0.1 g/d ALA. The groups did not differ significantly in the percentage of energy derived from protein, carbohydrate, alcohol, fat, saturated fatty acids (SFA), monounsaturated fatty acids (MUFA) or PUFA. Changes in the proportions of fatty acids in the plasma phospholipids (PL) indicated good compliance with the dietary intervention (Fig. 1). In summary, the change in plasma PL ALA in both of the ALA-supplemented groups was greater than that in the control group (P < 0.05). The change in the proportion of DHA in both of the EPA+DHA-supplemented groups also differed from the control group (all P < 0.05). Although plasma PL EPA levels doubled in all of the (n-3) PUFA-supplemented groups, only the change in plasma PL EPA after the 9.5 g/d ALA intervention differed from the change in the controls (P < 0.05). Further information on dietary intakes and plasma phospholipid data has been published (18).



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  		FIGURE 1 Absolute change in plasma phospholipid (PL) fatty acids from baseline to 6 mo after (n-3) PUFA and control diets in moderately hyperlipidemic subjects consuming 0.8 or 1.7 g/d eicosapentaenoic (EPA) + docosahexaenoic (DHA), 4.5 or 9.5 g/d {alpha}-linolenic acid (ALA) or control (linoleic acid; LA) for 6 mo. Values are means ± SEM, n = 29–30. *Significantly different from change in the control group, P < 0.05, Mann-Whitney test. Reproduced with permission by The American Journal of Clinical Nutrition (18).

 
There were no differences among the groups at baseline (ANOVA; P > 0.05). No significant treatment or time x treatment interactions were observed for any of the coagulation or fibrinolytic factors investigated (Table 2) when the data were expressed as a percentage change from baseline (data not shown). There were time-dependent increases in FXIIag (P = 0.001), PAI-I activity (P = 0.02) and tPA activity (P < 0.01) and a time-dependent decrease in the XIIa/XIIag ratio (P = 0.02) by 6 mo compared with baseline when the data for all groups were combined.


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  		TABLE 2 Effect of increased intakes of ALA and EPA + DHA on coagulation and fibrinolytic factors in moderately hyperlipidemic subjects1, 2

 

   DISCUSSION
TOP
 ABSTRACT
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
LITERATURE CITED
 
The effects of dietary ALA and EPA+DHA on blood coagulation and fibrinolytic factors were compared previously using dietary equivalent amounts of each (n-3) PUFA (5.5 g/d) in healthy men (11). There were no differences among the groups in FVIIc or PAI-1 activity, fibrinogen concentration, bleeding time or in collagen or ADP-induced platelet aggregation. However, this relatively short trial (4 wk) may have been insufficient for steady-state conditions within tissue phospholipids to be reached for either dietary intervention. The present study confirms that long-term increases in dietary EPA+DHA or biologically equivalent amounts of ALA do not differ in their effects on coagulation or fibrinolytic factors, even when steady-state tissue fatty acid composition is reached. In general, studies that have investigated the effects of an increase in ALA intake on hemostatic factors have compared ALA with a linoleic acid (LA) control and support our observations (16,26–28). In a comprehensive study of hemostatic factors (17), activated protein C resistance was the only factor to be affected by increased ALA intake, demonstrating an increase in anticoagulant potential. Although fibrinogen concentrations have been reported to be reduced after a 2-y ALA intervention program in subjects at high cardiac risk (26), other studies do not support this (16,17,27). Investigations of functional effects on hemostasis also support the lack of effect of ALA in modifying coagulation and fibrinolytic factors (16). No differences in bleeding time were reported after consumption of diets containing a greater proportion of total energy as ALA (4.6–6.3%) (29,30).

There is little agreement on the effects of LC (n-3) PUFA on clotting factors and fibrinolysis (6). In the present study, more modest intakes of EPA+DHA over a long period did not affect FVIIc activity in fasting subjects. These findings are in line with several studies (7,10,31), although another reported changes consistent with FVII activation (32). Similarly, there is no consensus on the overall effect of LC (n-3) PUFA on fibrinogen or PA1–1 concentrations although long-term intervention studies do not support effects of LC (n-3) PUFA on these factors. Feeding 4 g/d of fish oil concentrate to coronary artery disease patients for 9 mo did not affect fibrinogen concentration of FVII or PAI-1 activity, although a significant increase in PAI-1 antigen was observed (10). Supplementation with 2 g/d EPA+DHA for 5 mo did not affect tPA activity or tPA or PA1–1 concentrations (33). Our results support the lack of biologically important effects on these factors at dietary achievable levels of (n-3) PUFA.

FXIIa has been shown to be increased in men at high risk of CHD (34). At present, the investigation of LC (n-3) PUFA effects on FXII has been confined to one clinical trial (35) that reported no effect of fish oil on FXIIa in parenterally supplemented patients. In subjects consuming a diet rich in rapeseed oil, increased ALA intake did not affect FXIIc activity or FXIIa concentrations compared with a typical SFA-rich diet (16). This study supports the absence of any effect on FXII activity or concentration of either plant- or marine-derived (n-3) PUFA compared with LA as a control.

We previously reported a difference (P < 0.05) in the change in plasma TAG in subjects who consumed 1.7 g/d EPA+DHA diet (-7.7%) compared with those in the 9.5 g/d ALA group (+10.9%) (18). Similar directional trends for change in FVIIc were observed with decreases in the EPA+DHA groups and increases in the ALA groups, demonstrating internal consistency between the lipid and hemostatic results.

In summary, there was no significant long-term influence on the variables measured of either moderate doses of EPA+DHA or biologically equivalent amounts of ALA in moderately hyperlipidemic subjects compared with an (n-6) fatty acid control. However, more sensitive markers of in vivo hemostasis are required to confirm this. Overall, the results are in line with a growing consensus that dietary fat quality is not a strong regulator of many of the markers of blood coagulation and fibrinolysis (36) and that an antiarrhythmic effect of (n-3) PUFA (14,15) may be responsible for the protective action of LC (n-3) PUFA on CHD mortality at low levels of intake.


   FOOTNOTES
 
1 This study was part of a larger study (18) investigating the effects of {alpha}-linolenic acid and long chain (n-3) polyunsaturated fatty acids on risk factors for coronary heart disease. Back

2 Supported by a grant from the Department for Environment, Food and Rural Affairs (UK), Biotechnology and Biological Sciences Research Council, Roche Vitamins, Limited, Basel, Switzerland and Unilever Research, Vlaardingen, under the Agri-Food LINK programme (AFQ111). The spreads were prepared by Unilever Research and the capsules by Roche Vitamins, Limited. Back

4 Abbreviations used: ALA, {alpha}-linolenic acid; CHD, coronary heart disease; DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; LA, linoleic acid; LC, long chain; MUFA, monounsaturated fatty acid; PAI-1, plasminogen activator inhibitor-1; PL, phospholipid; SFA, saturated fatty acid; TAG, triacylglycerol; TC, total cholesterol; tPA, tissue plasminogen activator. Back

Manuscript received 5 December 2002. Initial review completed 19 December 2002. Revision accepted 27 March 2003.


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 ABSTRACT
 SUBJECTS AND METHODS
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 DISCUSSION
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