Download Dietary Fat and Platelet Function

343
Clinical Science (1983) 65, 343-350
EDITORL4.L R E V E W
Dietary fat and platelet function
T. A. B. SANDERS
Department of Nuhition, Queen Elizabeth College, University of London, London
Platelets are needed for haemostasis. Platelets
adhere to damaged tissue, activation being mediated
by exposed collagen, thrombin and ADP. The
activated platelets then release compounds that
cause vasoconstriction, such as thromboxane A2,
and activate the clotting cascade culminating in
the formation of a stable fibrin plug. Overactive
platelets, however, may play an important role in
causing coronary vasospasm and acute myocardial
infarction. For almost two decades it has been
widely held that the substitution of vegetable oils
for animal fats in the diet decreases the reactivity
of platelets. A reappraisal of this view seems long
overdue in the light of new knowledge concerning
the control of datelet function.
Total and saturated fat intakes
The typical western diet provides between 120 and
140g of 'fat daily, or about 40% of thf energy
intake. About half of this is saturated fat derived
mainly from dairy foods and meat. In contrast the
typical diet in most developing countries only
supplies about 50 g of fat, .which contains proportionately less saturated fat.
High intakes of saturated fat increase arterial
thrombosis tendency, as measured with the aorta
loop technique and platelet aggregation induced
by ADP in vivo in the rat [ l ] . However, measurements of platelet aggregation in vitro show an
increased response to thrombin, but not to ADP or
collagen [2]; the addition of stearic acid to the
diet increases this response [3].
Measurements of platelet aggregation in vitro
have shown that farmers with high intakes of dairy
fats have a high response to thrombin compared
with farmers who use mainly vegetable oils [2].
Correspondence: Dr T. A. B. Sanders, Depart- I
ment of Nutrition, Queen Elizabeth College,
University of London, Campden
Road, London
W8 7AH.
'
The response to thrombin can be reduced by decreasing the total fat intakeand partially replacing
the dairy fats with vegetable oils and margarine,
rich in lirloleic acid [2,4].
Polyunsaturated fats
Human diets contain two series of polyunsaturated
fatty acids, the w6 and 0 3 , derived from linoleic
acid (1 8 :206) and a-linolenic acid (1 8 :3w3)
respectively. Linoleic acid and a-linolenic acid are
made by plants but not by animals. A human
requirement for dietary linoleic acid has been
established and is in the order of 1% of the energy
Wake, an amount greatly exceeded by most
human diets [5]. Both linoleic acid and a-linolenic
acid can be further desaturated and chain-elongated
in animal but not plant tissues to form longchain
derivatives. Thus food of animal origin can provide
both linoleic acid and a-linolenic acid as well as
their longchain derivatives. Linoleic acid is usually
the predominant dietary polyunsaturated fatty
acid and most diets supply only very small amounts
of the long-chain derivatives, with the notable
exception of those containing large amounts of
seafood. The fat from fish and marine mammals
contains high proportions of eicosapentaenoic acid
(20 : 5w3, EPA) and docosahexaenoic acid (22 :
603) derived from the marine food chain.
Arachidonic acid metabolism and platelet function
Prostaglandin (PG) metabolites of arachidonic acid
(20 :4w6) with opposing effects, thromboxane
(TXAa and prostacyclin (PGId, produced i i ~different locations, are believed to regulate plateletvessel w'd interactions [6]. Platelets contain an
exceedingly high propodon of 20 :406, which
is converted via the prostaglandin endoperoxide
PGH2 mainly into thromboxane A2 (Fig. 1). This
substance iS a powerful VaSOCOnStriCtOr and S t h U lator of platelet aggregation. It has a short half-life
T. A. B. Sanders
344
w3 series
w6 series
Dietary source
Fatty acid
Vegetable oils
18: 2 w 6
Evening primrose
oil
IinTeic
1 8 :3 w 6
ylinolenic
1
(1)
20: 3w6+H1
Prostaglandin
(1)
2(
w6
H
-,
arachidonic
Fatty acid
Vegetable oils
18:3w3
a-linolenic
Prostaglandin
/EL(-)
dihomoilenic
Y
Offal, meat, eggs
Dietary source
Marine oils
eica
/
D,
(--I
TXA, (+
Marine oils
22 :
docosahexaenoic
+ +)
(3)
FIG. 1. Polyunsaturated fatty acids and their relationship t o prostaglandins affecting
platelet function. D and E, types of prostaglandin, with subscript numeral denoting
the number of double bonds in the prostaglandin. H, Prostaglandin endoperoxide;
I, prostacyclin; TX, thromboxane. Enzymes: (1) cyclo-oxygenase; (2) thromboxane
synthetase; (3) prostacyclin synthetase. +, Promotes platelet aggregation; -, inhibits
platelet aggregation.
and is rapidly degraded to thromboxane Bz.Low
doses of collagen or ADP generate small amounts
of thromboxane B2 and result in second phase
platelet aggregation, which is readily inhibited by
a wide variety of drugs, particularly non-steroidal
anti-inflammatory drugs that inhibit prostaglandin
production [7].However, far greater amounts of
thromboxane are produced when platelet aggregation is stimulated by thrombin or high doses of
collagen even though aggregation induced by these
agents operates independently of the prostaglandin
pathway. Prostacyclin antagonizes the effects of
thromboxane. It is produced by the vessel wall and
monocytes from endogenous 20:4w6 or from
PGHz derived from platelets. Changes in the
balance between thromboxane and prostacyclin
production are believed to be reflected in the
template bleeding time. For example, if thromboxane production is diminished and prostacyclin
production maintained then the bleeding time will
be prolonged.
Influence of dietary a6 fatty acids
Most human diets contain only small amounts of
arachidonic acid (20 : 4w6), about 0.1 g daily,
obtained from the consumption of offal, meat and
eggs, and so most of the 20 : 4w6 in the platelets
and blood vessel wall must be derived indirectly
from dietary linoleic acid. The desaturation and
chain elongation of linoleic acid is carefully regulated so that increasing the dietary intake of
linoleic acid above a threshold value of between
1 and 2% of the energy intake does not lead to
any further increase in platelet 20:406. The
consumption of preformed arachidonic acid, however, greatly enhances the proportion of 20 : 4w6
in plasma and platelet lipids. This change is accompanied by an increased sensitivity t o second phase
platelet aggregation induced by ADP [ 8 , 9 ] and
an increased urinary excretion of prostaglandin
metabolites.
Human platelet and plasma lipids contain small
amounts of dihomo-ylinoleic acid (20 : 3w6),
Dietary fat and platelet function
the precursor of the monoenoic prostaglandins.
This fatty acid is not converted into a thromboxane
or prostacyclin in vifro [7] but is converted mainly
into PGE1. Unlike arachidonic acid (20 : 4w6), the
addition of 20 :306 to human platelet-rich plasma
inhibits platelet aggregation. Naturally occurring
fats and oils do not contain 20 : 306. Therefore
20 :306 in platelets must be derived from dietary
linoleic (18 : 2w6) acid or dietary ylinolenic acid
(18 : 3w6), which is found in the oil of the evening
primrose. Second phase aggregation induced by
ADP was inhibited about 4 h after feeding with 1g
of 20 : 3w6 to human volunteers [101. The generation of PGEl, PGE2 and PGD2 was increased. PGEl
and PGD2 both have an anti-aggregatory effect on
platelets. The increased production of PGE2 could
have resulted from the inhibition of thromboxane
synthetase, because there was little evidence of
conversion of 2 0 : 3 0 6 into 2 0 : 4 0 6 . Sim &
McCraw [ l l ] showed that dietary 18:3w6 was
approximately half as potent as 20 : 3w6 in inhibiting second phase aggregation induced by ADP
in man. However, these feeding studies were
poorly controlled and involved a small number of
subjects, treated for varying periods.
The effect linoleic acid has on platelet aggregation depends upon the amount consumed. A
dietary deficiency of linoleic acid drastically
reduces the amount of 20 :406 in both platelet
and arterial wall lipids. Subsequently the capacity
to produce both thromboxane A2 and prostacyclin
(PGQ is reduced [l, 121. Arterial thrombosis
tendency is low. Second phase platelet aggregation
induced by ADP or low doses of collagen does not
occur but the response to thrombin is increased
[13]. Dietary linoleic acid restores the level of
20 :4w6 in platelet and arterial lipids, prostaglandin
production and second phase platelet aggregation.
Intakes of linoleic acid far greater than those
required to cure symptoms of dietary deficiency
do lower arterial thrombosis tendency in rats and
increase the capacity to produce prostacyclin
PG12 [l, 121. When vegetable oils and margarines,
rich in linoleic acid, replace dairy and other hard
fats in the diet the linoleic acid intakes can be
increased from 4% to 12% of the energy intake,
which is equivalent to an additional daily intake
of 16-20 g of linoleic acid. Under these conditions
,platelets aggregate less readily, as measured in vivo
by the fdtragometer method [14,15]. Increased
platelet life-span [16] and a reduction in heparin
thrombin clotting time have also been reported
[17, 181. In these studies it is impossible to discriminate between the effects of a decreased
saturated fat intake and those of an increased linoleic acid intake. Moreover, as edible oils were used
rather than pure fatty acids it is also possible that
345
the effects could be attributed to other constituents
in the oils.
Bleeding time is not prolonged by high intakes
of linoleic acid [14,19], but this is not surprising
since prostaglandin production is not inhibited [12].
Indeed, in rats the capacity to produce both thromboxane and prostacyclin may increase with the
intake of linoleic acid [20].
The mechanism by which high intakes of linoleic
acid reduce the sensitivity of platelets to activation
is uncertain. This might be mediated by an increased production of PGEl [21]. However, high
intakes of linoleic acid do not elevate the proportion of 20: 306 in either plasma or platelet lipids.
An increased capacity to produce prostacyclin
PGIz might explain the reduced rate of platelet
aggregation measured by the fdtragometer technique. The intravenous infusion of an oil emulsion
rich in linoleic acid leads to an increased production of 6-keto-PGFla in man [22]. However, it is
now known that prostacyclin is produced in response to mild endothelial injury such as the
insertion of an intravenous cannula or perfusion
with an irritative substance [23].
Influence of 0 3 fatty acids
It has been known for some time that rats fed on
fat-free diets supplemented with a-linolenic acid
(1 8 :3w3) have a bleeding tendency. Platelet aggregation and prostaglandin production are inhibited
both in vitro and in vivo in rats fed with linseed
oil, which is rich in a-linolenic acid [12,24]. This
can be attributed to the displacement of arachidonic acid (20:4w6) from platelet lipids by
20:5w3 (EPA), which is synthesized from (Ylinolenic acid. EPA is the precursor of the trienoic
prostaglandins [25] : thromboxane A3 is only
weakly active but PGDBand prostacyclin PGI3 are
potent inhibitors of platelet aggregation. EPA i s a
more potent inhibitor of human platelet aggregation in vitro than is 18:206, 18:303, 18:3w6
or 20: 306 [26,27]. Bleeding time is prolonged
in rabbits infused with the EPA but can be prevented by pretreating the a n i d s with aspirin [28].
EPA, however, is a poor substrate for cyclooxygenase, compared with arachidonic acid [25,
26,29,30]. Furthermore, trienoic prostaglandins
do not appear to be produced in significant
amounts by rats even if their tissue lipids contain
a high proportion of 20 :5w3 [12,3 11. However,
EPA is an effective competitive inhibitor for platelet cyclo-oxygenase [29,30].
Owren et al. [32] claimed that a single dose of
20 g of dietary a-linolenic acid decreases platelet
adhesiveness. However, Borchgrevinck et al. [33]
were unable to show any influence on bleeding
346
T.A. B. Sanders
time or platelet adhesiveness in patients with
coronary heart disease given 10-3Oml of linseed
oil daily for 3 months. Sanders & Younger [34],
however, showed that 20ml of linseed oil taken
daily for 2 weeks by healthy volunteers led to
only a very small increase in the proportion of
20 :5w3 but no change in that of 20 :406 in platelet lipids. In contrast, small amounts of preformed
20:5w3 as fish oil concentrate (MaxEPA, Seven
Seas Health Care, Hull, U.K.) led to a large increase
in the proportion of 20: 5w3 and a decrease in
that of 2 0 : 4 0 6 in platelet lipids.
Platelet function is impaired in Greenland
eskimos [35]. Bleeding time is prolonged and
second phase aggregation induced by ADP or by
low doses of collagen, but not by 20:4w6, is
inhibited. The proportion of 20:4w6 in platelet
lipids was greatly diminished and was replaced by
eicosapentaenoic acid (20: 5w3) and docosahexaenoic acid (22 :6w3). The average daily intake
of 20:5w3 and 22:6w3 by these eskimos was
about 5 and 6 g respectively but that of linoleic
acid was low (about 5 g). A lack of 20:4w6 for
the formation of pro-aggregatory prostaglandins
could explain their mild haemostatic defect.
Smaller amounts of 20:5w3 may also affect
platelet function. A study of Japanese fishermen
showed that higher concentrations of ADP were
required to result in half-maximal aggregation than
in a group of farmers [ 36] . The fishermen were
consuming about 250 g of fish daily, which would
provide about 2.5 g of 20 :5w3. Relatively small
amounts of 20:5w3 as a fish oil fraction lower
whole blood viscosity, which is believed to be a
measure of platelet stickiness [37]. Siess ef al. [38]
reported that platelet aggregation was inhibited by
low doses of collagen after 1 week in subjects who
had consumed 500-800 g of mackerel daily. These
changes were accompanied by an increase in the
proportion of 20:5w3 in the platelets and a decrease in 20:4w6. Depending upon the time of
year the fish was caught, this would have provided
4-8g of 2 0 : 5 ~ 3and 7-14g of 22:603 [39].
Siess ef ul. attributed the inhibition of platelet
aggregation to changes in platelet composition.
Other studies which have brought about comparable changes in platelet lipid composition by using
smaller amounts of 20 :5w3 and 22 :6w3 provided
as fish oils over a longer period have failed to show
any consistent change in platelet aggregation
measured in vifro [40-431. A recent uncontrolled
study in patients with ischaemic heart disease suggested that plasma concentrations of 0-thromboglobulin and platelet factor 4, which are indicators
of platelet aggregation in vivo, were lowered after
consumption of 20ml of MaxEPA daily for 5
weeks [44]. This study requires confirmation as
the measurement of plasma 0-thromboglobulin is
subject to large experimental errors, because
platelets can be activated by the venepuncture.
Template bleeding time is prolonged by high
intakes of fatty fish or fish oil supplements [4043,451, possibly because thromboxane A2 production is decreased. Arachidonic acid (20: 406)
is partially displaced from the platelet lipids by
20 :503 and 22 :6w3. This reduces the amount of
substrate for thromboxane formation. Furthermore, 20 :503 and 22 :603 present in the plasma
lipids or released from the platelet lipids would
also competitively inhibit the conversion of 20:
4w6 into thromboxane A2.The amount of thromboxane A2 generated during platelet aggregation is
far greater than the amount needed to cause platelet aggregation. Indeed, it has been suggested that
the main role of thromboxane A2 is to cause vasoconstriction [46]. In rats dietary 20:5w3 and
22 :603 inhibit the production of thromboxane
A% to a greater extent than that of prostacyclin
(PGId, with the consequence that bleeding times
are prolonged and arterial thrombosis tendency is
reduced [20,3 I]. Dietary supplementation with
menhaden oil, which is rich in 20: 5 0 3 and 22:
6w3, exerts a protective effect on experimental
cerebral infarction in cats [47] and experimental
myocardial infarction in dogs [48]. In both these
studies infarct size was reduced and there was
evidence of improved collateral circulation.
It is important to emphasize that different
types of fatty fish or fish oils were used in these
studies. It is difficult, therefore, to extrapolate the
results from one study to another. Moreover, in
studies where fatty fish replaced other items in the
diet, it is impossible to separate the effects brought
about by the addition of fish to the diet from
those brought about by the exclusion of other
foods. Studies using fish oil supplements are easier
to interpret, provided that the subjects consume
the oil. Compliance can be monitored by analysing
the fatty acid composition of platelet and erythrocyte phosphoglycerides [40,43J. However, fish
oils are not all the same [49]. Some fish oils,
especially those from salmon, mackerel and herring,
contain a high proportion of cetoleic acid (22:
lull), which may cause a transient myocardial
lipidosis similar to that caused by erucic acid (22 :
lw9) in several species of experimental animals
[50]; Sinclair [51] when following an eskimo diet
developed a thrombocytopenia, as did some of the
subjects on a salmon oil diet studied by Goodnight
ef nl. [41]. Similar changes occur in young men fed
on high emcic acid rapeseed oil [52]. The requirement for vitamin E may be increased if large
amounts of fatty fish or fish oils are consumed
[53]. Furthermore, precautions should be taken
Dietary fat and platelet function
to ensure that fish oil supplements do not contain
peroxidized fatty acids, which are known to be
toxic and can inhibit prostacyclii production [54].
The consumption of large amounts (15-50 ml/day)
of certain. fish-liver oils, especially shark-liver or
halibut-liver oil, should not be encouraged because
of their high vitamin A and D content. The earlier
human studies tended to use cod-liver oil [19,40]
or salmon oil [41], but more recent studies [34,
43-45] have used an oil blend called MaxEPA,
which has circumvented these objections.
A study by Dyerberg & Bang [551 on the influence of 10 ml of a 60% 20: 5w3 ethyl ester concentrate, which contained only a small proportion
of 22: 603, in 20 subjects for 3 weeks gave disappointing results. It has been known for some time
that fatty acid esters of fish oils, especially when
prepared by urea fractionation, often yield different results from those expected [8,49]. Firstly,
the absorption of the esters may be poor compared with that of the triglyceride, and secondly,
peroxidized fatty acids and their breakdown
products, such as aldehydes, hydroxy acids and
ketones, may be concentrated in the EPA rich
fraction.
Most investigators have ignored the possible
influence of 22:6w3 on platelet function. However, it shows a similar inhibitory effect-on platelet
aggregation in vitro to that of 20:5w3 (T. A. B.
Sanders & N. R. Bolster, unpublished work). It
would appear that a daily intake of 3-5 g of 20:
5w3 and 22:6w3 taken for at least 3 weeks
prolongs bleeding time by about 40%. This is
considerably less than the amount consumed by
Japanese fishermen. Whether smaller amounts
consumed over a longer term would have any
significant effect is unknown.
Plasma lipoproteins
The plasma lipoprotein environment seems to
influence platelet reactivity. Platelet malondialdehyde formation, which is primarily an indicator
of prostaglandin synthesis, is higher in hyperlipidaemic patients (Fredrickson 'types IIa, IIb, IV)
than in healthy controls [56]. However, platelet
thromboxane B2 production is enhanced by type
11hyperlipidaemia but not type IV hyperlipidaemia
[57]. Although individual lipoprotein fractions
have been blamed, it is important to remember
that several other plasma factors known to increase
platelet reactivity are higher in patients with
hyperlipidaemia, for example fibrinogen and
clotting factors VII and VIII [58]. However, platelets from patients with type IIa hypercholesterolaemia contain an increased amount of free
cholesterol relative to its principal solubilizer,
341
phospholipid, and are more sensitive to aggregating
agents in vitro [59]. Moreover, the addition of
plasma from patients with familial hypercholesterolaemia to washed platelets from healthy
volunteers increases the sensitivity of the platelets
to aggregating stimuli compared with autologous
plasma [60]. Furthermore, the incubation of
cholesterol rich liposomes with washed platelets
increases platelet sensitivity to aggregating agents
and enhances the synthesis of thromboxane B2,
by a partial redirection of arachidonic acid metabolism from the lipo-oxygenase pathway towards
the cyclo-oxygenase pathway [61]. It was proposed
that platelet membrane cholesterol is increased in
the presence of high concentrations of lowdensity
lipoprotein (LDL) cholesterol and that this makes
the membrane more rigid and, therefore, more
sensitive to aggregating stimuli [61]. However, in
liver disease where the membrane cholesterol :
phospholipid ratio is markedly altered, platelet
sensitivity to aggregating agents is not increased
[621-
Elevated concentrations of high-density lipoprotein (HDL) cholesterol are associated with a
reduced risk of atherosclerotic disease but do not
appear to lower the reactivity of platelets [63].
Platelets from patients with either type IV or type
IIa or IIb hyperlipidaemia &e less sensitive to the
inhibitory effects of prostacyclin [61]. It is not
possible to study the influence of high concentrations of triglycerides on platelet aggregation
in vitro by the turbidimetric method. Consequently, the influence of plasma triglyceride and
very-low-density lipoprotein concentrations have
on platelet function is a moot point.
It is well known that dietary fat intake can
modify the concentrations of plasma lipoproteins.
Saturated fatty acids have a strong hypercholesterolaemic effect whereas polyunsaturated fatty
acids have a weaker but opposite hypercholesterolaemic effect [64]. These effects are almost exclusively confined to changes in the proportion of
LDL cholesterol. The C2,-,-CZ polyunsaturated
fatty acids of the w3 series in addition show a
powerful hypotriglyceridaemic effect [40,43,64].
It is therefore possible that some of the effects of
dietary fat, especially saturated fat, on platelet
aggregate are mediated by way of its influence on
plasma lipid concentrations.
Conclusion
There is abundant evidence that a reduction in
total fat intake and the partial substitution of
vegetable oils rich in linoleic acid for dairy fats
does reduce the rate at which platelets aggregate.
This change, however, has no influence on haemo-
348
T.A. B. Sanders
stasis measured by template bleeding time because
thromboxane production is not inhibited. Ambiguous results were obtained from two prospective
studies [65,66] aimed at reducing the incidence
of coronary heart disease by modifying the dietary
fat intake in this way. Coronary vasospasm may
result in acute myocardial infarction and angina
pectoris [67]. This could be caused by thromboxane [68]. The consumption of modest amounts of
fish oils leads to an increase in bleeding time and
a reduction in thromboxane production. It is possible that the long-chain derivatives of a-linolenic
acid play an important role in modulating the
production of prostaglandins from arachidonic
acid (20:4 ~ 6 ) The
.
low incidence of acute myocardial infarction among both eskimos and Japanese
fishermen underlines the need for further studies
to assess the potential long-term benefits of consuming large amounts of fish or smaller amounts of
fish oil supplements.
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