Effects of alcohol on platelet functions

ELSEVIER Clinica Chimica Acta 246 (1996) 77-89

Effects of alcohol on platelet functions

Serge C. Renaud*, Jean-Claude Ruf

INSERM, Unit 330, 146 rue Leo-Saignat, 33076 Bordeaux Cedex, France

Received 24 March 1995; revision received 25 May 1995; accepted 29 May 1995

Abstntct

Recent epidemiologic studies have consistently shown that moderate intake of alcoholic beverages protect against morbidity and mortality from coronary heart disease and ischemic stroke. By contrast, alcohol drinking may also predispose to cerebral hemorrhage. These observations suggest an effect of alcohol similar to that of aspirin. Several studies in humans and animals have shown that the immediate effect of alcohol, either added in vitro to platelets or 10 to 20 min after ingestion, is to decrease platelet aggregation in response to most agonists (thrombin, ADP, epinephrine, collagen). Several hours later, as, in free-living populations deprived of drinking since the previous day it is mostly secondary aggregation to ADP and epinephrine and aggregation to collagen that are still inhibited in alcohol drinkers. By contrast, in binge drinkers or in alcoholics after alcohol withdrawal, response to aggregation, especially that induced by thrombin, is markedly increased. This rebound phenomenon, easily reproduced in rats, may explain ischemic strokes or sudden death known to occur after episodes of drunkenness. The platelet rebound effect of alcohol drink:ing was not observed with moderate red wine consumption in man. The protection afforded by wine has been recently duplicated in rats by grape tannins added to alcohol. This protection was associated with a decrease in the level of conjugated dienes, the first step in lipid peroxidation. In other words, wine drinking does not seem to be associated with the increased peroxidation usually observed with spirit drinking. Although further studies are required, the platelet rebound effect of alcohol drinking could be associated with an excess of lipid peroxides known to increase platelet reactivity, especially to thrombin.

Keywords: Platelet aggregation; Alcohol; Wine; Binge drinking; Lipid peroxides; Pros- tanoids; Sudden death; Coronary heart disease; Stroke

* Corresponding Author

0098-[;981/96/$15.00 © 1996 Elsevier Science B.V. All rights reserved SSDI 0009-8981(96)06228-6

78 S.C. Renaud, J.-C Ruf / Clinica Chimica Acta 246 (1996) 77-89

1. Introduction

The inverse relationship between morbidity and mortality from coronary heart disease (CHD) and the moderate consumption of alcoholic beverages, has been documented by ecologic, case-control and prospective studies involving close to 1 million subjects [,11. The mechanism of this protection has been associated with an increase in the level of HDL- cholesterol. However, in recent studies [2,3] it has been shown that the level of HDL-cholesterol can explain only 50% of the protective effect of alcoholic beverages.

When it has been examined [41, the protective effect of alcohol is essentially on myocardial infarction and cardiac death, i.e. coronary thrombosis, rather than on stable angina, i.e. coronary atherosclerosis. As a matter of fact, contrary to the previously accepted concept, alcohol drinking, or even liver cirrhosis, does not seem to be associated with a reduction of atherosclerotic lesions when comparison is made with ad- equate controls [,5-71. Such controls could be violent deaths but not death from CHD or other diseases also associated with severe atherosclerosis. When controls were violent deaths, less atherosclerosis has not been found in alcohol consumers [,5-71. Moreover, it has been shown in women [-6] that alcohol drinking protects from CHD and from ischemic stroke but predisposes to cerebral hemorrhage even when the data are adjusted for blood pressure. In Japanese men living in Hawaii [,8], as well as in Japan [,91, hemorrhagic stroke has also been attributed to intoxication after alcohol drinking as observed in many case reports [10]. All these observations suggest a direct effect of alcohol on hemostasis. Since hemostasis and arterial thrombosis both involve the formation of platelet aggregates stabilized by fibrin, the question raised is whether alcohol protects from CHD at least partly through an effect on platelet function.

2. Myocardial infarction and platelets

To protect from CHD, the main target of alcohol seems to be myocardial infarction rather than atherosclerosis per se [-1]. It is now well established that coronary thrombosis is responsible for myocardial infarction [11]. Thus the influence of alcohol on the formation of platelet aggregates should be further evaluated. An additional reason is that aspirin, an antiplatelet drug, markedly reduces coronary events in unstable angina [,12] as well as in primary prevention [-13], but predisposes to hemorrhagic stroke as does alcohol drinking. The main effect of aspirin is to decrease secondary platelet aggregation to ADP [,14] (by inhibiting thromboxane A 2 formation) and to adrenaline, like alcohol. It has also

S.C. Renaud, J.-C. Ruf l Clinica Chimica Acta 246 (1996) 77-89 79

been shown that alcohol inhibits thromboxane A 2 formation during ADP-induced aggregation [15].

Platelet aggregation has been known for years to be closely related to thrombotic tendency in animals [16,17]. In man, these platelet tests have been ,,;hown to predict coronary events [18]. They also have been closely associated with prevalent cases of myocardial infarction in 1800 men studied in Wales [19].

3. Acute effects of alcohol on platelet aggregation

Although Davis and Philips [20] had observed that ethanol in vitro inhibited platelet aggregation induced by norepinephrine and collagen, the first extensive studies in that field were performed by Haut and Cowan [21]. They demonstrated that alcohol added in vitro to human platelets, and ingested or even infused intravenously to men, markedly decreased platelet aggregation to thrombin, collagen, epinephrine and ADP, especially secondary aggregation to ADP.

In free-living populations, we were the first group to report that the response of platelets to ADP-induced aggregation was significantly inversely related to the consumption of alcohol [22]. In that case, since it was French farmers, the alcohol consumed was mostly wine. With thrombin-induced aggregation, an inverse relation was also observed but was not significant in this small study on 44 subjects. Subsequently, we reproduced the inhibitory effect of alcohol on platelet aggregation in rats drinking alcohol diluted to 6% with water [23]. In addition, we found that it was only in animals fed saturated fats that aggregation to both ADP and thrombin was markedly reduced by alcohol [23].

In acute studies in man, it was shown that collagen-induced platelet aggregation was inhibited 30 min following the ingestion of 1 ml ethanol per kg body weight [24]. The effect was lost in 60 min. In preliminary studies in man [25], platelet aggregation to collagen and ADP was inhibited within 10 min of alcohol ingestion (Fig. 1). However, it was followed by a rebound effect, especially obvious with aggregation to thrombin but also to ADP, as observed in rats deprived of alcohol for 18 h [25]. Therefore, acute studies in fasted subjects not taking blood samples within 20 min of alcohol ingestion, may not observe inhibitory effects on platelet aggregation, at least on aggregation induced by thrombin, but possibly by other agonists, depending on the dose of alcohol. For example in their study, Hillbom et al. [26] took blood 4 h after ingestion of 1.5 g alcohol/kg body weight. Compared to the results before alcohol ingestion, they observed a significant increase in secondary ADP-induced platelet aggregation which lasted for an additional 8 h. This rebound effect has

80 S.C. Renaud, J.-C. Ruf l Clinica Chimica Acta 246 (1996) 77-89

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Fig. l. Influence of alcohol ingestion (1 ml whisky/kg body weight) given immediately after the first blood removal (time 0) on ADP-induced aggregation (0.92/~mol/l platelet-rich plasma) in a healthy volunteer. P = primary, S = secondary aggregation. Ten min after the alcohol ingestion, there was a 25% reduction in the secondary aggregation to ADP. Nevertheless, in this subject, at 30 min, a 40% increase in the secondary aggregation to ADP was observed, followed by a 110% increase at 60 min. The instrument used was a Rubel-Renaud aggrego-coagulometer (Adapted from Renaud et al. 1-24]).

been well documented in alcoholics after alcohol withdrawal [27]. Its main interest is in explaining un toward effects of binge drinking on the cardiovascular system, as for example stroke [28] and sudden death after episodes of drunkenness [29,30].

4. Long-term effects in man

In farmers from three regions in U K (East and West Scotland, South England), we found 1-31] that platelet aggregation to ADP, collagen and epinephrine was significantly inversely related to the intake of alcohol. In further analyses [25], it was the secondary aggregation to A D P and to epinephrine that were the mos t closely inversely associated with alcohol in these subjects. In 250 farmers f rom France and Great Britain, the alcohol intake was significantly inversely related to epinephrine and collagen- induced aggregation after mult iple regression analysis [32]. The relation between secondary aggregat ion to A D P and alcohol intake was not evaluated in that study. Meade et al. [331 in approximately 1000 subjects, also observed an inverse relat ionship between ADP-induced aggregat ion and the intake of alcohol. In 1600 subjects from Caerphilly in Wales, we found [34] that the intake of alcohol, in a dose related manner as shown in Table 1, was inversely associated with the response of platelets to aggregation induced by collagen, ADP, and most significantly, secondary aggregation to ADP. By contrast , for each level of alcohol intake the response of platelets to th rombin was from 47 to 98% higher than in the non-drinkers. Nevertheless, as shown also in Table 1, the odds ratio of a


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high response to aggregation to ADP in our study [34-] was very similar, in relation to the intake of alcohol, to the relative risk of CHD in the study of Rimm et al. 1-35,] at Harvard. This suggests that there is a close relationship between the effect of alcohol on the aggregation to ADP and on the mortality from CHD. It is also confirmed by the fact that in the Caerphilly study, the aggregation test that was the most closely associated with myocardial infarction was the aggregation to ADP [19].

Another finding of interest in our study in Caerphilly [34] was that, as we discovered previously in rats 1-23], the protective effect of alcohol drinking on platelets was much more significant in subjects with a diet rich in saturated fats, for primary and secondary aggregation to ADP (shown in Table 1), as well as for collagen. W e do not have any definite explanation for this phenomenon but it could be related to the immediate effect of alcohol on membrane fluidity. Since alcohol acts rapidly (within seconds when added in vitro to platelets and minutes when ingested), it increases the fluidity of membranes as shown by previous investigators [36], possibly more efficiently in subjects with a high saturated fat diet. At the same time, it can be postulated that changes occur at the level of the receptors at the membrane surface. By contrast, increasing the fluidity of an already more fluid membrane [37], owing to its higher content in polyunsaturated fatty acids, may not result in the same beneficial effect. It remains to be determined whether the protective effect of alcohol on CHD is more efficient in subjects with a high intake of saturated fats. Neverthe- less, this observation might contribute to the explanation of the French paradox, i.e. a low mortality rate from CHD despite a high intake of saturated fat 1,38]. The high consumption of alcohol in the form of wine seems to be the logical explanation 1,39,], and the effect may be greater in France than in some other countries because of the high intake of dairy fat in France.

5. Alcohol and prostanoid synthesis

It has been consistently observed in human subjects that the secondary aggregation to ADP was more significantly decreased by alcohol than the first wave of aggregation 1,20,24,34,]. Since this secondary aggregation is associated with the release of TXA 2 (thromboxane), it can be postulated that alcohol should decrease the response to TXA 2 or synthesis of this substance as shown in man 1,40]. As a matter of fact, it has been demonstrated that alcohol inhibits the release of TXA 2 induced by collagen, epinephrine and ADP, although at different concentrations. Nevertheless, in our own studies in British farmers, we found that secondary aggregation to ADP and epinephrine, as well as aggregation to


collagen, were inhibited by alcohol to about the same extent [25]. Differences in the results between studies could be due to the sensitivity of the instruments used, the concentration of the agonists and the general conditions of the experiment. While in some studies, from 50 to 400 mg/100 ml of ethanol were required to inhibit the release of TXA 2, Mehta et al. [41] decreased the formation of TXA 2 by 41% by adding only 20 mg/100 ml of ethanol.

Finally, it has been confirmed recently in rabbits [42] that the decreased response of platelets to collagen was due to inhibition by alcohol of TXA 2 formation rather than to a reduced sensitivity to TXA 2. The mechanism suggested for alcohol to impair the formation of TXA 2 is by inhibiting the activity in platelets of phospholipase A 2 [15,43] which is responsible for the release from phospholipids of arachidonic acid, the precursor of TXA 2.

In addition to inhibiting platelet aggregation to several agonists and TXA 2 release, ethanol seems to have also beneficial effects on prostacyclin, another prostanoid with potent antiaggregatory effects. Exogenous administration of prostacyclin results in vasodilation and decrease in platelet adhesion and aggregation. In their studies on human platelets, Mehta et al. [41] demonstrated that ethanol, at very low concentration (10 mg/ 100 hal), potentiated the platelet aggregation inhibitory effects of prostacyclin. In addition, prostacyclin production was enhanced in the presence of ethanol.

As to the aggregation induced by thrombin, which is decreased only by acute administration of alcohol, this inhibition seems to be independent from TXA 2 [44]. It may be mediated via decreased thrombin binding sites or attinity to membrane receptors, or impairment of thrombin-specific signaling pathways.

6. Platelet rebound effect and lipid peroxidation

The reason why the inhibition of platelet aggregation to thrombin is not observed in free-living populations seems to be that the inhibitory effect: of alcohol under these conditions does not last several hours, even in moderate drinkers. Since blood removal is usually performed in the morning on fasted subjects deprived of alcohol since the previous day, the aggregation to thrombin is usually consistently higher than in non- drinkers. This has been confirmed by studies in animals [25,45]. When the animals drank diluted alcohol (6%) until venepuncture, aggregation to thrombin was inhibited by more than 60% (Fig. 2). By contrast, when the animals were deprived of alcohol for 18 h, we observed an increase in the platelet response to thrombin of more than 100%. This also was seen in men from Caerphilly as shown in Table 1, and the rebound effect can also

84 S.C. Renaud, J.-C Ruf l Clinica Chimica Acta 246 (1996) 77-89

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Fig. 2. Influence on thrombin-induced platelet aggregation in rats of alcohol and wine drinking, all beverages being diluted to 6% alcohol. The animals were given a butter-rich diet and the alcoholic beverages for at least 2 months before blood removal. The animals were either deprived of alcohol for 18 h prior to venepuncture or not deprived as indicated. Results are expressed in % aggregation compared with water drinking considered as 100% aggregation, from 12 animals per group. When the animals drank alcohol up to the time of the venepuncture, a similar inhibitory effect on platelet aggregation was observed with the three alcoholic beverages compared to water. When they were deprived of alcohol for 18 h, the group with alcohol alone, exhibited a more than 100% increase in the platelet response to thrombin. With red wine (C6tes du Rh6ne), there was not such a rebound effect. Final concentration of thrombin 0.6 U/mE (Adapted from Ruf et al. [45], with permission).

be observed with ADP-induced aggregation, 1 -2 h after ethanol ingestion in man (1 g and more/kg body weight) 1-25,26] or in alcoholics in the detoxification period 1-27]. This rebound effect explains why certain studies in man did not observe the inhibitory effect of alcohol when venepuncture was performed hours after alcohol ingestion.

So far, the mechanism responsible for the rebound phenomenon has not been clearly defined 1,40]. It has been postulated that a change occurring in the ratio LDL/HDL-choles te ro l that paralleled the time course of enhanced platelet aggregation, could be a contr ibutory factor to the haemostatic disorders 1-46].

In our studies in wine-drinking farmers, we observed that in fasted subjects deprived of alcohol drinking for at least 10 h, the wine drinkers still had a lower platelet response to thrombin-induced aggregation than the non-drinkers 1-22]. Therefore, in recent studies in rats, we compared the effects of red and white wine to that of alcohol.

As shown in Fig. 2, in animals drinking alcohol or wine until venepuncture, platelet aggregation was inhibited to the same extent in the three groups of rats receiving the same amount of alcohol in three different alcoholic beverages. However, when the rats were fasted and deprived of alcohol for 18 h, the rebound effect was not observed in animals given red wine, and only partly observed with white wine. A significantly higher level

S.C. Renaud, J,-C. Ruf l Clinica Chimica Acta 246 (1996) 77-89 85

of conjugated dienes (the first step in lipid peroxidation), only in the group given alcohol, suggested that the rebound effect could be due to the increased level of peroxides known to be associated with alcohol drinking 1-47]. Wine contains different substances that could protect against peroxi- dat ion and against the platelet rebound effect. These substances are glycerol with a concentration of approximately 0.8% in wine and tannins at a level of 0.05%. The tannins we used in these studies were either extracted from grape seeds or from wine itself with similar effects on platelets in rats. Tannins and glycerol were added separately to alcohol, at the levels contained in red wine, and their effects were compared to alcohol alone and to red wine. Results on platelet aggregation to thrombin are slaown in Fig. 3, and on the level of conjugated dienes in Fig. 4. Only tannins added to alcohol could reproduce the inhibitory effect of red wine on the rebound phenomenon observed with alcohol alone. A similar result was obtained concerning the conjugated dienes (Fig. 4). It was only the tannins added to alcohol that were able to protect against lipid peroxidation, much the same as red wine.

Al;Lhough further studies are required to confirm that the platelet rebound effect to thrombin is due to lipid peroxides, the present results are concordant with previous studies in rats treated with hormonal contracep- tives. Platelet aggregation to thrombin was also associated with an increased level of lipid peroxides [48-1. The hyperaggregability observed

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Fig. 3. Influence on thrombin-induced platelet aggregation of red wine, alcohol + glycerol, or ak:ohol + tannins (from white grape seeds) compared to alcohol alone (all beverages having 6% alcohol) in rats deprived of alcoholic beverages for 18 h. The experimental conditions were similar to those in Fig. 2 except that the comparison was with alcohol (100% aggregation). Red wine (Beaujolais) shows a somewhat similar reduction to the results in Fig. 2 in the platelet response to thrombin compared to alcohol alone. Only the group with tannins reproduced the effect of red wine on the platelet response to thrombin. (Adapted from Ruf et al. [45-1, with Permission ). (Note: Red wine contains more tannins than white wine, not necessarily because the red grape seeds contain more tannins. Rather it is the result of the alcoholic fermentation process for red wine which use grape seeds and skin, while for white wine it is performed in the absence of seeds and skin).

8 6 S.C. Renaud, J.-C Ruf l Clin&a Chimica Acta 246 (1996) 77-89

Di~nes (%) [ I

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Fig. 4. Results of conjugated dienes in plasma in the experiment shown in Fig. 2. Compared to alcohol, with red wine drinking, the level of conjugated dienes was significantly lower. A similar reduction in the level of conjugated dienes could be obtained by adding tannins to alcohol. (Adapted from Ruf et al. [45], with permission).

under these conditions could be prevented by adding to platelets different types of antioxidants such as vitamin E, glutathione, peroxidase and catalase [48].

As to red wine, it has been shown recently to increase antioxidant activity in serum [49]. In addition, phenolic substances from red wine seem to be more potent than vitamin E in inhibiting oxidation of human LDL 1-50]. Thus, it is conceivable that red wine owing to its antioxidant phenolic substances could protect platelets from the peroxidation associated with alcohol drinking.

7. Conclusions

Because the level of HDL-cholesterol in blood, or even of additional lipoprotein fractions, are easier to determine than platelet aggregation, much more work has been achieved in the field of lipoproteins in relation to alcohol intake and CHD. Nevertheless it seems that HDL-cholesterol can explain only 50% of the protective effect of a moderate drinking of alcohol on CHD [2]. The other 50% could be through an effect on arterial thrombosis.

Ethanol ingestion seems to carry an increased risk of both ischemic and hemorrhagic strokes [26-1 that certainly cannot be explained by the high level of HDL-cholesterol resulting from alcohol drinking. By contrast, on platelet aggregability, alcohol can either decrease or increase the response depending on the way alcohol is consumed, moderately and regularly, or excessively. Binge drinking seems to be associated with platelet rebound effects that could be responsible for stroke and sudden death after episodes of drunkenness. It depends also on the type of alcoholic beverages used.


Wine, as c o m p a r e d to spirits, seems to supply na tu ra l an t iox idan t s tha t inhibi t the increased lipid pe rox ida t i on associated with a lcohol dr inking.

M o d e r a t e wine dr ink ing b o t h in ra ts and in m a n does no t ap p ea r to be associated with the platelet r e b o u n d effect observed with the c o n s u m p t i o n of spirits, especial ly when excessive. Thus , the s tudy of platelet funct ions bo th in animals and m a n can justify, if required, tha t the c o n s u m p t i o n of a lcohol ic beverages has to be mode ra t e , preferably at meals, as is the c us tom in M e d i t e r r a n e a n countr ies .

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