Critique 268 – Alcohol intake including wine drinking is associated with decreased platelet reactivity in a large population sample

Authors

Pashek RE; Nkambule BB; Chan MV; Thibord F; Lachapelle AR; Cunha J; Chen M-H; Johnson AD

Citation

International Journal of Epidemiology, 00:1–12; 2023 https://doi.org/10.1093/ije/dyad099

Author’s Abstract

Background Alcohol consumption is linked to decreased platelet function. Whether this link is dependent on sex or type of beverage remains unclear.

Methods Cross-sectional data were obtained from the Framingham Heart Study (N=3427). Alcohol consumption was assessed by using standardized medical history and Harvard semi-quantitative food frequency questionnaires. Five bioassays measured 120 platelet reactivity traits across agonists in whole-blood and platelet-rich plasma samples. Linear mixed-effects models adjusted for age, sex and aspirin use, hypertension, body mass index, cholesterol, high-density lipoprotein, triglycerides, smoking and diabetes evaluated associations between platelet reactivity and alcohol consumption. Beta effects, the regression coefficients that estimate the amount of change in each unit of the predictor variable whereas all other predictor variables remain fixed, for heavy alcohol consumption were compared with effects of aspirin use.

Results Alcohol consumption was associated with decreased platelet reactivity, with more associations among wine and liquor compared with beer. Many platelet–alcohol associations in the full sample (86%, P<0.01) had larger effect sizes in females. Lower light transmission aggregometry adenosine diphosphate (1.82 mM) maximum aggregation (P=2.6E-3, 95% CI=–0.07, –0.02, β=–0.042) and area under the curve (P=7.7E-3, 95% CI=–0.07, –0.01, β=–0.039) were associated with white wine consumption; however, red wine had no associations with platelet reactivity. The effect of aspirin use was on average 11.3 (64.0) times greater than that of heavy drinking in our full sample.

Conclusions We confirm associations between alcohol consumption and decreased platelet reactivity. Effects appeared larger for liquor and wine intake and in our female cohort. Red wine consumption is not associated with lower platelet function, contrasting with prior population studies. Although we report an inhibitory relationship between alcohol intake and platelet function, these effects appear much smaller than that of aspirin use.

Forum comments

Background including previous results

The relationship between alcohol consumption and cardiovascular diseases (CVD) is intricate and multifactorial. Epidemiological data show that light-to-moderate alcohol consumption is associated with cardioprotective benefits for apparently healthy individuals (Ronksley et al., 2011; Maclure, 1993) and individuals who are at risk of atherothrombotic-related diseases such as myocardial infarction (MI), peripheral artery disease (Djoussé et al., 2000) and cardiac death (Mukamal et al., 2001). However, it is essential for the robustness of a lifestyle factor-disease relationship to substantiate such an association with mechanistic understanding. Fortunately, this is the case for the epidemiological associations between moderate alcohol consumption and cardiovascular diseases; many short-term human interventions show that numerous biomarkers for CVD are affected by moderate alcohol consumption in a way that is consistent with cardiovascular protection. This publication in the International Journal of Epidemiology (Pashek et al., 2023) extends that proof and, therefore, contributes to the strength of the J-shaped association. The authors hypothesize that the J- or U-shaped associations may be explained, at least in part by haemostatic mechanisms, namely platelet aggregate formation, and other measurements of platelet reactivity.

The role of alcohol consumption on haemostasis contributing to cardiovascular protection has been investigated for approximately four decades since the seminal publication of Renaud and de Lorgeril (1992). The actual relationship between the consumption of alcoholic beverages and coagulation/fibrinolysis was first observed by Stampfer et al. in 1988. A somewhat older review nicely summarizes this relationship (Lee and Lip, 2003) by stating that the lower levels of plasma fibrinogen with moderate alcohol intake may well contribute to the apparent protection alcohol confers against ischaemic coronary and cerebral events. Conversely, the phenomenon of platelet hyperaggregability with binge drinking may attenuate this benefit.

The process of haemostasis and thrombus formation depends on the fine balance between the coagulation and fibrinolysis. The latter process has been studied in intervention studies showing that both activation of tissue type plasminogen activator and plasminogen activator inhibitor are stimulated by moderate alcohol consumption resulting in a higher fibrinolysis potential the morning after moderate alcohol consumption (Hendriks et al., 1994). Moreover, coagulation may be less stimulated because fibrinogen levels are reduced by moderate alcohol consumption (Sierksma et al., 2001; Sierksma, van der Gaag, et al., 2002; Stote et al., 2016).

Ethanol, the component common to all alcoholic beverages, has specifically been shown to decrease coagulation and increase fibrinolysis. It affects the following haemostatic variables: fibrinogen; factor VII and factor VIII; platelet aggregatability; tissue type plasminogen activator (t-PA); urokinase type plasminogen activator (u-PA); and plasminogen activator inhibitor-1 (PAI-1).

These beneficial effects on haemostasis occur together with many other physiological changes consistent with cardiovascular protection. HDL cholesterol increases (Di Castelnuovo et al., 2022) accompanied by an increased HDL functionality, viz. increased reverse cholesterol transport (Rohatgi et al., 2014; Sierksma et al., 2004) and increased antioxidative capacity (van der Gaag et al., 1999; Wilkens et al., 2022), are both important mediators of cardiovascular protection. In addition, moderate alcohol consumption has been shown to improve glucose homeostasis (Schrieks et al., 2015) and decrease haemoglobin A1c in human intervention studies (Huang et al., 2017). Also, various inflammatory markers have been shown to be decreased (Sierksma, Van Der Gaag, et al., 2002).

Many of the experimental outcomes have been confirmed in epidemiological studies. Some epidemiological studies have examined the contribution of various biomarkers to the risk reduction of moderate alcohol consumers. It has been suggested that increased levels of high-density lipoprotein cholesterol, lower levels of haemoglobin A1c, and reduced fibrinogen levels attenuated 75% of risk among women and fully attenuated the cardiovascular protective association among men (Mukamal et al., 2005).  

The effects of alcoholic beverages on coagulation and fibrinolysis are, however, difficult to determine conclusively and cannot be generalised as there appear to be significant confounders to the interpretation of the research data. These confounders include differences in coagulation and fibrinolytic responses to the acute versus short-term and longer-term consumption (Veenstra et al., 1990; Johansen et al., 1999), and gender differences in fibrinolytic responses. For example, the fibrinolytic response of post-menopausal women, who consume alcohol in moderation is similar to that of middle-aged men who consume alcohol in moderation. The converse was seen, however, in a comparison of men and women with a mean age of 36.7 years and, presumably, primarily pre-menopausal women. Moderate alcohol consumption decreased the rate of fibrin formation, decreased clot strength, and decreased rate of fibrin cross-linking in the men but not in the women (Spoerke et al., 2010).

Diet is also a confounder where wine consumers on a diet high in saturated fat may experience more significant effects on coagulation and fibrinolysis than wine consumers on a different diet (Renaud et al., 1992; Mezzano et al., 2001).

Further, in relation to the wine-specific phenolic compounds,  there is in vitro evidence that wine-derived phenolic compounds may have an independent and additive effect on the reduction of platelet aggregation (Corvazier et al., 1984; Mower et al., 1984; Gryglewski et al., 1987; Seigneur et al., 1990; Pace-Asciak et al., 1995; Polette et al., 1996; Ruf, 2004), but the different flavonoid classes may exhibit different effects, particularly on arachidonic acid metabolism (Landolfi et al., 1984; Corvazier and Maclouf 1985). Specifically, wine-derived phenolic compounds have been observed to down-regulate cellular adhesion processes, which are responsible for the recruitment and activation of platelets and their aggregation at the site of vascular damage, hence reducing platelet aggregation (daLuz, 1999).

Pellegrini et al. (1996), however, could not demonstrate any difference on platelet aggregation and haemostatic variables in vivo between the consumption of red wine and an ethanol solution (equivalent to 30 g alcohol), and also demonstrated that the red wine stripped of phenolic compounds had no effect on platelet aggregation. Hence it was initially concluded that the ethanol component of red wine and not the wine-derived phenolic compounds reduced platelet aggregation. In addition, Pace-Asciak et al. (1996) argued, in contrast to Seigneur et al. (1990), that red and white wine were equally effective in vivo in reducing the plasma concentration of thromboxane B2 and platelet aggregation, and concluded that the predominant in vivo effect on these coagulations factors was due to the ethanol component common to both beverages. Research undertaken in animals (Demrow et al., 1994; Maalej et al., 1997, 81) did, however, demonstrate a difference on platelet aggregation between an infusion of red wine and an ethanol solution, such that, the red wine inhibited platelet aggregation at a significantly lower blood alcohol concentration than did the ethanol solution.

Platelet aggregability has also been observed to be dependent on the amount and pattern of ethanol consumption, such that ‘binge’ and/or excessive consumption was observed to be associated with platelet rebound effects or hyperaggregability, which are implicated in sudden deaths after episodes of excessive consumption and in alcoholics (Renaud and Ruf 1996).  Also, as suggested by Pashek et al. (2023), the type of alcoholic beverage consumed may also affect platelet aggregability. For example, the consumption of red wine, irrespective of the amount consumed, has not been observed to be associated with platelet rebound effects although the consumption of spirits is (Ruf et al., 1995). This suppression of hyper-aggregatability has been attributed to the inhibition of ethanol-induced lipid peroxidation by wine-derived phenolic compounds (Polette et al., 1996), as ethanol, especially in excessive amounts, is a pro- rather than an anti-oxidant (Puddey and Croft, 1997), such that the initiation of platelet aggregation may be induced by a high concentration of lipid peroxides (Renaud and Ruf, 1996).

Design and main outcomes

To study platelet aggregate formation and other measurements of platelet reactivity, data were obtained from some 3400 participants from the Framingham Heart Study in a cross-sectional analysis. Collected data included medical history and a semi-quantitative food frequency questionnaire quantitatively assessing weekly and monthly beverage specific alcohol consumption. Five bioassays were performed providing several platelet function tests with various platelet agonists resulting in numerous reactivity traits.

Drinking more than 8 drinks (± 112 g alcohol) per week for females and more than 15 drinks (± 210 g alcohol) per week for males is associated with decreased platelet reactivity in both females and males across a wide range of platelet traits. Habitual wine and liquor consumption showed the most associations with the largest effects on decreased platelet reactivity, particularly in females. Whereas red wine consumption was not associated with platelet reactivity, white wine consumption was associated with only 2 platelet reactivity traits. Aspirin use resulted in a much larger effect size (viz a stronger platelet inhibition) than heavy alcohol consumption.

Comments on methodology

This study, although cross-sectional in set-up, shows a detailed analysis of platelet reactivity traits across several agonists resulting in 120 distinct platelet traits. When analysing such high numbers of traits, significant outcomes my be found by chance specifically when groups are split up in smaller groups like beer, wine and liquor consumers.

The authors conclude that wine and liquor consumers showed stronger associations with reduced platelet aggregation as compared to beer consumers. Wine even had greater associations with platelet functions compared to liquor beverages attributed to the high phenolic compound and antioxidant content of wine. This suggestion, however, is not consistent with the outcome of the analysis comparing red wine and white wine consumers: red wine was not associated with any of the platelet reactivity traits, whereas white wine consumption was with a small number of these traits. This is surprising since red wine in general contains more phenolic compounds than white wine.

In their discussion the authors elaborate on the possible mechanisms that may be involved in the polyphenol/antioxidant pathways relevant for platelet aggregation inhibition. Polyphenols may act on platelet aggregation in an indirect way through nitric oxide production by endothelial-mediated vasodilatation or other mechanisms or even by specific grape composition of the wine and other factors. Unfortunately, the authors do not discuss the relevance of their ex vivo assays as biomarkers for in vivo haemostasis nor the results obtained on the effects of moderate alcohol consumption on haemostatic factors in vivo. Evaluation of platelet function uses specific methods for specific factors or effects, which may be limited in providing relevant physiological information (Israels, 2015; Wagner et al., 2022). There is also increasing awareness of the occurrence of rather broad interindividual variability in the haemostatic system (Kluft & Burggraaf, 2011).

The authors compared the associations between platelet reactivity traits and alcohol consumption with those between platelet reactivity traits and aspirin use. They showed that the inhibitions of platelet aggregation with aspirin use were much stronger than those with alcohol consumption leading to the key message that alcohol consumption is unlikely to be of great utility in thrombosis prevention. This comparison was only made for heavy alcohol consumption, however, mainly because the largest inhibitions of platelet aggregation occurred in heavy alcohol consumers. Heavy alcohol consumption is, therefore, not of great utility for thrombosis prevention nor is it for any other health related issue anyway.

The authors consider several additional limitations of the study results. Self-reported alcohol consumption, as in most epidemiological studies has drawbacks. Self-report is susceptible to inaccuracies due to recall, temporal and self-desirability biases. Often self-report leads into underreporting. Also, drinking pattern was not assessed which may have affected the outcome. The authors consider the results to highlight the effects of habitual alcohol consumption, since most acute effects of alcohol consumption were presumed to have subsided the next morning. This assumption may not be correct keeping in mind that moderate alcohol consumption does stimulate fibrinolysis activity in healthy volunteers the next morning (Hendriks et al., 1994).

Specific Comments from Forum Members

Forum member Skovenborg consider that “The ability of blood to flow freely in vessels relies on complex homeostasis that exists between blood cells (including platelets), plasma proteins, coagulation factors, inflammatory factors and cytokines, and the endothelial lining within the lumen of arteries and veins. When there is an imbalance with this physiologic process, there can be an increased risk of developing a thrombosis versus a coagulopathy (increased risk of bleeding). Pashek et al. (2023) looked at the association of alcohol consumption with 120 platelet reactivity traits and to perform a proper assessment of this very complicated study would require specialisation in platelet reactivity. It is possible, however, to call attention to some caveats and contradictions in the paper by Pashek et al. (2023) as follows:

•       Assessment of alcohol consumption: the self-reported alcohol consumption is susceptible to recall, temporal and underreporting bias as acknowledged by the authors. The measurement of weekly and monthly alcohol consumption precludes an assessment of drinking pattern;

•       Subgroup analyses: the authors make extensive use of subgroup analyses by breaking down study samples into subsets of participants based on a shared characteristic. Some of the subgroups are rather small; for example, just 72 of the 3427 study participants drank only red wine and the finding of no association with red wine consumption and platelet reactivity may be a result of bias or coincidence. Demrow & Folts (1994) found red wine superior to white wine in experiments with acute platelet thrombus formation (APTF) followed by embolization producing cyclic flow reductions (CFR) in stenosed and damaged canine coronary arteries;

•       Inhibition dose-response relationship: The study results suggested an inhibitory dose-response relationship between alcohol consumption and platelets, for example, they observed six, four and nine decreased platelet reactivity traits associated with the >2 to <8, >8 to <15 and >15 drinks per week alcohol consumption categories, respectively; and

• In the “Discussion” section the authors concluded: “Our results support previous findings that established an inhibitory relationship between moderate to heavy alcohol consumption and platelet activation and aggregation.” In the “Key messages” section, however, the authors only mention the association of decreased platelet reactivity and heavy drinking.”

Forum Member van Velden states that he “while agrees with the results, the field is still open for opinions on alcohol consumption and the influence of alcohol and lifestyle interactions.  A holistic approach is required, and moderate wine drinkers, for example, usually have a healthy lifestyle incorporating physical, mental and spiritual aspects as well.”

A personal note from Forum Member Ellison reads as follows: “Visiting France more than three decades ago, I marvelled at the meticulous work done by Serge Renaud for evaluating platelet function in his studies in Lyon.  They included his constructing a large laboratory in a trailer so that it could be towed into the field to measure platelet function immediately after blood was drawn.  I understood very little back then, and not much more now, as to the specific mechanisms by which platelet aggregation and vascular function relate to cardiovascular disease; at the time and even today it is a poorly understood and appreciated risk factor for myocardial infarction. It is good to see that research continues on how the consumption of alcohol and wine affect platelet and vascular function.  And even we aging epidemiologists now realize that it is not just blood cholesterol that affects the risk of heart attack, as we were taught so many years ago.”

Concluding comments from Forum Members

While Pashek et al. (2023) confirm previously observed associations between alcohol consumption and decreased platelet reactivity, our knowledge regarding the health effects of alcohol consumption might best be grouped into two complementary approaches. Observational studies, for example, have now reached epic proportions in sample size and duration, and feeding studies have assessed the immediate and short-term effects of alcohol on behaviour, biochemical pathways, and similar social or physiological endpoints. Clearly, neither of these approaches represents gold-standard evidence in biomedical research, that is, only a long-term randomized trial of clinical endpoints would meet that standard.  Long-term randomized trials of clinical endpoints have, however, particular limitations that necessitate caution in their interpretation. Existing clinical trial and epidemiological evidence as well as confirmatory studies such as Pashek et al. (2023) provide useful insight into the endpoints that a clinical trial of moderate alcohol consumption might be best poised to tackle (Mukamal et al. 2016).

The limited in vivo data available have definitely demonstrated a differential effect of the alcoholic beverages on haemostatic cardioprotective mechanisms, where spirits and wine promote haemostasis more efficaciously and effectively. More data are required, however, to establish the degree of differentiation between wine and the other alcoholic beverages in conferring cardioprotection, cancer-protection and protection against other degenerative diseases.

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Comments on this critique by the International Scientific Forum on Alcohol Research were provided by the following members:

Henk Hendriks, PhD, Netherlands

Creina Stockley, PhD, MBA, Independent consultant and Adjunct Senior Lecturer in the School of Agriculture, Food and Wine at the University of Adelaide, Australia

R Curtis Ellison, MD, Section of Preventive Medicine/Epidemiology, Boston University School of Medicine, Boston, MA, USA

Erik Skovenborg, MD, specialized in family medicine, member of the Scandinavian Medical Alcohol Board, Aarhus, Denmark

Pierre-Louis Teissedre, PhD, Faculty of Oenology–ISVV, University Victor Segalen Bordeaux 2, Bordeaux, France

Giovanni de Gaetano, MD, PhD, Department of Epidemiology and Prevention, IRCCS Istituto Neurologico Mediterraneo NEUROMED, Pozzilli, Italy

Harvey Finkel, MD, Hematology/Oncology, Retired (Formerly, Clinical Professor of Medicine, Boston University Medical Center, Boston, MA, USA)

David van Velden, MD, Department of Pathology, Stellenbosch University, Stellenbosch, South Africa

Arne Silvaas, MD, PhD, general practice and lipidology, Oslo University Hospital, Oslo, Norway