Vitamin C And Platelets

Basic, experimental, and clinical studies have provided definite evidence on the key role played by platelets in the process of atherothrombosis. Interventional trials with aspirin (a platelet COX-1 inhibitor),¹ thienopyridines such as ticlopidine or clopidogrel (a platelet P2Y₁₂ receptor inhibitor),² or the combination of the 2 drugs, ie, aspirin plus clopidogrel, reduced clinical outcomes in patients with acute coronary syndromes.³ A meta-analysis of trials with antiplatelet drugs in patients with stable atherosclerosis such as those with stable angina, peripheral arterial disease, or cerebrovascular disease confirmed the clinical efficacy of this drug category.⁴

Despite the success of interventional trials, the real world of atherothrombosis is complicated, with a high rate of morbility and mortality. Several issues related to the antiplatelet treatment may account for cardiovascular relapses. Poor compliance with an antiplatelet regimen may play a relevant role because the risk of adverse clinical outcome is higher in patients who do not adhere to aspirin treatment.⁵ Concomitant multiple antiatherosclerotic treatments are an important cause of poor aspirin compliance and should be taken into account in the monitoring of patients' adherence to antiplatelet treatment.⁶ Insufficient antiplatelet effect by the present armamentarium may be another relevant explanation for vascular relapses⁷; thus, prasugrel, a P2Y₁₂ receptor antagonist more potent than clopidogrel, improved vascular outcome in patients with acute coronary syndrome.⁸ Even if clinical investigation of more potent antiplatelet drugs represents an important future objective to improve the prevention of cardiovascular disease, a nonpharmacological approach to lower platelet function may be another intriguing prospective.

Observational and interventional studies have demonstrated that a significant reduction in cardiovascular events might be achieved by following particular diets or using specific nutrients.⁹ Relative to this, it is worthwhile to mention the significant reduction in cardiovascular events observed in subjects following the Mediterranean diet,¹⁰ a diet rich in fruits and vegetables,¹¹ or the Eskimo diet.¹² A potential explanation of such success is that these diets could reduce cardiovascular events by affecting platelet function. This review focuses on the strengths and weaknesses of clinical studies assessing whether diet per se or single components of "antiatherosclerotic diets" may represent a nonpharmacological antiplatelet approach potentially usable in the prevention of atherosclerotic progression and its clinical manifestations.

Nutrition, Cardiovascular Events, and Platelets

Since the classic study by Keys et al,¹³ it has been evident that people living in the South of Europe who follow the Mediterranean diet had lower incidence of cardiovascular disease compared with people living in the North of Europe. The Mediterranean diet is characterized by a high intake of fruits, vegetables, legumes, and monounsaturated fatty acids (essentially olive oil) and a moderate intake of fish and wine. The relevance of the Mediterranean diet in preventing cardiovascular disease has been documented by a large prospective study performed in 22 043 adults in Greece.¹⁰ During a median follow-up of 44 months, people who closely followed the Mediterranean diet had lower probability (−25%) of dying compared with those who adhered poorly to the diet.

The relationship between adherence to the Mediterranean diet and a reduction in mortality has been supported by a recent meta-analysis including >1 million people.¹⁴ The beneficial effect of the Mediterranean diet has been observed in healthy subjects and in those with previous cardiovascular diseases and includes a reduction in myocardial infarction and stroke.^15,16

Many nutrients in the Mediterranean diet may account for the reduction in cardiovascular events. Fruits and vegetables are thought to play an important role among them. This is consistently supported by observational studies in either healthy subjects or patients with coronary heart disease. For instance, the Nurses' Health Study and the Health Professionals' Follow-Up Study demonstrated that the consumption of fruits and vegetables is associated with reduced risk of coronary heart disease.¹⁷ The Indian Heart Study randomized 505 survivors of myocardial infarction to usual care or a diet rich in fruits, vegetables, nuts, and grains. After 1 year of follow-up, there were fewer cardiac events and a lower overall mortality in patients on the interventional diet.¹⁸

Nutrition based on high fish intake has also proved to protect against coronary heart disease. Since the pioneering studies in Greenland showing that the consumption of fish protects Eskimos against cardiovascular disease,¹⁹ many observational studies have provided support to this preliminary research. In a recent meta-analysis of these observational studies, the rate of weekly fish consumption inversely correlated with mortality from cardiovascular disease: Fish consumption up to 2 to 4 times weekly was associated with 38% risk reduction.²⁰ In addition, in the Physicians' Health Study, the risk of sudden death was inversely correlated with the blood concentration of n-3 fatty acids.²¹

An unanswered clinical question is whether plant-derived n-3 fatty acid α-linolenic has protective effects similar to those of the n-3 polyunsaturated fatty acids [eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)] of fish oil. In a recent study by Campos et al,²² higher intake of α-linolenic acid was associated with a significantly lower rate of nonfatal myocardial infarction in a population of healthy subjects or survivors of nonfatal myocardial infarction. A recent review, however, questioned the protective role of α-linolenic acid in protecting against cardiovascular disease.²³

Very few studies analyzed whether the beneficial effects of the above-mentioned diets influenced platelet function per se. In a prospective study performed in 42 healthy men, 21 were randomized to the Mediterranean diet and 21 to a high-fat diet. After 30 days of follow-up, subjects on the Mediterranean diet had longer bleeding time compared with those on a high-fat diet.²⁴ In a cross-sectional study, Dyerberg and Bang²⁵ compared bleeding time and platelet aggregation in 21 Eskimo volunteers and 21 matched Danish controls. Eskimos had significantly longer bleeding time and lower response to ADP-induced platelet aggregation compared with controls. On the contrary, many studies have analyzed whether constituents of the above-mentioned diets may affect platelet function when given to healthy subjects or patients at risk of cardiovascular disease. We review below the clinical trials assessing whether nutrients or supplements containing n-3, vitamins, or antioxidant molecules had some effect on platelet function and discuss whether they may be a tool to inhibit platelet function in clinical practice.

n-3 and Platelet Function

The Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico trial is one of the largest randomized controlled trials testing the effect of n-3 supplementation on cardiovascular events. In thus open-label, multicenter trial, 11 324 patients surviving a recent myocardial infarction were randomly assigned to ≈850 mg n-3 polyunsaturated fatty acids (EPA+DHA) or no supplement.²⁶ After 3.5 years of follow-up, there was a 10% reduction in the combination of vascular death and nonfatal myocardial infarction. Subgroup analysis revealed that the most favorable effect was for cardiovascular death (−17%). This finding was confirmed by a meta-analysis of the effect of fish oil on vascular outcomes that showed a significant reduction in vascular death in patients given fish oil.²⁷ Among the mechanisms potentially accounting for such a beneficial effect, a reduction in platelet function has been hypothesized.

We found 21 studies analyzing the effect of fish oil or the n-3 fatty acids EPA and DHA on platelet function. We excluded 14 studies because they were not controlled. Among the 7 controlled studies, 4 were done on healthy subjects and 3 on patients at risk of atherosclerosis (Table 1). The study population was treated with a quite different dosage of n-3; thus, the daily amount could range from as low as 1 g/d to as high as 4 g/d.^28–34 Among these studies, 2 showed no effect of n-3 on platelet aggregation^32,33; conversely, 5 showed inhibition of platelet function or prolongation of platelet survival. It is of note that such an inhibitory effect was not dose related because it was observed with 1 or 4 g/d. Apparently, n-3 supplementation has no side effect because none of these studies reported adverse reaction during the follow-up.

**Table 1. n-3 and Platelet Function**
Reference	Subjects	Intervention	Follow-Up	PA/Platelet Function/Platelet Survival	Platelet TxB₂	Serum TxB₂	Platelet Survival	Urinary TxB₂	sCD40L	sPs	Platelet-Monocyte Aggregation
PA indicates platelet aggregation; Tx, thromboxane; sCD40L, soluble CD40 ligand; sPs, soluble P selectin; HC, hypercholesterolemic; LA, linoleic acid; P, placebo; NE, not evaluated; HS, healthy subjects; AH, arterial hypertension; P-OM3, omega-3 fatty acids product; T2DM, type 2 diabetes mellitus; PUFA, polyunsaturated fatty acids; AMI, acute myocardial infarction; MDA, malondialdehyde; and ↔, no significant changes or differences.
Mori et al²⁸	120 HC and AH	EPA+DHA=3.65 g/d vs P (randomized study)	12 wk	↓ (≈−7%) Collagen- and (≈−9%) PAF-induced PA after omega 3-fatty acids	↓ (≈−10%) After omega 3-fatty acids (collagen induced)	NE	NE	NE	NE	NE	NE
Agren et al²⁹	55 HS	Control	15 wk	↓ Collagen (50 μg/mL)-induced PA in the fish diet (−36%) and the fish oil (−68%) groups	NE	NE	NE	NE	NE	NE	NE
		DHA oil (1.68 g DHA/d)
		Fish diet (1.05 g/d EPA+DHA)
		Fish oil (2.28 g/d of EPA+DHA; randomized study)
Pirich et al³⁰	26 HC	EPA (216 mg)+DHA (140 mg)+ γ-linolenic acid (390 mg)+LA (3480 mg)/d vs P (randomized, double-blind study)	6 wk	↑ (3%) Platelet survival (¹¹¹In-oxine-radiolabeled platelets) and ↓ (−6.7%) MDA formation in fish oil group	NE	↓ (−5.8%) In fish oil group	NE	↔	NE	NE	NE
Woodman et al³¹	59 Hypertensive, T2DM	EPA (4 g/d) vs DHA (4 g/d) vs olive oil (P) (randomized, double-blind trial)	6 wk	↓ (−16.9%) Collagen (1 μg/mL)-induced PA with DHA	↓ (−18.8%) With DHA	NE	NE	NE	NE	↔	NE
Aarsetøy et al³²	300 post-AMI (on day 4 to 6)	4 g/d n-3 fatty acids or corn oil (randomized study)	1 y	NE	NE	NE	NE	NE	↓ In both groups (−52.8% and −46%)	NE	NE
Larson et al³³	10 HS	P-OM3=4g (pilot study)	30 d	↔	NE	↔	NE	NE	NE	NE	NE
Din et al³⁴	14 HS	EPA+DHA=1g/d vs P (controlled study)	4 wk	NE	NE	NE	NE	NE	↔	↔	↓ (−35%)

We found 8 studies^35–42 that specifically investigated the effect of α-linolenic acid on platelet function. One compared the antiplatelet effect of α-linolenic acid versus EPA+DHA.³⁵ As in the case of fish oil, the studies analyzed quite different dosages of α-linolenic acid, with daily dosage ranging from as low as 0.86 g/d to as high as 5.9 g/d. The study population included healthy subjects^36–40 or patients at risk of atherosclerosis.^41,42 Globally considered, the studies did not consistently show an inhibitory effect of α-linolenic acid on platelet function. As in the case of fish oil, no side effects were recorded.

Together, these studies seem to suggest a different effect of fish- and plant-derived n-3 on platelet function. Thus, with few exceptions, an inhibitory effect of fish oil or EPA+DHA would emerge in human studies; this is in agreement with animal studies that consistently showed not only an inhibitory effect of platelet aggregation^43–45 but also an antithrombotic effect of fish oil supplementation.^46,47 Such changes have been attributed to a reduced decrease of thromboxane A₂ and an increase of the nonaggregating thromboxane A₃.⁴⁸

Olive Oil, Oleic Acid, and Platelet Function

Because olive oil is a key component of the Mediterranean diet, several studies have been done to asses whether olive oil or its principal component, oleic acid, is capable of affecting platelet function.^49–59 As far as olive oil is concerned, a daily dosage of 30 to 45 g/d has been assessed in 3 studies.^49–51 Globally considered, the trials do not support an antiplatelet effect of either olive oil or oleic acid in healthy patients or in those at risk of atherosclerosis. However, most studies were not controlled against placebo and included a small number of patients. Therefore, a larger sample size and more adequate study design are needed to further investigate whether olive oil or oleic acid has some effect on platelet function.

Wine, Polyphenols, and Platelet Function

Large epidemiological studies suggest the existence of an inverse relationship between moderate consumption of wine and cardiovascular risk. In one of the largest reports on this argument, Grønbaek et al⁶⁰ showed that moderate daily drinkers (3 to 5 glasses daily) had a lower risk of cardiovascular death compared with nondrinkers. This finding was confirmed by a meta-analysis that included 13 studies involving 209 418 people; thus, a 32% risk reduction of vascular disease was observed in people drinking 150 mL wine daily.⁶¹ Even if this finding may be biased by the coexistence of socioeconomic confounders potentially explaining the reduction of cardiovascular risk independently from wine intake,⁶² several hypotheses, including the inhibition of platelet function, have been postulated to explain such an inverse association.⁶³ We found cross-sectional and interventional studies comparing platelet function in wine consumers versus abstainers, nonconsumers, or subjects given red or white wine over the short or long term.^64–72

Globally considered, the studies inconsistently showed that short- or long-term wine intake is associated with an inhibition of platelet function in humans.^64–70 Negative results were also reported with dealcoholized wine,^71,72 which is in contrast to an animal study showing that dealcholized wine intake is associated with platelet inhibition.⁷³ The fact that experimental studies suggested a role for the nonalcoholic components of wine in inhibiting platelet function⁷⁴ raised the hypothesis that polyphenols, which are abundantly present in wine, possess an antiplatelet property. This also generated the hypothesis that the inhibition of platelet function could contribute to the reduction in cardiovascular events observed after high polyphenol intake.⁷⁵

Several sources of polyphenols have been investigated to test their antiplatelet effect in human. Grape juice, berries, pomegranate, apples, garlic, onion, tea, cocoa, tomato, and garlic have been tested to asses whether they possess antiplatelet activity.^76–100 Data obtained with grape juice and cocoa (Table 2) seem to show an antiplatelet effect more consistently than other sources of polyphenols. Thus, inhibition of platelet function was seen in all the studies of grape juice and in all but 1 study⁸⁶ with chocolate. These different findings may be related to the concentrations of polyphenols in the source of polyphenols investigated. This is likely to represent a crucial issue because the concentration of polyphenols in human blood seems to influence platelet function.⁹⁹ Accordingly, an inhibitory effect was observed with blood concentration >5 μmol/L,^99,101 which is consistent with in vitro study showing that 5 to 10 μmol/L polyphenols inhibits platelet recruitment via increase of nitric oxide production.^101,102 On the basis of these considerations, pharmacokinetic and pharmacodynamic studies should be done to assess whether polyphenol-rich nutrients may affect platelet function differently because of their polyphenol content. Additionally, because an experimental study provided evidence of an antithrombotic effect mediated by prolongation of primary hemostasis,¹⁰³ it is crucial to evaluate whether polyphenol supplementation increases the risk of bleeding.

**Table 2. Grape Juice, Chocolate (Dietary Polyphenols), and Platelet Function**
Reference	Subjects	Intervention/Design	Follow-Up	PA/P Act	PAC1	Platelet Microparticles	Ps	Plt No
HS indicates healthy subjects; HC, hypercholesterolemic patients; PA, platelet aggregation; PGJ, purple grape juice; Plt, platelet; Ps, P-selectin; NE, not evaluated; PAC1, recognizes the activated conformation of the fibrinogen-binding receptor glycoprotein (GP) IIb/IIIa; PFA-100 coll-epi CT, platelet function analyzer-collagen-epinephrine-induced closure times (Dade Behring International, Miami, Fla); AA, arachidonic acid; and ↔, no significant changes or differences.
Grape juice
Keevil et al⁷⁶	10 HS	5–7.5 mL/kg⁻¹ · d⁻¹ PGJ, orange juice, or grapefruit juice (randomized crossover design)	7–10 d each	↓ (−77%) Collagen (1 mg/L)-induced PA with PGJ	NE	NE	NE	↑ (≈70)
Freedman et al⁷⁷	20 HS	7 mL/kg⁻¹ · d⁻¹ PGJ (open study)	14 d	↓ (−33%) PMA-induced PA	NE	NE	NE	NE
Aviram et al⁷⁸	13 HS	50 mL PJ/d (1.5 mmol total polyphenols) (open study without control group)	2 wk	↓(−11%) Collagen (2 mg/L)-induced PA	NE	NE	NE	NE
Chocolate
Rein et al⁸¹	30 HS	300 mL Polyphenol-rich cocoa beverage (n=10) vs caffeine-containing control beverage (n=10) vs water (n=10) (nonrandomized open study)	6 h after beverage ingestion	↑ (31%) on PFA-100 coll-epi CT with cocoa beverage	↓ (epi: ≈−65%) (ADP: ≈−34% with cocoa)	↓ (≈−68%) With cocoa beverage	↓ (≈−26%) ADP-stimulated Ps with cocoa	NE
Pearson et al⁸²	16 HS	300 mL Flavanol-rich cocoa beverage (18.75 g flavanol-rich cocoa powder) (crossover design)	2, 6 h	↑ (≈9%) on PFA-100 coll-epi CT after 6 h from cocoa beverage	↓ (epi: ≈−70%) with cocoa after 2 h from cocoa beverage	NE	↔ Plt Ps	NE
Innes et al⁸³	30 HS	100 g Milk (20% cocoa) or dark (75% cocoa) chocolate vs white chocolate (randomized study)	4 h After chocolate consumption	↓(−93%) Collagen (0.5 μg/mL)-induced PA after dark chocolate	NE	NE	NE	NE
Murphy et al⁸⁴	32 HS	234 mg Cocoa flavanols vs placebo (blinded parallel-design study)	28 days	↓ (≈−28%) ADP ↓ (≈−16%) collagen-induced PA by cocoa	NE	NE	↓ (≈−8%) ADP (3 μmol/L) stimulated Ps with cocoa	NE
Heptinstall et al⁸⁵	12 HS	Beverage rich in 80 mg cocoa flavanols, 300 mg cocoa flavanols, 600 mg cocoa flavanols, 900 mg cocoa flavanols (double-blind randomized study)	2, 4, 6 h after cocoa consumption	↓ (≈−40%) Collagen (0.125 μg/mL)-induced PA 6 h after 600 or 900 mg cocoa flavanols	NE	NE	↓ (≈−25%) Ps on monocytes and neutrophils (collagen 0.125 μg/mL) 6 h after 900 mg cocoa	NE
Hermann et al⁸⁷	25 HS	40 g Dark vs 40 g white chocolate (4% cocoa) (randomized parallel study)	2 h after chocolate ingestion	↓(−36%) shear stress-dependent Plt adhesion by dark chocolate	NE	NE	NE	NE
Flammer et al⁸⁸	22 Heart transplant recipients	40 g Flavonoid-rich dark (70% cocoa) vs 40 g cocoa-free chocolate (double-blind, randomized study)	2 h after chocolate ingestion	↓(−22%) shear stress-dependent platelet adhesion by dark chocolate	NE	NE	NE	NE
Hamed et al⁸⁹	28 HS	Dark chocolate (700 mg flavonoids/d) (open study)	7 d	NE	↓ (≈ −36%) ADP ↓ (≈−33%) AA-induced GP IIb/IIIa act	NE	↔ Plt Ps	NE

Vitamins

Antioxidant vitamins, particularly vitamin E, have been given in primary and secondary interventional trials to see whether they can prevent cardiovascular events. The scientific background of these trials stems from the oxidative hypothesis of atherosclerosis suggesting that oxidative stress has a pivotal role in the initiation and progression of atherosclerosis.¹⁰⁴ Vitamin E is a chain-breaking antioxidant that prevents the propagation of free radical reaction.¹⁰⁵ A meta-analysis of these trials demonstrated that vitamin E supplementation does not favorably influence vascular outcome in patients with a low or high risk of vascular accidents.¹⁰⁶ The reason for this negative finding may merely depend on the fact that vitamin E supplementation has no impact on the progression of atherosclerosis, but methodological issues related to the design of the trials cannot be excluded. In particular, none of the trials used markers of oxidative stress as entry criteria,¹⁰⁷ nor was baseline antioxidant status considered a prerequisite for inclusion in the trial. In the Heart Protection Study, for instance, baseline levels of vitamin E were in the normal range, suggesting that patients included in this trial probably did not need any antioxidant treatment.¹⁰⁸ We recently underscored that at least one third of the patients included in the trials with vitamin E assumed that statins are also antioxidants, and this could have masked the effects of vitamin E.¹⁰⁹ Finally, the analysis of the trials with vitamin E was complicated by concomitant adverse side effects related to bleeding in the brain. Even if not all of the trials with vitamins examined this issue, there is evidence that cerebral hemorrhage may complicate vitamin supplementation. The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study^110,111 was one of the first showing that in male smokers 50 mg/d vitamin E or 20 mg/d β-carotene increased the risk of hemorrhagic stroke (Table 3). Notably, the increase in hemorrhagic stroke was confirmed in a large trial by Sesso et al,¹¹² who treated 14 641 US male physicians with 400 IU vitamin E every other day for 8 years, but it was not documented in another large trial in which 39 876 healthy women were treated with 600 IU/d vitamin E for 10.1 years.¹¹³ Such different gender responses to vitamin E seem to be corroborated by another study in 8171 women at risk of CVD¹¹⁴; in fact, no increase in hemorrhagic stroke was observed after 9.4 years of 600 IU/d vitamin E supplementation. In another study including men and women at risk of CVD and treated with 400 IU/d vitamin E for 4.5 years, no increase in hemorrhagic stroke was detected,¹¹⁵ but no information on the rate of hemorrhagic stroke in men and women was provided.

**Table 3. Vitamins and Bleeding**
Reference	Subjects	Design	Intervention	Follow-Up, y	Bleeding
ATBC indicates Alpha-Tocopherol, Beta Carotene Cancer; RR, relative risk; CI, confidence interval; HR, hazard ratio; and HOPE, Heart Outcomes Prevention Evaluation.
ATBC Trial¹¹⁰	29 133 Male smokers	Randomized, double-blind, placebo-controlled, primary-prevention trial	α-Tocopherol 50 mg/d	5–8	↑ Fatal hemorrhagic stroke (mortality rate per 10 000 person-y=7.8) in α-tocopherol vs non-α-tocopherol group
			β-Carotene 20 mg/d
			α-Tocopherol+β-carotene
			Placebo		↑ Fatal hemorrhagic stroke (mortality rate per 10 000 person-y=7.0) in β-carotene vs non-β-carotene group
ATBC Trial¹¹¹	28 519 Male smokers free of stroke at baseline	Randomized, double-blind, placebo-controlled, primary-prevention trial	α-Tocopherol 50 mg/d	6 (median)	↑ Subarachnoid hemorrhage in α-tocopherol vs non-α-tocopherol group (RR=1.50; 95% CI, 0.97–2.32; P=0.07)
			β-Carotene 20 mg/d
			α-Tocopherol+β-carotene
			Placebo		↑ Intracerebral hemorrhage in β-carotene respect to non β-carotene group (RR, 1.62; 95% CI, 1.10–2.36; P=0.01)
Physicians' Health Study II¹¹²	14 641 US male physicians	Randomized, double-blind, placebo-controlled, factorial trial	Vitamin E 400 IU every other day	8 (mean)	↑ Hemorrhagic stroke in active vitamin E group vs placebo vitamin E group (HR, 1.74; 95% CI, 1.04–2.91; P=0.04)
			Vitamin C 500 mg/d
			Placebo
Women's Health Study¹¹³	39 876 Apparently healthy US women	Randomized, double-blind, placebo-controlled, 2×2 factorial trial	Vitamin E 600 IU every other day	10.1 (mean)	↔ No increase in hemorrhagic stroke associated with vitamin E use
Women's Health Study¹¹³	39 876 Apparently healthy US women		Placebo	10.1 (mean)
Women's Antioxidant Cardiovascular Study¹¹⁴	8171 Female health professionals at increased risk	Randomized, double-blind, placebo-controlled trial	Vitamin C 500 mg/d	9.4 (mean)	↔ No significant increase in hemorrhagic stroke associated with vitamin E or β-carotene use
			Vitamin E 600 IU every other day
			β-Carotene 50 mg every other day
			Placebo
HOPE¹¹⁵	9541 At high risk for cardiovascular events	Double-blind, randomized trial with a 2×2 factorial design	Vitamin E from natural sources 400 IU daily	4.5 (mean)	↔ No increase in hemorrhagic stroke associated with vitamin E use
HOPE¹¹⁵	9541 At high risk for cardiovascular events	Double-blind, randomized trial with a 2×2 factorial design	An equivalent placebo daily	4.5 (mean)

The increase in bleeding tendency in the brain circulation could be attributed to an antiplatelet effect of vitamin E. The interplay between vitamin E and platelet function has been tested in healthy subjects or in patients at risk of cardiovascular disease such as those with diabetes or dyslipidemia. Among the 6 trials performed in healthy subjects,^116–121 the amount of daily doses of vitamin E ranged from 200 to 2000 IU, and follow-up lasted from 2 to 5 weeks. The results are not consistent with an inhibitory effect of vitamin E supplementation.

As shown in Table 4, among the 7 trials^122–128 in patients at risk of cardiovascular disease, 5 were performed in patients with diabetes mellitus. In these 5 trials,^122–126 the daily amount of vitamin E ranged from 100 to 600 IU, and follow-up lasted from 2 to 10 weeks. An antiplatelet effect was observed in all but 1 study; however, that study included patients who were also taking aspirin.¹²⁵ In the remaining 2 studies performed in smokers or patients with dyslipidemia, inhibition of or no change in platelet function, respectively, was reported.^127,128

**Table 4. Vitamin E and Platelet Function in Subjects With Atherosclerotic Risk Factors**
Reference	Subjects	Intervention/Design	Follow-Up	PA	TxB₂	sCD40L	sPs	Platelet NO
HS indicates healthy subjects; HC, hypercholesterolemic patients; T2DM, type 2 diabetes mellitus; T1DM, type 1 diabetes mellitus; sCD40L, soluble CD40 ligand; PA, platelet aggregation; sPs, soluble P-selectin; NE, not evaluated; Platelet NO, platelet nitric oxide production; urinary TxB₂, 11-dehydro-TxB₂ excretion; EC₅₀, half-maximal effective concentration; and ↔, no significant changes or differences.
Gisinger et al¹²²	22 T1DM	DL-α-tocopherol acetate (400 mg/d) vs placebo (double-blind, crossover study)	4 wk	NE	↓ (≈−67%) Collagen (0.15 μg) platelet TxB₂in DL-α-tocopherol acetate group	NE	NE	NE
Jain et al¹²³	29 T1DM	DL-α-tocopherol (100 IU/d) vs placebo (double-blind, controlled study)	3 mo	NE	↓ (≈−51%) Serum TxB₂ in DL-α-tocopherol group	NE	NE	NE
Davì et al¹²⁴	10 T2DM	L-α-tocopherol acetate (600 mg/d) (open study)	2 wk	NE	↓ (−43%) Urinary TxB₂	NE	NE	NE
Clarke et al¹²⁵	58 T2DM	α-Tocopherol (500 mg) vs γ-tocopherol-rich compound (500 mg, containing 60% γ-tocopherol) daily (randomized, controlled study)	6 wk	NE	↔ Serum and Urinary TxB₂	↔	↔	NE
Vignini et al¹²⁶	37 T2DM	Vitamin E 500 IU/d (open study)	10 wk	NE	NE	NE	NE	↑ At the 5th (≈20%) and 10th (≈50%) wk
Patrignani et al¹²⁷	46 Moderate cigarette smokers	Vitamin E 300, 600, or 1200 mg/d vs placebo (randomized, double-blind study)	3 wk	NE	↔ Serum TxB₂ and urinary TxB₂	NE	NE	NE
Williams et al¹²⁸	28 HC	Vitamin E 400 IU/d vs placebo (nonrandomized, controlled study)	6 wk	↑ (132%) EC₅₀ thrombin-induced PA with vitamin E	NE	NE	NE	NE

Globally considered, trials exploring the effect of vitamin E on platelet function inconsistently showed an inhibitory property in healthy subjects. The positive data obtained in diabetic patients are of some interest but are flawed by several methodological reasons, including nonsystematic analysis of oxidative stress and antioxidant status, open design, and small sample size.

The consequence of this argument is that inhibition of platelet function can hardly be considered a key element accounting for bleeding complications occurring after vitamin E administration. An alternative possibility is provided by a recent study showing that in vivo vitamin E exerts an anticoagulant effect because its administration is associated with reduced venous thromboembolism.¹²⁹ Thus, vitamin E interferes with vitamin K-dependent clotting factor activation and inhibits the monocyte expression of tissue factor, a glycoprotein that converts factor X to Xa.¹³⁰

Vitamin C is another antioxidant molecule that has been investigated to see whether it possesses antiplatelet activity. Vitamin C is a direct antioxidant because it quenches superoxide radicals.¹³¹ On platelet activation, platelets release superoxide radicals that in turn seem to be responsible for propagating platelet activation.¹³² Quenching superoxide radicals may therefore represent a tool to investigate the validity of such an assumption. Four studies^133–135 investigated whether short-term treatment with vitamin C, given either intravenously or orally, affects platelet function (Table 5). Globally considered, the studies showed inhibition of platelet function after intravenous^133,135 and oral^134,136 administration of vitamin C. Although the effect achieved after vitamin C given orally is difficult to explain, the inhibition observed after intravenous vitamin C administration raises important questions about the role of reactive oxygen species in platelet activation. Thus, in vivo vitamin C behaves as an antioxidant only if supraphysiological concentration, ie, ≈1 mmol/L, is reached; this concentration is achievable only when vitamin C is given intravenously.¹³⁷ It is therefore plausible that intravenous administration of vitamin C actually exerted an antioxidant effect that resulted in platelet reactive oxygen species inhibition and ultimately reduced platelet activation. Further study, however, is needed to support this hypothesis.

**Table 5. Ascorbic Acid and Platelet Function**
Reference	Subjects	Intervention/design	Follow-Up	PA	Platelet Microparticles	CD40L
HS indicates healthy subjects; PA, platelet aggregation; NE, not evaluated; CHF, chronic heart failure; GTN, glyceryl trinitrate; SNP, sodium nitroprusside; MI, myocardial infarction; and CD40L, platelet expression of CD40 ligand.
Pignatelli et al¹³³	10 HS	Vitamin C (1 g) IV vs placebo (double-blind, randomized, crossover study)	45 min	NE	NE	↓ (−68%) After vitamin C (collagen 4 μg/mL)
Wilkinson et al¹³⁴	8 HS	Vitamin C (2 g) oral administration vs placebo (double-blind, randomized study)	6 h	↓(−20%) ADP (8 μmol)-induced PA after vitamin C	NE	NE
Ellis et al¹³⁵	10 CHF	Vitamin C (2 g) IV vs placebo (double-blind, randomized, crossover study)	30 min	↑ (20%) The antiaggregatory effects of SNP and GTN after vitamin C (ADP 1 μmol)	NE	NE
Morel et al¹³⁶	61 MI	Vitamin C (1 g) oral administration vs placebo (randomized study)	5 d	NE	↓ (−10%) After vitamin C	NE

Mixture of Other Vitamins

The effect of a mixture of vitamins such as vitamins E, C, and β-carotene and/or selenium or polyunsaturated fatty acids with n-3 has been investigated in 5 studies.^138–142 The studies were conducted predominantly in healthy subjects or in patients with dyslipidemia and had a randomized controlled design. Overall, an inhibitory effect on platelet function was observed in all but 1 study.¹⁴⁰ Folic acid, vitamin B₆, and vitamin B₁₂ have also been thought to affect platelet function, but the results of interventional trials consistently did not support this hypothesis. Studies have been done in healthy subjects or in patients at risk of dementia.^143–145 The study by van Wyk et al¹⁴⁴ showed a weak inhibitory effect on agonist-induced platelet aggregation by 200 mg/d vitamin B₆; the other studies provided negative results.

Conclusions

Although epidemiological and interventional studies have demonstrated that diets such as the Mediterranean or Eskimo diet prevent cardiovascular disease, it is unclear whether these diets may actually affect platelet function. Appropriate study design and laboratory tests are needed to explore this issue in the future. There is evidence, however, that nutrients such as fish oil and polyphenol-rich nutrients may exert an antiplatelet activity. As far as fish oil is concerned, the majority of the ex vivo studies consistently showed an inhibition of platelet function. The plausibility of such an effect is based on the assumption that n-3 accumulation on platelet membrane results in lowering platelet thromboxane A₂ formation (see the Figure). As far as polyphenol-rich nutrients are concerned, ex vivo studies with grape juice and chocolate suggest a potential antiplatelet effect. As in the case of fish oil, these findings are biologically plausible because polyphenols possess an antioxidant property. Thus, they inhibit NADPH oxidase-dependent platelet superoxide anion formation or enhance platelet nitric oxide generation and/or bioactivity¹⁰²; both of these effects might have potential biological implications by modulating platelet recruitment (see the Figure). Despite this, methodological weaknesses related to study design, sample size, and follow-up duration and a lack of pharmacokinetic and pharmacodynamic studies preclude definite conclusions.

**Figure.** Platelet adhesion, activation, and recruitment.

Therefore, at this moment, any nutrient or supplements should not be considered an antiplatelet tool potentially usable for clinical purpose in healthy subjects or in patients at risk of cardiovascular disease. Conversely, careful attention should be given to the bleeding complications that may potentially occur after administration of the supplements to male subjects.

We thank Drs Andrea Brattini, Carmen Nigro, and Serena Di Santo for the excellent preparation of the manuscript.

Source of Funding

This work was supported by Progetti di Ricerca di Interesse Nazionale 2008, Ministero dell'Istruzione e dell'Università e della Ricerca granted to Dr Violi.

Disclosures

None.

Footnotes

Correspondence to Francesco Violi, MD, Divisione I Clinica Medica, Università Sapienza, Viale del Policlinico 155, Roma, 00161, Italy. E-mail [email protected]

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Vitamin C And Platelets

Source: https://www.ahajournals.org/doi/full/10.1161/circulationaha.109.880211

Vitamin C And Platelets