Table 3.

Dietary interventions with pure phenolic compounds, phenolic extracts and EVOO in humans.

Reference	Study design	Population	Groups/Intervention/Duration	Platelet indices	Outcomes
Oubiña P, 2001 [66]	Two armed, cross-over with no washout period between intervention trials	Non-obese, postmenopausal women (N = 14)	EVOO group: EVOO containing 74% oleic acid and 108 mg/Kg total polyphenols	ADP-induced ${\mathrm{TxB}}_2$ production in PRP	At the end of each feeding period:
			HOSO group: High oleic acid sunflower oil containing 73.5% oleic acid and 25 mg/Kg total polyphenols	24 h urine ${\mathrm{TxB}}_2$	ADP-induced ${\mathrm{TxB}}_2$ concentration in PRP was lower in the EVOO group (584 $\pm$ 356 pg/${\mathrm{10}}^8$ plts) compared to HOSO (698 $\pm$ 369 pg/${\mathrm{10}}^8$ plts)
			EVOO and HOSO represented the 62% of total lipid intake	24 h urine 6-keto-prostaglandin-F1$\alpha$	No significant differences in 24 h urine ${\mathrm{TxB}}_2$, 6-keto-prostaglandin-F1$\alpha$ and their ration between the two diets
			Each feeding period lasted 28 d
Visioli F, 2005 [67]	Two armed, randomized, cross-over with a run in period before treatments and a washout period between treatments	Mildly dyslipidemic patients (N = 22, 10 females)	ROO group: 40 mL/day of refined olive oil containing 2 mg/L phenolics	Serum ${\mathrm{TxB}}_2$	EVOO reduced serum ${\mathrm{TxB}}_2$ by 21%. No effect of ROO
			EVOO group: 40 mL/day of extra virgin olive oil containing 166mg/L total hydroxytyrosol (HT + HT esterified in OE)
			3 wks run in period (40 mL ROO) - 7 weeks first arm (40 mL EVOO/ROO) - 4 wks wash out (40 mL ROO) - 7 weeks second arm (40 mL ROO/EVOO)
Léger CL, 2005 [68]	Single arm, noncontrolled intervention	Type I diabetic patients (N = 5)	HT-rich phenolic extract from olive mill wastewaters consumed with breakfast for four consecutive days (1st day 25 mg HT, the following 3 days 12.5 mg)	Serum ${\mathrm{TxB}}_2$ after 30-min clotting	Significant decrease in the ${\mathrm{TxB}}_2$ release at day 4 as compared to day 0 (–46.8 $\pm$ 10.9%)
			The extract contained 53% HT, 13% TYR in the free form and 34% in elenolic and elenolic acid derivatives
Widmer RJ, 2013 [72]	Double-blind, controlled, parallel, randomized trial	Patients with early atherosclerosis assessed by a reactive hyperemia-peripheral arterial tonometry (N = 52)	EVOO group: 30 mL/day of EVOO (total polyphenols: 340 mg/Kg) (N = 28)	Platelet count	Reduction of platelet count after supplementation in the combined EVOO groups (Baseline: 242 × ${\mathrm{10}}^9$/L, 4 mo: 229 × ${\mathrm{10}}^9$/L)
			EVOO + EGCG: 30 mL/day of EVOO containing 280 mg/L EGCG (total polyphenols: 600 mg/Kg) (N = 24)		No difference between groups
			4 months
Carnevale R, 2014 [70]	Crossover, two armed, postprandial studies	Healthy subjects (N = 25)	Study 1	Platelet sNOX2-dp release	Study 1
			Phase 1: Mediterranean lunch	Platelet 8-iso-PGF2$\alpha$-III production	The Mediterranean lunch increased platelet ROS production (27%), platelet sNOX2-dp release (26%) and platelet 8-iso-PGF2$\alpha$-III production (45%)
			Phase 2: Mediterranean lunch + 10 g EVOO	Platelet ROS production by flow cytometry	The inclusion of 10g EVOO to the lunch almost completely blunted the increases of platelet ROS, sNOX2-dp and 8-iso-PGF2$\alpha$-III
			Study 2		Study 2
			Phase 1: Mediterranean lunch + 10 g Corn Oil (CO)		The Mediterranean lunch + CO increased platelet ROS production (38%), platelet sNOX2-dp release (48%) and platelet 8-iso-PGF2$\alpha$-III production (34%)
			Phase 2: Mediterranean lunch + 10 g EVOO		In the Mediterranean lunch + EVOO no significant changes 2 h after the meal
			30 d interval between phases
			Blood sampling before lunch and 2 h after lunch
Agrawal K, 2017 [71]	Randomized, double blind, placebo controlled, crossover acute study	Healthy subjects (N = 9)	40 mL EVOO tyrosol-poor with 1:2 oleacein/oleocanthal ratio	COL-induced maximum platelet aggregation in WB	Ibuprofen treatment reduced COL (3 µg/mL) induced platelet aggregation by 57.5 $\pm$ 32.9%
			40 mL EVOO tyrosol-poor with 2:1 oleacein/oleocanthal ratio	COL-induced oxylipin production in PRP	EVOO with 1:2 oleacein/oleocanthal ratio reduced COL (1 µg/mL) induced platelet aggregation by −35 $\pm$ 39%
			40 mL EVOO predominantly tyrosol		EVOO with 2:1 oleacein/oleocanthal ratio reduced COL (1 µg/mL) induced platelet aggregation by −13 $\pm$ 36%
			400 mg ibuprofen		Regression analyses showed that the oleocanthal provided was the strongest individual ΔPmax predictor (R = 0.563, p = 0.002)
			Blood sampling before and 2 hours after EVOO/ibuprofen consumption		Ibuprofen treatment decreased 1 µg/mL COL stimulated oxylipin concentrations
					EVOO intake did not change the 1 µg/mL COL-stimulated oxylipin production
Carnevale R, 2018 [45]	Randomized, double blind, placebo controlled, crossover postprandial study	Healthy subjects (N = 20)	Phase 1: Mediterranean lunch + placebo 20 mg	Platelet 8-iso-PGF2$\alpha$-III production	A significant difference between the treatments was found for platelet 8-iso-PGF2 and p47phox phosphorylation
			Phase 2: Mediterranean lunch + 20 mg OE	Platelet p47phox phosphoryaltion	Placebo-treated subjects showed increases of 8-iso- PGF2 (45%) and platelet p47phox phosphorylation (212%) 2 h after the meal
			Blood sampling before lunch and 2 h after lunch		OE treated subjects showed a lower increase of
					8-iso-PGF2 (8%) and platelet p47phox phosphorylation (42%)
Chiva-Blanch G, 2020 [65]	Multicentered, randomized, controlled trial	Subcohort of the PREDIMED study (older population at high CVD risk, N = 155)	Control: Advice on low-fat diet (N = 53)	Plasma platelet derived MVs (CD61, PAC-1 and CD62P positive MVs)	MD-Nuts significantly decreased mean platelet-derived cMV
			MD-EVOO: MD enriched with EVOO (N = 53)		Platelet-derived MVs concentrations were lower in the MD-Nuts group after one-year intervention compared with the LFD and EVOO interventions
			MD-Nuts: MD enriched with nuts (N = 49)
			1 year follow up
Rus A, 2020 [69]	Randomized, controlled, double-blind, 2-arm parallel study	Female patients diagnosed with fibromyalgia (according to the criteria of the American College of Rheumatology) (N = 30)	EVOO group: 50 mL/day of EVOO (248 mg/Kg total polyphenols)	Platelet count	No significant effect of EVOO on measured parameters
			ROO group: 50 mL/day of ROO (152 mg/Kg total polyphenols)	MPV	ROO increased MPV (Pre: 7.55 $\pm$ 0.46 fL, Post: 8.65 $\pm$ 1.02 fL) and lowered PDW (Pre: 59.9 $\pm$ 11.3%, Post: 48.4 $\pm$ 10.1%)
			2wks run in period (50 mL/day ROO) - 3wks intervention (50 mL/day EVOO or ROO)	PDW	Significant time x group effect for PDW (p = 0.035)
Hernáez A, 2021 [64]	Multicentered, randomized, controlled trial	Subcohort of the PREDIMED study (older population at high CVD risk, N = 3086)	Control: Advice on low-fat diet (N = 988)	Platelet count	Platelet count
			MD-EVOO: MD enriched with EVOO (N = 1128)		increased over time (+0.98 × ${\mathrm{10}}^9$ units/L/year) in the whole population
			MD-Nuts: MD enriched with nuts (N = 970)		Both MD interventions restrained the increase of platelet count in individuals with near-high baseline counts [Time x Group effect, ${\mathrm{10}}^9$ units/L/year 95% CI vs Control Diet, MD-EVOO: –2.48 (–5.36; 0.40), MD-Nuts: –4.13 (–7.17–1.09)]
			5 years follow up
					MD interventions were associated with a decreased risk of developing thrombocytopenia [HR, 95% CI for MD-EVOO: 0.36 (0.16; 0.80), for MD-Nuts: 0.56 (0.26–1.21)]
					Thrombocytopenia was associated with a higher risk of all-cause mortality [HR: 4.71 (2.69; 8.24)]. This association is stronger in the control diet and blunted in the MD groups

ADP, Adenosine diphosphate; CO, Corn Oil; COL, Collagen; CVD, Cardiovascular Disease; MD, Mediterranean diet; EGCG, epigallocatechin gallate; EVOO, Extra virgin olive oil; HOSO, high-oleic acid sunflower oil; HT, Hydroxytyrosol; MVs, microvesicles; LFD, low fat diet; MD, Mediterranean diet; MPV, Mean Platelet Volume; sNOX2-dp, soluble NOX2–derived peptide; OE, oleuropein; PDW, Platelet distribution width; PGF, prostaglandin; PRP, Platelet rich plasma; ROO, Refined Olive Oil; ROS, reactive oxygen species; TYR, Tyrosol; ${\mathrm{TxB}}_2$, Thromboxane B2.