Table 2.

Dietary intervention with OO phenolics/extracts in animal models.

Reference	Animal Model	Intervention groups	Administration	Duration of intervention	Assays of platelet function/composition	Results
De La Cruz, 2000 [55]	White New Zealand rabbits	NLD: Normolipemic standard diet (34% SFA)	Solid food mixed with VOO	6 weeks	ADP- and COL-induced platelet aggregation in WB	Increased EC50 values for ADP-(3.3 fold) and COL-(2.5 fold) aggregation in the SFAED + OLIV group compared to SFAED group
		SFAED: Atherogenic diet containing 48% SFA and 1% cholesterol			${\mathrm{TxB}}_2$ production during clotting	67% lower ${\mathrm{TxB}}_2$ production in SFAED + OLIV compared to SFAED
		NLD + OO: Normolipemic standard diet + 15% VOO			AA-induced lipid peroxides production in PRP	Lower lipid peroxides (57%) in SFAED + OLIV compared to SFAED
		SFAED + OO: Atherogenic diet + 15% VOO			Platelet-Subendothelium interactions	Lower thrombus formation in the subendothelium in the SFAED + OLIV group compared to SFAED group
Priora R, 2008 [59]	Rats (adult male Sprague-Dawley)	ROO: (1.25 mL/Kg BW) containing 8.4 mg/L MPC	Oral gavage	Acute or 12 days	ADP-induced platelet aggregation in PRP	Acute inhibition of platelet sensitivity to ADP only in the HC group
		LC: EVOO with low minor polar compounds (1.25 mL/Kg BW) containing 213 mg/L MPC				Both LC and HC inhibited ADP-induced platelet aggregation after 12 d administration
		HC: EVOO enriched with minor polar compounds (1.25 mL/Kg BW) containing 510 mg/L MPC				Only platelet reversible aggregation was inhibited by HC
González-Correa J, 2007 [58]	Rats (male Wistar)	Control: Saline	Oral gavage	30 days	COL-induced aggregation in WB	VOO 0.25 and 0.5 mL/Kg/day inhibited COL-induced aggregation by 36 and 47%
		VOO 0.25 mL/Kg/day			COL-induced ${\mathrm{TxB}}_2$ production in WB	VOO 0.25 and 0.5 mL/Kg/day inhibited COL-induced ${\mathrm{TxB}}_2$ production by 19 and 26%
		VOO 0.5 mL/Kg/day
		VOO contains a relatively low amount of phenols (0.19 mmol/Kg ortho-diphenols)
González-Correa J, 2008 [60]	Rats (male Wistar)	16 groups of animals (6 animals per group)	Oral gavage	7 days	COL-induced aggregation in WB	Inhibition of COL-induced aggregation by HT (${\mathrm{ID}}_{50}$: 48 mg/Kg/day), HTA (${\mathrm{ID}}_{50}$: 16 mg/Kg/day), ASA (${\mathrm{ID}}_{50}$: 2.4 mg/Kg/day) in a dose-dependent manner
		Control group (isotonic saline solution)			${\mathrm{Ca}}^{2+}$-induced ${\mathrm{TxB}}_2$ production in WB	Weak inhibition of ${\mathrm{Ca}}^{2+}$-induced ${\mathrm{TxB}}_2$ production by HT (30%) and HTA (37%) at a dose of 100 mg/Kg/day
		Six groups treated with HT (1, 5, 10, 20, 50, and 100 mg/Kg/day)
		Six groups treated with HT-
		AC (1, 5, 10, 20, 50, and 100 mg/Kg/day)
		Three groups treated with ASA (1, 5, and 10 mg/Kg/day).
De La Cruz, 2010 [56]	Rats (male Wistar)	Control, non-diabetic group	Oral gavage	3 months	COL-induced aggregation in WB	ASA reduced maximum intensity of platelet aggregation by 51%, VOO by 41 % and ASA plus
		Streptozotocin-induced diabetes			COL-induced ${\mathrm{TxB}}_2$ production in WB	VOO by 81 % compared to untreated diabetic rats
		Streptozotocin-induced diabetes + ASA (2 mg/Kg/day)				ASA reduced ex vivo ${\mathrm{TxB}}_2$ production by 98%, VOO by 46 % and ASA plus
		Streptozotocin-induced diabetes + VOO (0.5 mL/Kg/day)				VOO by 98 % compared to untreated diabetic rats
		Streptozotocin-induced diabetes + ASA (2 mg/Kg/day) + VOO (0.5 mL/Kg/day)
		VOO contained 250 mg/Kg total phenols
Muñoz-Marín J, 2013 [61]	Rats (male Wistar)	Control group: Saline	Oral gavage	7 days	COL-induced aggregation in WB	The alkyl ether derivatives reduced maximum intensity of aggregation in a dose and structure dependent manner. The highest inhibition was achieved by hexyl derivative (59%)
		HT groups: 20 and 50 mg/Kg/day			${\mathrm{Ca}}^{2+}$-induced ${\mathrm{TxB}}_2$ production in WB	The alkyl ether derivatives reduced ${\mathrm{TxB}}_2$ production in a dose and structure dependent manner. The highest inhibition was achieved by hexyl ether derivatives at 20 and 50 mg/Kg/day (58 and 61%, respectively)
		HT ethyl ether: 20 and 50 mg/Kg/day
		HT butyl ether: 20 and 50 mg/Kg/day
		HT hexyl ether: 20 and 50 mg/Kg/day
		HT octyl ether: 20 and 50 mg/Kg/day
		HT dodecyl ether: 20 and 50 mg/Kg/day
De La Cruz Cortés JP, 2021 [57]	Rats (male Wistar)	NDR: saline-treated non-diabetic rats	Oral gavage	2 months	COL-induced aggregation in WB	HT completely reversed the increase of maximum intensity of platelet aggregation observed in DR to levels lower than those observed in NDR
		Glycemic control rats			Urine 11-dH-${\mathrm{TxB}}_2$ levels	DHPG completely reversed the increase of maximum intensity of platelet aggregation observed in DR to levels lower than those observed in NDR in a dose dependent manner
		DR: Streptozotocin-induced, saline-treated, diabetic rats				Synergistic effect of HT and DHPG in inhibiting ex vivo platelet aggregation
		DR + HT: Diabetic rats treated with 5 mg/Kg/day HT				HT completely reversed the increase of urine 11-dH-${\mathrm{TxB}}_2$ levels observed in DR
		DR + DHPG-0.5: Diabetic rats treated with 0.5 mg/Kg/day DHPG				DHPG partially reversed the increase of urine 11-d-H-${\mathrm{TxB}}_2$ levels observed in DR
		DR + DHPG-1: Diabetic rats treated with 1 mg/Kg/day DHPG
		DR + HT + DHPG-0.5: Diabetic rats treated with 5 mg/Kg/day HT plus 0.5 mg/Kg/day DHPG
		DR + HT + DHPG-1: Diabetic rats treated with 5 mg/Kg/day HT plus 1 mg/Kg/day DHPG

AA, Arachidonic Acid; ADP, Adenosine diphosphate; ASA, Acetylsalicylic acid; COL, Collagen; DHPG, 3,4-dihydroxyphenylglycol; DR, diabetic rats; HC, high MPC concentration; HT, Hydroxytyrosol; HTA, hydroxytyrosol acetate; ${\mathrm{ID}}_{50}$, Inhibitory dose for 50% inhibiton; LC, low MPC concentration; MPC, minor polar compounds; NLD, normolipemic diet; NDR, Nondiabetic rats; PLT, platelet; SFAED, saturated fatty acid-enriched diet; ROO, Refined Olive Oil; ${\mathrm{TxB}}_2$, Thromboxane; VOO, virgin olive oil; WB, Whole Blood.