orin Hydrate (3,5,7,two ,four -pentahydroxyflavone) is usually a polyphenol compound that has been extensively studied for distinctive pharmacological activities in several human disorders, with slight side effects. Morin hydrate crucially inhibits platelet activation through inhibition of your PLC2-PKC cascade and subsequent suppression of Akt and MAPK activation. Furthermore, morin hydrate substantially increased the occlusion time of thrombotic platelet plug formation but didn’t impact the bleeding time in mice [94]. 5.six. Shear Stress-Induced Platelet Aggregation SIPA, which occurs under abnormally high shear tension, plays a vital role in the improvement of arterial thrombotic illnesses. Of note, SIPA is really a promising target to overcome bleeding considering that SIPA takes place only under pathological situations. In isolated human platelets, protocatechuic acid (PCA) decreased SIPA. Antithrombotic effects of PCA were confirmed in vivo within a rat arterial thrombosis model, exactly where PCA considerably delayed the arterial occlusion induced by FeCl3 . Of note, PCA did not increase bleeding times inside a rat tail transection model [95]. The effects of paeoniflorin showed inhibition of SIPA and considerably prevented arterial thrombosis in vivo devoid of prolonging bleeding time or blood clotting time in rats [96]. Cyanidin-3-glucoside inhibits human platelet activation, aggrega-Int. J. Mol. Sci. 2021, 22,7 oftion, and secretion and downregulates the collagen-GPVI signaling pathway and thrombus formation (both venous and arterial shear stresses) with no prolonging the bleeding time in mice [97]. Delphinidin-3-glucoside lowered thrombus development in human and murine blood in perfusion chambers at each low and higher shear rates, and no considerable distinction in tail bleeding instances was observed [98]. The antiplatelet action of tetramethylpyrazine was selective by inhibiting the platelet thrombus formation under higher shear prices [99]. Thrombosis, chronic inflammation, and fibrosis are in the end on the pathological interactions of activated endothelium, neutrophils, and platelets [100]. Either pure or food-derived polyphenols have already been reported to lower endothelial dysfunction and endothelial cell activation in vitro, ex vivo, and in animal models of endothelial dysfunction by decreasing oxidant production. For that reason, polyphenols decrease the interaction of platelets with activated endothelial cells by growing the availability of nitric oxide, therefore preventing platelet aggregation [101]. The effect of each bioactive compound on bleeding time is described in Table 1. The examples presented above exert their antiplatelet activities through the additive, cooperative, or synergic action from the bioactive compounds present in plants’ or fruits’ extracts (Figure 1).Figure 1. Antiplatelet targets of bioactive compounds devoid of bleeding risk. In red lines: inhibition, black arrows: activation. DHM: dihydromyricetin, PCA: protocatechuic acid. SQL: tripeptide H-Ser-Gln-Leu-OH.Int. J. Mol. Sci. 2021, 22,8 ofTable 1. Antiplatelet compounds with out growing bleeding timepound All-natural Sources Myricetin (from BRDT Formulation Syzygium cumini leaf) Syzygium cumini (L.) As quercitrin (3-rhamnoside) in numerous fruit and vegetables: apples, honey, raspberries, onions, red grapes, cherries, citrus 4-1BB review fruits Effects and Proposed Mechanisms Inhibition of aggregation induced by collagen or TRAP-6 Inhibition of fibrinogen binding and alpha-granule secretion induced by CRP The mechanism includes PDI inhibition Impaired CRP-induced