High-dose folate may improve platelet function in acute coronary syndrome and other pathologies associated with increased platelet oxidative stress

Abstract

Although nitric oxide of endothelial origin plays a major role in warding off inappropriate thrombus formation, platelets also express the "constitutive" isoform of nitric oxide synthase (cNOS). Activation of this enzyme by calcium influx during platelet aggregation provides an important feedback signal that dampens platelet recruitment. Platelets also express a membrane-bound NAD(P)H oxidase complex, activated by collagen receptors, that produces superoxide. Superoxide can directly quench NO; moreover, by giving rise to peroxynitrite, it can oxidize the cNOS cofactor tetrahydrobiopterin (BH4), thereby suppressing cNOS activity and converting it to superoxide generator. In a canine model of acute coronary syndrome, infusion of BH4 has been shown to prevent thrombus formation. Platelets from patients with acute coronary syndrome produce markedly less NO than do control platelets. A reasonable explanation for these findings is that episodic contact with collagen boosts platelet superoxide production, oxidizing BH4. Since 5-methyltetrahydrofolate can reduce oxidized BH4, or otherwise compensate for its deficiency, supplementation with its precursor folic acid may improve platelet function in acute coronary syndrome and possibly reduce risk for coronary thrombosis in other at-risk patients. Other research demonstrates that superoxide production is increased, and nitric oxide production diminished, in platelets of diabetics; the ability of glutathione--a peroxynitrite scavenger--to largely ameliorate these abnormalities, is consistent with a prominent role for BH4 deficiency in diabetic platelet malfunction. Reports that platelet NO production is decreased, and/or superoxide production increased, in patients with disorders associated with insulin resistance syndrome, suggest that BH4 deficiency--potentially remediable with high-dose folate--may likewise contribute to the platelet hyperreactivity noted in these disorders. Supplemental vitamin C and arginine also have the potential to boost platelet production of NO Increased intakes of taurine, magnesium, gamma-tocopherol, fish oil, and garlic may help to stabilize platelets by additional mechanisms. As a complement to the proven benefits of low-dose aspirin, a supplemental regimen emphasizing these nutrients in appropriate doses may act directly on platelets to further diminish risk for thrombotic episodes.