FOLIC-ACID DEFICIENCY ENHANCES ORAL CONTRACEPTIVE-INDUCED PLATELET HYPERACTIVITY

In previous studies conducted in female rats and in women, oral contra ceptives (OC) were found to induce a platelet hyperactivity that was r elated to an oxidative stress. Because cases of megaloblastic anemia h ave been reported to occur in women taking OC, these treatments are su spected of depleting folate stores. In the study presented herein, whi ch was conducted in rats, we sought to determine the influence of diet ary folic acid deficiency (FD) on the thrombogenicity of OC. Animals w ere fed for 6 weeks with either a folic acid-deficient diet (250 mu g/ kg folic acid) or a control diet (750 mu g/kg). One-half of the animal s in each group were treated with OC (ethinyl estradiol plus lynestren ol). FD and OC individually potentiated platelet aggregation in respon se to thrombin and ADP and the release and metabolism of arachidonic a cid, in particular, the biosynthesis of thromboxane. These platelet ac tivities were further enhanced in animals given both the folic acid-de ficient diet and the OC treatment. In addition, FD enhanced the pro-ox idant state in OC-treated rats characterized by (1) a fall in platelet and plasma n-3 fatty acids, (2) an increase in plasma lipid peroxidat ion products such as conjugated dienes, lipid peroxides, and thiobarbi turic reactive substances, (3) a rise in ex vivo erythrocyte susceptib ility to free radicals. Moreover, we found that OC treatment led to a reduction of plasma and erythrocyte folate concentrations associated w ith a moderate hyperhomocysteinemia. Under our experimental conditions , we did not find significant synergistic effects between OC and FD. W e propose that, although the untoward effects associated with the OC t reatment may not primarily be dependent on FD, the folic acid deficien cy magnified OC-induced oxidative stress, which resulted in platelet h yperactivity by elevating the pro-oxidant homocysteine plasma concentr ation. Despite the limitations of this animal model, the data of the p resent study suggest that in addition to cigarette smoking, inadequate folic acid intake might predispose those taking OC to vascular thromb osis.