ENHANCED PLATELET THROMBOXANE SYNTHESIS AND REDUCED MACROPHAGE-DEPENDENT FIBRINOLYTIC-ACTIVITY RELATED TO OXIDATIVE STRESS IN ORAL CONTRACEPTIVE-TREATED FEMALE RATS
P. Durand et D. Blache, ENHANCED PLATELET THROMBOXANE SYNTHESIS AND REDUCED MACROPHAGE-DEPENDENT FIBRINOLYTIC-ACTIVITY RELATED TO OXIDATIVE STRESS IN ORAL CONTRACEPTIVE-TREATED FEMALE RATS, Atherosclerosis, 121(2), 1996, pp. 205-216
In previous studies conducted in rats and in women, we have shown that
oral contraceptive (OC) administration induced a platelet hyperaggreg
ation simultaneously with an increased platelet lipid biosynthesis whi
ch might be related to lipid peroxidation. In the present study, we sp
ecifically studied the arachidonic acid and the fibrinolytic pathways
in relation to the fatty acid composition in female rats treated for 6
weeks with OC (ethinyl estradiol plus lynestrenol). We found that pla
telets of treated animals were not only hyper-responsive to thrombin a
nd ADP, but also to sodium arachidonate. In addition, the results of t
he thrombin-induced release of labeled arachidonic acid pre-incorporat
ed into platelet membrane phospholipids showed an increased biosynthes
is of lipoxygenase and cyclooxygenase metabolites after OC treatment.
These data indicated a stimulated platelet arachidonate metabolism in
OC animals compared to controls which was further confirmed by the inc
reased thrombin-induced production of thromboxane B-2 (TXB(2)) as meas
ured with a radioimmunoassay, The platelet thrombin-stimulated TXB(2)
biosynthesis was inhibited in vitro in the presence of 500 mu M aspiri
n and 1 mM vitamin E; the erythrocytes from OC animals compared with c
ontrols presented an enhanced in vitro susceptibility to free radical-
induced hemolysis. These data indicated that a free radical mediated-p
rocess might occur. This hypothesis is confirmed by an increase of pla
sma lipid peroxidation parameters (conjugated dienes, lipid peroxides,
thiobarbituric acid reactive substances). After OC-treatment, a decre
ase in plasma and platelet long chain polyunsaturated fatty acids, par
ticularly (n-3), is in keeping with this idea. Furthermore, the result
s of the peritoneal macrophage-dependent fibrinolytic activity indicat
ed that OC induced a drastic decrease in urokinase plasminogen activat
or activity which might further contribute to the platelet hyperactivi
ty. Altogether these data suggest that besides the reported increase i
n clotting factors, platelet hyperactivity, possibly through a stimula
ted free radical-induced arachidonic acid metabolism, might be involve
d in the known high thrombogenic risk observed in OC users.