Changes in Haemostatic Variables Induced by Oral Contraceptives Containing 50 μg or 30 μg Oestrogen: Absence of Dose-dependent Effect on PAI-1 Activity

Abstract

SummarySeveral studies have suggested a dose-response relation between the oestrogen content of oral contraceptive (OC) and the risk of both venous thrombosis and arterial disease, when oestrogen doses were higher than 50 μg. However, there is no clear epidemiological evidence for a decrease in thrombotic risk with formulations containing less than 50μg oestrogen. Therefore, we investigated haemostatic variables in users of OC containing either 30 μg (35 women) or 50μg (29 women) ethinyl estradiol as compared with non users (64 women) matched for age and smoking status. Mean values of antithrombin activity were significantly lower in 30 γg or 50 μg oestrogen users than in non users (96% and 98% vs 105%, respectively, p<0.001), but they were not significantly different between the two groups of OC users. There was a significant increase in mean values of factor VII antigen in women taking either 30μg or 50μg oestrogen as compared with non users (96% and 101% vs 85%, respectively, p<0.005). Although the difference between both groups of OC users was not significant, a positive linear trend in factor VII levels was observed within the 0-50μg oestrogen range (p <0.001). Mean levels of fibrinogen were slightly higher in 30μg or 50μg oestrogen users than in non users (2.71, 2.66 g/l vs 2.55 g/l, respectively,), but there was no significant difference between the three groups. Mean values of PAI-1 activity were significantly lower in both groups of OC users than in non users (4.89 and 4.63 AU/ml vs 6.47 AU/ml, respectively, p <0.02), but this decrease was not dose-dependent. There was no significant difference in haemostatic variables between 30 μg oestrogen preparations containing either 100μg (13 women), 150μg (3 women) or 200μg (19 women) levonorgestrel. In 50μg oestrogen preparations, the wide range of different types of progestogens did not allow valid assessment of proge- stogens effect. These data provide further evidence for an alteration of blood coagulation and fibrinolysis in OC users within the 30μg-50μg oestrogen range. However, despite a possible dose-dependent effect of oestrogen on factor VII, our results suggest no substantial change in PAI-1 activity and other markers of thrombogenic risk when oestrogen content of combined OC is decreased from 50μg to 30μg. The potential role of progestogens in haemostatic system needs further investigations.

Oral Contraceptives Highlight the Genotype-Specific Association Between Serum Phospholipids and Activated Factor VII

“…The levels of FVII and the concentrations of lipids in this study are consistent with those described in other reports of women on low-dose or sequential OC pills. In fact, the increase noted in FVII levels represents a well-documented effect of OCs, 14,[25][26][27][28][29][30][31] as does that of chol, TGs, HDL-chol, and apoA1 levels. 32,59 -62 Most of the studies 14,28,[61][62][63] and a recent review 31 have described an increase in FVIIc and FVIIAg levels that was roughly related to the estrogen dose.…”

“…19 -22 The effect of OCs on hemostatis is an increase in the levels of some coagulation factors (factors II, VII [FVII], IX, X, XI, and VIII; von Willebrand factor; and fibrinogen), of protein C, and of protein complexes and fragments related to the activation of coagulation (thrombin-antithrombin complexes and D-dimer); these enhance fibrinolysis and decrease the levels of antithrombin III, protein S, and C4b-binding protein. [23][24][25][26][27][28][29][30][31] Concerning FVII, a relationship between FVII levels, the dose of estrogen, [23][24][25][26][27][28]31 and progestogen (norethisterone but not D-norgestrel 32 ) was consistently found. It is difficult, though, to pinpoint whether these changes are due to the estrogen or the progestative compound, and it is still a matter of debate whether the excess CVD risk after the use of OCs is related to the resulting dyslipidemia, the hemostasis changes, or both.…”

Risk Factors for Heart Attack, Stroke, and Venous Thrombosis Associated With Hormonal Contraceptive Use

“…Changes in concentrations and activity of coagulation factors, including increased levels of factors II, VII,VIII, and X, were found in many other studies. [36][37][38] Walter et al, 39 conducted a small study of hemostatic response in users and nonusers of COCs during exercise. When compared to controls, women using COCs generally had a Zakharova et al 325 larger increase in levels of thrombin and fibrin formation.…”

Differential effects of estrogens and progestins on the anticoagulant tissue factor pathway inhibitor in the rat

“…Complete absence of AT is incompatible with life, and individuals with partial deficiencies have an increased incidence of venous thrombosis [28]. Many clinical studies have reported an ∼5-15% reduction in plasma AT in women taking OC and HT [8,14,15,[29][30][31]. In a recent placebo-controlled randomized trial of HT, a significant difference in AT levels was observed in women taking unopposed estradiol versus combined estradiol plus cyclical progestin, suggesting that the progestin may modulate AT plasma levels [13].…”