Changes in haemostasis after stopping the combined contraceptive pill: implications for major surgery.

OBJECTIVE: To investigate the changes in haemostasis in the three months immediately after stopping the combined contraceptive pill. DESIGN: Prospective randomised study. SETTING: Family planning centre in London. SUBJECTS: 24 women aged 35-45 investigated before, during, and after six months' use of combined oral contraceptives containing 30 micrograms ethinyl oestradiol together with the progestogens desogestrel or gestodene. MAIN OUTCOME MEASURES AND RESULTS: Blood samples were taken immediately before and after six months of oral contraceptive use and one, two, four, six, eight, and 12 weeks after the pill had been stopped. During the six months of oral contraceptive use the plasma concentration of factor X and fibrinogen increased and that of antithrombin III decreased. Between two and six weeks after stopping the pill a rebound phenomenon occurred with plasma concentrations of antithrombin III increasing (mean change from baseline at two weeks 0.06 IU/l and at six weeks 0.10 IU/l) and fibrinogen decreasing (0.26 g/l change at two weeks and 0.40 g/l at six weeks). Factor X concentrations fell gradually and the values at eight weeks were not significantly different from those found before the combined pill was started. CONCLUSION: The combined pill should be stopped at least four weeks before major surgery, which carries the risk of postoperative thrombosis, to allow the potentially prothrombotic haemostatic changes that occur during its use to be corrected.

PIP: This study investigated the changes in hemostasis in the 3 months immediately after cessation of the combined oral contraceptive (OC). This prospective, randomized study has based at a family planning center in London and 24 women, ages 35-45, were investigated before, during, and after 6 months use of these combined OCs containing 30 mcg ethinyl estradiol along with the progestogens desogestrel or gestodene. Blood samples were taken immediately before and after 6 months of OC use and 1,2,4,6,8, and 12 weeks after the pill had been stopped. During the 6 months of OC use, the plasma concentration of factor X and fibrinogen increased and that of antithrombin III decreased. Between 2-6 weeks after stopping the pill, a rebound phenomenon occurred with plasma concentrations of antithrombin III increasing (mean change from baseline at 2 weeks 0.06 IU/l and at 6 weeks 0.10 IU/l) and fibrinogen decreasing (0.26 g/l change at 2 weeks and 0.40 g/l at 6 weeks). Factor X concentrations fell gradually and the values at 8 weeks were not significantly different from those found before the combined pill was begun. The combined OC should be stopped at least 4 weeks prior to major surgery (which carries the risk of postoperative thrombosis) in order to allow the potentially prothrombotic hemostatic changes that occur during its use to reverse themselves.

Heparin cofactor II levels are increased by the use of combined oral contraceptives.

Heparin cofactor II (HCII) was assayed by a microtitre amidolytic substrate technique. A linear response was obtained up to 1.5 U/ml and HCII levels were not affected by freezing and thawing the plasma. The assay was validated by comparing HCII and antithrombin III (AT III) levels in AT-III-deficient plasmas and samples from critically ill patients. Higher HCII levels were found in healthy normal women than in healthy normal men (means 1.16 and 0.97 U/ml, respectively, P less than 0.01). A significant increase in HCII levels from 0.86 to 1.10 U/ml (mean values) was seen in healthy normal women starting on combined oral contraceptive (COC) preparations (P less than 0.001). Increased HCII levels were maintained over a 6-month period, but fell towards normal 14 days after stopping COC, although they were still significantly higher than before starting COCs. The discrepancy in HCII level between normal men and women may be due to COC use. In clinical studies, different reference ranges should be used for men and women, and the need for careful questioning about the use of COCs is emphasized.

PIP: Heparin cofactor II, a less well characterized heparin-dependent antithrombin factor than antithrombin III, was determined in 11 women before, during and after a 6 month trial of oral contraceptives, in 16 women aged 18-60, in 16 men aged 22-55, in 5 patients with known antithrombin III deficiency, and in a series of 16 patients in a critical care unit. The oral contraceptives used in the trial were Femodene (Schering, Burgess, Hill, U.K.) in 6 women and Marvelon (Organon, Cambridge, U.K.) in 5. The assay was an amidolytic microtiter method standardized against normal human serum. The assay was linear up to 1.5 U/ml, and HCII was not lost by repeated freezing and thawing. HCII levels were normal in patients with AT III deficiency, but ranged from 0.10-1.11 in intensive care patients. In normal subjects the mean HCII levels were 1.07 U/ml, and were significantly higher for women, 1.16, than for men, 0.97 U/ml. During intake of oral contraceptives, HCII rose significantly from 0.86 u/ml to 1.10 at cycle 1, 1.08 at cycle 3, and 1.19 at cycle 6. 2 weeks after stopping pills, the mean HCII level fell to 1.03. In contrast, AT III declined during pill cycles.

Changes in metabolism induced by oral contraceptives containing desogestrel and gestodene in older women.

Forty women aged 35-45 years were investigated to determine changes in haemostasis, lipids and lipoproteins whilst taking combined contraceptive pills containing the new third generation progestogens, desogestrel and gestodene. There was no statistically significant difference between the two preparations in any of the parameters studied. Women taking the combined pill showed increases in fibrinogen and factor X and a reduction in antithrombin III when compared with their control values. There were also small but significant increases in triglycerides and triglyceride-rich lipoproteins. Total high density lipoprotein cholesterol (HDL), high density lipoprotein-2 cholesterol (HDL2), high density lipoprotein-3 cholesterol (HDL3) and apolipoprotein A-1 were all increased at some stages of the treatment cycle, whereas low density lipoprotein cholesterol (LDL) showed a reduction in the first cycle of treatment. The changes in lipids and lipoproteins would not appear to increase the risk of cardiovascular disease, however the effects of the increase in the pro-coagulant factors are uncertain.