gestodene and Activated-Protein-C-Resistance

The use of oral contraceptives is a well-established acquired risk factor for venous thrombosis. In 1995, a number of epidemiological studies were published which suggested that women who use third generation oral contraceptives that contain desogestrel or gestodene as progestagen are exposed to a two- to threefold higher risk for venous thrombosis than women using second generation oral contraceptives which contain levonorgestrel. In this paper, the effects of oral contraceptives on the haemostatic system are discussed. It appears that plasma from oral contraceptive users is resistant to the anticoagulant action of activated protein C (APC). This phenomenon, called acquired APC resistance, is more pronounced in users of desogestrel or gestodene-containing oral contraceptives than in women who use oral contraceptive pills with levonorgestrel. On the basis of these observations, it was proposed that acquired APC resistance may be the mechanistic basis of the increased risk for venous thrombosis during oral contraceptive use and for the further increased thrombotic risk of third generation oral contraceptive users. Furthermore, the results of a recent cross-over study are discussed. This study indicated that a large number of other haemostatic parameters were changed during oral contraceptive use. Some of these changes were more pronounced on desogestrel-containing oral contraceptives. The cross-over study also showed that the increased fibrinolytic activity during OC use is counterbalanced by an enhanced activity of thrombin-activatable fibrinolysis inhibitor (TAFI), a protein that participates in the inhibition of fibrinolysis.

Topics: Activated Protein C Resistance; Contraceptives, Oral; Desogestrel; Female; Hemostasis; Humans; Norpregnenes; Risk Factors; Venous Thrombosis

The purpose of this study was to investigate whether the effect of transdermal estrogen therapy in postmenopausal women differs from that of oral therapy with regard to resistance to activated protein C (APC), an important risk factor for venous thrombosis, and levels of related proteins, such as protein S, protein C, and prothrombin.. In a randomized, double-blind, placebo-controlled study, 152 healthy hysterectomized postmenopausal women received daily either placebo (n=49), transdermal 17beta-estradiol (E2) 50 microg (tE2 group, n=33), oral E2 1 mg (oE2 group, n=37), or oral E2 1 mg combined with gestodene 25 microg (oE2+G group, n=33) for 13 28-day treatment cycles, followed by 4 cycles of placebo for each group. Plasma samples were collected at baseline and in cycles 4, 13, and 17. In cycle 13, significant increases versus baseline and placebo were found in normalized APC sensitivity ratios (nAPCsr) in all treated groups (tE2, +26.9%; oE2, +102.7%; oE2+G, +69.9%). Increases in nAPCsr were significantly higher in the oral treatment groups than in the tE2 group. In addition, compared with baseline and placebo, after 13 cycles, decreases were observed in total protein S (tE2, -4.1%; oE2, -7.9%; oE2+G, -5.8%), free protein S (tE2, -7.1%; oE2, -8.4%; oE2+G, -5.2%), and protein C in the oE2+G group (-6.4%), but these changes did not explain the increase in nAPCsr. Changes in prothrombin were small and also did not affect the nAPCsr.. Increases were observed in resistance to APC, which were more pronounced in the oral treatment groups than in the transdermal group. The increase in resistance to APC was not explained by changes in protein S, protein C, or prothrombin and may contribute to the increased incidence of venous thrombosis in users of hormone replacement therapy.

Topics: Activated Protein C Resistance; Administration, Cutaneous; Administration, Oral; Aged; Biomarkers; C-Reactive Protein; Double-Blind Method; Estradiol; Estrogen Replacement Therapy; Female; Hemostasis; Humans; Middle Aged; Norpregnenes; Postmenopause; Protein C; Protein S; Prothrombin; Risk Factors; Venous Thrombosis

We studied 67 healthy women who were randomly allocated to receive third generation gestodene (Gynera) or second generation levonorgestrel (Microgynon 30) combination of low-dose estrogen oral contraceptives (OCs) for their hemostatic effects over 2 years. Hemostatic changes were apparent within 3 months of OC use. Hematocrit (Hct) was not affected, but hemoglobin (Hb) concentration decreased by 18 months. Shortened prothrombin time (PT) and activated plasma thromboplastin time (APTT) were associated with elevated fibrinogen within the 12-month use of both OCs. Factor VII was reduced only in Micro 30 during the 18 months of use. Enhanced thrombin-antithrombin (TAT)-complex level was seen at 18 months of Gynera use. Prothrombin fragment1+2 (F1+2) rise was seen at 3 months with Micro 30. Reduced antithrombin III (ATIII) activity was seen at 18 months with Gynera and at 24 months with Micro 30. Increased protein C activity was seen at 3 months and reduced protein S occurred at 18 months of Gynera use. Tissue plasminogen activator (t-PA) activity was enhanced for 6 months in both OCs with raised D-dimer levels for 12 months with Gynera and 6 months with Micro 30. Decreased t-PA antigen was seen at 18 months and decreased urokinaselike plasminogen activator (u-PA) antigen occurred throughout the 24 months of both OCs use. Enhanced u-PA activity was only seen in Gynera users. Elevated plasminogen levels were apparent throughout both OCs use. PAI-1 levels were significantly decreased with Micro 30. With Gynera, the decreased PAI-1 activity was seen only at 18 months and PAI-1 antigen at 12 months. No change in platelets and von Willebrand factor (vWF) were seen in long-term OC use except that beta-thromboglobulin (beta-TG) showed decreased trends reaching statistical significance by 18 and 24 months of Micro 30 use and by 24 months of Gynera use. A further significant decrease in beta-TG, u-PA antigen, ATIII, and protein S levels were seen 3 months after pill stoppage compared with pretreatment levels. Activated protein C resistance (APCR) was negative in all subjects before and during OC use. The study indicated dynamic balance between coagulation and fibrinolysis with no endothelial activation. However, because some hemostatic markers showed wide fluctuations during OC use, a longer term study is warranted to investigate any adverse hemostatic changes that might enhance the risks of venous thromboembolism in Asian subjects known to be less prone to thrombosis.

Topics: Activated Protein C Resistance; Adolescent; Adult; Analysis of Variance; Antigens; Antithrombin III; beta-Thromboglobulin; Blood Platelets; Contraceptives, Oral, Synthetic; Factor VII; Female; Fibrin Fibrinogen Degradation Products; Fibrinogen; Hematocrit; Hemoglobins; Hemostasis; Humans; Levonorgestrel; Norpregnenes; Partial Thromboplastin Time; Peptide Fragments; Peptide Hydrolases; Plasminogen; Progesterone Congeners; Protein C; Protein S; Prothrombin; Thrombelastography; Time Factors; Tissue Plasminogen Activator; Urokinase-Type Plasminogen Activator; von Willebrand Factor

Topics: Activated Protein C Resistance; Contraceptives, Oral, Synthetic; Desogestrel; Female; Humans; Norpregnenes; Progesterone Congeners; Randomized Controlled Trials as Topic; Risk Factors; Thromboembolism