Second Chapter
Dr.Álvaro Monterrosa Castro, MD
Blood coagulation system
In his book on endocrinology gynecologist, León Speroff (7), points out that the final objective of the blood coagulation system is the production of thrombin, which is responsible for converting fibrinogen into a fibrin clot.Thrombin is produced from prothrombin by the action of coagulation factor Xa in the presence of factor V, calcium and phospholipids.Antithrombin III is one of the natural anticoagulants since it inhibits thrombin.
Protein C and protein S are two other important inhibitors of clot formation, being dependent on vitamin K. hemostatic system maintains the integrity of the vascular system (136).Normally, the coagulation system is maintained in a dynamic balance provided by the procoagulant and anticoagulant systems.
The mechanism of hemostasis protects the integrity of the vascular system, but the repair process of the tissues and hemostasis itself are complex processes.In which many cellular components (vascular endothelium, platelets) and humoral components (blood coagulation processes, coagulation inhibition and fibrinolysis) participate.The imbalance between the coagulation system and the fibrinolytic (anticoagulant) system causes alterations in hemostasis.Facilitating hemorrhagic events, thrombo-embolic and cardiovascular diseases (136,137).
The increase in fibrinogen and factors VII, VIII and X, as well as the increase in Plasminogen and the Plasminogen activator inhibitor -1, they will favor coagulability conditions.The same will happen if there is a decrease in antithrombin III, protein C, protein S and antiplasmin (7).
Combined oral contraceptives produce modifications in both the procoagulant and anticoagulant systems ( 41,27,136,137,138).
Procoagulant Mechanisms
Among the procoagulant mechanisms, the most important is the depression of the natural anticoagulant, Antithrombin III, which produces an elevation mild in the levels of Prothrombin, Factor VII, Factor IX and factor blood vessels, increasing platelet aggregability and presenting an increase in the total activity of the coagulation system (33).Protein C and protein S are two other major inhibitors of coagulation, they are dependent on vitamin K and are decreased by combined oral contraceptives (83,138).
There is a compensatory system anticoagulant, by increasing Plasminogen levels without effect on its inhibitor, alpha-antiplasmin.A rapid destruction of fibrin has been evident, since products of its degradation have been detected.Hyperinsulinemia is correlated with the Plasminogen Activator Inhibitor-1 factor, which leads to hypofibrinolysis, increased fibrin deposition and development of atherothrombosis.
The changes in the hemostatic variables produced by combined oral contraceptives are due to estrogens, since such modifications are not observed with progestin-only preparations (138).Combined oral contraceptives containing 50 ug/day of ethinyl estradiol cause increased production of coagulation factors, such as factor V, factor VIII, factor 136) cite several studies that support that in healthy users of combined oral contraceptives:
Without cardiovascular risk factors and non-smokers, activation of procoagulant systems has been reported, usually compensated by a similar activity of the profibrinolysis system, without disturbances in hemodynamic balance.Fruzzeti’s ruling is the same (139).Winkler et al (41) assert that microdose combined oral contraceptives have a less measurable effect on the coagulation system than the old preparations, and factors that inhibit coagulation appear to increase as much as procoagulant factors.
Combined oral contraceptives with low doses, both monophasic and multiphasic, do not have a significant clinical impact on the blood coagulation system.The microdose pills currently in use seem to maintain hemostatic balance (27,139), however they are contraindicated in women with a history of thromboembolic disease (41).
Tobacco use leads to a state of hypercoagulation ( 7).
Microdose pill
Smoking women who use the microdose pill for long periods have a more noticeable activation of the coagulation system, evidenced by shortening of the prothrombin time, increased fibrinogen, decreased antithrombin III and elevated plasminogen activity.
Fruzzeti (139) based on concepts that define that combined oral contraceptives of very low dose, have a negligible effect or no effect on procoagulant factors.She suggests that these formulations may be suitable for smoking women who wish to use combined oral contraceptives
Ultra-low dose formulations may also be suitable, but studies must be awaited to support this approach.Speroff (7) cites studies that indicate that combined oral contraceptives that include 20 ug/day of ethinyl estradiol have no effects on coagulation parameters, even in smokers.
Coata et al (27 ) assert that triphasic microdose oral contraceptives, which contain ethinyl estradiol and Gestodene, do not significantly affect the coagulation system, lipid metabolism or blood viscosity, concluding that there is an absence of significant effects that could represent a possible factor that increases the risk. of cardiovascular disease in young, healthy women.
The recent epidemiological observations reported in the Collaborative Study of the World Health Organization must be taken into account:
Published in 1995 (140,141) in relation to latest generation combined oral contraceptives and thromboembolic disease, which will be discussed later and which have generated a large amount of research as well as conflicting positions (137,142,143,144,145,146,147,148) Middeldorp et al (144) carried out a randomized, crossover, cycle-controlled study that included 27 healthy female volunteers.To establish differences in coagulation factors and markers of prothrombin formation, when second-generation combined oral contraceptives (ethinyl estradiol 30 ug/day plus levonorgestrel 150 ug/day) and third-generation combined oral contraceptives (ethinyl estradiol 30 ug/day plus desogestrel 150 ug/day.
With the use of both combinations, the levels of factors II, VII, increased and Factor V decreased during use of the pill that included desogestrel. Only one marker for increased clotting, prothrombin, experienced a significant increase while using both combined oral contraceptives.
The thrombin/antithrombin complex and fibrin were unchanged.These researchers conclude (144) that there are differences in the effects that oral contraceptives containing levonorgestrel and desogestrel produce on some coagulation factors.But it is unknown if these changes are the explanations for the differences reported in terms of risks of venous thromboembolism.
In a publication from July 2000, Tans et al (Ñ-4) based on the concept that combined oral contraceptives cause disturbances or modifications in procoagulant and anticoagulant patterns and may contribute to increasing the risk of thrombotic and embolic phenomena, a randomized crossover study was carried out to determine the effect produced by second generation oral contraceptives: ethinyl estradiol 30 ug/ day plus levonorgestrel and a third generation oral contraceptive: ethinyl estradiol 30 ug/day plus 150 ug/day of desogestrel.
The evaluation parameters were: antithrombin, alpha 2 macroglobulin, alpha 1 antitrypsin, inhibitor of protein C, protein C, free protein S and total protein S.
The study (145) allows us to conclude that the plasma anticoagulant activity in users of combined oral contraceptives that include desogestrel is more intensely impaired than that of users of oral contraceptives containing levonorgestrel.
Carter (146) believes that the increased risk of venous thromboembolism is due to the induction of resistance to activated protein C, which It is anticoagulant.Rosing et al (149) consider that acquired resistance to activated protein C explains the increased risk of venous thromboembolism in oral contraceptive users, although this remains to be confirmed.
Winkler et al (41) a In turn, they have studied the effects on the hemostatic system of the combination ofgestodenum 75 ug/day plus 20 ug/day of ethinyl estradiol and conclude that it has a balanced effect on hemostasis.Stimulating both the procoagulant and anticoagulant system and fibrinolytic activity.
When their results were compared with the combination of 75 ug/day of Gestodene and 30 ug/day of ethinyl estradiol, they obtained similar considerations, with statistical differences. not significant.
Van der Mooren et al (73) conducted a randomized, multicenter and comparative study for six cycles in 62 users of ultra-low dose oral contraceptives (15 ug/day of ethinyl estradiol plus 60 ug/day of Gestodene), compared with 62 users of very low-dose oral contraceptives (20 ug/day of ethinyl estradiol plus 150 ug/day of desogestrel) and found that both preparations in a similar way exerted a procoagulant effect accompanied by a compensatory increase in plasminogen and fibrinolytic activity.Changes consistent with previous studies and those carried out by other oral contraceptives (150,122,112).
No changes have been found in coagulation and fibrinolysis parameters, such as factor VII, fibrinogen, plasmin-antiplasmin complex, factor tissue plasminogen activator, antithrombin III, protein C and protein S, after several cycles of 30 ug/day of ethinyl estradiol plus 2 mg/day of dienogest (56).
In 2004, publish results of the double-blind, controlled, randomized study carried out in two centers in Germany by Wiegratz et al 151) where the effect of four oral contraceptive preparations on hemostatic parameters is assessed.25 women were entered into each group and received six cycles of contraception.
One group received pills of 30 ug/day of ethinyl estradiol plus 2 mg/day of dienogest, another group pills of 20 ug/day of ethinyl estradiol plus 2 mg/day of dienogest, a third group 20 ug/day of ethinyl estradiol plus 100 ug/day of Levonorgestrel and the fourth group a novel formula that included 10 ug/day of ethinyl estradiol plus 2 mg/day of estradiol valerate plus 2 mg/day of dienogest.
In all four groups, an increase in the levels of the following procoagulant factors was observed: fibrinogen, prothrombin, plasminogen, plasmin antiplasmin complex and anticoagulant factor: activated protein C .All four pills generated a decrease in anticoagulant factors: antithrombin activity.In the activated plasminogen inhibitor factor and gently reduced the sensitivity to activated protein C, while they did not significantly modify the thrombin antithrombin complex.
Notable difference was observed in both free and total protein S between the dienogest and levonorgestrel pills, the former causing a noticeable decrease in this protein, both free and total, an effect that was dose dependent on the ethinyl estradiol administered, the percentage of decrease being greater the higher the concentration of ethinyl estradiol contained in the preparation in the tablet.
The pill that included levonorgestrel induced a minimal, non-significant reduction in total protein S and a significant increase in protein S levels.
The four pills also modified the fibrinolysis parameters by increasing Dimer-D levels by 12-38%, significantly increased plasminogen and reduced activated plasminogen inhibitor by 44-78% (151).
As has been shown noted that combined oral contraceptives in their action on hemostatic parameters cause an increase in both procoagulant activity and fibrinolytic activity, many of the changes being caused by estrogen and becoming dose dependent.
By significantly reducing the dose of estrogen, modern pills have sought to reduce or eliminate the increase in procoagulant activity.The effect of the different progestins is still unclear, but they can to some extent modulate the changes induced by estrogen.
Wiegratz et al (93) conclude their article by noting that changes in coagulation and the fibrinolysis induced by combined oral contraceptives in healthy women do not sufficiently explain the increased risks of thromboembolic disease that have been established with them.There is no evidence of increased risk of cardiovascular disease in women who used combined oral contraceptives in the past.