Venous Thromboembolism

A retrospective study compared the venous impact of chlormadinone acetate, at antigonadotropic doses, versus no hormonal treatment in 204 women at high risk of venous thromboembolism. During follow-up (mean of 33 months)  nine episodes of VTE were observed:  three in women receiving CMA and six in untreated women.

Using the Cox model to adjust for confounding variables such as age,  thrombophilia and body mass index,  the relative risk of VTE associated with the use of CMA was not significant [relative risk:RR 0.8 (78). Therefore,  which is the risk of VTE in normal women taking hormonal contraceptives?

The risk of venous thromboembolism seems primarily dependent on the dose of ethinylestradiol;  although the potential contribution of the new progestins   in   reducing   vascular   risks   is   of   great   importance   (2,15,44,49).

Unfortunately, the major disadvantage of third generation HCs, according to most authors,  is the increased risk of vascular effects.  (22,55,79).  These events seem more pronounced during the first year of use (5,48 ).

In 1995, an important study reported that desogestrel and gestodene could increase the risk of venous thromboembolism and showed an antagonist effect of LNG on the EE-induced rise of factor VII activity and on the EE-induced reduction of total and free protein S (26,36,42)

In addition,  the effects of a combined oral contraceptive containing 20mcg EE and 75mcg gestodene (GSD) on hemostatic parameters were investigated.  Results showed no significant changes in fibrinogen,protein C, AT III or D-dimer during COC use.

While the increase in platelet count, decrease in protein S level,  prothrombin activity and activated partial thromboplastin time, and the prolongation of thrombin time were significant (80).

Furthermore, the thrombotic risk with the use of particular third-generation oral contraceptives was elevated among carriers of the factor V Leiden mutation.

This disorder is a common risk factor for venous thrombosis,which is associated with a 3 to 7-fold increased risk in heterozygous individuals (61,62,81,82). A plausible logical mechanism for the thrombotic effects of second and third-generation oral contraceptives is still lacking.

Rosing reported that oral contraceptive use leads to acquired activated protein C (APC) resistance and women using third-generation HCs are more resistant to the anticoagulant action of APC than users of second-generation HCs (83,84).

The difference could be explained by differential effects of progestagens on plasma sensitivity to activated protein C (APC).  A study assessed the effect of APC on endogenous thrombin potential (ETP) in the plasma of healthy women using either, combined HC or progestagen-only OC,and in non-users. Carriers of factor V Leiden were excluded.

Compared with non-users, there was no significant change in APC resistance in women using progestagen-only HC (chlormadinone acetate). Women who used combined HC were less sensitive to APC than non-users (P <0.001)  and the difference was significantly more pronounced in women using third-generation HC than in those who used second-generation OC containing levonorgestrel (P < 0.05).

Compared with HC containing levonorgestrel,  the use of norethisterone-containing HC was associated with an increased resistance to APC (P < 0.05). Women who used cyproterone-containing HC (n = 10) were less sensitive to APC than those using third-generation HC (P <0.05) or second-generation HC containing levonorgestrel (P < 0.05) (78,85).

Few data are available on involvement of progestins in the coagulation patho-mechanisms.  It is,  therefore,likely that the vascular effects of progestins are mediated through progestin receptors as well as through down-regulation of estradiol receptors [54,56,59].  Estrogen and progestin receptors are localized in endothelial and smooth muscle cells of the vessel wall, but there are differences in the response of vein and arteries to sex-steroids (49)

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