Reproductive aspects of the protein C system in women

Abstract

Of great importance to the reproductive system in women are the activating and inhibiting factors which maintain haemostatic balance. These play a prominent role in the prevention of abnormal bleeding, at ovulation as well as during menstruation, pregnancy and delivery. The coagulation cascade is primarily down regulated by the protein C system.

Objective: The aim was to study the possible impact of estradiol and progesterone on the protein C system in women during menstrual cycle, controlled ovarian hyperstimulation (COH), pregnancy as well as to determine a possible association between hypercoagulation and recurrent abortions.

Methods: Blood samples were drawn during; menstrual cycle days 1-3, 6-8, 13-14 and 20-24; during COH, when down regulated, at time for the peak value of estradiol, and at time for ovum pick up (OPU); during pregnancy weeks 12, 20, 28, 32, 36 and postpartum. In women with recurrent abortions and in controls, samples were collected at cycle day 5-8.

In all women estradiol and progesterone, factor V Leiden and activated protein C (APC) ratio were analyzed. In the pregnant women analysis of protein C inhibitor (PCI) was added. In the women with recurrent abortions several haemostatic factors were analyzed: cardiolipin antibodies, lupus anticoagulant, protein C, protein S, antithrombin and coagulation factors VIII and XIII as well as von Willebrand factor.

Results: Normal pregnancy; The response to APC as well as PCI concentrations exhibited a continuously decreased activity throughout pregnancy, and correlated significantly. Postpartum both APC ratio and the concentration of PC1 rose, to levels similar to those observed in non-pregnant women. Menstrual cycle, The women exhibiting the highest levels of estradiol at the time for ovulation had the lowest response to APC in the luteal phase, suggesting that the level of estradiol at the time of ovulation is of importance for the response to APC during the luteal phase. Still, no direct correlation was found between the estradiol or progesterone levels, and the APC ratios. When women during normal menstrual cycle were compared to women undergoing COH, no significant difference in their response to APC was observed. Recurrent abortion A marked difference was observed between women with primary and secondary abortions. In the parous women the only significant difference from the control group was overweight. Enhanced coagulation, due to the factor V Leiden mutation was revealed in 27.8% of women with primary recurrent abortions. In addition, 54.2% women with primary recurrent abortions had at least one factor that might contribute to hypercoagulation.

Conclusions: The levels of estradiol and progesterone per se did not seem to affect the response to A-PC, although the level of estradiol at time of ovulation may have an impact on the response to APC during luteal phase, in normal menstrual cycle. The time for blood sampling within the menstrual cycle was not of clinical importance for the analyze of APC ratio. With advance of normal pregnancy, decrease of PC1 function, correspond to decreases of APC ratios, due to activated coagulation.

In women with primary recurrent abortions, hypercoagulation was a common phenomenon mainly caused by the Leiden mutation. This might indicate a reduced placental perfusion, and an increased risk for micro thrombosis in the placenta.