Protein-Z Deficiency and/or Protein Z Polymorphisms in First Trimester Pregnancy Complications

Protein Z (PZ) is a vitamin K-dependent coagulation factor; it is a glycoprotein that inhibits activated factor Xa, acting as a co-factor to PZ-dependent protease inhibitor, enhancing its action approximately by 1000 times. PZ levels in normal individuals vary greatly, as a result of PZ gene polymorphisms. PZ deficiency has been involved in the pathogenesis of ischemic strokes and pregnancy complications. Gris et al [Blood 2002;99(7):2606–08] first described a possible role of PZ deficiency (PZ <= 1mg/L) in women with fetal loss between the beginning of the 10th and the end of the 15th week of gestation. In a recent meta-analysis [Sofi et al, Thrombosis and Haemostasis 2010;103(4):749–56] PZ deficiency was associated with increased risk of pre-eclampsia and fetal loss, as well as with increased risk of arterial and venous thrombotic events.

We studied a total of 314 women, 70 women with three or more consecutive spontaneous abortions (group A), 145 women with less than 3 early spontaneous abortions (group B) and 99 control women with at least one normal pregnancy and negative history of a thrombotic complication (group C). All women were tested for congenital and acquired thrombophilia such as antithrombin, protein C and S levels, homocysteine levels, lupus anticoagulant (PTTLa), factor V Leiden mutation, prothrombin G20210A gene polymorphism and PZ levels. We also investigated protein Z polymorphism F79A in a subgroup of our patients. Measurements were made at least 3 months apart from a thrombotic event. Differences between groups were assessed with ANOVA and chi-squared tests for continuous and categorical variables respectively.

Statistically significant difference was found in PZ levels between the three groups. Mean PZ level was 1.23mg/dL, 1.31mg/dL και 1.61mg/dL (p<0.00001) in groups A, B, C respectively. Post-hoc Bonferroni analysis revealed a significant difference between groups A and C (p=0.0003) and between groups B and C (p=0.001). The percentage of PZ deficiency (95% condidence interval) was 40% (28%–52%), 38% (30%–46%) and 18% (11%–26%) respectively (p=0.001). Both group A (OddsRatio[OR]=3) and group B (OR=2.75) have a statistically greater PZ deficiency than control group C. The other parameters did not differ significantly between the three groups.

Spontaneous abortions are common in women especially in first trimester. Thrombophilia has a major role in pregnancy complications. In these women that one cannot find some of the well established thrombophilic factors, searching for other possible deficiencies is necessary. The role of PZ deficiency has been investigated thoroughly in the last decade with sometimes conflicting results. To the best of our knowledge, this is the first Greek study investigating the possible role of protein Z deficiency in women with early pregnancy losses. From our study it is evident that PZ deficiency is an independent risk factor for early pregnancy losses. From our study it seems that the other thrombophic factors may play a minor role. A plausible pathophysiologic explanation is the occurrence of microthrombi due to atherosclerotic lesions soon after the development of materno-placental circulation. The role of PZ gene polymorphisms in PZ levels and in thrombotic complications remains to be investigated further. According to preliminary results from a sub-group of our patients (Topalidou et al, Thrombosis Research 2009;124:24–27), the presence of the intron F79A polymorphism was associated with significantly lower PZ levels, but was unrelated to unexplained early pregnancy losses.

No relevant conflicts of interest to declare.