Placental insufficiency is widely accepted to be the primary cause of FGR, but the causes of placental insufficiency are various and complex [15]. Specifically, constricted spiral arteries and increased coagulation are contribute to fetal hypoxia and inappropriate nutrition exchange [16]. Hence, it is of important to explore the pathogenesis of coagulation dysfunction to improve the clinical diagnosis and therapy of FGR.
PZ is vitamin K-dependent serum protein and commonly synthesized by vascular endothelial cells [17]. Its structure is similar to other K-dependent factors, such as VII, IX, and protein C [18]. Previous studies showed that PZ can acts an anticoagulant, like protein C and protein S. ZPI is a member of serpin superfamily and could rapidly inhibit activation of factor Xa with the requirement of PZ, calcium, and perocoagulant phospholipids, or suppress the activation of factor XI in the absence of the aforementioned cofactors [19]. Previous studies demonstrated that abnormal expression of serum PZ was related to adverse pregnancy outcomes, such as intrauterine foetal death, hypertensive disorders of pregnancy, recurrent spontaneous abortion, etc. [20–22]. Souri et al. had documented that serum PZ and ZPI levels in healthy pregnant women were significantly higher than that in the non-pregnant women [23]. In this study, serum PZ and ZPI levels in the childbearing age without pregnant women (BC group) were also higher than that in the healthy pregnant women (HC group). Further explorations showed that serum PZ expression was positively correlated with expression of ZPI in both HC and FGR groups. According to these evidences, we speculated that the hypercoagulable nature of pregnancy might be the possible reasons, which might lead to a compensatory increased synthesis of PZ and ZPI in the liver and inhibit the activation of FXa, reducing the risk of thrombosis in pregnant women.
At present, the correlations between the expression of PZ and ZPI and FGR were still not elucidated. Quack et al. found that serum PZ level in normal pregnant women gradually increased with the increasing gestational age and returned to a normal level within three months after delivery [24]. Brettelle et al. had .demonstrated that nearly half of pregnant women with serum PZ deficiency had placental vascular abnormalities, and thus pointed out that the decrease in serum PZ level may be related to FGR [21]. However, Gowri et al. fount that no statistical significance was identified in the reduction of serum PZ level in pregnant women with FGR [25]. In this study, the serum PZ and ZPI levels were significantly downregulated in the FGR group compared with the normal pregnancy control, but no significant changes were identified in the second and third trimesters of pregnancy in both the normal pregnancy and FGR groups, indicating that insufficient serum PZ and ZPI levels may be a risk factor for FGR. In addition, further investigations showed that that serum concentrations of PZ and ZPI were negatively correlated with FGR. Considering of these findings, the diagnostic values of PZ and ZPI were determined with ROCs curve, and found that both PZ and ZPI presented higher diagnostic values. Combined these results, we speculated that deficiencies of PZ and ZPI might contribute to the development of FGR and could be utilized for the FGR screening in clinic.
Normal pregnancy is associated with a complicated of haematological variations, resulting in a hypercoagulable state [26]. PC, PS, and ATIII are three vitamin K-dependent anticoagulant proteins that are key roles in the coagulation regulation [27]. A previous study showed that PS was significantly decreased during pregnancy, ATIII was slightly decreased, but the PC expression was largely variated [28]. In the current study, significantly differences were identified in the expression of serum PC and PS, but not ATIII, between BC and HC women. These findings suggested that PS and ATIII might play key role during pregnancy, but the exact mechanism of them remains unknown.
A previous study showed that low levels of serum PS might be an increased risk for adverse outcomes at early pregnancy, including pre-eclampsia and hypertension, which might contribute to the development of FGR [29]. Besides, low expression of PC was also associated with the increased pregnancy loss [30]. Feotal thrombotic vascular has been emphasized recently in adverse pregnancy and low levels of PS, PC, and antithrombin were considered as risk factors for venous thromboembolism [31, 32]. Previous studies had reported that deficiency of serum PS is associated with the development of FGR and acquired PS deficiency is mainly related to autoantibodies, which might enhance thrombosis, resulting in insufficient placental blood perfusion and development of FGR [33, 34]. In this study, PS and ATIII were significantly decreased in FGR compared with the HC group, which provide direct evidence that PS and ATIII were play critical role in the pathogenesis of FGR.
For further investigation, the expression of PC, PS, and ATIII in the second and third trimesters were also determined and showed no markedly changes between these two trimesters. Combined with PC expression variation between the HC and FGR, the diagnostic values of PS and ATIII were determined and both PS and ATIII presented significantly diagnostic values, but the specificity and sensitivity were not satisfied. Although PS combined ATIII presented a better diagnostic value than single of each, the diagnostic specificity was still less than 0.7. Considering the diagnostic values of PZ and ZPI, the diagnostic value of PZ, ZPI, PS, combined ATIII for FGR was assessed and presented a better than single index or two indices with an AUC of 0.935, a sensitivity of 0.920, and a specificity of 0.800, indicating that combined use of the four had the highest clinical prediction value.
In conclusion, the reduction of serum PZ, ZPI, PS, and ATIII levels might associated with the coagulation dysfunction in pregnant women with FGR. With these expression changes, PZ, ZPI, PS, and ATIII were all presented significant diagnostic value for FGR and combined all of them showed the best diagnostic value for FGR screening. Therefore, it is of importance to detect the variations of PZ, ZPI, PS, and ATIII in pregnancy serum to improve the screening and therapy of FGR.