Journal of Pregnancy abnormal placental development, generalized endothelial activation, and the release of antiangiogenic factors toxic to the fenestrated endothelium of glomeruli, the choroid plexus, and liver sinusoids—a sequence of events that culmi- nates in clinical preeclampsia [39]. The link between com- plement activation and pathogenic events in preeclampsia identiﬁes potential biomarkers to predict patients at risk for preeclampsia and new targets to prevent its complications. 5. PE and Coagulation Factors As implied in the preceding section, insuﬃcient and/or inad- equate trophoblastic invasion of the maternal spiral arteries leads to reduced uteroplacental blood ﬂow causing focal decidual hypoxia, and thus VEGF [40–42]. This in turn results in activation of the decidual endothelial cells and the aberrant expression of tissue factor (TF) [40, 43]. In addition, under pathological conditions, other cells, such as macrophages present in the maternal fetal interface, can also generate TF. TF generates thrombin that further induces endothelial cell TF expression and inﬂammatory cytokines [40]. Both VEGF and TF induce aberrant angiogenesis and poor vessel maintenance reﬂected by endothelial cell fenes- trations and induction of a prothrombotic surface and utero- placental vascular insuﬃciency [44]. Under physiological conditions, TF is not expressed by endothelial cells. By contrast, endothelial TF expression is observed in pathologic conditions such as sepsis, atheroscle- rosis, and rapid but malformed vessel growth associated with malignancies and allograft rejection [45–47]. Indeed, ex- pression of TF by the endothelium is a pathological conse- quence of cross-talk between coagulation and inﬂammatory cytokines [45]. Expression of TF transforms endothelial cell membrane from an anticoagulant to a procoagulant surface and promotes intravascular thrombosis [48, 49]. Interestingly, the uteroplacental vasculature of pregnancies complicated by PE and IUGR display vascular features sim- ilar to those seen in allograft rejection [50]. A recent study by Di Paolo et al. demonstrated high expression of TF mRNA in the vascular endothelium of vessels in the decidua basalis of pregnancies complicated by PE and IUGR but not in normal pregnancies [51]. Tissue factor, the critical initiator of the coagulation cas- cade, is induced during pregnancy in the maternal decidua [52, 53] and is plentiful in the placenta and amniotic ﬂuid [54–57]. It has been well documented that patients with diseases leading to aberrantly increased circulating TF ex- pression have a much higher rate of vascular thromboembo- lism (VTE) [58–61]. Speciﬁcally, patients are at risk for car- diovascular diseases, sepsis, hematologic, and coagulation disorders such as disseminated intravascular coagulation [62–67]. In these diseases, as well as in cancer and diabetes, plasma TF is related to increased blood thrombogenicity [67]. Interestingly, plasma levels of thrombomodulin activ- ity, tissue factor activity, and procoagulant phospholipids were signiﬁcantly elevated in women with PE versus normal pregnant and nonpregnant women [68]. Moreover, the cir- culating TF has been identiﬁed on circulating microparticles 3 (MPs). These MPs are small vesicles released from injured or activated cells, primarily leukocytes and endothelial cells [58, 69]. TF-bearing MPs in pregnancy also arise from syn- cytiotrophoblasts [70] and excess syncytiotrophoblast mi- croparticles have been found in the circulation of women with PE [71]. Unfortunately, VTE is one of the leading caus- es of morbidity and mortality during pregnancy [72]. A high- er prevalence of risk factors for VTE has been found in women with PE and fetal loss [73].The principal factors that result in venous thrombosis consist of the classic triad of Vir- chow: venous stasis, vascular damage, and hypercoagulabili- ty, all of which occur during normal pregnancies [74]. A shift of the hemostatic balance in the direction of hypercoag- ulability during pregnancy is believed to be evolutionarily advantageous in reducing hemorrhage, however, this could also contribute to the increased risk of venous thromboem- bolic processes [75]. Studies from our laboratory have demonstrated that TF is normally expressed by decidual cells [76]. Indeed, immunohistochemical staining for TF has been observed in the decidualized endometrial stromal cells, but not in endothelial cells [77–79]. In contrast, we noted that basal plate uteroplacental vessel segments from cases of low birth weight with villous evidence of maternal uter- oplacental malperfusion had increased percent of strong pos- itive endothelial immunostaining for TF [40]. 6. Thrombin Activation of Endometrial Endothelial Cells Vascular injury initiates clotting when plasma-derived fac- tor VII binds to the extracellular domain of perivascular cell membrane-bound TF. The resulting TF/VIIa complex promotes hemostasis via a series of changes initiated by the extracellular cleavage of prothrombin to thrombin [76]. The aberrant expression of TF in vessels from deciduas with activated endothelium led us to study this phe- nomenon in further detail. We proposed that aberrantly expressed TF in decidual vessels would in turn result in thrombin production and further endothelial activation. In vitro experiments were carried out with cultured human endometrial endothelial cells (HEECs) [40]. Treatment with 2.5 U of thrombin demonstrated the induction of TF protein and mRNA expression [40]. Moreover, thrombin-induced inﬂammatory cytokine expression in HEECs. Speciﬁ- cally thrombin signiﬁcantly upregulated mRNA expression for regulated upon activation, normal T-cell expressed, and secreted (RANTES) chemokine, growth-related onco- gene (Gro)-β, Gro-γ, granulocyte chemotactic protein (GCP)-2, granulocyte-macrophage colony stimulating fac- tor (GM-CSF), monocyte chemotactic protein-1 (MCP-1), interleukin-8 (IL-8), and macrophage inﬂammatory protein 3α (MIP3α) [40]. This increase in proinﬂammatory chemok- ines are expected to result in endothelial dysfunction or in- appropriate endothelial cell activation which are the most common clinical manifestations in PE, including enhanced endothelial-cell permeability and platelet aggregation [80]. Moreover, the overexpression of these chemokines is consis- tent with observations made in our laboratory [81, 82] as