thromboplastin and Fetal-Growth-Retardation

The paternal antigens presented by the fetus could be considered foreign by the mother's immune system and elicit an immune response. Here we show that the complement system functions as an effector in fetal rejection in two different mouse models of pregnancy loss. In a mouse model of fetal loss and growth restriction (IUGR) induced by antiphospholipid antibodies (aPL), we found that complement activation is a crucial and early mediator of pregnancy loss. We demonstrated that C5a-C5aR interaction and neutrophils are key mediators of fetal injury. We identified tissue factor (TF) as a critical intermediate that, acting downstream of C5 activation, enhances neutrophil activity and trophoblast injury. In an antibody-independent mouse model of spontaneous miscarriage and IUGR (CBAxDBA) we also identified C5a as an essential mediator. Complement activation caused dysregulation of the angiogenic factors (deficiency of free vascular endothelial growth factor (VEGF) and elevated levels of soluble VEGF receptor 1) required for normal placental development. Inhibition of complement activation prevented angiogenesis failure and rescued pregnancies. Our studies in antibody-dependent and antibody-independent models of pregnancy complications identified complement activation as the crucial mediator of damage and will allow development of new interventions to prevent pregnancy loss and IUGR.

Topics: Abortion, Spontaneous; Animals; Antibodies, Antiphospholipid; Anticoagulants; Complement Activation; Complement C5a; Complement Inactivating Agents; Female; Fetal Death; Fetal Growth Retardation; Growth Inhibitors; Humans; Macrophages; Mice; Neutrophils; Oxidative Stress; Pregnancy; Receptor, Anaphylatoxin C5a; Thromboplastin; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-1

Tissue factor (TF), the major activator of the extrinsic pathway of coagulation, is abundant in the placenta and decidua. The aim of this study was to determine the maternal plasma concentrations of TF and its primary inhibitor, tissue factor pathway inhibitor (TFPI), in women who delivered small for gestational age (SGA) neonates, and in pre-eclampsia.. A cross-sectional study included the following groups: 1) women with normal pregnancies (n = 86); 2) patients who delivered SGA neonates (n = 61) and 3) women with pre-eclampsia (n = 133). Maternal plasma concentrations of TF and TFPI were measured by a sensitive immunoassay. Non-parametric statistics were used for analysis.. 1) Women with pre-eclampsia had a significantly higher median plasma concentration of TF than patients with a normal pregnancy (median: 1187 pg/mL; range: 69-11675 vs. median: 291.5 pg/mL; range: 6.3-2662.2; p < 0.0001, respectively); 2) Similarly, TFPI concentrations were higher in pre-eclampsia than in normal pregnancy (median: 87.5 ng/mL; range 25.4-165.1 vs. median: 66.1 ng/mL; range: 14.3-86.5; p < 0.0001, respectively); 3) Surprisingly, mothers with SGA neonates had a lower median maternal plasma concentration of TF (median: 112.2 pg/mL; range: 25.6-1225.3) than women with a normal pregnancy (p < 0.0001).. 1) Maternal plasma concentrations of TF in patients with pre-eclampsia, but not in those who delivered an SGA neonate, were higher than in women with normal pregnancies; 2) Although the role of immunoreactive plasma TF in coagulation remains controversial, our observations suggest that changes are present in the context of complications of pregnancy.

Topics: Adult; Cross-Sectional Studies; Female; Fetal Growth Retardation; Humans; Infant, Newborn; Infant, Small for Gestational Age; Lipoproteins; Placenta; Pre-Eclampsia; Pregnancy; Thromboplastin; Young Adult

Preeclampsia (PE), intrauterine growth restriction (IUGR) and abruption with or without fetal loss are associated with reduced uteroplacental blood flow, decidual vasculopathy, endothelial cell dysfunction, thrombosis, inflammation and hemorrhage. Our hypothesis is that reduced uteroplacental blood flow causes focal decidual hypoxia that generates vascular endothelial growth factor (VEGF). The latter acts directly on decidual endothelial cells to induce aberrant expression of tissue factor (TF), the primary initiator of coagulation. This in turn generates thrombin that induces: i) further TF expression; and ii) inflammatory cytokines. Both VEGF and TF induce aberrant angiogenesis-vessel maintenance reflected by endothelial cell fenestrations and induction of a prothrombotic surface causing both the decidual hemorrhage (i.e. abruption) and thrombosis (i.e. uteroplacental vascular insufficiency) observed in these adverse pregnancy outcomes. This novel hypothesis is supported by our finding of TF expression in decidual endothelium of pregnancies complicated by IUGR and/or fetal loss. Moreover, treatment of cultured endometrial endothelial cells with VEGF or thrombin induces TF protein and mRNA expression. Quantitative RT-PCR analysis indicates that thrombin enhances (>10-fold) the output of diverse inflammatory cytokines in these cultures. The greatest effect (>2-log) was seen on macrophage inflammatory protein 3alpha (MIP3alpha). In vitro, thrombin results in endometrial endothelial cell aggregations and changes in the apoptotic pathway. Thus, we postulate that reductions in uteroplacental flow initiate a cascade of molecular effects leading to hypoxia, thrombosis, inflammation, and endothelial cell dysfunction resulting in untoward pregnancy outcomes.

Topics: Angiogenic Proteins; Apoptosis Regulatory Proteins; Cell Aggregation; Cells, Cultured; Cytokines; Decidua; Endometrium; Endothelial Cells; Female; Fetal Growth Retardation; Gene Expression Regulation; Gestational Age; Humans; NF-kappa B; Placental Circulation; Pregnancy; Pregnancy Complications; RNA, Messenger; Thrombin; Thromboplastin; Time Factors; Vascular Endothelial Growth Factor A

Tissue factor (TF) is an integral membrane glycoprotein that is believed to be the physiologic initiator of the blood coagulation cascade. Disruption of the mouse tissue factor gene leads to embryonic lethality between days E9.5-E11.5 of gestation. On E9.5, TF(-/-) embryos appear indistinguishable from their TF(+/+) and TF(+/-) littermates. By E10.5, TF(-/-) embryos are severely growth retarded, appear nearly bloodless, and are in most cases dead. Initial observations suggest that TF(-/-) embryos are dying of circulatory failure. Approximately 15% of the TF(-/-) embryos survive beyond E10.5, but none complete gestation. Heterozygotes appear normal and free of bleeding complications.

Topics: Animals; Blood Coagulation; Chimera; Embryo, Mammalian; Female; Fetal Death; Fetal Growth Retardation; Gene Targeting; Genetic Vectors; Gestational Age; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Thromboplastin

We discovered a "lupus' anticoagulant in 2 out of 42 women with a history of repeated abortions, intrauterine growth retardation and intrauterine death of unknown origin. The "lupus' anticoagulant was detected by an abnormal dilute tissue thromboplastin assay(prothrombin time performed with dilute thromboplastin). The production of prostacyclin by fresh or exhausted rings of rat aorta was decreased by the plasma of one of these two patients with a "lupus' anticoagulant. In view of the increasing evidence for a physiological role of prostacyclin in pregnancy and fetal life, we suggest that an inhibition of prostacyclin production could compromise fetal outcome.

Topics: Abortion, Habitual; Adult; Animals; Aorta; Biological Assay; Blood Coagulation Factors; Epoprostenol; Female; Fetal Death; Fetal Growth Retardation; Humans; Lupus Coagulation Inhibitor; Partial Thromboplastin Time; Pregnancy; Prostaglandins; Prothrombin Time; Rats; Thromboplastin