Tissue factor is required for uterine hemostasis and maintenance of the placental labyrinth during gestation

Abstract

We employed a novel mouse line that expresses low levels of human tissue factor (TF) in the absence of murine TF to analyze the role of TF in gestation. Low-TF female mice had a 14-18% incidence of fatal postpartum uterine hemorrhage, suggesting that TF plays an important role in uterine hemostasis. Low-TF female mice mated with low-TF male mice had a 42% incidence of fatal midgestational hemorrhage (n ‫؍‬ 41), whereas no fatal midgestational hemorrhages were observed in low-TF female mice mated with wild-type male mice (n ‫؍‬ 43). Placentas of low-TF embryos from both low-TF and normal (؉͞؊) TF females were abnormal and contained numerous maternal blood pools in the labyrinth. Placentas of TF null embryos surviving beyond embryonic day 10.5 exhibited similar defects. The mouse maternal-embryonic placental barrier consists of four cellular layers (layers I, II, and III and endothelial cells), where layer I lines the maternal lacunae. Comparison of TF-deficient placentas with control placentas by immunohistochemical and ultrastructural analyses revealed thinning of layer I and a reduction in the number of cellular contacts of layer I trophoblasts spanning the maternal blood space between adjacent trabeculae. These structural changes in low-TF and TF null placentas result in enlarged maternal lacunae, as determined by morphometric analysis, and placental hemorrhage, which leads to midgestational death of low-TF female mice. This study demonstrated that TF is required for uterine hemostasis and revealed an unexpected role of TF in the maintenance of the placental labyrinth.

Pravastatin prevents miscarriages in mice: role of tissue factor in placental and fetal injury

“…[35][36][37] TF is best known as the primary cellular initiator of blood coagulation. 38 Although TF is required for uterine hemostasis and maintenance of the placental labyrinth during gestation, 39 increased placental TF expression can result in pregnancy complications such as preeclampsia (PE). 40,41 We previously demonstrated that pregnancy loss induced by antiphospholipid antibodies in mice is associated with increased TF expression.…”

The retinoblastoma gene family members pRB and p107 coactivate the AP-1-dependent mouse tissue factor promoter in fibroblasts

“…Although the primary function of TF in the adult is to initiate blood coagulation (reviewed in Edgington et al, 1991), recent studies suggest that TF may contribute to blood vessel maturation in the developing embryo (Bugge et al, 1996;Carmeliet et al, 1996), to maintenance of the placental labyrinth during gestation (Erlich et al, 1999), and to tumor angiogenesis (Contrino et al, 1996). Tissue factor has also been implicated as a determinant of metastatic potential in melanoma cells (Mueller et al, 1992;Bromberg et al, 1995) and expression of TF in the stromal compartment of breast carcinomas has been shown to correlate with progression to invasive cancer (Contrino et al, 1996;Vrana et al, 1996).…”

Disruption of the Endothelial Cell Protein C Receptor Gene in Mice Causes Placental Thrombosis and Early Embryonic Lethality

“…This may be critical as the placenta represents a hypercoagulable environment. Indeed, embryonic placental tissue factor procoagulant activity in the trophoblasts is essential for normal placental development (27). Furthermore, it seems that maternal fibrinogen and its conversion to fibrin is also required (in controlled quantities) for placental stabilization and the anchoring of placental trophoblasts to the maternal decidua (28).…”