thromboplastin and Uterine-Hemorrhage

Human pregnancy requires robust hemostasis to prevent hemorrhage during extravillous trophoblast (EVT) invasion of the decidualized endometrium, modification of spiral arteries and post-partum processes. However, decidual hemorrhage (abruption) can occur throughout pregnancy from poorly transformed spiral arteries, causing fetal death or spontaneous preterm birth (PTB), or it can promote the aberrant placentation observed in intrauterine growth restriction (IUGR) and pre-eclampsia; all leading causes of perinatal or maternal morbidity and mortality. In non-fertile cycles, the decidua undergoes controlled menstrual bleeding. Abnormal uterine bleeding (AUB) accompanying progestin-only, long-acting, reversible contraception (pLARC) accounts for most discontinuations of these safe and highly effective agents, thereby contributing to unwanted pregnancies and abortion. The aim of this study was to investigate the role of decidual cells in uterine hemostasis, menstruation, inflammation, adverse pregnancy outcomes and abnormal uterine bleeding.. We conducted a critical review of the literature arising from PubMed searches up to December 2015, regarding in situ and in vitro expression and regulation of several specific proteins involved in uterine hemostasis in decidua and cycling endometrium. In addition, we discussed clinical and molecular mechanisms associated with pLARC-induced AUB and pregnancy complications with abruptions, chorioamnionitis or pre-eclampsia.. Progestin-induced decidualization of estradiol-primed human endometrial stromal cells (HESCs) increases in vivo and in vitro expression of tissue factor (TF) and type-1 plasminogen activator inhibitor (PAI-1) while inhibiting plasminogen activators (PAs), matrix metalloproteinases (MMPs), and the vasoconstrictor, endothelin-1 (ET-1). These changes in decidual cell-derived regulators of hemostasis, fibrinolysis, extracellular matrix (ECM) turnover, and vascular tone prevent hemorrhage during EVT invasion and vascular remodeling. In non-fertile cycles, progesterone withdrawal reduces TF and PAI-1 while increasing PA, MMPs and ET-1, causing menstrual-associated bleeding, fibrinolysis, ECM degradation and ischemia. First trimester decidual hemorrhage elicits later adverse outcomes including pregnancy loss, pre-eclampsia, abruption, IUGR and PTB. Decidual hemorrhage generates excess thrombin that binds to decidual cell-expressed protease-activated receptors (PARs) to induce chemokines promoting shallow placentation; such bleeding later in pregnancy generates thrombin to down-regulate decidual cell progesterone receptors and up-regulate cytokines and MMPs linked to PTB. Endometria of pLARC users display ischemia-induced excess vasculogenesis and progestin inhibition of spiral artery vascular smooth muscle cell proliferation and migration leading to dilated fragile vessels prone to bleeding. Moreover, aberrant TF-derived thrombin signaling also contributes to the pathogenesis of endometriosis via induction of angiogenesis, inflammation and cell survival.. Perivascular decidualized HESCs promote endometrial hemostasis during placentation yet facilitate menstruation through progestational regulation of hemostatic, proteolytic, and vasoactive proteins. Pathological endometrial hemorrhage elicits excess local thrombin generation, which contributes to pLARC associated AUB, endometriosis and adverse pregnancy outcomes through several biochemical mechanisms.

Topics: Decidua; Embryo Implantation; Endometrium; Female; Hemostasis; Humans; Menstrual Cycle; Plasminogen Activator Inhibitor 1; Pre-Eclampsia; Pregnancy; Pregnancy Outcome; Progestins; Thromboplastin; Uterine Hemorrhage

Factor VII binds trans-membrane tissue factor to initiate hemostasis by forming thrombin. Tissue factor expression is enhanced in decidualized human endometrial stromal cells during the luteal phase. Long-term progestin only contraceptives elicit: 1) abnormal uterine bleeding from fragile vessels at focal bleeding sites, 2) paradoxically high tissue factor expression at bleeding sites; 3) reduced endometrial blood flow promoting local hypoxia and enhancing reactive oxygen species levels; and 4) aberrant angiogenesis reflecting increased stromal cell-expressed vascular endothelial growth factor, decreased Angiopoietin-1 and increased endothelial cell-expressed Angiopoietin-2. Aberrantly high local vascular permeability enhances circulating factor VII to decidualized stromal cell-expressed tissue factor to generate excess thrombin. Hypoxia-thrombin interactions augment expression of vascular endothelial growth factor and interleukin-8 by stromal cells. Thrombin, vascular endothelial growth factor and interleukin-8 synergistically augment angiogenesis in a milieu of reactive oxygen species-induced endothelial cell activation. The resulting enhanced vessel fragility promotes abnormal uterine bleeding.

Topics: Animals; Cell Hypoxia; Contraceptive Agents, Female; Decidua; Endometrium; Female; Hemostasis; Humans; Interleukin-8; Neovascularization, Physiologic; Progestins; Reactive Oxygen Species; Stromal Cells; Thrombin; Thromboplastin; Uterine Hemorrhage; Vascular Endothelial Growth Factor A

Vascular injury increases access and binding of plasma-derived factor VII to perivascular cell membrane-bound tissue factor (TF). The resulting TF/VIIa complex promotes hemostasis by cleaving pro-thrombin to thrombin leading to the fibrin clot. In human pregnancy, decidual cell-expressed TF prevents decidual hemorrhage (abruption). During placentation, trophoblasts remodel decidual spiral arteries into high conductance vessels. Shallow trophoblast invasion impedes decidual vascular conversion, producing an inadequate uteroplacental blood flow that elicits abruption-related placental ischemia. Thrombin induces several biological effects via cell surface protease activated receptors. In first trimester human DCs thrombin increases synthesis of sFlt-1, which elicits placental ischemia by impeding angiogenesis-related decidual vascular remodeling. During pregnacy, the fibrillar collagen-rich amnion and choriodecidua extracellular matrix (ECM) provides greater than additive tensile strength and structural integrity. Thrombin acts as an autocrine/paracrine mediator that degrades these ECMs by augmenting decidual cell expression of: 1) matrix metalloproteinases and 2) interleukin-8, a key mediator of abruption-associated decidual infiltration of neutrophils, which express several ECM degrading proteases. Among the cell types at the maternal fetal interface at term, TF expression is highest in decidual cells indicating that this TF meets the hemostatic demands of labor and delivery. TF expression in cultured term decidual cells is enhanced by progestin and thrombin suggesting that the maintenance of elevated circulating progesterone provides hemostatic protection and that abruption-generated thrombin acts in an autocrine/paracrine fashion on decidual cells to promote hemostasis via enhanced TF expression.

Topics: Abruptio Placentae; Animals; Decidua; Female; Hemostasis; Humans; Mice; Mice, Transgenic; Pregnancy; Pregnancy Complications, Hematologic; Thrombin; Thromboplastin; Uterine Hemorrhage; Uterus

Vaginal bleeding is a risk factor for preterm PROM (PPROM). A disorder of decidual hemostasis has been implicated in the genesis of PROM. Indeed, excessive thrombin generation has been demonstrated in PPROM both before and at the time of diagnosis. Decidua is a potent source of tissue factor (TF), the most powerful natural pro-coagulant. A decidual hemostatic disorder may link vaginal bleeding, PPROM and placental abruption. This study was conducted to determine the behaviour of maternal TF and its natural inhibitor, the tissue factor pathway inhibitor (TFPI) in PPROM.. This cross-sectional study included women with PPROM (n = 123) and women with normal pregnancies (n = 86). Plasma concentrations of TF and TFPI were measured by a sensitive immunoassay. Non-parametric statistics were used for analysis.. (1) The median maternal plasma TF concentration was significantly higher in patients with PPROM than in women with normal pregnancies (median: 369.5 pg/mL; range: 3.27-2551 pg/mL vs. median: 291.5 pg/mL; range: 6.3-2662.2 pg/mL respectively, p = 0.001); (2) the median maternal TFPI plasma concentration was significantly lower in patients with PPROM than in women with normal pregnancies (median: 58.7 ng/mL; range: 26.3-116 ng/mL vs. median: 66.1 ng/mL; range: 14.3-86.5 ng/mL respectively, p = 0.019); (3) there was no correlation between the plasma concentration of TF and TFPI and the gestational age at sample collection; and (4) among patients with PPROM there was no association between the presence of intra-amniotic infection or inflammation and median plasma concentrations of TF and TFPI.. (1) Patients with PPROM have a higher median plasma concentration of TF and a lower median plasma concentration of TFPI than women with normal pregnancies. (2) These findings suggest that PPROM is associated with specific changes in the hemostatic/coagulation system.

Topics: Amniotic Fluid; Chorioamnionitis; Cross-Sectional Studies; Female; Fetal Membranes, Premature Rupture; Gestational Age; Hemostatic Disorders; Humans; Lipoproteins; Mothers; Pregnancy; Pregnancy Complications, Hematologic; Pregnancy Complications, Infectious; Thromboplastin; Uterine Hemorrhage

Tibolone is a highly effective postmenopausal hormone treatment that has its biological activity dependent on metabolism to 3alpha- and 3beta-OH tibolone, which bind solely to the estrogen receptor. Despite the high levels of estrogen receptor-binding metabolites in the circulation, the endometrium becomes atrophic, suggesting inactivation of the estrogen response in this tissue which may be due to the progestogenic activity of tibolone and the Delta-4 tibolone metabolite. We evaluated the effects of tibolone and its metabolites on tissue factor (TF) and plasminogen activator inhibitor type 1 (PAI-1) expression in human endometrial stromal cells (HESCs). Since TF and PAI-1 exhibit long-term in vivo and in vitro up-regulation by progestin they serve as endpoints for assessing chronic effects of progestin exposure. Confluent HESCs were primed in serum-containing medium with vehicle control, 10(-8)mol/L estradiol, 10(-7)mol/L medroxyprogesterone acetate, or 10(-8) to 10(-6)mol/L tibolone or its metabolites, then switched to a defined medium with corresponding vehicle or steroids. After 24h, ELISAs indicated that the progestin elevated TF (6.2-fold +/-3.0; p<0.05) and PAI-1 (eight-fold +/-2.1; p<0.05) levels, whereas the cells were refractory to estradiol exposure. Tibolone and Delta-4 tibolone (10(-8) to 10(-6)mol/L) were as effective as 10(-7)mol/L medroxyprogesterone acetate in enhancing TF and PAI-1 output (p<0.05). Unexpectedly, at the higher concentrations 3alpha- and 3beta-OH tibolone also elevated TF and PAI-1 expression (p<0.05). Western blotting confirmed the ELISA results. Our findings suggest that HESCs metabolize 3alpha- and 3beta-OH tibolone to tibolone and subsequently to Delta-4 tibolone, which can both stimulate the progesterone receptor. Since TF and PAI-1 promote hemostasis by complementary mechanisms, our findings account for the reduced occurrence of abnormal uterine bleeding associated with tibolone therapy.

Topics: Androgen Antagonists; Cells, Cultured; Endometrium; Female; Gene Expression Regulation; Humans; Norpregnenes; Plasminogen Activator Inhibitor 1; Progestins; Receptors, Estrogen; Receptors, Progesterone; Stromal Cells; Thromboplastin; Uterine Hemorrhage

Abnormal uterine bleeding accounts for the unacceptably high discontinuation rate of progestin-only contraceptives. Previously, we found that in-vivo and in-vitro decidualization of human endometrial stromal cells was associated with elevated concentrations of tissue factor (TF), the primary initiator of haemostasis. Moreover, enhanced TF expression required progesterone receptor (PR) and epidermal growth factor receptor (EGFR) mediation. In the current study, endometrial biopsies were sampled from bleeding (BL) and non-bleeding (NBL) sites under camera-directed hysteroscopic guidance after Depo-provera injections. When compared with control biopsies, immunohistochemical examination revealed that 3 months of Depo-provera contraception reduced TF concentrations at the BL sites. However, there were ample EGFR and PR concentrations at BL and NBL sites. Moreover, there was a trend towards the appearance of pathologically enlarged blood vessels at the BL sites. The use of Western blotting revealed that after 3 months of Depo-provera, concentrations of both PRB and PRA isoforms were lower at BL versus NBL sites with decreased PRA concentrations attaining statistical significance. Separate sampling of endometrial BL and NBL sites as shown here for Depo-provera contraception could prove particularly useful in identifying local factors that determine the onset of bleeding during the more protracted time-course of Norplant contraception.

Topics: Biopsy; Blotting, Western; Contraceptive Agents, Female; Endometrium; ErbB Receptors; Female; Hemostasis; Humans; Hysteroscopy; Immunohistochemistry; Medroxyprogesterone Acetate; Progestins; Receptors, Progesterone; Stromal Cells; Thromboplastin; Uterine Hemorrhage

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.

Topics: Animals; Crosses, Genetic; Female; Hemostasis; Humans; Male; Mice; Mice, Knockout; Placenta; Pregnancy; Puerperal Disorders; Thromboplastin; Uterine Hemorrhage; Uterus

A high incidence of irregular uterine bleeding is the primary patient complaint limiting the utility of long term, progestin-only contraceptive agents such as Norplant. The onset of hemorrhage requires both inadequate hemostasis and impaired vascular integrity. Thus, we first tested whether Norplant-associated endometrial bleeding was accompanied by altered expression of perivascular stromal cell tissue factor (TF), the primary initiator of hemostasis. Norplant effects on TF messenger ribonucleic acid (mRNA) and protein expression by endometrial stromal cells were assessed by in situ hybridization and immunohistochemical examination of endometrial biopsies obtained from normally cycling control women (n = 14) and from patients experiencing Norplant-induced abnormal uterine bleeding (n = 24). TF mRNA and protein expression was increased 150% in secretory vs. proliferative phase endometrial specimens. By contrast, endometrial TF mRNA and protein levels were reduced during 1-6 months of Norplant treatment by about 2-fold (P < 0.05 for protein) compared to the values for control secretory phase specimens. These changes were consistent with observations that patients on Norplant begin to bleed during this interval. Further reductions of TF mRNA and protein levels to 2- and 3-fold of those in secretory phase control specimens were observed in endometria obtained after 6-12 months of Norplant therapy (P < 0.05 and P < 0.01, respectively). A modest rebound in TF mRNA and protein expression was observed after 12 months of Norplant therapy, which occurred commensurate with reduced patient complaints of abnormal uterine bleeding. Pathologically enlarged venous sinusoids were ubiquitous in endometrial specimens obtained after Norplant therapy. The combination of fragile blood vessels and reduced TF expression may account for bleeding in patients receiving Norplant therapy.

Topics: Contraceptive Agents, Female; Endometrium; Female; Humans; Immunohistochemistry; Levonorgestrel; RNA, Messenger; Staining and Labeling; Stromal Cells; Thromboplastin; Uterine Hemorrhage

Topics: Abortion, Induced; Amniotic Fluid; Blood Cell Count; Blood Coagulation Disorders; Blood Coagulation Tests; Blood Platelets; Factor VIII; Female; Fibrin; Fibrinogen; Humans; Hypertonic Solutions; Plasminogen; Pregnancy; Serum Globulins; Sodium Chloride; Solubility; Thromboplastin; Time Factors; Uterine Hemorrhage

Topics: Adult; Blood Coagulation Tests; Calcium; Climacteric; Curettage; Endometrium; Female; Hemostasis; Humans; Menopause; Middle Aged; Thromboplastin; Tissue Extracts; Uterine Hemorrhage

Topics: Blood Coagulation Disorders; Blood Coagulation Tests; Female; Humans; Menstruation Disturbances; Thromboplastin; Uterine Hemorrhage

Topics: Abortion, Missed; Abruptio Placentae; Adolescent; Adult; Aprotinin; Blood Coagulation Tests; Female; Hematoma; Hemorrhagic Disorders; Humans; Pregnancy; Pregnancy Complications, Hematologic; Thromboplastin; Uterine Hemorrhage

Topics: Abruptio Placentae; Afibrinogenemia; Aminocaproates; Aminocaproic Acid; Blood Coagulation Tests; Blood Transfusion; Calcium; Dexamethasone; Drug Therapy; Female; Fetal Death; Fibrinogen; Fibrinolysin; Hemorrhagic Disorders; Humans; Pregnancy; Pregnancy Complications, Hematologic; Thrombin; Thromboplastin; Tolonium Chloride; Uterine Hemorrhage