thromboplastin and Endometriosis

Tissue factor (TF), is a cellular receptor that binds the ligand factor VII/VIIa to initiate the blood coagulation cascade. In addition to its role as the initiator of the hemostatic cascade, TF is known to be involved in angiogenesis via an interaction with factor VIIa and protease-activated receptor-2 (PAR-2). In this article we review previous studies from our laboratory demonstrating that the pattern and level of TF expression is altered in multiple cell types derived from eutopic and ectopic endometrium from women with endometriosis compared with normal endometrium. We posit that the inflammatory environment that occurs in ectopic and eutopic endometrium from patients with disease results in high TF expression that in turn, signals via PAR-2 to further produce inflammatory cytokine or chemokine production and macrophage recruitment. Thus, our studies suggest that TF might be an ideal target for therapeutic intervention in endometriosis.

Topics: Animals; Cell Proliferation; Cytokines; Endometriosis; Endometrium; Female; Gene Expression Regulation; Humans; Immunohistochemistry; Infertility, Female; Inflammation; Mice; Models, Biological; Neovascularization, Pathologic; Thromboplastin

There has been increasing interest in the study of new pathogenic mechanisms in endometriosis (END), including the coagulation/fibrinolysis system and its link with inflammation and tissue remodeling. It has been suggested that END patients, especially with deep-infiltrating (DE) forms, could present a hypercoagulable state revealing higher levels of proinflammatory and procoagulant markers, such as total circulating microparticles (cMPs) and cMP-TF (tissue factor), released by cells in response to damage, activation, or apoptosis. However, no previous study has assessed the effect of END hormonal treatments on cMP and cMP-TF levels. Therefore, the aim of this study was to evaluate the impact of these treatments on cMP and cMP-TF levels in DE patients. Three groups were compared: DE patients receiving a continuous combined oral contraceptive regimen (CCOCR) (n = 41), DE patients without CCOCR (n = 45), and a control group (n = 43). cMP and cMP-TF levels were evaluated in platelet-free plasma. A significant decrease in the total cMP levels was found in the DE group with CCOCR versus the group without CCOCR, reflecting a higher chronic inflammatory status in DE patients that decreased with the treatment. cMP-TF levels were higher in DE patients receiving CCOCR versus those not receiving CCOCR, suggesting that treatments containing estrogens play a predominant role in suppressing the inhibitory pathway of TF.

Topics: Blood Coagulation; Cell-Derived Microparticles; Endometriosis; Ethinyl Estradiol; Female; Humans; Inflammation; Norpregnenes; Thromboplastin

Endometriosis (EMS) is a disease that shows immune dysfunction and chronic inflammation characteristics, suggesting a role of complement system in its pathophysiology. To find out the hub genes and pathways involved in the pathogenesis of EMs, three raw microarray datasets were recruited from the Gene Expression Omnibus database (GEO). Then, a series of bioinformatics technologies including gene ontology (GO), Hallmark pathway enrichment, protein-protein interaction (PPI) network and gene co-expression correlation analysis were performed to identify hub genes. The hub genes were further verified by the Real-time quantitative polymerase chain reaction (RT-PCR) and Western Blot (WB). We identified 129 differentially expressed genes (DEGs) in EMs, of which 78 were up-regulated and 51 were down-regulated. Through GO functional enrichment analysis, we found that the DEGs are mainly enriched in cell adhesion, extracellular matrix remodeling, chemokine regulation, angiogenesis regulation, epithelial cell proliferation, et al. In Hallmark pathway enrichment analysis, coagulation pathway showed great significance and the terms in which included the central complement factors. Moreover, the genes were dominating in PPI network. Combined co-expression analysis with experimental verification, we found that the up-regulated expression of complement (C1S, C1QA, C1R, and C3) was positively related to tissue factor (TF) in EMs. In this study, we discovered the over expression complement and the positive correlation between complement and TF in EMs, which suggested that interaction of complement and coagulation system may play a role within the pathophysiology of EMS.

Topics: Blood Coagulation Factors; Complement C1q; Complement C1r; Complement C1s; Complement C3; Complement System Proteins; Endometriosis; Female; Gene Expression Profiling; Gene Ontology; Gene Regulatory Networks; Humans; Protein Interaction Maps; Signal Transduction; Thromboplastin

Endometriosis is a common condition in reproductive-aged women characterized by ectopic endometrial lesions of varied appearance, including red, white, blue, black or powder burn coloration, which contribute to chronic pain and infertility. The immunoconjugate molecule (Icon) targets Tissue Factor, a transmembrane receptor for Factor VII/VIIa that is aberrantly expressed in the endothelium supporting ectopic endometrial tissue. Icon has been shown to cause regression of endometriosis in a murine model of disease but prior to this study had not been tested in non-human primates. This study evaluated Icon as a novel treatment for endometriosis in non-human primates (Papio anubis) using an adenoviral vector (AdIcon) delivery system. Female baboons (n = 15) underwent surgical induction of endometriosis. After laparoscopic confirmation of endometriosis lesions 6-weeks post-surgery, the treatment group (n = 7) received weekly intraperitoneal injections of viral particles carrying the sequence for Icon, resulting in expression of the protein, while the control group (n = 8) received no treatment. Icon preferentially reduced the number and volume of red vascularized lesions. Icon may present a novel treatment for endometriosis by degrading red vascularized lesions, likely by targeting tissue factor aberrantly expressed in the lesion vasculature.

Topics: Adenoviridae; Adnexal Diseases; Amino Acid Substitution; Animals; Endometriosis; Factor VII; Female; Genetic Therapy; Genetic Vectors; Humans; Immunoconjugates; Immunoglobulin Fc Fragments; Immunoglobulin G; Molecular Targeted Therapy; Mutation; Neovascularization, Pathologic; Papio anubis; Pelvis; Peptide Fragments; Random Allocation; Recombinant Fusion Proteins; Thromboplastin

Do platelets play any role in the development of endometriosis?. Activated platelets aggregate in endometriotic lesions and play important roles in the development of endometriosis.. Platelets play important roles in cancer development and metastasis but there is no published study on their role in the development of endometriosis, even though endometriotic lesions undergo repeated cycles of tissue injury and repair, which characteristically involve platelets.. Cross-sectional clinical studies of women with and without endometriosis, in vitro experimentation, and animal studies using platelet and/or macrophage depletion.. Immunohistochemistry analysis of ectopic/eutopic endometrial tissues from 58 women with and 47 without endometriosis. Proliferation assay, cell cycle analysis by flow cytometry, gene expression and protein analysis for COX-2, VEGF, MMP-9, and Bcl-2 using primary cell culture, and evaluation of the rate of platelet activation induced by peritoneal fluid from women with and without endometriosis. Two mouse experiments, one that evaluated the effect of platelet depletion on lesion development and its associated phenotypic changes, and the other, the effect of platelet and/or macrophage depletion.. We found that platelets aggregated in endometriotic lesions, concomitant with elevated VEGF expression and microvessel density. Co-culture of endometriotic stromal cells with platelets enhanced cellular proliferation, and increased the expression of COX-2, MMP-9, VEGF, and Bcl-2. IL-1β-induced COX-2 up-regulation and increased production of the coagulant TXA(2) in endometriotic stromal cells. Tissue factor (TF) expression was elevated in endometriosis and TF concentrations were significantly elevated both in the supernatant of cultured primary endometriotic stromal cells and in peritoneal fluid from women with endometriosis. Platelet depletion resulted in significantly reduced lesion size and improved hyperalgesia in mice with induced endometriosis.. This study is limited by its cross-sectional design and by its focus on ovarian endometriomas.. The demonstration that platelets are involved in the development of endometriosis provides a rationale for the use of anti-coagulants to treat endometriosis, and opens prospects for developing novel biomarkers for diagnostic or prognostic purposes.. Financial support for this study was provided by grants from the National Science Foundation of China, a grant from the Shanghai Science and Technology Commission, support from the Key Specialty Project of the Ministry of Health, People's Republic of China. None of the authors has any conflict of interest to disclose.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Animals; Blood Platelets; Cell Cycle; Cell Proliferation; Cross-Sectional Studies; Endometriosis; Endometrium; Female; Gene Expression Profiling; Gene Expression Regulation; Healthy Volunteers; Humans; Interleukin-1beta; Macrophages; Male; Mice; Mice, Inbred C57BL; Ovary; Platelet Activation; Platelet Aggregation; Prognosis; Thrombin; Thromboplastin; Thromboxane B2

Little is known about the roles of TF and PAR-2 in endometriosis. This article investigated the expression of TF and PAR-2 in ectopic and eutopic endometrium with endometriosis and their relationship with the menstrual cycle.. Ectopic and eutopic endometrium tissues from 42 women with ovarian endometrioma and endometrium tissues from 20 women without endometriosis were obtained. All the samples were assessed for TF and PAR-2 protein location using immunohistochemistry and for relative TF and PAR-2 mRNA expression using real-time florescent quantitative polymerase chain reaction (FQ-PCR).. Total TF and PAR-2 expression were significantly higher in ectopic and eutopic endometrium of women with endometriosis when compared with controls. Moreover, TF expression in ectopic and eutopic endometrium and PAR-2 expression in ectopic endometrium were significantly increased through the whole menstrual cycle. However, in eutopic endometrium with endometriosis, PAR-2 expression only in secretory phase was higher than its cycle-matched normal controls. There is no such difference in the proliferative phase.. The abnormal co-upregulated expression of TF and PAR-2 in eutopic and ectopic endometrium may affect the development and growth of endometriotic lesions and highlighted the pathologic role of TF and PAR-2 in eutopic endometrium in endometriosis.

Topics: Adult; Case-Control Studies; Endometriosis; Endometrium; Female; Gene Expression; Humans; Immunohistochemistry; Menstrual Cycle; Real-Time Polymerase Chain Reaction; Receptor, PAR-2; RNA, Messenger; Thromboplastin

Heavy menstrual bleeding and dysmenorrhea are two top complaints from women with symptomatic adenomyosis, yet their etiology is poorly understood. Tissue factor (TF) has been shown to be upregulated in endometriosis and at the endometrial bleeding sites of women with long-term progestin only contraception. We sought to investigate the expression and localization of TF in eutopic and ectopic endometrium of women with adenomyosis and in endometrium of women without adenomyosis. We also sought to determine the relationship, if any, between TF immunoreactivity and the amount of menses, uterus size and severity of dysmenorrhea.. We retrieved tissue samples of eutopic and ectopic endometrium from 50 women with adenomyosis and of endometrium from 18 women without adenomyosis. The tissue sections were subjected to immunostaining and microscopic evaluation to assess the presence and localization of TF in both proliferative and secretory phases in both eutopic and ectopic endometrium and normal endometrium. Information on the amount of menses, severity of dysmenorrhea and other information were collected.. We found that TF immunoreactivity was significantly increased in both eutopic and ectopic endometrium as compared with normal endometrium. In addition, we found that the elevated TF immunoreactivity is associated with heavy menses and increased severity of dysmenorrhea.. These results suggest that TF is involved in adenomyosis-associated heavy menstrual bleeding and dysmenorrhea and thus may be a potential therapeutic target in treating symptomatic adenomyosis and perhaps also chronic pelvic pain in women with adenomyosis.

Topics: Adult; Dysmenorrhea; Endometriosis; Endometrium; Female; Humans; Immunohistochemistry; Menstruation; Middle Aged; Severity of Illness Index; Thromboplastin; Uterus

Endometriosis is a major cause of chronic pain, infertility, medical and surgical interventions, and health care expenditures. Tissue factor (TF), the primary initiator of coagulation and a modulator of angiogenesis, is not normally expressed by the endothelium; however, prior studies have demonstrated that both blood vessels in solid tumors and choroidal tissue in macular degeneration express endothelial TF. The present study describes the anomalous expression of TF by endothelial cells in endometriotic lesions. The immunoconjugate molecule (Icon), which binds with high affinity and specificity to this aberrant endothelial TF, has been shown to induce a cytolytic immune response that eradicates tumor and choroidal blood vessels. Using an athymic mouse model of endometriosis, we now report that Icon largely destroys endometriotic implants by vascular disruption without apparent toxicity, reduced fertility, or subsequent teratogenic effects. Unlike antiangiogenic treatments that can only target developing angiogenesis, Icon eliminates pre-existing pathological vessels. Thus, Icon could serve as a novel, nontoxic, fertility-preserving, and effective treatment for endometriosis.

Topics: Adult; Animals; CHO Cells; Cricetinae; Cricetulus; Drug Delivery Systems; Endometriosis; Endothelium, Vascular; Female; Humans; Immunoconjugates; Immunoglobulin Fc Fragments; Immunotherapy; Mice; Mice, Nude; Middle Aged; Neovascularization, Pathologic; Peritoneal Diseases; Thromboplastin; Transplantation, Heterologous