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 interlerukin-8 synergis-tically augment angiogenesis in a milieu of reactive oxygen species-induced endothelial cell activation. The resulting enhanced vessel fragility promotes abnormal uterine bleeding.
KeywordsTissue factor; endometrium; hemostasis; angiogenesis; bleeding
TISSUE FACTOR EXPRESSION BY DECIDUALIZED HUMAN ENDOMETRIAL STROMAL CELLS PROMOTES HEMOSTASISInfertile human menstrual cycles terminate in sloughing of the functional endometrial layer in the menstrual fluid. Restoration begins in the follicular phase of the next cycle as increased circulating estradiol (E 2 ) levels induce proliferation of epithelial and stromal cells. After ovulation, rising plasma progesterone levels block mitosis and initiate differentiation of the E 2 -primed cells. In the luteal phase, the glandular epithelial cells secrete implantationpromoting products into the uterine lumen, the luminal epithelial cells become receptive to blastocyst attachment, and the stromal cells decidualize. The decidualization reaction is initiated around blood vessels and under the glands and then spreads throughout the luteal