Ph.D Thesis

Ph.D StudentSnir Ayelet
SubjectCoagulation and Angiogenesis in Placenta
DepartmentDepartment of Medicine
Supervisors PROFESSOR EMERITUS Benjamin Brenner
MRS Noemi Lanir
Full Thesis text - in Hebrew Full thesis text - Hebrew Version


The placenta is a highly vascularized organ with unique blood supply from both fetal and maternal circulation. Trophoblasts are in contact with maternal blood and involved in local haemostasis. Differentiated trophoblasts acquire partial endothelial phenotype, but unlike endothelium, trophoblasts express high levels of tissue factor (TF) and its active form is balanced by several mechanisms. When this balance is disturbed, fibrin accumulation in placenta might lead to pregnancy complications, while lack of fibrin is associated with early abortions and fetal loss.

We hypothesized that procoagulant changes in differentiated trophoblasts are associated with angiogensis and villi remodeling, and we investigated the possible role of trophoblasts TF in placental haemostatic and angiogenic mechanisms. Trophoblasts were cultured from first trimester placentas and cells were characterized by immunofluorescent staining for epithelial, endocrine and endothelial markers. Trophoblast expressed active cell surface TF that generated thrombin in FVII dependent manner. TF activity and expression were increased during culturing, a finding that could be related to the differentiation of trophoblasts in culture. TF activity on cell surface was significantly lower than TF activity in cell lysate, a difference that may reflect a state of encrypted TF in cells. FVII cuased increased VEGF level, suggesting that procoagulant activity on trophoblasts is associated with angiogenic stimuli

As TF associated activation of coagulation lead to fibrin deposition, effect of fibrin on first trimester trophoblasts and placental villi was investigated. Increased proliferation and cell spreading were observed when cells were cultured on fibrin and increased sprouting was demonstrated in placental villi implanted in fibrin.

TF induced cross-linking of FXIII depleted fibrin, whereas addition of FXIII further increased cross-linking, cell proliferation and spreading, suggesting a role of cross-linking in trophoblasts remodeling. When cells and placental villi fragments were cultured on fibrin, TF level was reduced while VEGF level was increased. Presence of αIIbβ3 in trophoblasts and in first term placentas was first demonstrated in this study. Antibodies for this integrin as well as RGD peptides partialy inhibited cell adhesion, but not cell spreading on fibrin, indicating involvement of αIIbβ3 integrin in trophoblasts adhesion to fibrin. We suggest that fibrin depositions following placental injury and activation of coagulation induce cell proliferation, spreading and villi remodeling that may affect trophoblasts functions and increase angiogenesis of villi, while inhibiting further fibrin accumulation by reducing TF levels.  Abnormalities in fibrin- trophoblasts interactions may be associated with impaired placental repair mechanisms and fetal growth.