Study question: What is the effect of estrogen on heparanase procogulant activity?
Summary answer: Estrogen increases heparanase procoagulant activity.
What is known already: Estrogen therapy increases the risk of thrombosis and was previously found to up-regulate heparanase expression. Heparanase is involved in angiogenesis and metastasis, and has been shown to form a complex with tissue factor (TF) and also shown to enhance the generation of factor Xa.
Study design, size, duration: A case-control study. Thirty-four healthy women using oral contraceptives (OC) and 41 women not using hormonal therapy and not pregnant per history were enrolled, over a 5-month period, at the Rambam Medical Center, Haifa, Israel. In vitro, estrogen receptor-positive (MCF-7) and -negative (MDA-231) cell lines were incubated with estrogen, tamoxifen and ICI-182.780 a pure estrogen receptor antagonist. The cell medium was evaluated for TF/heparanase complex activity, TF activity and heparanase procoagulant activity by chromogenic substrate.
Participants/materials, setting, methods: Exclusion criteria included age <18 years, post-menopausal women, concomitant medications other than supplement minerals and vitamins, acute or chronic illness.
Main results and the role of chance: The study demonstrates increased risk of high heparanase procoagulant activity in OC users. When a cutoff level of 0.25 (absorbance 405-490 nm) was set, the odds ratio was 131 (P < 0.0001). When all results were studied by quartiles, in quartiles 3 and 4 the results were almost exclusively of the OC users (P < 0.0001). In cell cultures, estrogen and tamoxifen increased heparanase procoagulant activity in the medium of estrogen receptor-positive (MCF-7) cells.
Limitations, reasons for caution: The main limitation of the current study is that the two estrogens given to the women and cell cultures, ethinyl estradiol (EE) and 17-β-estradiol (E2), respectively, may have different effects on the coagulation system, although an increase in heparanase procoagulant activity was demonstrated in both of them. Although the sample size of the study group was limited, significant differences in the activation of the extrinsic coagulation pathway were demonstrated.
Wider implications of the findings: The clinical relevance of the heparanase procoagulant activity assay as a screening tool in thrombophilia work-up should further be elucidated.
Keywords: coagulation; estrogen; heparanase; oral contraceptives; tamoxifen.