Estrogen upregulates lactoferrin to induce hypercoagulability for hemostatic protection during pregnancy Available to Purchase

• Estrogen upregulates lactoferrin expression during pregnancy, inducing hypercoagulability and increasing the risk of thromboembolic events

• Lactoferrin-driven potentiation of FXIa may function as a protective mechanism against peripartum bleeding

Venous thromboembolism (VTE) remains a leading contributor to maternal morbidity and mortality during pregnancy and the immediate postpartum period. Although pregnancy is recognized as a hypercoagulable state, the molecular mechanisms underlying this prothrombotic shift are incompletely characterized. In this study, lactoferrin was identified as an enhancer of coagulation factor XIa (FXIa) activity. Elevated plasma concentrations of lactoferrin were observed in pregnant women and were found to be estrogen-dependent, mediated through estrogen response elements (EREs) within the lactoferrin gene promoter. In murine models, pregnancy-induced thrombotic pathology was ameliorated by either genetic knockout of lactoferrin or pharmacological blockade using HS9, a peptide that selectively inhibits lactoferrin-mediated potentiation of FXIa. Notably, HS9 (1 mg/kg) exhibited a substantially reduced hemorrhagic profile relative to low molecular weight heparin. These findings establish lactoferrin as a physiological modulator of gestational hypercoagulability and implicate it as a promising therapeutic target for pregnancy-associated VTE, with the potential to mitigate thrombotic risk while preserving hemostatic integrity.