Estrogen upregulates lactoferrin to induce hypercoagulability for hemostatic protection during pregnancy

ABSTRACT: 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 remain 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 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 compared with low-molecular-weight heparin. These findings identify lactoferrin as a physiological modulator of gestational hypercoagulability and implicate it as a potential therapeutic target for pregnancy-associated VTE, with the capacity to reduce thrombotic risk while preserving hemostatic integrity.