The perinatal period is characterized by critical physiological challenges, including a high risk of hemorrhage during childbirth and a sharp increase in susceptibility to venous thromboembolism (VTE), a leading cause of maternal morbidity and mortality. The mechanism by which the body maintains hemostatic balance under this competing "bleeding–thrombosis" pressure has long remained unclear.

A research team led by Prof. LAI Ren from the Kunming Institute of Zoology of the Chinese Academy of Sciences has found that lactoferrin is a central regulator of pregnancy-associated hypercoagulability. They demonstrated that estrogen significantly increases lactoferrin levels, which enhances the activity of coagulation factor XIa (FXIa) and promotes thrombin generation and thrombus formation.

This study was published in Blood on December 18.

The researchers observed that plasma lactoferrin levels in pregnant women were significantly higher than in non-pregnant controls. Furthermore, pregnant women with VTE exhibited even higher levels of this protein - a phenomenon consistently validated in mouse pregnancy models.

They demonstrated that the significant increase in estrogen during pregnancy transcriptionally upregulates lactoferrin expression via estrogen response elements (EREs) within the lactoferrin gene promoter, thereby driving pregnancy-associated thrombosis.

In lactoferrin-knockout mice, both plasma recalcification time (PRT) and activated partial thromboplastin time (aPTT) were significantly prolonged, while the weight of inferior vena cava thrombi and plaque area were markedly reduced.

Treatments involving lactoferrin antibodies, lactoferrin knockout, or the specific interfering peptide HS9 (targeting the lactoferrin - FXIa interaction) all significantly inhibited thrombosis in pregnant mice. Notably, the HS9 demonstrated a significantly lower bleeding risk at effective anticoagulant doses compared to heparin.

This study establishes lactoferrin as a key regulator of the pregnancy-associated hypercoagulable state, upregulated under estrogen control, and elucidates the lactoferrin-FXIa axis as a potential therapeutic target for anticoagulation, providing a novel and safer strategy for the prevention and management of VTE during pregnancy.

Furthermore, the study reveals an intriguing biological trade-off. As a vital nutritional protein in breast milk, lactoferrin is significantly upregulated by estrogen during the perinatal period. This regulatory process serves two purposes: providing essential nutrients to the newborn and offering hemostatic protection against maternal hemorrhage. However, it also induces a maternal tendency toward hypercoagulability and thrombotic risk. The researchers suggested that this trade-off is likely a physiological adaptation designed to balance the risks of maternal bleeding and thrombosis while ensuring the nutritional supply to the newborn.

This work was supported by the National Key Research and Development Program of China, the National Natural Science Foundation of China, the Yunnan Provincial Science and Technology Department, among others.

The mechanism of the lactoferrin-mediated regulation of perinatal coagulation homeostasis. (Image by LAI Ren)