Human milk triggers coagulation via tissue factor–exposing extracellular vesicles

Abstract

Almost a century ago, it was discovered that human milk activates the coagulation system, but the milk component that triggers coagulation had until now been unidentified. In the present study, we identify this component and demonstrate that extracellular vesicles (EVs) present in normal human milk expose coagulant tissue factor (TF). This coagulant activity withstands digestive conditions, mimicking those of breastfed infants, but is sensitive to pasteurization of pooled donor milk, which is routinely used in neonatal intensive care units. In contrast to human milk, bovine milk, the basis of most infant formulas, lacks coagulant activity. Currently, the physiological function of TF-exposing vesicles in human milk is unknown, but we speculate that these vesicles may be protective for infants. Another explanation could be nipple skin damage, which occurs in most breastfeeding women. Milk-derived TF-exposing EVs may seal the wound and thereby reduce bleeding and breast inflammation.

Extracellular Vesicles in Human Milk

“…However, in our hands, using a sensitive flow cytometry capable of detecting single EVs with a diameter >160 nm, we were hardly able to detect EVs from leukocytes, monocytes, B-cells, and T-cells. Platelet-derived EVs were also not detectable, indicating that both immune cell-derived and blood cell-derived EVs are scarce or absent [33]. Whether these EVs are indeed hardly present, or whether most are still undetected due to their small size and the limited number of exposed antigens one needs to label and identify such (single) EVs, awaits further studies.…”

“…The cellular origin of milk EVs is mostly unexplored. Human milk contains EVs exposing epithelial cell adhesion molecule (EpCAM), and such EVs likely originate from the mammary epithelium [33]. Bovine milk also contains such EVs [34].…”

“…However, in our hands, using a sensitive flow cytometry capable of detecting single EVs with a diameter >160 nm, we were hardly able to detect EVs from The cellular origin of milk EVs is mostly unexplored. Human milk contains EVs exposing epithelial cell adhesion molecule (EpCAM), and such EVs likely originate from the mammary epithelium [33]. Bovine milk also contains such EVs [34].…”

Ruminant Milk-Derived Extracellular Vesicles: A Nutritional and Therapeutic Opportunity?

“… [ 255 ] Human Coagulant potential of human milk, owing to the presence of tissue factor (TF)-exposing EVs, but not found in cow milk. [ 256 ] Human Protective effect against experimental-induced NEC in vitro (IEC-6 and FHs 74 Int cell lines) and in vivo (Sprague Dawley pups). [ 257 ] Human + Cow Attenuation of inflammatory cytokine expression and nuclear factor (NF)-κB activation in vitro (LPS-stimulated RAW 264.7).…”

Novel mechanism regulating tissue factor activity

“…TF is expressed by extravascular cells under physiological conditions, and TF is present on EVs in normal human body fluids such as saliva, urine, and milk. 3 , 4 TF is also found in the blood, where it is expressed by monocytes and endothelial cells during infection and inflammation. TF triggers coagulation by binding FVII, thereby promoting the formation of active FVII (FVIIa).…”