Gifts in fluid: Function of tissue factor and coagulation factor VII in human body fluids
Cells release small particles, which are called extracellular vesicles (EVs). EVs are present in human body fluids, but their function is unknown. We investigated why normal human body fluids contain EVs, and how such EVs may play a role in physiology. We show that EVs present in human milk and other body fluids expose a protein called tissue factor (TF). TF triggers the clotting of blood, which helps to stop bleeding and reduces the risk of infection. The presence of these TF-exposing EVs in milk explains observations from the 1930-ies that bleeding can be stopped by applying milk-soaked gauzes. The blood clotting activity of milk survives conditions simulating the infants’ gastric and pancreatic digestion, suggesting that milk may possibly contribute to gastrointestinal haemostasis in infants. We also show that measuring the ability of human milk to trigger blood plasma clotting may be useful to evaluate milk pasteurization, a procedure applied when milk is stored in hospital biobanks. Furthermore, we demonstrate that EVs in amniotic fluid, milk, saliva and urine expose not only TF but also its ligand, coagulation factor VII (FVII). In fact, the presence of the complex of TF and FVII on EVs explains why EVs efficiently trigger blood clotting. The complex of TF and FVII also has non-haemostatic functions such as regulation of epithelial permeability, and we provide evidence that FVII, present in amniotic fluid, may interact with TF present on fetal epithelial cells, and we show that this interaction may play a role in regulating epithelial permeability. Taken together, this thesis contributes to our understanding how EVs present in body fluids may contribute to protection by promoting haemostasis and regulation of epithelial permeability.
https://pure.uva.nl/ws/files/87588346/Thesis.pdf
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https://dare.uva.nl/personal/pure/en/publications/gifts-in-fluid