We read with great interest the article written by Mitchell et al on the role of placenta-derived extracellular vesicles in normal and complicated pregnancies and their utility as biomarkers and therapeutic interventions. The authors have thoroughly explained the role of exosomes in relation to pregnancy and the problems related to isolation methodology. However, the precise role played by exosomes in complicated pregnancies is still not known.
The term, extracellular vesicles, also includes the population called microparticles (MP). Cell-derived MPs are phospholipid vesicles, 0.1–1 μm in size. They are basic markers of cell death and cell activation, and any condition that may cause either of these will definitely lead to elevated MP levels of different cell types. Because of the mechanism of production, the majority carry phosphatidylserine and tissue factor on their surface along with antigens from the cells from which they are derived, giving them their procoagulant attribute. Apart from being prothrombotic, they also have other attributes like being associated with vascular dysfunction, proinflammatory, proangiogenic, and immunomodulatory.
Exosomes, on the other hand, as the authors have appropriately described, are 40–120 nm in size, defined by an endosomal biogenesis and are specifically packaged with signaling molecules and are released by exocytosis. Thus, although they regulate activities like angiogenesis, proliferation, metabolism, etc, they themselves like MPs are not procoagulant or markers indicating cell activation and death.
We found significantly elevated annexin V, tissue factor, and endothelial MPs in women with unexplained recurrent pregnancy loss when compared with controls, which suggest an ongoing systemic state of activation or damage, which may just become exaggerated or symptomatic at the onset of pregnancy. This is seen in our second study, in which we found exaggerated MP levels at the start of pregnancy, and they continued to increase as pregnancy progressed in untreated women, which subsequently resulted in pregnancy loss. However, the MP levels decreased in women on anticoagulant therapy and resulted in successful pregnancy outcome in 70% cases in whom the MP levels normalized by the third trimester.
Thus, we agree with the authors that placenta-derived exosomes may play a role in healthy and complicated pregnancy. However, we believe that procoagulant MPs may be a better and more crucial biomarker to predict any kind of activation or cell death. Placenta damage or abruption may be detected by elevated levels of MPs at an early stage and anticoagulant therapy may be monitored by the decrease in levels as seen in our earlier study. Thus, along with placenta-derived exosomes, placenta-derived MPs also should be looked into for their ultimate clinical utility.