Placental corticotrophin‐releasing hormone mRNA and microparticles in maternal plasma are not measures of placental shedding of debris: a rebuttal

Abstract

To cite this article: Buimer M, Lok CAR, Nieuwland R, Ris-Stalpers C, van der Post JAM. Placental corticotrophin-releasing hormone mRNA and microparticles in maternal plasma are not measures of placental shedding of debris: a rebuttal. J Thromb Haemost 2008; 6: 1837-8.See also Freeman DJ, Tham K, Brown EA, Rumley A, Lowe GD, Greer IA. Fetal corticotrophin-releasing hormone mRNA, but not phosphatidylserine-exposing microparticles, in maternal plasma are associated with factor VII activity in pre-eclampsia. The interesting article by Freeman et al. [1] reports an association between F-VII activity and corticotrophin-releasing hormone (CRH) mRNA but not number of circulating microparticles (MP) in pre-eclamptic patients. Their findings depend on the presumption that fetal CRH mRNA and number of MP are measures of placental shedding of debris. It is questionable whether this is the case.The placental CRH system is a functional part of the fetal environment [2,3]. It is without doubt influenced by fetal stress and other factors associated with preterm delivery [4] and fetal growth restriction [5]. This makes placental CRH prone to confounding by fetal growth restriction and preterm delivery, which were different between the groups in the study by Freeman.Furthermore, although a 1-6% fraction [6] of the MP population originates in the placenta, the majority (>95%) is derived from platelets [7]. As the prothrombinase assay measures the overall procoagulant activity of total MP, it is not specific for placenta-derived MP. To quantify placentaderived MP, both flow cytometry and ELISA using NDOG2 or ED822 antibodies are more suitable [8]. Interpreting the concentration of circulating MP is further complicated by hemoconcentration and elevated platelet turnover in preeclampsia. Moreover, a fraction of the total MP population may be attached to maternal blood or endothelial cells.In the presented study, total numbers of MP were comparable between groups. However, these data do not exclude involvement of specifically placenta-derived MP in the inflammatory response of pre-eclampsia because these MP were shown to trigger cytokine production by monocytes [9].Finally, apart from quantification of MP, the presence of proteins on the MP membrane is of importance. Both positive and negative effects of MP have been reported that at least partially depend on the status of the parental cell. For example, MP from apoptotic T-cells impair relaxation, whereas MP from activated T-cells can increase NO release, thus promoting vasodilation [10].Taken together, one can question if CRH mRNA and number of MP are appropriate markers of placental debris, which makes it hard to interpret the reported results and to use these measurements as indicators for placental dysfunction in pre-eclampsia.

Placental corticotrophin‐releasing hormone RNA and microparticles in maternal plasma are not measures of placental shedding of debris: reply to a rebuttal

“…We agree with Buimer et al. [1] that the total number of microparticles in maternal plasma is not a measure of placental shedding of debris. We made our view clear in the discussion of our article [2] that ‘the total microparticle population (in maternal plasma) comprises a mixture of fetal and maternal‐derived microparticles and is not a specific marker of placental debris.’ We did not claim that the overall procoagulant activity of total microparticles was specific for placenta‐derived microparticles and stated ‘our prothrombinase assay would detect total PS‐exposing microparticles and would be unable to distinguish between fetal and maternal‐derived material.’…”

“…While the letter of Buimer et al. [1] refers to our study as measuring the number or concentration of microparticles, this is not the case. Our interest in microparticle prothrombinase activity, and fetal CRH mRNA, in maternal plasma was in their interaction with the maternal coagulation system.…”