Syncytiotrophoblast Microvesicles Released from Pre-Eclampsia Placentae Exhibit Increased Tissue Factor Activity

Chris Gardiner,Paul Harrison,Christopher W G Redman,Dionne S Tannetta,Ian L Sargent,Carol A Simms,David S Milstone

doi:10.1371/journal.pone.0026313

Chris Gardiner, Paul Harrison + Show 5 more

Open Access

https://doi.org/10.1371/journal.pone.0026313

Copy DOI

Abstract

BackgroundPre-eclampsia is a complication of pregnancy associated with activation of coagulation. It is caused by the placenta, which sheds increased amounts of syncytiotrophoblast microvesicles (STBM) into the maternal circulation. We hypothesized that STBM could contribute to the haemostatic activation observed in pre-eclampsia.Methodology/Principal FindingsSTBM were collected by perfusion of the maternal side of placentae from healthy pregnant women and women with pre-eclampsia at caesarean section. Calibrated automated thrombography was used to assess thrombin generation triggered by STBM-borne tissue factor in platelet poor plasma (PPP). No thrombin was detected in PPP alone but the addition of STBM initiated thrombin generation in 14/16 cases. Pre-eclampsia STBM significantly shortened the lag time (LagT, P = 0.01) and time to peak thrombin generation (TTP, P = 0.005) when compared to normal STBM. Blockade of tissue factor eliminated thrombin generation, while inhibition of tissue factor pathway inhibitor significantly shortened LagT (p = 0.01) and TTP (P<0.0001), with a concomitant increase in endogenous thrombin potential.Conclusions/SignificanceSTBM triggered thrombin generation in normal plasma in a tissue factor dependent manner, indicating that TF activity is expressed by STBM. This is more pronounced in STBM shed from pre-eclampsia placentae. As more STBM are shed in pre-eclampsia these observations give insight into the disordered haemostasis observed in this condition.

Highlights

Pre-eclampsia is a relatively common pregnancy-specific disorder affecting around 3% of pregnancies and is a major cause of fetal and maternal mortality and morbidity worldwide
Endogenous thrombin potential (ETP) and peak thrombin formation were significantly increased by the addition of pre-eclampsia syncytiotrophoblast microvesicles (STBM) compared to normal STBM, with concomitant reductions in median lag time to start of thrombin generation (LagT) and TTP (3.8 [IQR 2.4–6.8] v 8.3 [IQR 7.3–45.0] and 7.3 [IQR 4.6–12.4] v 15.8 [IQR 14.3– 55.4] minutes respectively) (Fig. 1A)
The presence, or otherwise, of tissue factor on the syncytiotrophoblast with the potential to initiate coagulation, in direct contact with maternal blood, has been controversial subject for many years. This controversy arises in part from poor methodological standardization which has led to conflicting reports

Summary

Introduction

Pre-eclampsia is a relatively common pregnancy-specific disorder affecting around 3% of pregnancies and is a major cause of fetal and maternal mortality and morbidity worldwide. It is characterized by hypertension, proteinuria, endothelial dysfunction and systemic activation of an inflammatory response [1]. The placental syncytiotrophoblast releases microvesicles (STBM) and soluble inflammatory mediators in [2] to the maternal circulation [2], leading to a low-level physiological inflammatory response. Pre-eclampsia is a complication of pregnancy associated with activation of coagulation It is caused by the placenta, which sheds increased amounts of syncytiotrophoblast microvesicles (STBM) into the maternal circulation. We hypothesized that STBM could contribute to the haemostatic activation observed in pre-eclampsia

Methods

Results

Conclusion