Elevated plasma TFPI activity causes attenuated TF-dependent thrombin generation in early onset preeclampsia

Abstract

Early onset preeclampsia (EOP) is a pregnancy-specific proinflammatory disorder that is characterised by competing thrombotic and bleeding risks. It was the aim of this study to characterise thrombin generation, a major determinant of thrombotic and bleeding risk, in order to better understand the haemostatic balance in patients with EOP. Patients with EOP were recruited at the Rotunda Hospital, Dublin. Twenty-six cases of EOP were recruited over a 21-month period, out of 15,299 deliveries at the Rotunda. Blood samples were collected into sodium citrate plus corn trypsin inhibitor anticoagulated vacutainers, platelet-poor plasma was prepared, and calibrated automated thrombography was used to assess thrombin generation. Results were compared to age and sex-matched non-pregnant controls (n=13) and age- and gestation-matched pregnant controls (n=20). The rate and extent of thrombin generation triggered by low-dose tissue factor (TF) was significantly reduced in patients with EOP compared to pregnant controls, most significantly in cases of severe EOP. EOP patients displayed a trend towards an increased response to endogenous activated protein C and thrombomodulin relative to pregnant controls. Plasma tissue factor pathway inhibitor (TFPI) activity was increased in EOP patients. Inhibition of TFPI abolished the attenuation of thrombin generation stimulated by low-dose TF. In conclusion, patients with EOP are characterised by an attenuated coagulation response characterised by reduced thrombin generation stimulated by low-dose TF and elevated plasma TFPI activity. These changes in coagulation may modulate thrombotic risk and bleeding risk in patients with EOP.

Levels of serum Hoxb3 and sFlt‐1 in pre‐eclamptic patients and their effects on pregnancy outcomes

“…Additionally, abnormally increasing coagulation activity promotes the release of a large amount of tissue thromboplastin, and prothrombin activation generates thrombin and fibrin. This causes maternal placental thrombosis, placental atherosclerosis, poor blood supply and poor blood circulation 38 . Consequently, post‐partum hemorrhage and other adverse reactions are induced.…”

VTE risk assessment in pregnancy

“…In a recent systematic review and meta‐analysis restricted to recent studies in which VTE cases were validated, the pooled incidence rate of VTE during the antepartum period was 118 (95% CI, 101‐137) per 100 000 person‐years and 424 (95% CI, 238‐755) per 100 000 person‐years during the postpartum period . Mechanisms underlying this pregnancy‐related increase in VTE risk include venous stasis, pelvic venous compression by the gravid uterus, pulsatile compression of the left iliac vein by the right iliac artery and changes in pro‐ and anticoagulant and fibrinolytic pathways . For example, plasma endogenous thrombin potential and plasminogen activator inhibitor‐1 levels are significantly higher in pregnant women compared with nonpregnant controls …”

“…include venous stasis, pelvic venous compression by the gravid uterus, pulsatile compression of the left iliac vein by the right iliac artery and changes in pro-and anticoagulant and fibrinolytic pathways. [5][6][7][8] For example, plasma endogenous thrombin potential and plasminogen activator inhibitor-1 levels are significantly higher in pregnant women compared with nonpregnant controls. 7,8 In pregnancy, platelets undergo morphological changes and their activation is increased.…”

“…[5][6][7][8] For example, plasma endogenous thrombin potential and plasminogen activator inhibitor-1 levels are significantly higher in pregnant women compared with nonpregnant controls. 7,8 In pregnancy, platelets undergo morphological changes and their activation is increased. 9 Upon activation, platelets release a multitude of signaling (soluble and vesicular) factors collectively termed the platelet releasate (PR), 10 which plays important roles in hemostasis, wound healing, and inflammatory response.…”

Data_Sheet_2.docx

“…Patients with early onset of preeclampsia (EOP), characterized by competing thrombotic and bleeding risks, show an attenuated coagulation response with reduced thrombin generation stimulated by low-dose TF and elevated activity of plasma TFPI (Egan et al, 2017). Normalized Enrichment score (NES), FDR and nominal p-value were reported for each comparison.…”