Exploratory study on the reversal of warfarin with rFVIIa in healthy subjects.

The use of warfarin has a well-known bleeding risk. Recombinant activated factor VII (rFVIIa) is a non-plasma-derived, rapid-acting, and rapidly infused potential treatment. This randomized, single-center, placebo-controlled, double-blinded, dose-escalation, exploratory phase 1 trial assessed safety and effects of rFVIIa in reversing warfarin-induced changes in bleeding and coagulation parameters, using a punch biopsy-induced bleeding model in healthy subjects. The effects of warfarin (experiment 1) and rFVIIa (5-80 microg/kg; experiment 2) were evaluated. Outcomes were bleeding duration, blood loss, coagulation parameters, and safety. Warfarin treatment significantly increased bleeding duration and blood loss from pretreatment (experiment 1, 12 subjects). However, these parameters after rFVIIa treatment were not significantly different from placebo (experiment 2, 85 subjects). Mean activated partial thromboplastin time, prothrombin time, and international normalized ratio were reduced from warfarin-elevated levels. rFVIIa (80 microg/kg) significantly reversed warfarin effects on all thromboelastography parameters, compared with placebo (P < .05), and returned the thrombin generation speed to baseline. There were no thromboembolic or serious adverse events. In this exploratory trial, the reversal of warfarin effects was observed in the thromboelastography, thrombin generation, and clotting assays. However, this reversal did not translate to improvements in the bleeding model parameters evaluated in the punch biopsy model. Trial registration is exempt (phase 1).

Maternal hyperinsulinism and glycaemic status in the first trimester of pregnancy are associated with the development of pregnancy-induced hypertension and gestational diabetes.

OBJECTIVE: To evaluate the relationships across a range of glucose and insulin measures at 12 weeks of gestation with the development of pregnancy-induced hypertension (PIH), gestational diabetes mellitus (GDM) and birth size. MATERIALS AND METHODS: Prospective study of pregnant women booking before 15th week of gestation. At the first antenatal visit, standard measures of height, weight, blood pressure (BP) and social status were recorded, and blood sample was drawn for measurements of fasting glucose and plasma insulin. Oral glucose tolerance test with 75  g glucose load was performed after overnight fast. Odds ratios (ORs) with 95% CI were calculated to determine the risk of developing PIH or GDM depending on quartiles of blood glucose or tertiles of plasma insulin levels. RESULTS: One thousand six hundred and fifty pregnant women were included in the study. Of them, 1484 delivered a live infant of whom 70 were preterm, 166 did not complete the study, 155 mothers developed PIH (10.4%), 18 were diagnosed with GDM (1.2%) and four had both PIH and GDM. At 12 weeks of gestation, women who became hypertensive were heavier (P<0.001), with higher BMI (P<0.001) than controls. Both systolic (P<0.001) and diastolic BPs (P<0.001) were already higher in women who developed PIH. Fasting insulin concentrations were higher in PIH group (P<0.002). Fasting glucose level >6.8 mmol/l was associated with the likelihood of delivering a macrosomic baby (OR 3.1 (95% CI: 1.21-8.0); P=0.02); the effect was heightened in multiparous mothers (OR 4.0 (95% CI: 1.4-11.1); P=0.01). Fasting plasma insulin had, however, no effect on size at birth in this study. CONCLUSIONS: Our data suggest that women who develop PIH may be metabolically challenged at early stages of pregnancy with hyperinsulinism, insulin insensitivity and slightly higher BP.