Examining the transplacental passage of apixaban using the dually perfused human placenta

Abstract

• Apixaban is a novel oral anticoagulant that has not been studied in pregnant patients.• Our objective was to determine the rate and extent of the placental transfer of apixaban.• Apixaban rapidly crosses the ex vivo term human placenta from maternal to fetal circulation.• Fetal apixaban levels in vivo are estimated to be 35-90% of the corresponding maternal levels.Summary. Background: Apixaban is a novel oral anticoagulant that is increasingly being prescribed to women of reproductive age. However, information regarding its placental transfer is non-existent. Objective: To determine the rate and extent of placental transfer of apixaban, using the human placenta ex vivo. Methods: Placentae collected after Caesarean or vaginal delivery of healthy term infants were perfused in the respective maternal and fetal circulation. At the start of the experiment, apixaban was added to the maternal circulation at a concentration of 150 ng mL À1 , and samples from maternal and fetal reservoirs were collected over 3 h. Results: There was a rapid decline of apixaban in the maternal compartment, followed by emergence in the fetal compartment with a median fetal-to-maternal drug concentration ratio of 0.77 (interquartile range [IQR], 0.76-0.81) and fetal concentration of 39.0 ng mL À1 (IQR, 36.8-40.6) after 3 h (n = 5).The perfusion results were subsequently adjusted to account for differences in the concentration of plasma proteins in maternal and fetal blood, as apixaban remains highly bound to albumin and alpha-1 acid glycoprotein. After the adjustment, the predicted fetal-to-maternal ratio of total (bound plus unbound) apixaban concentrations in vivo ranged from 0.35 to 0.90. Conclusions: We conclude that unbound apixaban rapidly crosses from the maternal to fetal circulation. We further predict that total apixaban concentrations in cord blood in vivo are 35-90% of the corresponding maternal levels, suggesting that apixaban could have a possible adverse effect on fetal and neonatal coagulation.

Direct-Acting Oral Anticoagulants (DOACs) in Cirrhosis and Cirrhosis-Associated Portal Vein Thrombosis

“…92 Bapat et al evaluated the transplacental PKs of dabigatran, rivaroxaban, and apixaban using a dual perfusion ex vivo full-term human placenta model. [93][94][95] Dabigatran crossed into the fetal circulation slowly, reaching 17% of the maternal levels after 3 hours. 93 On the other hand, rivaroxaban and apixaban moved quickly into the fetal circulation in this model, reaching 69% and 77%, respectively, of the maternal circulation drug levels at 3 hours.…”

Thrombosis and hemostasis health in pregnancy: Registries from the International Society on Thrombosis and Haemostasis

“…Many patients receiving DOACs for venous thromboembolism are of reproductive age, but there are limited data about the safety of DOACs in pregnancy. Both animal and human placental models have demonstrated that all DOACs cross the placenta, [37][38][39] and the risk of reproductive toxicity at therapeutic to toxic dosages was documented in animals. Therefore, the ISTH guidance statement advises against the use of DOACs during pregnancy and in women planning pregnancy.…”

Preventing venous thromboembolism during pregnancy and postpartum: crossing the threshold

“…2,66 Warfarin and LMWH are safe while breastfeeding 2 ; any DOACs should be avoided in breastfeeding. 67,68 Correspondence Leslie Skeith, Division of Hematology, Department of Medicine, The Ottawa Hospital-General Campus, 501 Smyth Rd, Box 201, Ottawa, ON K1H 8M2, Canada; e-mail: leslie.skeith@gmail.com.…”