Andexanet alfa or prothrombin complex concentrate for acute reversal of oral factor Xa inhibitors: monitoring of antidote effects.

This study in vitro comprehensively assessed reversal of the anticoagulant effects of rivaroxaban, an oral factor Xa inhibitor, using andexanet alfa and various prothrombin complex concentrate (PCC) products in a battery of tests. In static coagulation assays, andexanet alpha outperformed PCCs except for activated PCC being more effective in standard coagulation times. However, in a flow chamber model mimicking arterial shear, both andexanet alpha and high-concentration PCC restored fibrin formation, but not platelet adhesion. In the Russell's viper venom test and anti-Xa assay, only andexanet alpha could be tested for efficacy. The antidote effects of andexanet alpha and PCCs in restoring coagulation can be qualitatively or selectively demonstrated using in vitro coagulation tests.

A direct oral factor Xa inhibitor edoxaban ameliorates neointimal hyperplasia following vascular injury and thrombosis in apolipoprotein E-deficient mice.

Vascular injury activates the coagulation cascade. Some studies report that coagulation factor Xa and thrombin are implicated in proliferation of vascular smooth muscle cells and neointimal hyperplasia after vascular injury. The aim of this study was to determine the effect of an oral direct factor Xa inhibitor, edoxaban, on neointimal hyperplasia following the carotid artery injury in apolipoprotein E (ApoE)-deficient mice. Vascular injury was induced by the application of 10% ferric chloride to the carotid artery for 3 min in ApoE-deficient mice. After vascular injury, all animals were fed with high-cholesterol chow for 6 weeks. Edoxaban at 15 mg/kg was orally administered to the mice 1 h before (n = 10) or 1 h after (n = 9) ferric chloride injury, and thereafter 10 mg/kg edoxaban was orally administered b.i.d. for 6 weeks. Thrombus formation and neointimal hyperplasia were evaluated. Treatment with 15 mg/kg edoxaban before vascular injury almost completely inhibited thrombus formation, and following chronic administration of edoxaban significantly suppressed neointimal hyperplasia. In the mice treated with edoxaban after vascular injury, there was wide interindividual variability. In some mice (four out of nine) the neointimal hyperplasia was inhibited like in edoxaban-pretreated mice, but there was no statistical difference compared with control. This study demonstrated that inhibition of the coagulation and thrombosis by edoxaban ameliorated neointimal hyperplasia caused by vascular injury and high-cholesterol diets in ApoE-deficient mice. This suggests that factor Xa has a crucial role in the formation of neointima following vascular injury.The abstract should be followed by 3-4 bullet points that highlight major findings. The final bullet point should emphasize future directions for research.

Anticoagulation of pediatric patients with venous thromboembolism in 2023.

Venous thromboembolism (VTE) is a rare and heterozygous disease in children. Management of VTE in children is complicated by age-related differences in epidemiology, recurrent VTE and bleeding risk, hemostatic proteins and pharmacokinetics of anticoagulants. Recently, the choice of anticoagulation has expanded to oral factor IIa and Xa inhibitors, which have been authorized for children for treatment of acute VTE and extended secondary prevention. These drugs have several properties that make them extremely suitable for use in children, including oral administration, antithrombin independence, less interactions with food and drugs and no need for monitoring. Unfortunately, the phase 3 studies had many exclusion criteria, and only a few term neonates and infants were included in these studies. Additional real-world data is needed to make evidence-based recommendations in these age and patient groups, as well.

Pharmacokinetics, safety, and tolerability of edoxaban in end-stage renal disease subjects undergoing haemodialysis.

Edoxaban is an oral, direct, once-daily, factor Xa inhibitor developed for stroke prevention in patients with atrial fibrillation and for the treatment and secondary prevention of recurrent thromboembolism in patients with acute symptomatic venous thromboembolism. Among elderly patients who require anticoagulation therapies, some may have end-stage renal disease (ESRD). This open-label, phase 1, randomised, two-way crossover study was conducted to evaluate the pharmacokinetics of edoxaban in 10 subjects on haemodialysis. Eligible subjects with ESRD on chronic haemodialysis received a single, oral dose of edoxaban 15 mg 2 hours (h) prior to (on-dialysis) or in between (off-dialysis) haemodialysis sessions. Haemodialysis resulted in a minor decrease in mean total exposure (AUC0-∞; 676.2 ng·h/ml) as compared with that observed in subjects off-dialysis (691.7 ng·h/ml). Mean maximum observed plasma concentration (Cmax) values were comparable between on-dialysis and off-dialysis treatments (53.3 vs 56.3 ng/ml, respectively). Mean apparent total body clearance (CL/F) values were 24.1 and 22.5 l/h during the on-dialysis and off-dialysis treatment periods, respectively. Dialyser clearance was 5.7 l/h and haemodialysis clearance was 6.1 l/h. Haemodialysis clearance was only 6.1 l/h, suggesting that it only accounts for one-fourth of the total clearance in these subjects. A single, oral dose of 15 mg of edoxaban was well tolerated by subjects with ESRD. In conclusion, based on these single-dose PK data, a supplementary dose of edoxaban may not be required following a haemodialysis session. Importantly, haemodialysis is not an effective mechanism for removal of edoxaban from the blood.

Acute stroke in patients on new direct oral anticoagulants: how to manage, how to treat?

INTRODUCTION: For a long time, vitamin K antagonists (VKA) were the only available oral anticoagulants for clinical use. It is conceivable that the number of patients treated with novel direct oral anticoagulants (NOAC) will increase, due to the easy handling and the favorable risk-benefit profile compared with VKA. It is, therefore, expected that clinicians will be increasingly confronted with the question on how to treat acute ischemic stroke (AIS) if there is an indication for thrombolysis or how to manage intracranial bleedings. AREAS COVERED: In this review, we discuss controversies on thrombolysis in patients anticoagulated with NOAC, the dilemma of when to restart anticoagulation after AIS, and whether (and when) to re-institute oral anticoagulation after a brain hemorrhage. We provide suggestions for the management of these situations. EXPERT OPINION: Thrombolysis for patients with ischemic stroke who were given warfarin at subtherapeutic International normalized ratio values (≤ 1.7) may be considered according to guideline. Thrombolysis is contraindicated if intake of NOAC is reported in a patient, but no other information is available on-time of last intake of NOAC. Prothrombin complex concentrate have been proposed as a plausible, but unproven therapy to reverse the anticoagulant effects of NOACs.