Defibrotide Interactions with Newer Oral Anticoagulants and Antithrombotic Agents
Authors: Fareed Jawed , Hoppensteadt Debra , Iqbal Omer , Cunanan Josephine , Bansal Vinod , Abro Schuharazad , Wahi Rakesh 
Published: October 2019

Abstract
Abstract 3411
Defibrotide is a polydisperse mixture of porcine-derived single-stranded oligonucleotides which has been used for multiple clinical indications. Recent clinical trials of defibrotide indicate that this drug may provide benefits both for the treatment and prophylaxis of hepatic veno-occlusive disease (VOD) in hematopoietic stem cell therapy. In VOD it is believed that defibrotide exerts two distinct effects; 1. Endothelial cell protection and 2. Restoration of the thrombotic-fibrinolytic balance. Although antithrombotic in nature, defibrotide does not produce any systemic anticoagulant effects atthe selected dose of 25 mg/kg/day Conventional oral anticoagulants are routinely not used in veno-occlusive disease however heparin is often used in the management of these patients. More recently, newer oral anticoagulant drugs such as dabigatran, apixiban and rivaroxiban have been approved for the management of post orthopaedic surgical venous thrombosis and stroke prevention in atrial fibrillation. The current study was undertaken to investigate the effect of defibrotide on the anticoagulant and antiprotease effects of the newer oral anticoagulant drugs in the whole blood, plasma and platelet rich plasma based systems.

Materials and Methods
Native whole blood was drawn from 25 normal healthy individuals and supplemented with 100 μg/mL defibrotide and 250 ng/mL of each of the individual oral anticoagulant drugs alone and with defibrotide. Activated clotting time (ACT) measurements were made on a Hemachron instrument using celite ACT tubes. For the plasma based anticoagulant studies, a fixed concentration of defibrotide of 100 μg/mL was supplemented with defibrotide to pool plasma alone and with each of the individual oral anticoagulantagents in a concentration range of 0–1000 ng/mL. To investigate the effect of defibrotide on agonist induced platelet aggregation platelet rich plasma was prepared with varying amounts of defibrotide (0–100ug/ml). Such agonsits as ADP, epinephrine, collagen and arachodonic acid were used. To test the effects of newer oral anticoagulants, each agent was supplemented at 250–500ng/ml to the defibrotide enriched PRP (100ug/ml) and agonist induced aggregation studies were carried out in comparison to saline and defibrotide control. To test the effect of defibrotide on the conventional oral anticoagulant agents, plasma samples from patients with INR range of 1.5–3.0 were supplemented with 100ug/ml and the PT/INR was re-determined using Innovin® reagent.

Results
In the whole blood studies apixaban and rivaroxaban did not produce any prolongation of the whole blood ACT. However, dabigatran produced a modest increase in the ACT at 250 ng/mL. In the anticoagulant assays, supplementation of these agents did not result in any prolongation of the PT with defibrotide and newer oral anticoagulants. In the aPTT assay, the apixaban and rivaroxaban did not have any interaction, at a concentration greater than 500 ng/mL. Dabigatran shows a slight interaction in the aPTT assay. Defibrotide, did not produce any alterations of the effect on the agonist (ADP, epinephrine, collagen, arachidonic acid) induced aggregation of platelets in concentrations up to 100 μg/mL. Studies carried out where defibrotide at 100 μg/mL is combined with 250 ng/mL of each of the new anticoagulants does not show any modification of the aggregation responses. Defibrotide supplementation to anti-platelet therapy treated patient's blood collected did not result in any augmentation of the observed inhibitory responses. Defibrotide did not produce any changes in the PT/INR values of plasma samples collected from warfarin treated patients at concentrations of up to 100 μg/ml.

Conclusions
These studies indicate that in a concentration range of 0–1000 ng/mL the new anticoagulants do not exhibit any significant interactions with defibrotide. Since dabigatran exhibits some anticoagulant effect of its own, minor interactions with defibrotide may be observed. Based on the indications for the new oral anticoagulant drugs, their circulating levels and rapid clearance, it is unlikely that defibrotide will produce any interactions with these drugs.

Disclosures:
No relevant conflicts of interest to declare.