Comparative Studies on the Oral Anticoagulant Activities of Orally Active Anti‐Xa and Anti‐IIa Agents in Whole Blood and Plasma and their Neutralization by FEIBA
Authors: Raina Rithik , Mehrotra Siddharth , Venkitasubramony Vishnu , Hoppensteadt Debra , Iqbal Omer , Siddiqui Fakiha , Jeske Walter , Fareed Jawed 
Published: June 2021

Introduction

Orally bioavailable anticoagulants include, Apixaban, Betrixaban, Edoxaban, and Rivaroxaban which are anti Xa drugs approved for various indications. Dabigatran is an anti‐IIa drug which is primarily approved for atrial fibrillation. While these drugs are claimed to have targeted actions toward Factor Xa or IIa, current data suggests that their actions may involve other target sites. This study was designed to compare the relative anticoagulant effects of each of these drugs in whole blood and retrieved plasma, using PT, aPTT and TT tests. Additionally the neutralization of these drugs by an activated prothrombin complex concentrate FEIBA was also investigated.

Materials

Powdered forms of Apixaban, Betrixaban, Edoxaban, Rivaroxaban and Dabigatran were obtained from commercial sources. All drugs were dissolved at a stock concentration of 1 mg/mL in saline. Working concentrations were prepared at 100 ug/mL and 10 ug/mL. Freshly drawn citrated whole blood from healthy volunteers (n=10) was supplemented with each of these agents at a graded concentration of 0 to 1 ug/mL. Whole Blood, PT and aPTT were measured using the ST4 (Diagnostica Stago) instrument. Whole blood supplemented with each of these drugs was centrifuged to obtain retrieved plasma from each of these agents. The retrieved plasma was also analyzed for PT and aPTT. All results were compiled in terms of mean and standard deviation. These studies were repeated in the presence of 0.1 U/mL of FEIBA to determine the relative neutralization of their anticoagulant effects.

Results

All of the five drugs produced concentration dependent anticoagulant effects in both the PT and aPTT tests. In the whole blood, the PT prolongation was different for each agent, with the rank order Dabigatran > Edoxaban > Betrixaban > Rivaroxaban > Apixaban > Saline. The prolongation of the aPTT in the whole blood followed the rank order Betrixaban > Dabigatran > Rivaroxaban > Edoxaban = Apixaban > Saline. All five drugs produced an increase in the PT in the retreat plasma with rank order Dabigatran > Edoxaban > Apixaban > Rivaroxaban > Betrixaban > Saline. In the aPTT assay the increase in clotting times followed the rank order Dabigatran > Betrixaban > Rivaroxaban > Edoxaban > Apixaban. FEIBA supplementation at a 0.1 U/ml to each of the drugs supplemented at 1 ug/ml markedly neutralized their anticoagulant effects in the PT and aPTT assay systems. At this concentration FEIBA did not have any significant effects on the PT and aPTT assays.

Conclusions

These studies suggest that in comparison to the anti‐Xa agents, Dabigatran produces relatively stronger anticoagulant effects in the PT and aPTT assays in both whole blood and retrieved plasma. FEIBA at a relatively low level of 0.1 U/ml was capable of neutralizing the anticoagulant effects of the newer oral anticoagulant drugs and may be helpful in the control of potential bleeding complications with these drugs.

Support or Funding Information

None.

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.