Population Based Differences in the Anticoagulant and Antiprotease Responses of Newer and Oral Anticoagulant Drugs
Authors: Masood Soofia , Hoppensteadt Debra , Cunanan Josephine , Khan Hussein , Abro Schuharazad , Bartosiak Kimberly , Fareed Jawed 
Published: October 2019

Abstract
Abstract 3421

Introduction:
Most of the screening of the newer anticoagulant drugs is usually carried out in normal human blood derived plasma and its products. Therefore endogenous compositional factors in different patient groups which may result in altering the anticoagulant and antiprotease effects of these drugs are not taken into account. Recently an oral anti-IIa agent Dabigatran and an anti-Xa agent namely Rivaroxaban are approved for clinical usage in the US. An additional anti-Xa drug namely Apixaban is approved in Europe and is under review by the US FDA. The pharmacologic properties of these drugs and their mechanism of action are distinct from one another. Therefore their endogenous interactions with blood and vascular sites also differ. The purpose of this study is to evaluate the differential anticoagulant responses of these agents in plasma samples from different patient populations groups such as the liver diseases (LD), acute coronary syndrome (ACS), end stage renal disease (ESRD), sepsis associated coagulopathy (SAC), cancer (C) and diabetes (D) in comparison to normal plasma.

Materials and Methods:
Plasma samples were collected from healthy normal male and female individuals (n=50) served as a control group. In addition plasma samples from various patient groups such as LD, ESRD, ACS, SAC, C and D and elevated aPTT, intrinsic defect (ID) and elevated PT extrinsic defect (ED) were collected ( n=30–50). These plasma samples were individually supplemented with Dabigatran, Rivaroxaban and Apixaban, at a concentration of 0.125 and 0.25ug/ml. Such tests as PT/INR, aPTT, TT and Heptest times and prothrombinase induced clotting time (PiCT) were measured using standard assays. The same samples were also analyzed for thrombin generation inhibition and anti-Xa and anti-IIa activities. Additionally pooled LD and SAC samples along with normal plasma were supplemented in a graded concentration of 0–1000 ng/ml with each of these anticoagulants. Concentration response curves were constructed for each of these agents in all the tests employed for the anticoagulant, antiprotease and thrombin generation studies.

Results:
In comparison to the normal plasma, different patient group plasma samples exhibited variable anticoagulant and thrombin generation inhibitory activities. In particular LD patients showed a stronger anticoagulant response with all agents, however Dabigatran produced the most profound effects. While these agents only produced a modest effect in the PT/INR assay, other coagulation tests were significantly elevated, in particular the PiCT tests. In comparison to both Apixaban and Rivaroxaban, Dabigatran produced the most pronounced prolongation of the aPTT, Heptest time, PiCT and TT. The results with Apixaban and Rivaroxaban were comparable. In the intrinsically defected plasma samples a similar trend was noted and Dabigatran produced the most pronounced prolongation in contrast to both Apixaban and Rivaroxaban. Similarly in the extrinsic defective plasma samples the Dabigatran produced the most pronounced prolongation of all of the tests in comparison to Apixaban and Rivaroxaban. The anti-protease (anti-Xa and anti-IIa) activities in different plasma matrices did not differ markedly. Population based differences were noted in other groups such as ACS, ESRD, SAC, C and D. The individual groups of the special patient populations showed wide scatter. The concentration response curves also differed from one population to another population.

Conclusion:
While all three anticoagulants produced stronger anticoagulant effects in LD, Dabigatran produced most markedly higher elevation of clotting responses. Rivaroxaban and Apixaban produced relatively weaker responses and differed from one another. Interestingly in the thrombin generation inhibition assays, Dabigatran produced relatively weaker effects in both normal and LD. Assay based variations among three agents were pronounced in patient populations. These studies clearly suggest that the anticoagulant and thrombin generation inhibitory effects of newer anticoagulants markedly differ in normal plasma and patient plasmas, however the antiprotease effects are similar. Therefore population based differences in the anticoagulant responses may alter their anticoagulant effects in different patient populations. These variations may account for the differential safety and efficacy of these drugs.

Disclosures:
No relevant conflicts of interest to declare.