Large inter-individual variation of the pharmacodynamic effect of anticoagulant drugs on thrombin generation

Abstract

Anticoagulation by a standard dosage of an inhibitor of thrombin generation presupposes predictable pharmacokinetics and pharmacodynamics of the anticoagulant. We determined the inter-individual variation of the effect on thrombin generation of a fixed concentration of direct and antithrombin-mediated inhibitors of thrombin and factor Xa. Thrombin generation was determined by calibrated automated thrombinography in platelet-poor plasma from 44 apparently healthy subjects which was spiked with fixed concentrations of otamixaban, melagatran, unfractionated heparin, dermatan sulfate and pentasaccharide. The variability of the inhibitory effect of the different anticoagulants within the population was determined using the coefficient of variation, i.e. the standard deviation expressed as a percentage of the mean. The inter-individual coefficients of variation of the endogenous thrombin potential and peak height before inhibition were 18% and 16%, respectively and became 20%-24% and 24%-43% after inhibition. The average inhibition of endogenous thrombin potential and peak height (ETP, peak) brought about by the anticoagulants was respectively: otamixaban (27%, 83%), melagatran (56%, 63%), unfractionated heparin (43%, 58%), dermatan sulfate (68%, 57%) and pentasaccharide (25%, 67%). This study demonstrates that the addition of a fixed concentration of any type of anticoagulant tested causes an inhibition that is highly variable from one individual to another. In this respect there is no difference between direct inhibitors of thrombin and factor Xa and heparin(-like) inhibitors acting on the same factors.

Figure 1.

Effect of anticoagulants on thrombin generation in normal pooled plasma. Thin black line: no anticoagulant added; line of Xs: 200 nM otamixaban; closed dots: 400 nM melagatran; thin gray line: 0.08 U/mL unfractionated heparin; bold black line: 20 μg/mL dermatan sulfate; open dots: 0.9 μg/mL pentasaccharide.

Figure 2.

Dose-response curves of ETP and peak height in normal pooled plasma. Open triangles: % inhibition of peak height; closed dots: % inhibition of endogenous thrombin potential (with 5% error bars). (A) otamixaban (B) melagatran, (C) unfractionated heparin, (D) dermatan sulfate, (E) pentasaccharide.