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

Unfractionated and Low-Molecular-Weight Heparin and the Phosphodiesterase Inhibitors, IBMX and Cilostazol, Block Ex Vivo Equid Herpesvirus Type-1-Induced Platelet Activation

“…This can likely be explained by individual differences in coagulation factor concentrations, which are required by the virus to generate thrombin. A similar biological variability in the suppression of thrombin generation by various drugs, including heparin, has been reported in healthy human volunteers (29). This variability can be partly explained by documented differences between healthy individuals in thrombin generation (30), potentially due to variable coagulation factor concentrations and platelet procoagulant activity (31).…”

Rivaroxaban and warfarin achieve effective anticoagulation, as assessed by inhibition of TG and in-vivo markers of coagulation activation, in patients with venous thromboembolism

“…The ETP is considered to depend on the propagation and termination phases of the TG process and has been reported to show decreased sensitivity to direct Xa inhibitors during in-vitro studies [24,25]. This is assumed to be due to inhibition of the positive feedback action of FXa on factor VII, which results in prolongation of the lag time and a slow start of prothrombinase complex formation and hence, a longer time to peak TG [26,27]. The TG test, as a global measure of anticoagulation, can assess the anticoagulant effects of both rivaroxaban and warfarin, and effects on the ETP should be assessed in combination with the other TG parameters.…”

Rivaroxaban pharmacodynamics in healthy volunteers evaluated with thrombin generation and the active protein C system: Modeling and assessing interindividual variability

“…15–22,26–31 However, some persistent issues remain regarding the most appropriate experimental conditions among different methods, including TF concentrations . Moreover, data regarding the magnitude of TG parameter interindividual variability in subjects receiving direct Xa inhibitors are scarce …”