Abstract 2219: Biochemical and Pharmacological Validation of the Antithrombotic Anticoagulant Potential of Fondaparinux, Enoxaparin and Otamixaban as it Impacts the Management of ACS
There is a considerable debate on the use of fondaparinux (F) in ACS where clinical efficacy is shown but catheter clot formation is reported. Studies were conducted to compare F with a low molecular weight heparin (enoxaparin, E), and a synthetic direct XaI (otamixaban, O) with high anti-FXa activity. Native blood from normals (n = 30) and ACS patients (n = 30) were supplemented with graded amounts of the drugs to study their comparative actions in simulated arterial thrombosis systems. To mimic the hemostatic activation in ACS and during interventional procedures, studies with the celite activated whole blood ACT and a tissue factor/celite activated ACT showed no anticoagulant activity by F and E up to 12.5 ug/ml but significant activity by O at <0.1 ug/ml. O and E but not F inhibited the formation of microparticles in tissue factor activated whole blood. Thrombin and FXa mediated fibrino-kinetics in plasma was strongly inhibited by O followed by E with no effect by F. To mimic contact system activation as induced by indwelling catheters, the glass activated whole blood clotting assay showed no anticoagulant activity with F but concentration dependent activity with E and O in which O was markedly stronger. Thrombin generation induced via the extrinsic and intrinsic pathways as detected by thrombin, F1.2, TAT and FPA was reduced by E, markedly reduced by O, but not affected by F up to 10 ug/ml. In the plasma-based PT and aPTT O produced a pronounced inhibition of clotting whereas E had a weak effect and F had no effect. O inhibited platelet activation as determined by thromboxane generation and serotonin release, E produced a slightly weaker effect, F did not have any effect. E produced a pronounced inhibition of the generation of TAFIa whereas O had a weak effect but F had no effect. The results in the normal and ACS patients blood systems followed similar trends. In conclusion, these results demonstrate a weak anticoagulant and antithrombotic nature of F in comparison to E and O which may explain the observed catheter clots suggesting that F is not a universal anticoagulant. F may involve other endogenous mechanisms beyond the AT mediated FXa inhibitory effects studied here or that it is potentiated by interactions with simultaneously used drugs (heparin, aspirin, clopidogrel).