Danaparoid Other names: Danaparoid sodium

Danaparoid sodium has been shown both in animal models and in human studies to be an effective antithrombotic substance. At therapeutic doses danaparoid sodium has no or only a minor effect on haemostatic plug formation, platelet function and platelet aggregability with no significant effect on bleeding time at the recommended doses. Occasionally, after high intravenous or subcutaneous doses, a prolonged bleeding time has been observed.

The anticoagulant activity of danaparoid sodium in clotting assays such as prothrombin time, activated partial thromboplastin time, kaolin cephalin clotting time and prothrombin time is small, and characterised by a very flat dose-response curve up to relatively high doses.

The ultimate step in blood coagulation, the fibrinogen-fibrin conversion, is critically dependent on prothrombin generation to which Factor Xa and thrombin contribute substantially. The anticoagulant profile of danaparoid sodium is characterised by a high ratio of anti-factor Xa/antithrombin activities, resulting in an effective inhibition of thrombin generation and thrombus formation. The anti-Xa activity is mediated by antithrombin-III and is not inactivated by endogenous heparin-neutralising factors. The small antithrombin activity is mediated by heparin co-factor II and antithrombin-III. The heparan sulphate fraction with low affinity for antithrombin-III, lacking significant effects on coagulation factors Xa and IIa in vitro, has been shown in animal studies to contribute substantially to the antithrombotic activity by an as yet unexplained mechanism.

Danaparoid sodium shows low cross-reactivity (<10%) with the heparin induced antibody. This can be explained by the absence of heparin in danaparoid sodium and its low degree of sulphation.

Pharmacokinetic studies have primarily been based on the kinetics of relevant anticoagulant activities of danaparoid sodium, because no specific chemical assay methods are available. In animal models the time courses of the thrombin generation inhibitory activity and antithrombotic activities of danaparoid sodium were strongly related.

The absolute bioavailability of danaparoid sodium after subcutaneous administration approaches 100%. In humans the time to reach peak plasma anti-Xa activity levels is approximately 4-5 hours.

The half-lives of elimination of anti-Xa and thrombin generation inhibiting activities of approximately 25 hours and 7 hours respectively, after both subcutaneous and intravenous administration are independent of the dose. Steady-state levels of plasma anti-Xa activity are usually reached within 4-5 days of dosing. Measured by thrombin generation inhibiting activity steady-state levels are reached earlier, i.e. within 1-2 days.

Danaparoid sodium is mainly eliminated by renal excretion and animal experiments indicate that the liver is not involved in its metabolism. In patients with severely impaired renal function the half-life of elimination of plasma anti-factor Xa activity may be prolonged.