indication

Approved for: (1) prophylaxis of VTE for up to one month post surgery in patients undergoing orthopedic surgery of the lower limbs such as hip fracture, hip replacement and knee surgery; (2) prophylaxis of VTE patients undergoing abdominal surgery who are at high risk of thromboembolic complications (e.g. patients undergoing abdominal cancer surgery); (3) treatment of acute DVT and PE; (4) management of UA and NSTEMI for the prevention of death and subsequent myocardial infarction (MI); and (5) management of STEMI for the prevention of death and myocardial reinfarction in patients who are managed with thrombolytics or who are initially to receive no form of reperfusion therapy. Fondaparinux should not be used as the sole anticoagulant during percutaneous coronary intervention (PCI) due to an increased risk of guiding catheter thrombosis.

pharmacology

Fondaparinux binds specifically to the natural anticoagulant factor, ATIII. Binding to ATIII potentiates the neutralizing action of ATIII on Factor Xa 300-times. Neutralization of Factor Xa decreases the conversion of prothrombin to thrombin, which subsequently decreases the conversion of fibrinogen to fibrin (loose meshwork). The decrease in thrombin also decreases the activation of Factor XIII, which decreases the conversion of fibrin in its loose meshwork form to its stabilized meshwork form. Disruption of the coagulation cascade effectively decreases the formation of blood clots. Fondaparinux does not inactivate thrombin (activated Factor II). According to the manufacturer, fondaparinux has no known effect on platelet function. In studies comparing fondaparinux to enoxaparin, decreases in platelet levels were observed in similar numbers of patients from both groups (2-5%) (PMID 11794148, 12049860). At the recommended dose, Fondaparinux does not affect fibrinolytic activity or bleeding time. There is no antidote for fondaparinux. Monitoring of the anticoagulant activity of fondaparinux is not generally required. The anti-factor Xa assay may be used to monitor therapy in special populations such as those with renal impairment or who are pregnant. Complete blood count (CBC) and kidney function should be monitored during treatment.

mechanism of action

The antithrombotic activity of fondaparinux is the result of ATIII-mediated selective inhibition of Factor Xa. By selectively binding to ATIII, Fondaparinux potentiates (about 300 times) the neutralization of Factor Xa by ATIII. Neutralization of Factor Xa interrupts the blood coagulation cascade and thus inhibits thrombin formation and thrombus development. It is thought that fondaparinux is unlikely to induce thrombocytopenia via a heparin-induced thrombocytopenia (HIT)-like mechanism given its chemical structure (PMID 19825921). As a result, fondaparinux has been used as an alternative anticoagulant in heparin-induced thrombocytopenia (HIT) patients (PMID 19737996, 19432027, 18217156). However, it is important to note that rare cases of HIT have been reported in patients treated with fondaparinux (PMID 20351685, 20351686).

toxicity

As with other anticoagulants, the main concern is increased bleed risk. The risk of hemorrhage may increase with decreased renal function, body mass less than 50 kg, and moderate to severe hepatic function.

biotransformation

Not metabolized

absorption

100% bioavailability when administered subcutaneously

half life

17-21 hours

route of elimination

In individuals with normal kidney function, fondaparinux is eliminated in urine mainly as unchanged drug.

drug interactions

Drotrecogin alfa: Drotrecogin alfa may increase the adverse effects of fondaparinux, resulting in excessive bleeding. Concomitant use should be avoided.

Ginkgo biloba: Additive anticoagulant/antiplatelet effects may increase bleed risk. Concomitant therapy should be avoided.