Andexanet alfa

Andexanet alfa is a recombinant human coagulation Factor Xa that promotes blood coagulation. It was developed by Portola Pharmaceuticals and was approved in in May 2018. It is marketed as Andexxa for intravenous injection or infusion and is indicated for the reversal of anticoagulation in combination with rivaroxaban and apixaban in cases of life-threatening or uncontrolled bleeding. Rivaroxaban and apixaban are Factor Xa inhibitors that promote anticoagulation in situations where blood clotting is unfavourable, such as in deep vein thrombosis and pulmonary embolism. However, the use of these agents is associated with a risk for uncontrollable bleeding episodes that can lead to can cause serious or fatal bleeding. Andexanet alfa is currently under regulatory review by the European Union and is undergoing clinical development in Japan .

Andexanet alfa works by binding to Factor Xa inhibitors and prevent them from interacting with endogenous Factor Xa. It displayed high affinity (0.53–1.53 nmol/L) to apixaban, betrixaban, edoxaban and rivaroxaban . However, the effectiveness of andexanet alfa on treating bleeding related to any FXa inhibitors other than apixaban and rivaroxaban was not demonstrated, thus such use is limited . Its pharmacokinetic properties are not reported to be affected by factor Xa inhibitors . Andexanet alfa retains the structural similarity to that of endogenous human factor Xa, but exists in its mature functional form without the need for activation via the intrinsic or extrinsic coagulation pathways and remains catalytically inactive due to structural modification . The procoagulation potential of andexanet alfa is eliminated through the removal of a 34-residue fragment containing Gla: via this truncation, andexanet alfa is unable to bind to membrane surfaces and assemble the prothrombinase complex . It also prevents andexanet alfa from taking up space on phospholipid surface membranes, so that native FXa may bind and assemble the prothrominase complex . The amino acid residue modification from serine to alanine in the binding site of the catalytic domain allows more effective binding to FXa inhibitors and deters the andexanet alfa from converting prothrombin to thrombin .