Andexanet alfa, Recombinant human coagulation Factor Xa

Specification

• Cat#: THP-0048
• Product Name: Andexanet alfa, Recombinant human coagulation Factor Xa
• Description: The product is a recombinant human coagulation Factor Xa that promotes blood coagulation. The product works by binding to Factor Xa inhibitors and prevent them from interacting with endogenous Factor Xa. The product 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 the product is eliminated through the removal of a 34-residue fragment containing Gla: via this truncation, it is unable to bind to membrane surfaces and assemble the prothrombinase complex. It also prevents the product 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 it from converting prothrombin to thrombin.
• Sequences: ANSFLFWNKYKDGDQCETSPCQNQGKCKDGLGEYTCTCLEGFEGKNCELFTRKLCSLDNGDCDQFCHEEQNSVVCSCARGYTLADNGKACIPTGPYPCGKQTLERRKRRKRIVGGQECKDGECPWQALLINEENEGFCGGTILSEFYILTAAHCLYQAKRFKVRVGDRNTEQEEGGEAVHEVEVVIKHNRFTKETYDFDIAVLRLKTPITFRMNVAPACLPERDWAESTLMTQKTGIVSGFGRTHEKGRQSTRLKMLEVPYVDRNSCKLSSSFIITQNMFCAGYDTKQEDACQGDAGGPHVTRFKDTYFVTGIVSWGEGCARKGKYGIYTKVTAFLKWIDRSMKTRGLPKAKSHAPEVITSSPLK
• Species: Human
• Molecular Weight: Not Available
• Purity: >99% by SDS-Page and HPLC analysis
• Cas No: 1262449-58-0
• Formula: Not Available
• Endotoxin Level: <0.001 EU per 1 μg of the peptide by the LAL method
• Biological Activity: 100 mg/10mL
• Storage: Lyophilized protein should be stored at < -20°C, though stable at room temperature for 3 weeks. Reconstituted protein solution can be stored at 2-8 °C for 1 week. Aliquots of reconstituted samples are stable at < -20°C for 3 months.

Pharmaceutical Information

• Pharmaceutical Application: Andexanet alfa
• Applications: The product is indicated for patients treated with Rivaroxaban and Apixaban, when reversal of anticoagulation is needed due to life-threatening or uncontrolled bleeding. The product has not been shown to be effective for, and is not indicated for, the treatment of bleeding related to any Factor Xa inhibitors other than apixaban and rivaroxaban.
• Examples of Clinical Use: Rivaroxaban and Apixaban
• Pharmacodynamics: In vitro, the product was shown to dose-dependently reverse the activity of apixaban, betrixaban, edoxaban, rivaroxaban, enoxaparin and fondaparinux on Factor Xa in human and rat plasma. In a randomized placebo-controlled study of healthy elderly volunteers, co-administration of the product bolus with 5 mg of apixaban twice daily resulted in a reduction of anti-factor Xa activity by 94% compared to 21% among those who received placebo, and thrombin generation was fully restored in 100%. The anti-factor Xa activity was reduced by 92% and thrombin generation was fully restored in 96% of the subjects upon the product bolus administration in subjects receiving 20 mg of rivaroxaban daily. A multicenter, prospective, open-label, single-group study involving elderly patients with acute major bleeding within 18 hours after the administration of a factor Xa inhibitor was performed. In this study, the median anti-factor Xa activity in patients receiving rivaroxaban and apixaban was reduced by 89% and 93%, respectively, upon administration of the product infusion. In dose-ranging studies of healthy volunteers, the anti-FXa activity activity was observed within two minutes after the completion of the bolus administration. Elevation of Tissue Factor (TF)-initiated thrombin generation above the baseline range (prior to anticoagulation) occurred within two minutes following a bolus administration of the product and was maintained throughout the duration of the continuous infusion. The anti-FXa activity returned to the placebo levels approximately 2 hours after completion of a bolus or continuous infusion. In contrast, TFPI activity in plasma was sustained for at least 22 hours following the product administration.
• Mechanism of action: Factor Xa inhibitors promote anticoagulation by binding to both free Factor Xa in plasma and Factor Xa attached to the prothrombinase complex. This ultimately leads to the blockade of thrombin generation or clot formation. Andexanet alfa is a factor Xa decoy that binds to factor Xa inhibitors such as apixaban and rivaroxaban with high affinity and prevents them from binding to endogenous factor Xa. It was also shown to sequester factor Xa inhibitors, leading to reversing their anticoagulant effects and restoring the activity of endogenous factor Xa. Andexanet alfa may also achieve procoagulation via binding and inhibiting the activity of Tissue Factor Pathway Inhibitor (TFPI), which is an endogenous inhibitor of Factor Xa. Inhibition of TFPI by andexanet alfa resulted in a transient increase in the level of prothrombin fragments 1 and 2, thrombin-antithrombin complex and D-dimer. Subsequently, this may result in increased tissue factor-initiated thrombin generation. Since it is a genetically modified variant of human factor Xa, andexanet alfa is not able to cleave and activate prothrombin nor assemble into the prothrombinase complex.
• Affected organisms: Not Available
• Targets: Target 1. Tissue factor pathway inhibitor