IXa

Factor IXa (FIXa) is the activated form of coagulation factor IX, a vitamin K–dependent serine protease that plays a central role in blood coagulation. In the presence of calcium and phospholipid surfaces, FIXa participates in the intrinsic tenase complex with its cofactor factor VIIIa, promoting the conversion of factor X to factor Xa and thereby contributing to thrombin generation and clot formation. Activation to FIXa can occur via factor XIa in the intrinsic pathway or via the tissue factor–VIIa complex of the extrinsic pathway.

Mechanistically, FIXa is the catalytic subunit of the tenase complex. The FIXa–VIIIa complex binds calcium and phospholipid membranes, aligning factor X for efficient cleavage to Xa. This cascade ultimately leads to the formation of thrombin and fibrin. Factor IX itself is synthesized in the liver as a zymogen and contains a gamma-carboxyglutamate-rich domain that facilitates binding to phospholipid surfaces, as well as epidermal growth factor–like and serine protease domains that carry out proteolysis.

Regulation of FIXa activity occurs through natural inhibitors such as antithrombin, whose activity is enhanced by heparin. Other regulatory pathways, including the protein C system and TFPI, modulate overall coagulation flux, helping to limit excessive clot formation.

Clinically, congenital factor IX deficiency causes Hemophilia B (Christmas disease), characterized by spontaneous or traumatic bleeding and a prolonged activated partial thromboplastin time (aPTT). Laboratory assessment of FIX activity guides diagnosis and management. Treatment involves factor IX replacement therapy, using plasma-derived or recombinant concentrates; inhibitors to factor IX can complicate management, and gene therapy research continues to explore long-term options.