Prothrombin (factor II, FII) is a vitamin K-dependent glycoprotein produced in the liver. The concentration of prothrombin in plasma is ~100 micrograms/milliliters (~1.4 micrometers). Prothrombin is a single chain molecule with a molecular weight of 72 kDa. Prothrombin consists of a catalytic domain followed by two kringle structures and an amino-terminal domain containing 10 gamma-carboxy-glutamic acid (gla) residues. These gla residues allow prothrombin to bind to membranes that contain acidic phospholipids in a calcium dependent manner. The binding to membranes is required for effective presentation of prothrombin as a substrate for activation by the prothrombinase complex, which consists of activated factor X, activated cofactor V and calcium on phospholipid membrane. Activation by prothrombinase occurs by sequential cleavage after residue Arg³²⁰then after Arg²⁷¹to produce the active protease alpha-thrombin (37 kDa) and the byproduct prothrombin fragment 1.2 (35 kDa). The product thrombin further cleaves prothrombin fragment 1.2 after residue Arg¹⁵⁵ into individual prothrombin fragments 1 and 2. The activity of alpha-thrombin in plasma is inhibited primarily by antithrombin and the rate of inhibition is accelerated 1000-fold in the presence of optimal concentrations of heparin. Other physiological inhibitors of thrombin in the absence of heparin include alpha2-macroglobulin and alpha1-antitrypsin.