Description of Prothrombin – Factor II

Prothrombin (factor II, F.II) is a vitamin K-dependent glycoprotein produced in the liver.  The concentration of prothrombin in plasma is ~100 μg/ml (~1.4 μM).  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 γ-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 Arg320 then after Arg271 to produce the active protease α-thrombin (37 kDa) and the by-product 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 α-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 α2macroglobulin and alpha-1-antitrypsin ¹-³.

References and Reviews

1. Mann KG; Prothrombin and Thrombin; in Hemostasis and Thrombosis, 3rd Edition, eds. RW Colman, J Hirsh, VJ Marder and EW Salzman, pp. 184-199, J.B. Lippincott Co., Philadelphia PA, USA, 1994.
2. Mann KG; Prothrombin; Methods in Enzymology 45, pp 123-156, 1976.
3. Downing MW, Bloom JW, Mann KG; Comparison of the Inhibition of Thrombin by Three Plasma Protease Inhibitors; Biochemistry 17, pp 2649-2653, 1978.