Figure 1. Clot formation. Fibrin generation involves a series of consecutive activation events, where inactive proteins are converted to active ones after cleavage by enzymes called proteases. Each activation results in the generation of a new protease which now acts on a subsequent protein, in a cascade-like fashion, that ultimately produces fibrin. Most of these proteases require cofactors to function. Anticoagulants (e.g. protein C and protein S) act to turn off coagulation. The targets for these inhibitors are indicated by a dashed line. The fibrin clot is transitory and eventually disappears. Clot dissolution proceeds by a complex process called fibrinolysis, followed by remodelling of the endothelium to restore the tissue to its original state. Enzymes: VII, factor VII; VIIa, activated factor VII; IXa, activated factor IX; Xa, activated factor X; XIa, activated factor XI; XIIIa, activated factor XIII; APC, activated protein C; PT, prothrombin; T, thrombin. Cofactors: Va, activated factor V; VIIIa, activated factor VIII; PS, protein S; TF, tissue factor. Inhibitors: AT, antithrombin; TFPI, tissue factor pathway inhibitor. FN, fibrinogen.

Figure 2. The haemostatic response to injury. When the endothelium is disrupted by injury, tissue factor (which is not present on platelets, or on endothelial cells under normal physiological conditions) is exposed to factor VIIa to initiate the complex series of reactions, described in Figure 1, which give rise to fibrin. The fibrin monomer, which is composed of three different proteins, undergoes polymerization and binds with platelets to the subendothelium to form a haemostatic plug, called the thrombus. Platelets normally circulate in a resting form but are activated at the site of injury, releasing many different chemicals from granules inside the cell (indicated here as grains in the circulating platelets) which are important to platelet adhesion, aggregation and coagulation. Clot formation is restricted to the site of injury by a number of regulatory mechanisms. One example shown here is the activation of protein C on endothelial cells located away from the site of injury. Details for the reactions are described in the text.

Figure 3. Structure of factor IX. Factor IX that circulates in blood has 415 amino acids and the intracellular form (most of the clotting factors are synthesized in liver) has an additional 46 amino acids (indicated as –46 to –1). During secretion, these 46 amino acids are removed by two different proteases, as indicated by the arrows. Factor IX is processed further by factor XIa, which cleaves at the two sites indicated by the arrows to release an activation peptide and to generate activated factor IX (factor IXa). The shaded bars show several bonds, called disulfide bonds, that help stabilize the three-dimensional structure of factor IX. As described in the text, three different kinds of amino acid modifications occur in factor IX: the addition of carbohydrates at six locations (indicated by circles and diamonds), the addition of a hydroxyl group to one amino acid (in the growth factor domain) and carboxylation of 12 amino acids (indicated by the ‘Y’s in the Gla domain). The three circled letters represent key residues required for factor IXa activity.