However prior to the use of modern characterisation techniques investigators named mutations for the town or city where the individual suffering from the deficiency resided i.e. the antithrombin mutation was designated a toponym. Modern mutational characterisation has since shown that many individual antithrombin toponyms are actually the result of the same genetic mutation, for example antithrombin-Toyama, is equivalent to antithrombin-Kumamoto, -Amien, -Tours, -Paris-1, -Paris-2, -Alger, -Padua-2 and -Barcelona. Medical uses
Antithrombin is used as a protein therapeutic that can be purified from human plasma or produced recombinantly (for example Atryn, which is produced in the milk of genetically modified goats). It is approved by the FDA as an anticoagulant for the prevention of clots before, during, or after surgery or birthing in patients with hereditary antithrombin deficiency.It has been studied in sepsis to reduce diffuse intravascular coagulation and other outcomes. It has not been found to confer any benefit in critically ill people with sepsis. Cleaved and latent antithrombin
Cleavage at the reactive site results in entrapment of the thrombin protease, with movement of the cleaved reactive site loop together with the bound protease, such that the
loop forms an extra sixth strand in the middle of beta sheet A. This movement of the reactive site loop can also be induced without cleavage, with the resulting crystallographic structure being identical to that of the physiologically latent conformation of plasminogen activator inhibitor-1 (PAI-1).
For this reason the conformation of antithrombin in which the reactive site loop is incorporated uncleaved into the main body of the protein is referred to as latent antithrombin. In contrast to PAI-1 the transition for antithrombin from a normal or native conformation to a latent conformation is irreversible. Native antithrombin can be converted to latent antithrombin (L-antithrombin) by heating alone or heating in the presence of citrate. However, without extreme heating and at 37 °C (body temperature) 10% of all antithrombin circulating in the blood is converted to the L-antithrombin over a 24-hour period. The structure of L-antithrombin is shown in Figure 6. The 3-dimensional structure of native antithrombin was first determined in 1994. Unexpectedly the protein crystallized as a heterodimer composed of one molecule of native antithrombin and one molecule of latent antithrombin. Latent antithrombin on formation immediately links to a molecule of native antithrombin to form the heterodimer, and it is not until the concentration of latent antithrombin exceeds 50% of the total antithrombin that it can be detected analytically. Not only is the latent form of antithrombin inactive against its target coagulation proteases, but its dimerisation with an otherwise active native antithrombin molecule also results in the native molecules inactivation.