the mutation of codon 129, CGA→TGA (UGA after transcription), replaces a normal codon for arginine with a termination codon. Type II antithrombin deficiency
Type II antithrombin deficiency is characterized by normal antithrombin levels but reduced antithrombin activity in the blood of affected individuals. It was originally proposed that type II deficiency be further divided into three subgroups (IIa, IIb, and IIc) depending on which antithrombin functional activity is reduced or retained. Subgroup IIa - Decreased thrombin inactivation, decreased factor Xa inactivation and decreased heparin affinity. Subgroup IIb - Decreased thrombin inactivation and normal heparin affinity. Subgroup IIc - Normal thrombin inactivation, normal factor Xa inactivation and decreased heparin affinity.In the revised system of classification again adopted by the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis, type II antithrombin deficiency remains subdivided into three subgroups: the already mentioned type II PE, along with type II RS, where mutations effect the reactive site and type II HBS, where mutations effect the antithrombin heparin binding site. For the purposes of an antithrombin mutational database compiled by members of the Plasma Coagulation Inhibitors Subcommittee of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis, type IIa cases are now classified as type II PE, type IIb cases as type II RS and type IIc cases as type II HBS. Toponyms
Presently it is relatively easy to characterise a specific antithrombin genetic mutation.
Role in disease
Evidence for the important role antithrombin plays in regulating normal blood coagulation is demonstrated by the correlation between inherited or acquired antithrombin deficiencies and an increased risk of any affected individual developing thrombotic disease. Antithrombin deficiency generally comes to light when a patient suffers recurrent venous thrombosis and pulmonary embolism. Acquired antithrombin deficiency
Acquired antithrombin deficiency occurs as a result of three distinctly different mechanisms. The first mechanism is increased excretion which may occur with renal failure associated with proteinuria nephrotic syndrome. The second mechanism results from decreased production as seen in liver failure or cirrhosis or an immature liver secondary to premature birth. The third mechanism results from accelerated consumption which is most pronounced as consequence of severe injury trauma but also may be seen on a lesser scale as a result of interventions such as major surgery or cardiopulmonary bypass. Inherited antithrombin deficiency
The incidence of inherited antithrombin deficiency has been estimated at between 1:2000 and 1:5000 in the normal population, with the first family suffering from inherited antithrombin deficiency being described in 1965. Subsequently, it was proposed that the classification of inherited antithrombin deficiency be designated as either type I or type II, based upon functional and immunochemical antithrombin analyses. Maintenance of an adequate level of antithrombin activity, which is at least 70% that of a normal functional level, is essential to ensure effective inhibition of blood coagulation proteases. Typically as a result of type I or type II antithrombin deficiency, functional antithrombin levels are reduced to below 50% of normal.