Molecular basis of inherited human antithrombin deficiency

Abstract

Figures 1 and 4 summarize the various AT mutations that have been described. The molecular elucidation, over the past decade, of the various AT deficiency types has provided important new insights into functional-structural relationships of AT. This knowledge, together with data provided by monoclonal antibodies and x-ray crystallographic studies of related molecules, has provided important new insights as to how the AT molecule functions in vivo. Finally, such knowledge might, in the foreseeable future, lead to the production of AT molecules that are specifically genetically engineered to be of use in a variety of clinical situations.

Intrapartum placement of an inferior vena cava filter for a woman with hereditary antithrombin III deficiency: Its role in the prevention of fatal pulmonary embolism

“…Antithrombin III is an α‐globulin with a molecular weight of 65 000, and plays a role in the regulation of hemostasis by inactivating thrombin and other activated coagulation factors. The genes that regulate the production of AT‐III are on chromosome 1, and approximately 40 mutations have been reported 1 . Hereditary deficiency of AT‐III is an uncommon hypercoagulable state, and the risk of thrombosis is even higher during pregnancy and puerperium, with an incidence of over 70% in the absence of anticoagulant therapy 2–4 .…”

Deletion mutagenesis of heparin cofactor II: defining the minimum size of a thrombin inhibiting serpin

“…Thirdly, Tollefsen and colleagues had previously shown, using recombinant forms of the highly homologous human AT expressed in bacteria, that the amino-terminus of the protein was important for glycosaminoglycan-accelerated thrombin inhibition. The proximity of the reactive centre of the molecule (Leu425-Ser426) to the carboxyl terminus, and the abundance of naturally occuring mutants that abrogate serpin function found in this area [12], was also a consideration in choosing to perform deletion analysis on the amino-terminal end of the molecule.…”

“…While much has been learned concerning the structure and function of both active and inactive serpins, the molecular details of how serpins function remain to be worked out. Analysis of point mutations, both natural and engineered, has contributed to our understanding of the importance of the reactive centre region, and to other regions of serpin molecules involved in cofactor interactions (for reviews, see [12,13]). We have chosen to use deletion mutagenesis to map the minimum essential form of HCII that is sufficient for complex formation with thrombin.…”

Uses of antithrombin III concentrate in congenital and acquired deficiency states

“…Congenital AT 111 deficiency, inherited in an autosomal dominant fashion, is characterized by recurrent thromboembolic episodes occurring at an early age, positive family history, and heparin resistance, defined as reduced responsiveness to heparin using in vitro measurements of co-agulation (e.g., activated partial thromboplastin time [APTT]). 14J5 According to Blajchman et a1., 16 AT I11 deficiency can be classified into four types: in Type I, there is a reduction in AT I11 synthesis; me 2 and m e 3 represent qualitative defects in either the TAT interaction or heparin cofactor activity (the ability of heparin to catalyze AT I11 activity); and m e 4 encompasses all other unclassifiable cases. Because most persons with congenital AT I11 deficiency are heterozygous, with only a few homozygous persons having been reported, classification schemes do not generally address zygosity.…”