Antithrombin: Its physiological importance and role in DIC

Antithrombin (AT) is a single-chain glycoprotein in plasma and belongs to t he family of the serpins. It is synthesized in liver parenchymal cells, and its plasma concentration is between 112-140 mg/L. AT is a unique inhibitor of the clotting system and neutralizes most of the enzymes generated durin g activation of the clotting cascade, especially thrombin, factors Xa and M a. Equimolar, irreversible complexes are formed between AT and the enzymes, The interaction between AT and the activated clotting factors is at least 1,000-fold increased in the presence of heparins. Heparins bind to multiple sites of the AT molecule resulting in a steric reconfiguration. Heparins c ontain a specific pentasaccharide unit which is the minimum requirement for AT binding. The glycosaminoglycan (GAG) heparan sulfate found on endotheli al cell surfaces also contains this pentasaccharide and can thus "activate" AT. It is believed that much of the physiological inactivation of enzymes by AT occurs on the endothelium, mediated by heparan sulfate. The binding o f AT to the GAGs also releases prostacyclin which possesses strong antiinfl ammatory properties. Deficiencies of AT are inherited or acquired. Only acquired defects due to increased consumption are discussed, most notably AT in DIG, especially DIC in sepsis. During acute DIG, clotting factors and inhibitors are consumed faster than they can be reproduced. This consumption of AT is of great sign ificance in DIC and sepsis, and plasma AT levels predict outcome. AT levels drop early in sepsis and laboratory signs of DIC can already be found in p atients with SIRS and early sepsis. The important role of AT in DIC and sep sis is the basis for considering antithrombin concentrates as an additional therapeutic modality.