Clinical review: Molecular mechanisms underlying the role of antithrombin in sepsis

Antithrombin is a vitamin K independent glycoprotein and an essential inhibitor of thrombin and other serine proteases such as factors Xa and IXa [1]. Acquired antithrombin deficiency is more frequent than congenital deficiency and develops primarily through increased consumption or loss of antithrombin. The reduced plasma level in acquired deficiency is a strong predictor of a severe disease course, particularly in patients who have suffered trauma or severe sepsis. Increased consumption of antithrombin occurs primarily in disseminated intravascular coagulation (DIC) [2-8]. A diagnosis of DIC is made after taking into consideration the triggering disease, clinical picture, and unambiguous and striking hemostatic findings such as a drop in thrombocytes, loss of antithrombin activity, increased concentrations of D-dimers or fibrin monomers [7].Based on the assumed inhibition by antithrombin of activated clotting factors in the circulating vascular system, concentrated human plasmatic antithrombin was administered in the setting of DIC in isolated cases [2,4-6,8], in animal experiments [6,9-13], and in clinical studies [14-18] with the aim of interrupting the complex cycle of DIC and preventing multiple organ failure. In these studies the duration of DIC was significantly shortened and organ functions were improved, but no significant reduction in mortality in the antithrombin groups was achieved. Proof of reduced lethality from DIC with administration of concentrated human plasmatic antithrombin in prospective controlled clinical studies has not yet been reported.The largest number of patients with acquired antithrombin deficiency treated with human plasmatic antithrombin in a prospective controlled clinical study can be found in the KyberSept trial [19]. Patients with severe sepsis were recruited for this study independent of the cause or duration of sepsis and irrespective of the presence or absence of DIC. Therapeutic doses of heparin were not permitted because of