Antithrombin: Inhibition of Thrombin and Autoprothrombin C (F-Xa) as a Mutual Depletion System

Antithrombin was already recognized at the beginning of this century on the basis that thrombin gradually lost its clotting activity in blood and serum (60). Contejean in 1895 (15) recognized that there occurred a considerable increase in anticoagulant activity with peptone intoxication in dogs. Thrombin inactivator was subsequently considered by Bordet and Gengou (9), Morawitz (51), and Muraschew (52) indepen dently in 1904. In 1901 Bordet and Gengou (8) had demonstrated an antithrombic substance in guinea pigs immunized with rabbit sera, but they assumed the reaction was a specific immune response. Bordet and Gengou (9) also suspected that another substance became inactivated. We translate their statement from the French: "When the serum is stored, the power to coagulate fibrinogen in an oxalated medium de creases more manifestly and more rapidly than the production-exciting property." This latter property must have been autoprothrombin 0 (F-Xa). Mellanby (45), workillg with chicken plasma in 1909, was the first to demonstrate the presence of an excess of antithrombic activity ("antifibrin-ferment" ) in the cir culating blood relative to thrombin clotting activity. These observations were later supported by Gasser (22). In addition, Mellanby also demonstrated that acetone could destroy this antithrombic activity. He also studied the time course of inhibition, ob serving a very slow rate of inactivation during the approach to a relatively constant level of activity. Rettger (58), Collingwood and MacMahon (13, 14), Lansberg (39), Howell (27-29), Whipple (92, 93), and Weymouth (91) were also actively engaged at this time. In his Harvey