Some factors influencing the anticoagulant action of heparin.

IT has been generally assumed that the anticoagulant action of heparin is due to direct combination with prothrombin, thrombin, or kinase. The chief experimental facts on this point have been confirmed by Mustard & Jaques [1937] and may be summarized as follows. When citrated plasma and thrombin are used to test the action of heparin, the heparin acts as an antithrombin [Howell, 1925]. When kinase is added, it neutralizes the action of heparin. It is thus possible to "titrate " heparin against kinase [Fischer & Astrup, 1935]. If the prothrombin is removed from the plasma with alumina gel, the heparin is still active but the corresponding action of kinase is largely abolished [Quick, 1936]. Heparin thus acts as an antikinase indirectly. Its anticoagulant action is that of an antithrombin. It has been frequently suggested (originally by Howell) that heparin also acts as an antiprothrombin, and recently Brinkhous et al. [1939] have obtained direct evidence of such an antiprothrombin action. In this paper, however, only the antithrombin action of heparin will be considered. The question of the anticoagulant action of heparin is complicated by the influence of various factors outside the known clotting system. Mellanby [1934] concluded that the presence of neutral salts was necessary for the action of heparin: Howell & Holt [1918] concluded that the serum proteins, particularly the euglobulin fraction, were necessary. We have not found any evidence that salt is necessary for the action of heparin but have confirmed the work of Howell & Holt and of Quick, that the presence of serum protein is essential