ON THE ACTION OF HEPARIN AND ITS RELATION TO THROMBOPLASTIN

Abstract

The speed of clotting is expressed by the equation: Clotting time = k/(concentra-tion of thrombin). With constant temp. and pH the correction factor, k, is dependent upon the concn. of electrolytes, decreasing as the concn. of neutral salts is increased. The linear ratio is destroyed even by the addition of minute amounts of heparin. Therefore, the direct proportion observed between the clotting time of dog, rabbit, and human plasma, and the concn. of thrombin, indicates that the blood of these species contains no demonstrable amounts of heparin. Guinea pig plasma does not show this direct relationship, and fails to clot with high dilutions of thrombin. Heparin itself is not an antithrombin since it does not inhibit the clotting of purified fibrinogen by thrombin, but in accordance with Howell, produces when added to plasma a true antithrombin. For the production of this antithrombin the presence of neutral salts is necessary since heparin has little antithrombic action in plasma from which electrolytes have been removed by dialysis against distilled water. Thromboplastin does not directly neutralize heparin, for even when present in excess, the clotting of prothrombin-free plasma (aluminum hydroxide treated) by thrombin is progressively delayed and eventually inhibited by increasing concns. of heparin. The acceleration in clotting of recalcified plasma by thromboplastin is antagonized by heparin, but this effect is much more marked in human than in rabbit plasma. Since the latter contains a much higher concn. of prothrombin, the deduction is made that thromboplastin antagonizes the anticoagulative action of heparin by accelerating the conversion of prothrombin to thrombin and that the latter is the true antagonist of the inhibitory substance produced by heparin in plasma.