Protein Thrombokinase and Lipoid Thromboplastin as Distinct Factors with Complementary Functions *

Two classes of biologic agents can accelerate the production of thrombin from partially purified prothrombin. One class is well represented by platelets, the other by a factor obtainable from the plasma globulins. Representatives of both classes are found not only in blood, but also in crude tissue extracts. These two classes of agents are distinct; and they serve different functions in the clotting process. The two groups of factors as studied in this laboratory"'18 correspond essentially to two old factors; and these factors will be called by their old, familiar names. When Morawitz" introduced the term "thrombokinase" in 1904, he likened the activation of prothrombin by thrombokinase to the activation of trypsinogen by enterokinase. Pursuing this analogy, he considered the possibility that thrombokinase, like enterokinase, was an enzyme. Moreover, he explicitly recognized that thrombokinase was available in ordinary oxalated plasma.'2 Several further inferences made by Morawitz may or may not have been correct; nevertheless, his brilliant theory cannot be ignored. And it would be hard to deny that a basic property for defining thrombokinase, as conceived by him and as construed by later authors, was its capacity to activate prothrombin. When Nolf'" introduced the term "thromboplastic substances" in 1908, he considered these substances to be "only adjuvants." He did not propose that they activated prothrombin. In 1911-1912, Howell"' specifically denied that thromboplastin was a direct activator of prothrombin; and he further stated ". . . thrombokinase in the sense used by Morawitz does not exist...." To Howell, thromboplastin was a factor found in preparations of brain cephalin and in platelets; and it functioned by "neutralizing" antithrombin. In 1935, Howell" reiterated these views, but identified the anticoagulant as heparin rather than antithrombin. After thromboplastin has disposed of heparin, "prothrombin is activated to thrombin by calcium without the cooperation of an organic kinase." Thrombokinase and thromboplastin, originally conceived so differently, have sometimes been treated as if they were identical. There have been many reasons. The problem has long been obscured by a haze of unproven assumptions. Perhaps the most misleading of these has been the notion that