962 PHYSIOLOGY 



the interaction of the two substances was simply a first stage and that thrombin 

 was formed in this process for the subsequent conversion of the fibrinogen into 

 fibrin. 



Attention, however, was largely diverted from Wooldridge's work by the 

 discovery of the necessity of calcium salts for clotting. Green had already 

 shown that the clotting of many forms of salt plasma could be hastened by the 

 addition of calcium sulphate, whereas the coagulation of serous fluids was not 

 affected by this salt. Green suggested that possibly a zymogen of the ferment 

 was activated by the calcium salt. The absolute necessity of the presence of 

 this salt was first demonstrated by Arthus and Pages (1890) on oxalate and 

 fluoride plasma. At first Arthus was inclined to regard the part played by 

 calcium salts in the coagulation of the blood as analogous in all respects to that 

 played in the coagulation of milk by rennet, and suggested that the conversion of 

 fibrinogen into fibrin was actually the combination of fibrinogen with calcium 

 salts, the combination being effected by the agency of the ferment. It was shown, 

 however, by Pekelharing that the power of lime salts to produce clotting in 

 oxalate plasma was annulled if the body precipitable by cold had been previously 

 removed, and Hammarsten proved conclusively that the action of calcium 

 salts was on this prothrombin and not on the fibrinogen, careful analyses of 

 fibrinogen and fibrin respectively giving practically equal figures for calcium. 

 Hammarsten pointed out moreover that fibrin ferment would convert fibrinogen 

 into fibrin in the total absence of soluble calcium salts and even in the presence 

 of a slight excess of oxalate. 



Later experiments have had reference chiefly to the nature of the pro- 

 thrombin precipitate and to the question of the origin of the fibrin ferment from 

 the blood-plasma. Recent advances in the subject were much facilitated by 

 the discovery by Delezenne that birds' blood could be prevented from clotting 

 by the simple expedient of collecting it free from any contact with the tissues. 

 A careful study of this blood and a comparison of its behaviour with that of 

 other forms of uncoagulable plasma by Fuld and Spiro, and especially by 

 Morawitz, have resulted in the further separation of the precursor of fibrin into 

 two substances, thrombokinase and thrombogen. Further investigations by 

 Nolf have dealt especially with the question of the interaction which is con- 

 tinually taking place between the vessel wall and the contained blood, and which 

 may result, according to the circumstances, in the diminution or increase in the 

 coagulability of the blood. According to Nolf the essential factors in the pro- 

 duction of blood-clotting are three proteins, namely, fibrinogen, thrombogen, 

 and thrombozym. The two former are produced in the liver, while the throm- 

 bozym is formed from the leucocytes. The clotting depends, not on a ferment 

 action, but on a mutual interaction and precipitation of colloids with, as a result, 

 either fibrin or thrombin. Thrombin differs from fibrin merely in containing 

 less fibrinogen. For this reaction to take place the presence of calcium is 

 necessary as well as certain thromboplastic substances which act as centres of 

 precipitation. The fluid condition of the blood in the vessels depends on the 

 presence of an an ti thrombin formed in the liver. Nolf thus agrees with Wool- 

 dridge in regarding tlirombin as a product of coagulation rather than a cause. 

 Thrombin, according to him, is merely an unsaturated compound which is 

 capable of taking up or uniting with more fibrinogen to form fibrin. Nolf would 

 regard the formation of fibrin as an important preparatory step in the nutrition 

 of the cells. He compares these actions occurring in the blood to the actions 

 of digestive ferments on proteins. Just as casein is first precipitated and then 

 digested by pepsin, so fibrinogen is first precipitated as fibrin by union with 

 thrombozym and thrombogen. This fibrin is then hydrolysed and dissolved by 

 the further action of the thrombozym, which he regards as essentially proteolytic 



