852 PHYSIOLOGY 



imagined that the interaction of thrombokinase and thrombogen resulted in the direct 

 production of fibrin as well as ferment, instead of recognising that 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 fluid 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 combina- 

 tion being effected by the agency of the ferment. It was shown, however, by Pekel- 

 haring 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 prothrombin 

 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 continually 

 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 production of blood-clotting 

 are three proteins, namely, fibrinogen, thrombogen, and thrombozym. The two former 

 are produced in the liver, while the thrombozym 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 vessel depends on the presence 

 of antithrombin formed in the liver. Nolf thus agrees with Wooldridge in regarding 

 thrombin 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 import- 

 ant 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 

 in character. That the whole blood does not coagulate within the vessels he explains 

 by assuming that the cells of the blood and tissues are covered normally with an ultra- 

 microscopic layer -of fibrin. This forms a neutral surface, like a paraffined vessel, 

 which has no thromboplastic effect upon the plasma. 



According to Mellanby the prothrombin in the plasma is constantly associated with 

 the fibrinogen. It may be converted to thrombin either by the action of calcium and 

 thrombokinase, or by the action of calcium and alkali, or possibly by the action of 



