BLOOD CLOTTING 103 



Thrombin does not exist in blood plasma, for if a clean and paraffined 

 glass tube is inserted into an artery and the blood collected under al- 

 cohol, the precipitate after standing a few weeks will yield no thrombin 

 when triturated with water. Quite clearly, therefore, the thrombin is 

 produced at the time the blood clots, and the question arises, What is 

 it produced from? It will be remembered that, when the blood is ex- 

 amined under the microscope during the clotting process, the fibrin 

 threads are seen to- start from foci which correspond to the blood plate- 

 lets. It would appear therefore that the thrombin must be derived from 

 some substance that is shed forth from the platelets during the disin- 

 tegration which they undergo shortly after the blood is shed. The sub- 

 stance is called prothrombin. The platelets or their precursors, the 

 megacaryocytes of red bone marrow, are probably not its only source, 

 for clotting may occur in the complete absence of platelets, when it 

 appears to come from the leucocytes. Prothrombin appears plentifully 

 in the fluid used to perfuse red bone marrow outside the body (Drinker 

 and Drinker 9 ). 



To sum up what we have so far learned, it may be stated that the 

 process of clotting starts with the disintegration of blood platelets and 

 probably of leucocytes, as a result of which there is shed forth into the 

 plasma a substance called prothrombin, which immediately afterward 

 becomes activated or converted into thrombin. The thrombin then at- 

 tacks a protein present in plasma called fibrinogen, producing from it in 

 thread-like form the insoluble protein, fibrin. But this does not com- 

 plete the history, for at least two other important factors come into 

 play; the one is the presence of soluble calcium salts, and the other that 

 of peculiar substances derived from the tissues outside the blood vessels 

 and called thromboplastic substances or thromboplastin (Howell). We 

 must now consider the action of these two factors. 



The Influence of Calcium Salts. As already explained, the proof that 

 soluble calcium salts are necessary for clotting is furnished by the ob- 

 servation that the process is entirely prevented when the freshly drawn 

 blood is mixed with soluble oxalate. To this proof, however, objection 

 might be made on the score that the oxalate per se inhibited the clotting. 

 That such is not the case is indicated by the fact that, if the oxalated 

 blood or plasma is dialyzed against physiologic saline solution till all 

 the soluble oxalate has been removed from it, clotting is still absent but 

 immediately supervenes if some soluble calcium salts are added. The 

 question arises as to how the calcium ion acts. Two possibilities exist: 



(1) that it 'is concerned in the conversion of fibrinogen to fibrin, and 



(2) that it is necessary for converting prothrombin into thrombin. It 

 can quite readily be shown that it is by the second of these processes 



