886 PHYSIOLOGY 



thrombin. It cannot be at this stage of the process that the calcium salts 

 exercise their influence, since ' fibrin ferment ' or thrombin will cause the 

 coagulation of fibrinogen in the total absence of soluble calcium salts and 

 even in the presence of a slight amount of ammonium oxalate. Moreover 

 Hammarsten has shown that the calcium content of fibrin is no greater than 

 that of the fibrinogen from which it is formed. 



The fact that a solution of pure fibrinogen is made to clot by thrombin 

 and by this alone renders such a solution an excellent reagent for the presence 

 of the ' ferment.' By this means we can show that thrombin is absent in 

 circulating blood. If blood be received direct from the vessels into absolute 

 alcohol and the precipitate, after coagulation by alcohol, be extracted by 

 water, the extract is found to contain no trace of ferment. The same state- 

 ment applies to fresh oxalate plasma. If however oxalate plasma be made 

 to clot by the addition of calcium salts, the serum squeezed from the clot 

 is found to contain thrombin. In the process of coagulation therefore, not 

 only is there a conversion of fibrinogen to fibrin, but there is an actual 

 formation of the agent which is responsible for this change, namely, thrombin 

 or fibrin ferment. Our next step therefore must be to inquire into the 

 precursors of the thrombin and the conditions of its formation. 



If oxalate plasma be cooled to C. for two or three days, a scanty 

 granular precipitate is produced. This can be centrifuged off or separated 

 by filtration through several thicknesses of paper. It is then found that the 

 remaining plasma can no longer be made to coagulate by the addition of 

 lime salts, although it still contains fibrinogen, which is converted into fibrin 

 on the addition of thrombin. If the precipitate be collected and treated 

 with calcium chloride and the mixture added to the oxalate plasma, the 

 latter clots. The same effect is produced if the precipitate plus calcium 

 be added to a pure solution of fibrinogen. We must conclude that the pre- 

 cipitate, though itself not fibrin ferment, will give rise to fibrin ferment on 

 treatment with lime salts. It was therefore designated by Hammarsten 

 ' prothrombin/ and regarded as the precursor of thrombin. 



Thus far practically all workers on the subject are agreed. Coagulation 

 of the blood is due finally to the interaction of thrombin and fibrinogen. 

 The fibrinogen is present as such in the circulating plasma. Thrombin is 

 not contained in the circulating blood, but is produced from some precursor 

 or precursors after the blood has been shed. For the production of thrombin 

 the presence of calcium salts is necessary. Further research on the nature 

 of the precursor * prothrombin ' has shown that the matter is not quite so 

 simple as imagined by Hammarsten. In the following account we shall 

 adhere chiefly to that given by Morawitz, reserving most of the criticisms 

 and limitations to be made to this theory for the historical sketch of the 

 theories of clotting at the end of this section. 



Oxalate plasma, which has been separated from the precipitate of pro- 

 thrombin, can be made to coagulate by the addition of extracts of almost any 

 animal tissues together with lime salts, and these therefore were supposed 

 to contain prothrombin similar to that obtained by cooling oxalate plasma. 



