THE COAGULATION OF THE BLOOD 847 



them the name of nucleo-proteins or whether we should not rather classify 

 them with the phospho-proteins which play so great a part in the building up 

 of the cytoplasmic part of the cell. We may explain the action of these 

 tissue extracts as due to their containing thrombokinase.* Their injection 

 would resemble therefore the liberation of thrombokinase which normally 

 occurs when blood leaves the vessels. More difficult to understand is the 

 result of injecting small amounts of these tissue extracts or large amounts 

 in small doses. A minute quantity of tissue extract injected into the blood- 

 stream produces, not intravascular clotting, but a delay of the coagulation 

 time. Repeated injections of small doses may absolutely annul the coagula- 

 bility of the blood, which can be collected by opening the blood-vessels and 

 will remain unclotted for many days. The same double effect may be 

 observed even with a larger dose. In rabbits and in dogs after a full meal 

 the intravascular coagulation which occurs is complete, extending through 

 the whole vascular system. If, however, the injection be made into a fasting 

 dog the thrombosis produced is limited to the portal vein. There is a sudden 

 fall of blood-pressure, from which the animal gradually recovers. If a vessel 

 be opened during the period of low pressure the blood which flows out is 

 totally uncoagulable, and if the animal be killed at this time a clot will be 

 found filling up the whole portal vein. Wooldridge described these two 

 effects of injection of tissue extracts, namely the coagulation and the loss of 

 coagulability, as the positive and negative phases respectively. Since the 

 negative phase has not been observed in any form of extra- vascular plasma 

 we must ascribe it to a reaction on the part of the living cells, and probably, 

 since it is so rapid in its establishment, to the action of the cells lining the 

 blood-vessels. The interest of these observations lies in the relation which 

 they bear to the production of immunity. If a toxin such as that of diph- 

 theria or tetanus be injected into an animal, an anti-toxin is produced in 

 the course of two or three days. If now further doses of toxin be injected 

 its first effect is to destroy the whole of the anti-toxin present in the circu- 

 lating blood. In the course of a day or two the anti-toxin gradually returns, 

 and at the end of three days is found in larger quantities in the blood than 

 were present before the second injection. Every toxin has therefore a 

 positive as well as a negative phase of action. Tissue extracts in their 

 effect on coagulation have a similar positive and negative phase, but these 

 phases are established within a few seconds instead of taking two or three 

 days for their development. One cannot but believe that a renewed study 

 of the conditions of intravascular clotting might shed important light on the 

 chemical mechanism of production of immunity. 



FATE OF THE FIBRIN FERMENT. The substances which interact for 

 the production of thrombin in shed blood as well as thrombin itself are not 

 entirely used up in the process of clotting. Blood serum, though free from 

 fibrinogen, contains traces of thrombokinase (which can be precipitated by 



* According to Howell, these tissue fibrinogens consist of phosphatides in associa- 

 tion with protein. When separated from the protein they are thermostable, and their 

 thromboplastic effect is due to their power of neutralising antithrombin. 



