956 PHYSIOLOGY 



thrombokinase. Their injection would resemble therefore the libera- 

 tion 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 

 coagulability 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 diphtheria 

 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 

 circulating 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 develop- 

 ment. 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 irnmunity. 



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 the addition of dilute acetic acid) and throm- 



