BLOOD CLOTTING 109 



frequent injections of small amounts of the above material are made, 

 instead of intravascular clotting, a delay in the coagulation time is 

 likely to occur. Indeed, repeated injections of small amounts may en- 

 tirely remove the clotting power of the blood. The readiness with which 

 this so-called "negative phase" appears, seems to depend on the nutri- 

 tive condition of the animal at the time of injection. If a large dose is 

 injected into a fasting dog, for example, thrombosis is confined to the 

 portal area, whereas if it is injected into a recently fed animal, the 

 thrombosis is universal throughout the vascular system. The develop- 

 ment of the negative phase is undoubtedly dependent upon some reac- 

 tion on the part of the living cells of the organism, since it does not occur 

 on the addition of similar substances to blood outside the body. The 

 reaction is, indeed, akin to that by which immune bodies in general are 

 produced. For example, a toxin injected in large amount has a cer- 

 tain toxic effect, but in repeated small doses with intervening intervals 

 it leads to the production of an antitoxin. So with the substance in 

 question; a large dose injected at one time causes a positive effect clot- 

 ting but smaller doses frequently injected, the opposite effect want of 

 clotting. It is probable, as suggested by Starling, that more intensive 

 study of the conditions causing intravascular clotting will throw con- 

 siderable light on the general question of the production of immunity. 



Measurement of the Clotting Time 



To measiire the clotting ti/me of drawn samples of blood, several conditions must 

 be observed. These have been tabulated by Addis 1 * as follows: 



1. The specimens of blood must always be obtained by exactly the same technic. It 

 would introduce serious errors to compare the clotting time of one specimen of blood 

 received from an incision of the skin (ear lobe) with that of another collected in a 

 syringe by venipuncture. 



2. The temperature conditions must always be the same. Probably 25 C. is the best 

 temperature to use. Higher temperatures are unsuitable for two reasons: first, be- 

 cause during its collection the blood will have become cooled to about or below this 

 point, and time would be consumed in raising it higher; and second, because the time 

 of coagulation is more and more shortened for each degree that the temperature is 

 raised, this acceleration becoming especially pronounced for temperatures above 25 C. 

 Quite apart from the liability to incur errors incident to measurement of shorter 

 periods of time, observations at higher temperatures necessitate most rigorous adher- 

 ence to a fixed temperature of the water-bath. Temperatures much below 25 C. are 

 unsuitable, because the clotting sets in gradually and it is difficult to tell precisely 

 when it occurs. 



3. The blood must always be collected in the same sort of vessel and come in con- 

 tact with the same kind and amount of foreign material. To this it may be added 

 that the receiving vessel must be scrupulously clean; any trace of old blood clot or of 

 serum is especially to be guarded against. 



4. The end point must be sharp. It is here that the greatest technical difficulties 

 are met with in making precise measurements, and it is greatly to be desired that 



