COAGULATION 43 



a share in its production, even if its presence has not hitherto been 

 demonstrated in the internal coat (L. Loeb) . So that living blood 

 within the living vessels may be said to be acted upon by two sets 

 of influences, one tending to favour coagulation, the other to oppose 

 it. In the clotting of extravascular plasma, free from corpuscles, 

 we may indeed see the continuation, under modified conditions, of 

 a normal process always going on within the bloodvessels. Under 

 normal conditions, the processes that make for coagulation never 

 obtain the upper hand. 



Indeed the margin of safety within which what may be called 

 the thrombo-regulative mechanism works seems to be surprisingly 

 wide, and the equilibrium in the circulating blood far more stable 

 than observations on clotting outside of the body might lead us to 

 suppose. Very considerable quantities of thrombin or of de- 

 fibrinated blood or serum containing thrombin can be injected into 

 the blood-stream without ill effect. According to Howell, the 

 presence of the abnormally great amount of thrombin causes the 

 formation of sufficient antithrombin to neutralize it, probably by a 

 protective reflex secretion. In like manner the injection of tissue 

 extracts or a solution ol thrombo plastic substance (thrombokinase) 

 prepared from them by precipitation does not necessarily induce 

 coagulation in the vessels. On the contrary, when injected slowly 

 or in small amount into the veins of an animal, it abolishes for a 

 time the power of coagulation of the blood; and when this ' nega- 

 tive phase,' as it is called, has been once established, even a very 

 large and rapid injection produces no further effect, possibly because 

 an antibody which neutralizes the action of thrombokinase has 

 been produced. In both cases the limits of safety can be over- 

 stepped, and intravascular clotting induced by the injection either 

 of thrombin or of thrombokinase. When a considerable quantity 

 of the active substance in tissue extract is introduced at the first 

 injection, extensive coagulation in the vessels instantly ensues; the 

 animal dies in a few minutes; and the right side of the heart, the 

 venae cavae, the portal vein, and perhaps the pulmonary arteries, 

 may be found choked with thrombi. Here the injected thrombo- 

 kinase is responsible for the clotting, thrombogen and calcium being 

 already present. Curiously enough, intravascular coagulation fails 

 to be produced in a certain proportion of cases when albino animals 

 are injected with material from pigmented animals, while there is 

 no absolute failure of coagulation when albinos are injected with 

 material from albinos, and no failure when pigmented animals are 

 injected with material either from other pigmented animals or from 

 albinos. Intravascular coagulation on injection of tissue extracts 

 is especially striking in birds. 



To a certain extent the action of tissue extracts in coagulation 

 can be imitated by other substances of animal origin, such as the 



