316 DISTURBANCES OF CIRCULATION 



of the liver and intestines, although earlier writers have variously described its 

 formation in the bone marrow, leucocytes, liver or intestines. The amount of 

 fibrinogen present in the blood is actually quite small, the fibrin formed in nor- 

 mal clotting being but 0.1 to 0.4 per cent, of the weight of the blood. Acted 

 upon by the fibrin-ferment, it yields the characteristic insoluble protein fibrin, in 

 crystalline form under favorable conditions, ^^ but we do not know definitely what 

 changes the fibrinogen undergoes in this process. Fibrin resembles in its insolu- 

 bility the proteins coagulated by heat, alcohol, etc., but when kept aseptically for 

 some time, it becomes again dissolved; this process of fibrinolysis probably de- 

 pends upon proteolytic enzymes, which fibrin, in common with other substances 

 of similar physical nature, has the property of dragging out of solution and holding 

 firmly. Undoubtedly entangled leucocytes are also an important factor in the 

 fibrinolysis,^' which is greatly increased in phosphorus poisoning and when the 

 liver is excluded from the circulation, a fact suggesting that the liver may form 

 inhibiting substances. 



Theories of Fibrin Formation. — The great problem is the nature and the place 

 and manner of origin of the fibrin-forming enzyme, generally called fibrin-jerment 

 (also plasmase, thrombin and coagulin). The most fundamental theory of the 

 origin and nature of fibrin-ferment is that of Alexander Schmidt, which may be 

 briefly described as follows: The ferment, Schmidt believed, exists in the plasma 

 in an inactive (prozyme or zymogen) form, which he called prothrombin Lpon 

 disintegration of the leucocytes there is set free a substance, which, acting upon 

 the prothrombin, converts it into the active thrombin; this activating agent 

 Schmidt designated as the zymoplastic substance. With various modifications 

 this stands to the present day as a basic theory. 



It having been shown that calcium facilitates the formation of fibrin, Pekel- 

 haring advanced the idea that the prothrombin does not exist in the plasma, but 

 is liberated from the leucocytes, and, combining with the calcium of the plasma, 

 forms the thrombin. Morawitz considers three substances necessary for the 

 formation of thrombin. (1) the prothrombin or throjnbogen, which he believes 

 originates in the blood-plates; (2) the zymoplastic stibstance or thrombokinase, 

 which is liberated from the leucocytes into the plasma; (3) calcium salts. Howell,''* 

 however, explains coagulation as follows: Circulating blood normally contains 

 all the necessary factors for fibrin formation, i. e., fibrinogen, prothrombin and 

 calcium. But there is also present an inhibiting substance, antithrombin,^^ which 

 prevents the calcium from activating the prothrombin into thrombin. In shed 

 blood there appears a thromboplastin, derived from the platelets or the tissues, 

 which neutralizes the antithrombin and thus permits thrombin to form. Rett- 

 ger^'^ holds that the coagulation of the blood is not a true enzyme action at all, 

 while Bordet and Delange*^ consider that thrombin is formed by the interaction 

 of cytozyme from the platelets or tissue cells, and serozyme of the plasma. Mathews 

 follows Woolridge and considers the clotting of the blood as essentially the crj^s- 

 tallization of a phospholipin-protein compound, blood plasma, the stability of 

 which compound is easily upset in many ways. The fibrin threads are essen- 

 tially liquid crystals coming out of a saturated solution, the blood plasma, which 

 is practically a dilute protoplasm. It will not serve our purpose, however, to go 

 further into the hypotheses and disputes over these questions, which are detailed 

 more fully in the literature previously cited, but it may be stated that mimerous 

 American observers have found Howell's theory to fit well with both experimental 

 and clinical observations on the variations in the coagulability of the blood. 



The question has been raised as to whether the leucocytes or platelets secrete 

 their fibrin-forming constituent (be it thrombokinase or prothrombin is a matter 



''^ See Howell, Amer. Jour. Physiol., 1914 (35), 143; Hekma, Internat. Zeit. 

 physik. chem. Biol., 1915 (2), 279. 



"' Sec Morawitz, loc. cit.; also Rulot, Arch, internat. d. Physiol., 1904 (1), 152. 



8* Amor. .Jour. Physiol, 1911 (29), 187. 



** The antithrombin is formecl by the action of a phosphatid from the liver 

 (heparin) upon a pro-antithrombin (Howell and Holt, Amer. Jour. Phvsiol., 191S 

 (47), 328). 



«« Amer. Jour. Physiol., 1909 (24), 40(). 



«^ Ann. Inst. Pasteur., 1912 (20), ()57. See also Leo and Vincent, Arch. Int. 

 Med., 1914 (13), 398. 



