combination of circumstances must exist in order that the blood may coagulate, and that so long as it circulates through the vessel under normal conditions these circumstances are never physiologically present. In the blood plasma several albuminous bodies are contained. One of these is a globulin so nearly allied to fibrin in its general characteristics that it is believed to be the mother substance from which fibrin is formed, and to this substance the name fibrinogen has been given. This substance is also present in various exudations, but because of the absence of fibrin ferment, these fluids are not spontaneously coagulable. The fact that the presence of calcium salts is indispensable to the action of fibrin ferment, and that their precipitation by oxalates prevents coagulation, gives rise to the assumption that fibrin ferment or thrombin arises from the union of a parent ferment, prothrombin, with a soluble salt of calcium, and this is acknowledged to be the case. Fibrin ferment can readily be separated from the blood and identified as a nucleo-proteid. It does not exist in circulating blood. Not only is the coagulating principle absent from circulating blood, but that which spurts from a vessel does not contain it during the first few seconds. Very soon, however, this principle appears, provokes coagulation, and is found in the serum which exudes from the clot. Plasmas which are spontaneously incoagulable are so merely because they do not contain fibrin ferment, such as the oxalated plasma above mentioned. If this plasma contained fibrin ferment it would coagulate. If to oxalated plasma is added a small quantity of serum coming from the normal anterior coagulation, even if this serum has been mixed with oxalate before being added, coagulation will occur. This shows that oxalated plasma does not contain a coagulating principle with which the serum is abundantly provided, and also that the presence of oxalates does not prevent the ferment from transforming fibrinogen into fibrin.

According to the classical doctrine relating to the origin of blood and lymph coagulation, the phenomenon is associated with and dependent upon an anatomical destruction of a white corpuscle. In other words, a true leucolysis is supposed to occur involving a majority of the leucocytes; they escape from the vessels and a liberation of fibrin ferment occurs. This hypothesis is regarded by many physiologists as erroneous, and it is contended that the leucocytes are not destroyed and that the co

agulating ferment escapes from the leucocytes as a physiological secretion according to the loss of osmosis. Dastre considers the emission of ferment-forming substance from the leucocyte to be due to divers conditions of the surrounding media, the most important of which is the osmotic condition (hypotonia).

The production of fibrin ferment must then be regarded as a manifestation of the physiological activity of the leucocytes. Anticoagulating substances acting upon the formation of fibrin ferment act either by fixing the calcium of the plasma or by preventing the liberation of nucleo-albumin from the cell. Some may act in both ways; the oxalates act by precipitating calcium, the nucleo-albumin passes into solution in the plasma, remaining there unmodified because of the absence of calcium salts. The extract obtained from the leech's head acts by preventing the liberation of nucleo-albumin from the cell. Besides this, it possesses the property to a certain extent of opposing the action of the ferment. The active ingredient in peptone plasma which prevents coagulation is proteose, which, acting upon leucocytes, sets free two antagonistic substances, one coagulating, the other non-coagulating. The first is retained by the liver, the second passes into the blood and prevents coagulation. Effects similar to those induced by proteose are induced by injection of eel's blood serum and by extract of lobster muscle.

Wooldridge was the first investigator to experimentally produce intra-vascular coagulation. He obtained this result by injecting nucleo-albumin of the thymus gland. Injected suddenly into the jugular vein of certain animals this substance produces almost instantaneous coagulation, followed by death in a few minutes. Snake venom gives the same results as the thymus nucleo-albumins. The explanation for this action of nucleo-albumins is that they act in the blood like prothrombin, unite with calcium salts to form ferment and thus bring fibrinogen to coagulation. Finally, the accelerating influence upon coagulation of contact of the blood with the tissues themselves is very important. As was before stated, if the blood of birds is removed from the vessels by means of a paraffin canula its coagulation is considerably delayed, while if it comes into contact with the tissues of the animal it almost instantly coagulates. The acceleration is due partly to the presence of nucleo-proteids in the tissues which act like fibrin ferment and partly to the physico-chemical character

of the tissues acting upon the leucocytes. Very recent experiments by Bouchard show that the provocative elements of coagulation are rare in the portion of blood first extravasated, but become abundant in the last.

We have reviewed the main facts connected with the physiology of blood coagulation in order that we may more critically analyze the methods for controlling internal hemorrhage which are in use today and which depend for their activity upon an effort to accelerate the process. First and foremost among these methods is the use of the salts of calcium. Sir Ambrose Wright, of England, was largely instrumental in popularizing the calcium salts in the treatment of hemorrhage. He claimed to have obtained good results in hemophilia and hemorrhage by the administration of calcium salts hypodermically and by mouth. He stated that the addition of one-fourth to one-half per cent. calcium chloride solution to the extravascular blood of hemophilics reduces the clotting time and that the internal administration of calcium salts is of great benefit in these cases. Wright believed that typhoid hemorrhage can be controlled and also prevented by the internal administration of calcium. He also thought that the calcium content of the blood is increased after the internal administration of the salts, particularly the lactate, which he states is more rapidly absorbed. Wright's claims are open to criticism from several points. It is worthy of mention that they have been attacked lately in this country by Robertson, Illman and Duncan. These authors have repeated Wright's experiments, with the exception of those upon hemophilics, using the latter's technic in determining coagulation time. They found that the coagulation time of the blood is noticeably retarded during the febrile stage of acute infectious diseases. This observation is in agreement with the findings of Wright. Contrary to his investigations, however, they found that the calcium salts. have no effect upon coagulation time nor upon the quantity of calcium in the blood. A critical examination of the physiological and pharmacological action of calcium tends only to increase one's scepticism of its practical availability as a hemostatic. Even the soluble salts of lime are absorbed with great difficulty and slowness from the alimentary canal. They retard fluid absorption in the intestine and it is presumed that they would act as saline purgatives were they not so readily precipitated by

alkaline salts.

Almost all the lime taken as food or drug is passed through the bowel unchanged, whether the salt administered is a soluble or insoluble one. The small quantity which gains admission to the blood circulates as an albuminate and is slowly excreted. The only way materially to increase the lime salts in the blood is to inject them directly subcutaneously or into the vessel. The excess then becomes gradually withdrawn from the blood and excreted, partly by the urine as carbamate, but mostly by the epithelium of the colon. The small quantity of calcium absorbed from the stomach and intestine has no effect except to replace lost calcium in the tissues. But the food always contains an abundance of calcium salts, and given as medicine the latter have no specific action except that elicited by the cathion, as the bromide ion in calcium bromide, the hydroxyl ion in calcium hydrate. When injected, however, directly into the blood the soluble calcium salts are poisonous, and Wright has reported some instances of sloughing following their hypodermic injection.

Although it is true, then, that the administration of lime salts by ordinary methods can never produce any excess of lime in the blood, the question arises as to whether the organism ever suffers from a deficiency of lime in the tissues and whether this deficiency if it exists can be remedied by giving the salts of lime. In the young and growing animal such deficiency is provocative of disease. Rickets is one of these diseases, but here the difficulty is not with any deficiency of lime in the food or in the blood, but to inability on the part of the bones to appropriate the calcium which is offered to them in abundance. The presence of traces

of lime in the tissues has been shown to be necessary for the efficiency of heart action, voluntary muscle activity, nerve irritability, epithelial function, etc., and its relation to coagulation has been already sufficiently discussed. But when we come to the proposition to treat with calcium cases in which the blood seems less capable of clotting than normally, as in hemophilia, the difficulties. become immediately apparent. In the first place, it is not possible to increase the calcium content of the blood by the internal administration of the metal. In the second place, the absence or deficiency of coagulation in these diseases is not due to lack of lime salts in the blood. Finally, the clinical evidence is not very strong in its favor.

The extension of lime salts to the treatment of all forms of internal hemorrhage, pulmonary, gastric, intestinal, cerebral and visceral, has taken place. In these cases, however, it is not even contended that the coagulability of the blood is reduced. The arrest of the hemorrhage is due to other factors rather than to the calcium.

Closely related to the calcium treatment of hemorrhage is that by gelatin. This substance contains a small quantity of calcium. The introduction of this substance into medicine as an internal and local hemostatic was due to certain investigations reported in France, in which the coagulation time was reported to be shortened. Later investigations have not confirmed these results. Clinical reports in a great variety of conditions-aneurism, hemoptysis, gastric, intestinal, renal, uterine and other bleeding-have been conflicting. Tetanus has occurred in some cases. As local hemostatic it is much inferior to adrenalin, and internally it is valueless. The use of gelatin for this purpose is fast disappearing and bids fair soon to become obsolete.

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Another method of provoking internal hemostasis which is supposed to be founded on physiological induction is the treatment by injection of various blood sera. Leary has recently reported twenty cases of various hemorrhagic conditions treated by the hypodermic injection of fresh rabbit-blood serum. The credit, if any there be, of first using animal sera in the treatment of hemorrhage, is properly given to Weil, who wrote in 1905 upon the pathogeny and serum treatment of hemophilia. Leary appears to base the treatment upon the following data. Firstly, he claims physiologists have long recognized that the contact of blood with fresh serum or tissue juices hastens coagulation. The latter part only of this statement is strictly correct. Blood serum as usually prepared is defibrinated and does not contain fibrin ferment, consequently being devoid of fibrinogen and thrombin it cannot coagulate spontaneously nor stimulate coagulation. Secondly, Schmidt's experiments seem to show that during coagulation an excess of fibrin ferment is set free and is contained in the serum after separation of the clot. If this is strictly true why does not the injection of serum into the veins of an animal provoke intravascular clotting? Thirdly, Kohler demonstrated many years ago that the filtrate obtained after mincing a freshly formed clot if injected intravenously in quantity into the animal from which the