ferment in the circulating blood. Just how this is done is not positively known, but there is evidence that it may be due mainly to a defensive action of the liver. Delezenne' states that when blood-serum is circulated through a liver it loses its power of inducing coagulation in a coagulable liquid, that is, probably its contained fibrin ferment is altered or destroyed. It seems probable that this action of the liver may be of importance in the normal circulation in maintaining the non-coagulability of the blood in the living animal. Moreover, injection of leucocytes sometimes diminishes instead of increasing the coagulability of blood, making the so-called "negative phase" of the injection. To explain this latter fact, it may be said that leucocytes give rise on disintegration to a complex nucleo-proteid known as nucleo-histon. Nucleo-histon in turn is said to be broken up in the circulation, with the formation of a second nucleo-proteid, leuconuclein, that favors coagulation, and a proteid body, histon, that has a retarding influence on coagulation. The predominance of the latter substance may account for the "negative phase" under the conditions described.

Why Blood does not Clot within the Blood-vessels.-The reason that blood remains fluid while in the living blood-vessels, but clots quickly after being shed or after being brought into contact with a foreign substance in any way, has already been stated in describing the theories of coagulation, but will be restated here in more categorical form. Briefly, then, blood does not clot within the blood-vessels because fibrin-ferment is not present in sufficient quantities at any one time. Leucocytes and blood-plates probably disintegrate here and there within the circulation, but the small amount of ferment thus formed is insufficient to act upon the blood, and the ferment is quickly destroyed or changed, probably by an action of the liver as stated above. When blood is shed, however, the formed elements break down in mass, as it were, liberating a relatively large amount of nucleo-proteids, which, together with the calcium salts, produce fibrin from the fibrinogen.

Means of Hastening or of Retarding Coagulation.-Blood coagulates normally within a few minutes, but the process may be hastened by increasing the extent of foreign surface with which it comes in contact. Thus, moving the liquid when in quantity, or the application of a sponge or a handkerchief to a wound, will hasten the onset of clotting. This is easily understood when it is remembered that nucleo-proteids arise from the breaking down of leucocytes and blood-plates, and that these corpuscles go to pieces more rapidly when in contact with a dead surface. It has been proposed also to hasten clotting in case of hemorrhage by the use of ferment solutions. Hot sponges or cloths applied to a wound will hasten clotting, probably by accelerating the formation of ferment and the chemical changes of clotting. Coagulation may be retarded or be prevented altogether by a variety of means, of which the following are the most important:

1. By Cooling.-This method succeeds well only in blood that clots slowly-for example, the blood of the horse or the terrapin. Blood from 1 Travaux de Physiologie, Université de Montpellier, 1898.

these animals received into narrow vessels surrounded by crushed ice may be kept fluid for an indefinite time. The blood-corpuscles soon sink, so that this method is an excellent one for obtaining pure blood-plasma. The cooling probably prevents clotting by keeping the corpuscles intact.

2. By the Action of Neutral Salts.-Blood received at once from the bloodvessels into a solution of such neutral salts as sodium sulphate or magnesium sulphate, and well mixed, will not clot. In this case also the corpuscles settle slowly, or they may be centrifugalized, and specimens of plasma can be obtained. For this purpose horse's or cat's blood is to be preferred. Such plasma is known as "salted plasma ;" it is frequently used in experiments in coagulation—for example, in testing the efficacy of a given ferment solution. The best salt to use is MgSO, in solutions of 27 per cent.: 1 part by volume of this solution is usually mixed with 4 parts of blood; if cat's blood is used a smaller amount may be taken-1 part of the solution to 9 of blood. Salted plasma or salted blood again clots when diluted sufficiently with water or when ferment solutions are added to it. How the salts prevent coagulation is not definitely known-possibly by preventing the disintegration of corpuscles and the formation of ferment, possibly by altering the chemical properties of the proteids.

3. By the Action of Albumose Solutions.-Certain of the products of proteid digestion, peptones and albumoses, when injected into the circulation. retard clotting for a long time. For injection into dogs one uses 0.3 gram to each kilogram of animal. If the blood is withdrawn shortly after the injection, it will remain fluid for a long time. The peptone solutions, on the contrary, have no effect on the clotting of blood if added to it in a glass outside the body. This curious action of peptone has been much discussed. In an interesting paper by Delezenne, referred to on the previous page, two important facts are brought out that furnish the author a basis for a credible theory of the anticoagulating effect of the injections. It has been shown, in the first place, that the peptone injections cause a marked and rapid destruction of blood leucocytes. Secondly, that if blood and peptone are circulated together through a living liver the mixture not only does not clot itself, but will prevent clotting when added to freshly drawn blood. The hypothesis to explain these facts and also the action of peptone on coagulation is that the peptone by destroying the leucocytes sets free nucleo-proteid and histon (see p. 61); the former of these by forming fibrin ferment would promote coagulation, but in passing through the liver it is destroyed or neutralized in some way, and the histon left in the blood is the substance that retards the clotting. It would be desirable, in connection with this hypothesis, if chemical proof were furnished that histon is present in the blood after peptone injections.

4. Many other organic substances have an effect similar to peptone when injected into the circulation or in some cases when mixed with shed blood. For example, extracts of leech's head, extracts of the muscle of the crayfish, the serum of the eel, a number of bacterial toxins, and many of the soluble

enzymes such as pepsin, trypsin, diastase, etc. The hypothesis used to explain the action of peptone may possibly apply also to these cases.

5. By the Action of Oxalate Solutions.-If blood as it flows from the vessels is mixed with solutions of potassium or sodium oxalate in proportion sufficient to make a total strength of 0.1 per cent. or more of these salts, coagulation will be prevented entirely. Addition of an excess of water will not produce clotting in this case, but solutions of some soluble calcium salt will quickly start the process. The explanation of the action of the oxalate solutions is simple: they are supposed to precipitate the calcium as insoluble calcium oxalate.

Total Quantity of Blood in the Body.-The total quantity of blood in the body has been determined approximately for man and a number of the lower animals. The method used in such determinations consists essentially in first bleeding the animal as thoroughly as possible and weighing the quantity of blood thus obtained, and afterward washing out the blood-vessels with water and estimating the amount of hæmoglobin in the washings. The results are as follows: Man, 7.7 per cent. () of the body-weight; that is, a man weighing 68 kilos. has about 5236 grams, or 4965 c.c., of blood in his body; dog, 7.7 per cent.; rabbit and cat, 5 per cent. ; new-born human being, 5.26 per cent.; and birds, 10 per cent. Moreover, the distribution of this blood in the tissues of the body at any one time has been estimated by Ranke,' from experiments on freshly-killed rabbits, as follows:

It will be seen from inspection of this table that in the rabbit the blood of the body is distributed at any one time about as follows: one-fourth to the heart, lungs, and great blood-vessels; one-fourth to the liver; one-fourth to the resting muscles; and one-fourth to the remaining organs.

Regeneration of the Blood after Hemorrhage.-A large portion of the entire quantity of blood in the body may be lost suddenly by hemorrhage without producing a fatal result. The extent of hemorrhage that can be recovered from safely has been investigated upon a number of animals. Although the results show more or less individual variation, it can be said that in dogs a hemorrhage of from 2 to 3 per cent. of the body-weight is recovered from easily, while a loss of 4.5 per cent., more than half the entire blood, will probably prove fatal. In cats a hemorrhage of from 2 to 3 per

1893.

Taken from Vierordt's Anatomische, physiologische und physikalische Daten und Tabellen, Jena,

2 Fredericq: Travaux du Laboratoire ( Université de Liége), 1885, t. i. P 189.

cent. of the body-weight is not usually followed by a fatal result. Just what percentage of loss can be borne by the human being has not been determined, but it is probable that a healthy individual may recover without serious difficulty from the loss of a quantity of blood amounting to as much as 3 per cent. of the body-weight. It is known that if liquids that are isotonic to the blood, such as a 0.9 per cent. solution of NaCl, are injected into the veins immediately after a severe hemorrhage, recovery will be more certain ; in fact, it is possible by this means to restore persons after a hemorrhage that would otherwise have been fatal. In addition to the mechanical effects on blood pressure such an infusion tends to put into circulation all the red corpuscles. Ordinarily the number of red corpuscles is greater than that necessary for a barely sufficient supply of oxygen, and increasing the bulk of liquid in the vessels after a severe hemorrhage makes more effective as oxygen-carriers the remaining red corpuscles, inasmuch as it insures a more rapid circulation. If a hemorrhage has not been fatal, experiments on lower animals show that the plasma of the blood is regenerated with great rapidity, the blood regaining its normal volume within a few hours in slight hemorrhages, and in from twenty-four to forty-eight hours if the loss of blood has been severe; but the number of red corpuscles and the hæmoglobin are regenerated more slowly, getting back to normal only after a number of days or after several weeks.

Blood-transfusion.-Shortly after the discovery of the circulation of the blood (Harvey, 1628), the operation was introduced of transfusing blood from one individual to another or from some of the lower animals to man. Extravagant hopes were held as to the value of such transfusion not only as a means of replacing the blood lost by hemorrhage, but also as a cure for various infirmities and diseases. Then and subsequently, fatal as well as successful results followed the operation. It is now known to be a dangerous undertaking, mainly for two reasons: first, the strange blood, whether transfused directly or after defibrination, is liable to contain a quantity of fibrin ferment sufficient to cause intravascular clotting; secondly, the serum of one animal may be toxic to another or cause a destruction of its blood-corpuscles. Owing to this globulicidal and toxic action, which has previously been referred to (p. 36), the injection of foreign blood is likely to be directly injurious instead of beneficial. In cases of loss of blood from severe hemorrhage, therefore, it is far safer to inject a neutral liquid, such as the so-called "physiological saltsolution"-a solution of NaCl of such a strength (0.9 per cent.) as to be isotonic with the blood-serum. The volume of the circulating liquid is thereby augmented, and all the red corpuscles are made more efficient as oxygencarriers, partly owing to the fact that the bulk and velocity of the circulation are increased, and partly because the corpuscles are kept from stagnation in the capillary areas.

Some Preliminary Considerations upon the Processes of Diffusion and Osmosis, and their Importance in the Nutritive Exchanges of the Body.

In recent years the physical conceptions of the nature of the processes of diffusion and osmosis have changed considerably. As these newer conceptions are entering largely into current medical literature, it seems advisable to give a brief description of them for the use of those students of physiology who may be unacquainted with the modern nomenclature. The very limited space that can be devoted to the subject forbids anything more than a condensed elementary presentation. For fuller information reference must be made to special treatises.1

Diffusion, Dialysis, and Osmosis.—When two gases are brought into contact a homogeneous mixture of the two is soon obtained. This interpenetration of the gases is spoken of as diffusion, and it is due to the continual movements of the gaseous molecules to and fro within the limits of the confining space. So also when two miscible liquids or solutions are brought into contact a diffusion occurs for the same reason, the movements of the molecules finally effecting a homogeneous mixture. If the two liquids happen to be separated by a membrane, diffusion will still occur, provided the membrane is permeable to the liquid molecules, and in time the liquids on the two sides will be mixtures having a uniform composition. Not only water molecules, but the molecules of many substances in solution, such as sugar, may pass to and fro through membranes, so that two liquids separated from each other by an intervening membrane and originally unlike in composition may finally, by the act of diffusion, come to have the same composition. Diffusion of this kind through a membrane is frequently spoken of as dialysis or osmosis. In the body we deal with aqueous solutions of various substances that are separated from each other by living membranes, such as the walls of the bloodcapillaries or of the alimentary canal, and the laws of diffusion through membranes are of immediate importance in explaining the passage of water and dissolved substances through these living septa. In aqueous solutions such as we have in the body we must take into account the movements of the molecules of the solvent, water, as well as of the substances dissolved. These latter may have different degrees of diffusibility as compared with one another or with the water molecules, and it frequently happens that a membrane that is permeable to water molecules is less permeable or even impermeable to the molecules of the substances in solution. For this reason the diffusion stream of water and of the dissolved substances may be differentiated, as it were, to a greater or less extent. In recent years it seems to have become customary to limit the term osmosis to the stream of water molecules passing through a membrane, while the term dialysis, or diffusion, is applied to the passage of the molecules of the substances in solution. The osmotic stream of water under varying conditions is especially important, and in connection with this process it is necessary to define the term osmotic pressure as applied to solutions.

Osmotic Pressure.-If we imagine two masses of water separated by a permeable membrane, we can readily understand that as many water molecules will pass through from one side as from the other; the two streams in fact will neutralize each other, and the volumes of the two masses of water will remain unchanged. The movement of the water molecules in this case is not actually observed, but it is assumed to take place on the theory that the liquid molecules are continually in motion and that the membrane, being permeable, offers no obstacle to their movements. If, now, on one side of the membrane we place a solution of some crystalloid substance. such as common salt, and on the other side pure water, then it will be found that an excess of water will pass from

' Consult: H. C. Jones, The Theory of Electrolytic Dissociation, 1900; "Diffusion, Osmosis, and Filtration," by E. W. Reid, in Schäfer's Text-book of Physiology, 1898; Solution and Electrolysis, by W. C. D. Whetham, Cambridge Natural Science Manuals, 1895.

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