Volume 4, Slice 1 Part 28 (1/2)
Having ascertained that the clotting is due to the action of thrombin upon fibrinogen, we now see that the next step to be explained is the origin of thrombin. It has been shown that the final step in its formation consists in the combination of another substance, termed prothrombin, with calcium. Any soluble calcium salt is found to be effective in this respect, and conversely the removal of soluble calcium (e.g. by sodium oxalate) will prevent the formation of thrombin and therefore of clotting.
In the next place it can be proved that prothrombin does not exist as such in circulating blood, so that the problem becomes an inquiry as to the origin of prothrombin. Experiment has shown that in its turn prothrombin arises from yet another precursor, which is named thrombogen, and that thrombogen also is not to be found in circulating blood but only makes its appearance after the blood is shed. The conversion of thrombogen into prothrombin has been proved to be due to the action of a second ferment which has been named thrombokinase, and this latter is again absent from living blood. Hence the question arises, whence are derived thrombogen and thrombokinase? In the study of this question it has been found that if the blood of birds be collected direct from an artery through a perfectly clean cannula into a clean and dust-free gla.s.s vessel, it does not clot spontaneously. The plasma collected from such blood is found to contain thrombogen but no thrombokinase. A somewhat similar plasma may be prepared from a mammal's blood by collecting samples of blood from an artery into vessels which have been thoroughly coated with paraffin, though in this instance thrombogen may be absent as well as thrombokinase. If plasma containing thrombogen but no thrombokinase be treated with a saline extract of any tissues it will soon clot. The saline extract contains thrombokinase.
This ferment can therefore be derived from most tissues, including also the white blood corpuscles and the platelets. Thrombogen is produced from the leucocytes, but it is not yet certain whether it is also formed from the platelets. The discovery of the origin of the thrombokinase from tissue cells explains a fact that has long been known, namely, that if in collecting blood, it is allowed to flow over cut tissues, clotting is most markedly accelerated. The fact that birds' blood if very carefully collected will not clot spontaneously tends to prove that thrombokinase is not derived from the leucocytes, and makes probable its origin from the platelets, for it is known that birds' blood apparently does not contain platelets, at any rate in the form in which they are found in mammalian blood. When examining the general properties of platelets, attention was drawn to the remarkably rapid manner in which they undergo change on coming into contact with a foreign surface. It is apparently the actual contact which initiates these changes, changes which are fundamentally chemical in character, resulting in the production of thrombokinase and possibly also of thrombogen.
Thus as our knowledge at present stands the following statement gives a recapitulated account of the changes which const.i.tute the many phases of clotting. When blood escapes from a blood-vessel it comes into contact with a foreign surface, either a tissue or the damaged walls of the cut vessel. Very speedily this contact results in the discharge of thrombogen and thrombokinase, the former from the white blood corpuscles and also possibly from the platelets, the latter from the platelets or from the tissue with which the blood comes in contact. The interaction of these two bodies next results in the formation of prothrombin, which, combining with the calcium of any soluble lime salt present, forms thrombin or fibrin-ferment. The last step in the change is the action of thrombin upon fibrinogen to form fibrin, and the clot is complete.
The intrinsic value to the animal of these changes is quite plain. The power of clotting and thus stopping haemorrhage is of essential importance, and yet this clotting must not occur within the living blood-vessels, or it would speedily result in death. That the tissues should be able to accelerate the process is of very obvious value. That the inner lining of the blood-vessels does not act as a foreign tissue is possibly due to the extreme smoothness of their surface.
Further, an animal must always be exposed to a possible danger in the absorption of some thrombin from a ma.s.s of clotted blood still retained within the body, and we know that if a quant.i.ty of active ferment be injected into the blood-stream intravascular clotting does result. Under all usual conditions this is obviated, the protective mechanism being of a twofold character. First, it is found that thrombin becomes converted very quickly into an inactive modification. Serum, for instance, very quickly loses its power of inducing clotting in fibrinogen solutions.
Secondly, the body has been found to possess the power of making a substance, ant.i.thrombin, which can combine with thrombin forming a substance which is quite inactive as far as clotting is concerned.
Finally, there is evidence that normal blood contains a small quant.i.ty of this substance, ant.i.thrombin, and that under certain conditions the amount present may be enormously increased. (T. G. Br.)
_Pathology of the Blood._
The changes in the blood in disease are probably as numerous and varied as the diseases which attack the body, for the blood is not only the medium of respiration, but also of nutrition, of defence against organisms and of many other functions, none of which can be affected without corresponding alterations occurring in the circulating fluid.
The immense majority of these changes are, however, so subtle that they escape detection by our present methods. But in certain directions, notably in regard to the relations with micro-organisms, changes in the blood-plasma can be made out, though they are not a.s.sociated in all cases with changes in the formed elements which float in it, nor with any obvious microscopical or chemical alterations.
Immunity.
The phenomena of immunity to the attacks of bacteria or their toxins, of agglutinative action, of opsonic action, of the precipitin tests, and of haemolysis, are all largely dependent on the inherent or acquired characters of the blood serum. It is a commonplace that different people vary in their susceptibility to the attacks of different organisms, and different species of animals also vary greatly. This ”natural immunity”
is due partly to the power possessed by the leucocytes or white blood corpuscles of taking into their bodies and digesting or holding in an inert state organisms which reach the blood--phagocytosis,--partly to certain bodies in the blood serum which have a bactericidal action, or whose presence enables the phagocytes to deal more easily with the organisms. This natural immunity can be heightened when it exists, or an artificial immunity can be produced in various ways. Doses of organisms or their toxins can be injected on one or several occasions, and provided that the lethal dose be not reached, in most cases an increased power of resistance is produced. The organisms may be injected alive in a virulent condition, or with their virulence lessened by heat or cold, by antiseptics, by cultivation in the presence of oxygen, or by pa.s.sage through other animals, or they may first be killed, or their toxins alone injected. The method chosen in each case depends on the organism dealt with. The result of this treatment is that in the animal treated protective substances appear in the serum, and these substances can be transferred to the serum of another animal or of man; in other words the active immunity of the experimental animal can be translated into the pa.s.sive immunity of man. According to the nature of the substances injected into the former, its serum may be ant.i.toxic, if it has been immunized against any particular toxin, or antibacterial, if against an organism. Familiar examples of these are, of the former diphtheria ant.i.toxin, of the latter anti-plague and anti-typhoid sera. An ant.i.toxin exerts its effects by actual combination with the respective toxin, the combination being inert. It is probable that the ultimate source of the ant.i.toxin is to be found in the living cells of the tissues and that it pa.s.ses from them into the blood. The action of an antibacterial serum depends on the presence in it of a substance known as ”immune-body,”
which has a special affinity and power of combining with the bacterium used. In order that it may exert this power it requires the presence of a substance normally present in the serum known as ”complement.” The development of these ”anti-bodies,” though it has been studied mainly in connexion with bacteria and their toxins, is not confined to their action, but can be demonstrated in regard to many other substances, such as ferments, tissue cells, red corpuscles, &c. In some animals, for example, the blood serum has the power of dissolving the red corpuscles of an animal of different species; e.g. the guinea-pig's serum is ”haemolytic” to the red corpuscles of the ox. This haemolytic power (haemolysis) can be increased by repeated injections of red corpuscles from the other animal, in this case also, as in the bacterial case, by the production and action of immune-body and complement. The antiserum produced in the case of the red corpuscles may sometimes, if injected into the first animal, whose red corpuscles were used, cause extensive destruction of its red corpuscles, with haemoglobinuria, and sometimes a fatal result.
Opsonic action depends on the presence of a substance, the ”opsonin,” in the serum of an immunized animal, which makes the organism in question more easily taken up by the phagocytes (leucocytes) of the blood. The opsonin becomes fixed to the organisms. It is present to a certain extent in normal serum, but can be greatly increased by the process of immunization; and the ”opsonic index,” or relation between the number of organisms taken up by leucocytes when treated with the serum of a healthy person or ”control,” and with the serum of a person affected with any bacterial disease and under treatment by immunization, is regarded by some as representing the degree of immunity produced.
Agglutinative action is evidence of the presence in a serum of a somewhat similar set of substances, known as ”agglutinins.” When a portion of an antiserum is added to an emulsion of the corresponding organism, the organisms, if they are motile, cease to move, and in any case become gathered together into clumps. In all probability several different bodies are concerned in this process. This reaction, in its practical applications at least, may be regarded as a reaction of infection rather than of immunization as ordinarily understood, for it is found that the blood serum of patients suffering from typhoid, Malta fever, cholera, and many other bacterial diseases, agglutinates the corresponding organisms. This fact has come to be of great importance in diagnosis.
The precipitin test depends on a somewhat a.n.a.logous reaction. If the serum of an animal be injected repeatedly into another animal of different species, a ”precipitin” appears in the serum of the animal treated, which causes a precipitate when added to the serum of the first animal. The special importance of this fact is that it can be utilized as a method of distinguis.h.i.+ng between human blood and that of animals, which is often of importance in medical jurisprudence.
In this summary the facts adduced are practically all biological, and are due to the extraordinary activity with which the study of bacteriology (q.v.) has been pursued in recent years. The chemistry of the blood has not hitherto been found to give information of clinical or diagnostic importance, and nothing need here be added to what is said above on the physiology of the blood. Enough has been said, however, to show the extraordinary complexity of the apparently simple blood serum.
The methods at present employed in examining the blood clinically are: the enumeration of the red and white corpuscles per cubic millimetre; the estimation of the percentage of haemoglobin and of the specific gravity of the blood; the microscopic examination of freshly-drawn blood and of blood films made upon cover-gla.s.ses, fixed and stained. In special cases the alkalinity and the rapidity of coagulation may be ascertained, or the blood may be examined bacteriologically. We have no universally accepted means of estimating, during life, the total amount of blood in the body, though the method of J.S. Haldane and J. Lorrain Smith, in which the total oxygen capacity of the blood is estimated, and its total volume worked out from that datum, has seemed to promise important results (_Journ. of Physiol_. vol. xxv. p. 331, 1900). After death the amount of blood sometimes seems to be increased, and sometimes, as in ”pernicious anaemia,” it is certainly diminished. But the high counts of red corpuscles which are occasionally reported as evidence of plethora or increase of the total blood are really only indications of concentration of the fluid except in certain rare cases.
It is necessary, therefore, in examining blood diseases, to confine ourselves to the study of the blood-unit, which is always taken as the cubic millimetre, without reference to the number of units in the body.
Anaemia.
_Anaemia_ is often used as a generic term for all blood diseases, for in almost all of them the haemoglobin is diminished, either as a result of diminution in the number of the red corpuscles in which it is contained, or because the individual red corpuscles contain a smaller amount of haemoglobin than the normal. As haemoglobin is the medium of respiratory interchange, its diminution causes obvious symptoms, which are much more easily appreciated by the patient than those caused by alterations in the plasma or the leucocytes. It is customary to divide anaemias into ”primary” and ”secondary”: the primary are those for which no adequate cause has as yet been discovered; the secondary, those whose cause is known. Among the former are usually included chlorosis, pernicious anaemia, and sometimes the leucocythaemias; among the latter, the anaemias due to such agencies as malignant disease, malaria, chronic metallic poisoning, chronic haemorrhage, tubercle, Bright's disease, infective processes, intestinal parasites, &c. As our knowledge advances, however, this distinction will probably be given up, for the causes of several of the primary anaemias have been discovered. For example, the anaemia due to _bothriocephalus_, an intestinal parasite, is clinically indistinguishable from the other forms of pernicious anaemia with which it used to be included, and leucocythaemia has been declared by Lowit, though probably erroneously, to be due to a blood parasite closely related to that of malaria. In all these conditions there is a considerable similarity in the symptoms produced and in the pathological anatomy. The general symptoms are pallor of the skin and mucous membranes, weakness and la.s.situde, shortness of breath, palpitation, a tendency to fainting, and usually also gastro-intestinal disturbance, headache and neuralgia. The heart is often dilated, and on auscultation the systolic murmurs a.s.sociated with that condition are heard. In fatal cases the internal organs are found to be pale, and very often their cells contain an excessive amount of fat. In many anaemias there is a special tendency to haemorrhage. Most of the above symptoms and organic changes are directly due to diminished respiratory interchange from the loss of haemoglobin, and to its effect on the various organs involved. The diagnosis depends ultimately in all cases upon the examination of the blood.
Though the relative proportions of the leucocytes are probably continually undergoing change even in health, especially as the result of taking food, the number of red corpuscles remains much more constant.
Through the agency of some unknown mechanism, the supply of fresh red corpuscles from the bone-marrow keeps pace with the destruction of effete corpuscles, and in health each corpuscle contains a definite and constant amount of haemoglobin. The disturbance of this arrangement in anaemia may be due to loss or to increased destruction of corpuscles, to the supply of a smaller number of new ones, to a diminution of the amount of haemoglobin in the individual new corpuscles, or to a combination of these causes. It is most easy to ill.u.s.trate this by describing what happens after a haemorrhage. If this is small, the loss is replaced by the fully-formed corpuscles held in reserve in the marrow, and there is no disturbance. If it is larger, the amount of fluid lost is first made up by fluid drawn from the tissues, so that the number of corpuscles is apparently diminished by dilution of the blood; the erythroblasts, or formative red corpuscles, of the bone-marrow are stimulated to proliferation, and new corpuscles are quickly thrown into the circulation. These are apt, however, to be small and to contain a subnormal amount of haemoglobin, and it is only after some time that they are destroyed and their place taken by normal corpuscles. If the loss has been very great, nucleated red corpuscles may even be carried into the blood-stream. The blood possesses a great power of recovery, if time be given it, because the organ (bone-marrow) which forms so many of its elements never, in health, works at high pressure. Only a part of the marrow, the so-called red marrow, is normally occupied by erythroblastic tissue, the rest of the medullary cavity of the bones being taken up by fat. If any long-continued demand for red corpuscles is made, the fat is absorbed, and its place gradually taken by red marrow. This compensatory change is found in all chronic anaemias, no matter what their cause may be, except in some rare cases in which the marrow does not react.