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From these considerations it is obviously necessary to derive the description of leukaemic blood from pure uncomplicated cases; and to construct it with the aid of standard methods. In this manner a type is obtained so characteristic, as to render diagnosis absolutely certain from the blood alone.
It is needful here to emphasise this hundred-fold repeated experience with special distinctness, for some recent authors do not even yet allow the full diagnostic importance of the blood examination. v. Limbeck says in the latest edition of his clinical Pathology of the Blood, "That one should not regard the blood changes as an invariably reliable diagnostic resource in myelogenic leukaemia; and that the diagnosis of leukaemia should not rest on the presence or significance of one or more cells. Not only the general features of the case, but the blood condition as well should be considered." To these remarks the objection must be made that up to the present no serious haematologist will have had to diagnose a leukaemic disease principally "from the presence of one or more cells." In the work of Ehrlich and his pupils at least, it has always been shewn that the character of a leukaemic condition is only settled by a concurrence of a large number of single symptoms, of which each one is indispensable for the diagnosis, and which taken together are absolutely conclusive. With these premises it is indisputable that the microscopic examination of the blood alone on dry preparations, without the assistance of any other clinical method, can decide whether a patient suffers from leukaemia, and whether it belongs to the lymphatic or myelogenic variety.
The microscopic picture of myelogenic leukaemia, disregarding the almost constant increase of the white blood corpuscles, has a varied, highly inconstant character. This arises from the co-operation of several anomalies, namely:
A. that in addition to the polynuclear cells, their early stages, the mononuclear granulated corpuscles likewise circulate in the blood;
B. that all three types of granulated cells, the neutrophil, eosinophil, and mast cells participate in the increase of the white blood corpuscles;
C. that atypical cell-forms appear, e.g. dwarf forms of all the kinds of white corpuscles; and further mitotic nuclear figures;
D. that the blood always contains nucleated red blood corpuscles, often in great numbers.
1. We begin with the discussion of the mononuclear neutrophil cells, Ehrlich's "myelocytes." They are present so abundantly in the blood of medullary leukaemia as to impart to the whole picture a predominantly mononuclear character. As we have frequently mentioned, myelocytes occur normally only in the bone-marrow, not in the circulating blood. Their eminent importance for the diagnosis of myelogenic leukaemia, where they have been regularly found by the best observers, is in no way diminished by their transitory appearance in a few other conditions (see pages 77, 78). Though they have been occasionally found, according to Tuerk's investigations, in the critical period of pneumonia as parts of a general leucocytosis, the danger of confusion with leukaemic blood changes is non-existent. This is guarded against by (1) the much smaller increase of the white cells; (2) the diminution of the eosinophil and mast cells; (3) the fact, that the myelocytes of leukaemic blood are nearly always considerably larger; (4) the preponderating polynuclear character of the leucocytosis, which is not effaced by the small percentage amount of myelocytes (at most 12%): (5) the incomparably smaller absolute number of myelocytes. In the most pronounced case of Tuerk's, for example, in which the percentage number of myelocytes amounted to 11.9, calculation of their absolute number gives at most 1000 myelocytes per mm.^{3} This is a figure which bears no comparison with that obtaining in leukaemia, where 50,000-100,000 myelocytes per mm.^{3} and over occur in cases that are in no way extreme.
2. The mononuclear eosinophil cells. Before the introduction of the staining method, Mosler had described large, coarsely granulated cells, "marrow cells," as characteristic for myelogenic leukaemia. These are to be regarded as for the most part identical with the mononuclear eosinophil cells, noticed by Mueller and Rieder as peculiar, and aptly described by them as the eosinophil analogues of the preceding group. They appear as large elements with oval, feebly staining nucleus. Undeniably a valuable sign of leukaemia, they are not nearly so important as the mononuclear neutrophil cells, as follows from the numerical superiority of the latter. To regard the presence of "eosinophil myelocytes" as absolute proof of the existence of a leukaemia is inadmissible, since they are occasionally present in small numbers in other diseases.
3. The absolute increase of the eosinophil cells. In his first paper on leukaemia, Ehrlich stated that the absolute number of polynuclear eosinophils is always much increased in myelogenic leukaemia. This assertion of Ehrlich has been received under some protest; v. Limbeck in his text-book even speaks of an "alleged" increase of the eosinophil cells. The well-known work of Mueller and Rieder has more particularly given rise to this opposition, and thrown doubt on the diagnostic importance of the eosinophil cells. These authors however base their contradiction on false premises.
For Ehrlich did not speak of a rise of the percentage of the eosinophil cells, but only of an increase in their absolute number. If in a case of leukaemia only the normal percentage number of eosinophils is found, it indicates, all the same, a great absolute increase; and Mueller and Rieder would themselves have fully confirmed Ehrlich's statement, had they only calculated the absolute figures in a few of their cases. Selecting from the seven cases in this paper, those where it is possible from the given data to obtain the absolute number of the eosinophil cells, we get the following results:
Case 29 3.5% eos. 14,000 per mm.^{3} " 30 3.9% " 8,000 " " 31 3.4% " 11,000 "
The figure given by Zappert as a high normal value is 250. In these cases there is an average number of 11,000, that is 50 times as great. The observations then of Mueller and Rieder themselves suffice fully to confirm Ehrlich's statement.
The absolute number of eosinophil cells depends naturally to a certain extent on the relative proportion of white to red corpuscles, and the greater the relative number of leucocytes, the greater should be the number of eosinophils. Zappert, for instance, found the following figures in his cases:
Proportion of white Absolute number to red corpuscles. of eosinophils.
1:24 3,000-4,560 1:18 3,300 1:15 7,000 1:13 8,700 1:11 6,000 1:7.6 8,300 1:7.0 7,600 1:7.0 29,000 1:5.0 14,000 1:3.8 34,000.
Apart from the approximate parallelism between the two rows of figures, this abstract shews that the minimal value—3,000 eosinophils with a proportion of white to red of 1:24—still amounts to 15 times the normal. The maximal figure found by Zappert of 30,000 is moreover by no means to be considered extreme. Cases of leukaemia are not infrequent in which we find 100,000 eosinophils per mm.^{3} and over.
From these figures it must be admitted that the absolute increase of the eosinophil cells in medullary leukaemia is not "alleged" (v. Limbeck) but on the contrary is very real and considerable.
That the absolute and relative number of eosinophil cells may markedly sink in certain complications of leukaemia, constitutes no exception to the law that the eosinophil cells are increased in myelogenic leukaemia. In this connexion the self-evident principle must be observed, that only analogous conditions are comparable. The standard of comparison for a leukaemic patient suffering from severe sepsis is not the blood of a healthy person with normal numerical proportions, but that of a patient similarly attacked by a severe sepsis. Now we know that in sepsis the number of eosinophil cells is enormously diminished, so that Zappert, in five cases of this nature, was unable to recognise any eosinophils in the blood. In contrast to this stands a case of myelogenic leukaemia described by Rieder and Mueller, complicated by a severe and lethally ending suppurative process. In consequence of the acute neutrophil leucocytosis brought about by the septic infection, the number of eosinophils sank rapidly from 3.5% to 0.43% (4 hours before death). The absolute number of eosinophil cells however in this terminal stage still amounted to 1400-1500 per mm.^{3}, and was therefore, in comparison with an uncomplicated sepsis, very much raised. Writers should not have disputed the importance of the eosinophil cells for the diagnosis of leukaemia from cases like these; on the contrary they should have seen in them a decisive confirmation of the constancy of the absolute increase of the eosinophils in leukaemic blood.
At the time when Ehrlich formulated his proposition on the diagnostic importance of the eosinophil cells in leukaemia, the simple eosinophil leucocytosis (see p. 148), first discovered later by the investigation of asthma etc., was unknown. For no confusion can arise between leukaemia, and conditions accompanied by eosinophilia, as they can be distinguished on clinical grounds alone. The blood moreover provides ample means for a differential diagnosis: (1) the total increase of the white cells in this case seldom reaches degrees that remind one of leukaemia; (2) the eosinophil cells are exclusively polynuclear; (3) mast cells and neutrophil myelocytes are almost entirely absent.
In favour of the diagnostic value of the absolute increase of the eosinophil cells are those cases too, where with a blood condition closely recalling leukaemia, the absence of eosinophil cells excludes the diagnosis of that disease. In a case of carcinoma of the bone-marrow, described by Epstein, with an anaemic constitution of the blood (nearly always present it may be mentioned in leukaemia), there was found a marked increase of the white blood corpuscles, numerous neutrophil myelocytes and nucleated red corpuscles. Anyone holding, as Mueller and Rieder do, that the number of eosinophil cells need not be considered in the diagnosis, must in this case have diagnosed myelogenic leukaemia. This however was according to Ehrlich's system impossible owing to the complete absence of eosinophil cells.
From all these observations it follows that an absolute increase of eosinophil cells is indispensable for the diagnosis of leukaemia.
4. The absolute increase of the mast cells. The mast cells are always increased in myelogenic leukaemia. They may be counted in leukaemic blood with the aid of the triacid or eosine-methylene blue stain. As shewn by the former they appear as polynuclear cells free from granules, since their granulation takes on no dye of the triacid mixture.
In all cases of myelogenic leukaemia the increase of mast cells is absolute and considerable. Generally they are equally or half as numerous as the eosinophils, occasionally they may exceed the latter in number. Hence it follows that the mast cells undergo an increase in number relatively greater than the eosinophil cells, for they normally amount only to some 0.28%. They are perhaps of greater diagnostic value than the eosinophils, because up to the present time we know of no other condition (in contradistinction to eosinophil leucocytosis) in which a marked increase of the mast cells occurs.
5. Atypical forms of the white corpuscles. Amongst these are to be mentioned: (a) dwarf forms of the polynuclear neutrophils and of the eosinophil elements respectively. As a rule they resemble normal polynuclear cells on a small scale. (b) Dwarf forms of the mononuclear neutrophil and eosinophil leucocytes, which correspond to the pseudo-lymphocytes described elsewhere (see p. 78). The importance of these dwarf forms for leukaemia is as yet insufficiently explained; and it is difficult to decide whether they are already small forms on reaching the blood-stream, or whether they are there produced by division of a large cell. (c) Cells with mitoses. Formerly particular weight was laid on the observation of mitoses, for they were regarded as evidence that the increase of white blood corpuscles was brought about in the circulating blood itself, an assumption specially supported by Loewit.
A large number of authors (H. F. Mueller, Wertheim, Rieder) have demonstrated mitoses, particularly of the myelocytes, in the circulating blood in leukaemia. No diagnostic importance of any kind can however be ascribed to them. They are found in all cases only in very small numbers. Thus Mueller says that he generally must look through many thousands of white cells before meeting one mitosis. Only in one case did he find the figures of nuclear division somewhat more abundant, where there was one mitosis only to several hundreds of leucocytes.
These really negative observations shew that the mitoses play a completely negligeable part in the increase of the cells in the blood itself. For the diagnosis of leukaemia they are valueless.
6. Nucleated red corpuscles form a constant constituent of leukaemic blood. In different cases their number is very varying; in one case they occur extremely sparingly, in another every field contains very many. The normoblastic type is found most frequently, but side by side with it, megaloblasts and forms transitional between the two are occasionally found. Mitoses within the red blood discs have been described by different authors, but possess no theoretic or clinical importance. The appearance of erythroblasts in leukaemia may be either a specific phenomenon, or merely the expression of an anaemia accompanying the leukaemia. We are inclined to the first supposition, since the occurrence in such numbers of nucleated red cells is hardly ever observed in other anaemias of the same severity.
So much for the characteristics of leukaemic blood, upon which the diagnosis of the disease is made. We must add that although in any case of medullary leukaemia each particular factor described is to be recognised, yet the manner of its appearance, its numerical relation to the others and to the total blood varies extremely. Apart from the degree of increase of the leucocytes, no one case is the same as another with regard to the other anomalies. In one case the blood bears a large-celled, mononuclear neutrophil character; in another the increase of the eosinophil cells predominates; in a third the nucleated red blood corpuscles preponderate; in a fourth we see a flooding of the blood with mast cells. And hence results a multiplicity of combinations, and each single case has its own individual features[34].
* * * * *
It is of special importance to study the changes due to certain intercurrent diseases in the blood picture of medullary leukaemia. This point has recently been the object of detailed investigation, in particular by A. Fraenkel, Lichtheim and others[35]. According to these authors, under the influence of febrile diseases the total number of leucocytes may be enormously decreased. The blood moreover is altered, so that the myelaemic characteristics become less marked, and the polynuclear neutrophil elements largely preponderate. The latter may attain the percentage numbers of common leucocytosis up to 90% and over.
We will here mention a few rare cases, demanding special attention, shewing the alterations leukaemic blood may undergo, and occasionally presenting almost insuperable difficulties in diagnosis. We find but a single case of this kind mentioned in the literature. Zappert reported a patient, who in February, 1892, had shewn the typical signs of myelogenic leukaemia. Amongst others the relation of white to red cells was found to be 1:4.92, and 1400 eosinophil cells per mm.^{3} (3.4%) were counted. At the end of September of the same year the patient was brought in a miserable condition to the hospital, where she soon died with gradually failing strength. During this period of observation the proportion of white to red was 1:1.5; the percentage of eosinophils, 0.43; the mononuclears, most of which had no neutrophil granulation, amounted to 70% of the leucocytes. Zappert expressly mentions that these mononuclear cells were in no way similar to the lymphocytes in general appearance. At the autopsy Zappert found the bone-marrow studded with non-granulated mononuclear cells, and the eosinophil cells were much more scanty than is usually the case in leukaemic bone-marrow. Blachstein, under Ehrlich's direction, investigated a second case of this kind. This patient had also been the subject of exact clinical investigations for some time on account of a myelogenic leukaemia. During the time he was last in hospital the blood could only be examined a day before the fatal termination, the direct consequence of a septic complication. With a markedly leukaemic constitution of the blood there were found 62% polynuclear cells, 17.5% mononuclear about the size of the ordinary myelocyte, 0.75% eosinophil cells, nucleated red blood corpuscles in moderate amount. The preponderance of polynuclear and the small number of eosinophil cells is readily explainable from the septic infection; on the other hand the absence of granules in the mononuclear cells is most surprising.
These two observations can only be interpreted by assuming a loss, in certain terminal stages, on the part of the organism, of its power of forming neutrophil substances. Similar conditions occur in non-leukaemic conditions; for example in a striking case of posthaemorrhagic anaemia described by Ehrlich. It is of great importance to direct attention to these cases, which up to the present have been practically disregarded—for ignorance of their occurrence may easily give rise to gross errors concerning the nature and origin of the mononuclear cells, and to the manufacture of a lienal form of leukaemia.
* * * * *
Finally we have to discuss the important question, how the origin of myelaemic blood is to be explained. According to our conceptions two possibilities come under consideration. Either we have to deal with a passive inflow of bone-marrow elements, or with an active emigration from the bone-marrow into the circulation. This important and difficult question is certainly not fully ripe for discussion. The most weighty objection to be raised against an active emigration of the bone-marrow cells is derived from the behaviour of the white blood corpuscles on the warm microscopic stage. These investigations have been performed by a number of authors of whom may be mentioned Biesiadecki, Neumann, Hayem, Loewit, Mayet, Gilbert, and particularly H. F. Mueller on the ground of his summary of this subject. Concerning the behaviour of the forms of cell here involved, all authors are agreed that under no conditions do the lymphocytes shew the smallest spontaneous movement; whilst the polynuclear neutrophil cells always exhibit vigorous contractility. With regard to the forms most characteristic of leukaemic blood the statements are partially contradictory. Some authors deny all spontaneous movement of these cells; but most of them report observations from which it follows that a certain power of spontaneous movement is not to be gainsaid. It will be admitted that in questions of this kind, negative results are weakened by positive data. Thus Jolly recently described similar observations as follows: "C'etaient des changements de forme sur place, lents et peu considerables, formations de bosselures a grands rayons, passage d'une forme arrondie a une forme ovulaire ou bilobee etc. Ces mouvements etaient visibles dans les observations I et IV et appartenaient surtout a des globules de grande taille." It is naturally impossible to decide if these minute movements suffice for a spontaneous locomotion. But one cannot exclude off-hand the supposition that they do. It is indeed supported by a further observation of Jolly on the mononuclear eosinophil cells of the marrow. Hitherto it was taken for established that these cells are completely devoid of spontaneous movement. Jolly however was recently able to examine a specimen from a case of typical leukaemia, in which nearly all the eosinophil cells shewed active movement. He says: "Ces globules granuleux actifs presentaient des mouvements de progression et des changements de forme caracteristiques et rapides; cependant je n'ai pas vu ces globules presenter de pseudopodes effiles; de plus, leurs contours restaient presque toujours assez nettement arretes. Ces particularites correspondent exactement a la description, qu'a donnee depuis longtemps Max Schultze des mouvements des cellules granuleuses du sang normal." Examination of dry specimens from the same case shewed, as Jolly expressly mentioned, that the blood contained, as leukaemic blood always does, polynuclear and mononuclear eosinophil cells. In contrast then with all earlier observations, Jolly has demonstrated an active spontaneous movement of the mononuclear eosinophil cells. The amoeboid movement of the mononuclear cells is so seldom seen, not because they lack this function, but obviously from defects in the methods of investigation, which as is manifest are rather rough and wholly unsuited for delicate biological processes. There are many instances in the literature of the failures of this method, even in the case of cells with undisputed mobility. Thus Rieder failed to observe any contractility in the majority of polynuclear leucocytes in a case of malignant lymphoma, whereas according to all other observations they possess this property without exception.
We think then we must draw the conclusion that the feeble mobility of the mononuclear cells, both eosinophilous and polynuclear, is only apparent, and is owing to the gross method of investigation. In reality they doubtless have mobility sufficient for emigration.
A further, but much less weighty objection to the view that myelogenic leukaemia is an active leucocytosis is, that pus artificially produced in leukaemic patients has nearly always the histological constitution of normal pus. But from our previous detailed remarks we should only expect a myelaemic constitution of the pus, if the specific morbid agent of leukaemia were present in a concentrated form at the place of inflammation. Just as we saw in pemphigus, Neusser's eosinophilous suppuration occurred only in the specific pemphigus bullae, but not in the foci of suppuration that were artificially produced. We know that the myelocytes are in no way positively influenced by the chemiotactic stimuli of ordinary infectious agents. On the contrary, it clearly follows from the above-mentioned observations on the transformation of leukaemic blood under the influence of infectious diseases, that the common bacterial poisons act in a negatively chemiotactic sense, both on the eosinophil and on the neutrophil mononuclear cells. Under these circumstances we should indeed expect that artificially produced suppuration in leukaemic patients would have, not a myelaemic, but a polynuclear neutrophil character.
It will be the task of further investigations to examine accurately inflammatory products, e.g. pleuritic exudations, in leukaemic patients, with the object of elucidating the question, whether under special conditions of disease all the leucocytes characteristic for leukaemia may not be able to wander from the blood. Thus in a case of pleurisy in a leukaemic patient, Ehrlich received the impression from the preparations that a "myeloid" emigration had in fact occurred, carrying all the elements in the blood into the exudation. This observation does not prove the point, for numerical estimation of the proportion of white to red blood corpuscles in the exudation was not made. And these estimations are necessary in order to prove indisputably the active emigration of the white blood corpuscles into the exudation, and to exclude their purely mechanical passage, per rhexin, from the blood-stream.
The hypothesis of the active origin of myelaemia is considerably supported by a further train of argument. In leukaemia, besides the myelocytes, the polynuclear leucocytes are also enormously increased, and their active emigration is beyond doubt. And the view, that the mononuclear cells are washed into the blood, excludes that of a single mode of origin of the leukaemic blood condition; and commits us to a highly artificial explanation of its production.
The morphological changes of leukaemic blood under the influence of infectious diseases can only be explained from the standpoint of the emigration theory. For if the white blood corpuscles were mechanically carried out of the bone-marrow as a whole, it is incomprehensible that a bacterial infection should alter this process to a polynuclear leucocytosis. This change of character is easily explained on the other hand, as we have above shewn more in detail, by the assumption that ordinary bacterial poisons act positively chemiotactically only on the polynuclear neutrophil cells, but negatively on the other forms.
We explain the origin of leukaemic blood by the emigration into the blood under the influence of the specific leukaemic agent, not only of the formed polynuclear elements, but also of their mononuclear, eosinophil and neutrophil early stages; and to classify myelogenic leukaemia with the active leucocytoses.
FOOTNOTES:
[25] Naturally an ordinary leucocytosis may be combined with a lymphaemia. We have already mentioned elsewhere (see page 102) that in the leucocytosis of digestion or of diseases of the intestine in children, such a coincidence occurs.
[26] The so-called agony leucocytosis we do not regard as a true leucocytosis, but only as the expression of a stoppage of the circulation caused by that condition. This produces an accumulation of the white corpuscles on the vessel walls, especially in the peripheral parts of the body which are as a rule used for clinical investigation. A leucocytosis is thus simulated.
[27] It is also of interest to notice the behaviour of the eosinophil cells in the passive form of leucocytosis, lymphaemia. A priori both conditions could be combined. As C. S. Engel has established in the congenital syphilis of children a simultaneous marked increase of lymphocytes and eosinophil cells is found. The lymphocytosis in these cases is probably due to the anatomical changes of the lymph glands, and the eosinophilia to specific chemiotactic attraction.
[28] In his monograph on Bothriocephalus anaemia Schauman, with reference to the behaviour of the eosinophil cells, states that he has found them in but few cases of this disease.
[29] This view has lately received striking confirmation from the interesting experiment of Baeumer, who produced on himself by means of continued stimulation with Urticaria ureus a considerable increase in four days of the mast cells in the irritated portions of the skin.
[30] That a well-marked basophil leucocytosis has not so far been observed may be thus explained. The substances which attract the mast cells are very rarely produced in the body; much more seldom than the corresponding substances attractive for the eosinophils. In morbid conditions, where substances attracting the mast cells were present, it might be possible to find a suppuration of mast cells, or a mast cell leucocytosis as well. In this connection an observation of Albert Neisser is of the greatest interest. He met with (private communication) one, out of numberless cases of gonorrhoea, in which the purulent secretion consisted entirely of mast cells.
[31] Unger has recently published completely analogous observations on the human breast for the mast cells. Under the influence of stagnation of the milk he saw an invasion of the gland tissue by typical mast cells.
[32] A very interesting observation of Goldmann's deserves mention here. Goldmann found in preparations of the pancreas of proteus sanguineus, containing parasites, that the eosinophil cells in the neighbourhood of the encapsuled parasites were much increased, whereas they were sought for in vain, in more distant parts.
[33] A case observed some time back by Ehrlich may here be mentioned as a characteristic example. A woman received a blow in the region of the spleen by a fall from the roof, which gradually led to a marked splenic enlargement. As no other symptoms appeared, the surgeon in charge proposed splenectomy, on the assumption of a pure splenic leukaemia. Examination of the blood, however, shewed a condition fully corresponding with myelogenic leukaemia, and thus prevented surgical interference.
[34] Ehrlich was once able to recognise, by balancing the different forms of cells, the blood preparations after the loss of their labels from some ten cases of leukaemia.
[35] Literature given by A. Fraenkel.
V. DIMINUTION OF THE WHITE BLOOD CORPUSCLES (LEUKOPENIA).
Diminution of the white blood corpuscles plays—comparatively with their increase—a very unimportant role in clinical observations. It occurs in but few groups of diseases, and but seldom attains a marked degree. Koblanck has described a most marked fall in the number of the colourless cells, in the following remarkable blood condition. In a strong man, 25 years of age, whose internal organs were found to be healthy, short epileptiform attacks occurred, in one of which death took place. The autopsy gave no indication of the cause of death. Two examinations of the blood were made in the course of the three days he was under observation. In one of these, out of ten cover-glass preparations, not a single white blood corpuscle was found, and in the second only one example.
We have mentioned this case here, because it is remarkable as an extreme leukopenia never before observed. An explanation however is impossible owing to the obscurity of the general clinical condition.
For the rest the conditions, under which a considerable diminution of the leucocytes occurs, are very well-known. We distinguish two chief groups:
1. Leukopenia from destruction of a portion of the white blood corpuscles (Loewit);
2. Leukopenia from deficient inflow of white corpuscles:
[alpha]. in infectious diseases from negative chemiotaxis;
[beta]. in anaemia etc. from defective action of the bone-marrow.
We have entered more fully into the leukopenia experimentally produced by Loewit, in the chapter on leucocytosis. We there explained, that according to present views, we have to deal, not with an actual destruction of the white elements, but merely with an altered distribution within the blood-stream.
Amongst the infectious diseases where an hypoleucocytosis occurs, typhoid fever must first be mentioned. The diminution is chiefly at the expense of the polynuclear cells. Uncomplicated measles too, generally runs its course with a marked leukopenia, specially distinct during the breaking out and at the height of the exanthem. These cases of infectious leukopenia are to be explained, not by a destruction of white corpuscles, but rather by a diminished inflow, brought about by the circulation of substances negatively chemiotactic for the polynuclear elements.
Leukopenia has still another meaning in certain cases of severe anaemia, where it indicates a highly unfavourable prognosis. Ehrlich has described (Charite Annalen 1888) a case of posthaemorrhagic anaemia ending fatally, where an extreme diminution of the leucocytes occurred. Exact figures shewed that the greater proportion (80%) of white blood corpuscles consisted of lymphocytes, whilst the polynuclears amounted to 14% (instead of 70-72% normally). Eosinophil cells and nucleated red blood corpuscles were entirely absent. Ehrlich explained these phenomena by a deficient activity of the bone-marrow, which found expression in the insufficient formation of red and white blood corpuscles. As the anatomical basis of this deficient activity, he conjectured that in this case the fatty marrow of the big long bones could not have been changed to blood forming red marrow, as is the rule in severe anaemias. In two cases the autopsy fully confirmed this diagnosis made during life.
The blood platelets.—The haemoconiae.
The blood-platelets were first described by Hayem, later by Bizzozero, as a third formed element of normal blood. They are roundish or oval discs free from haemoglobin. They are extremely unstable under mechanical, thermal, and chemical influences. Their size amounts to some 3 mu. Specially characteristic is their tendency, the result of their extraordinary stickiness, to run together into largish clumps, "grape clusters." This circumstance greatly facilitates the distinction of the blood platelets from the other formed elements, but renders their enumeration most difficult. The apparatus usually used for counting the blood corpuscles is, for this reason, deceptive; for the platelets rapidly cling to its walls and remain there. All early authors (e.g. Bizzozero) endeavoured to obviate this error by some particular diluting fluid; but a number of these elements still remained fastened to the walls of the capillary tube of the mixing apparatus.
Recently Brodie and Russell have recommended a new mixture in which the platelets remain quite isolated, and are stained at the same time. They allow the drop of blood as it comes from the puncture to enter a drop of the fluid, and then estimate the relative proportion of red blood corpuscles to platelets[36]. The prescription for their solution is as follows:
Dahlia-glycerin, 2% solution of common salt ... equal parts.
Another method, used by the majority of more recent authors, is the relative enumeration of blood platelets in the stain dry specimen. Ehrlich found that the blood platelets were picked out by their deep red colour, corresponding to the amount of alkali they contain, in preparations treated by the iodine eosine method (see p. 46). Rabl's new method is much more complicated and in no way more serviceable, depending on a stain with iron haematoxylin recommended by E. Haidenhain for demonstration of the centrosomes. A process of Rosin's, not yet published, is more convenient. It consists in fixing the dry preparation for 20 minutes in osmic acid vapour, and staining in a concentrated watery solution of methylene blue.
* * * * *
With regard to the significance of the blood platelets, most authors, of whom we should before all mention Hayem, Bizzozero, Laker, assume justifiably that they are preformed in the living blood. The view opposed to this, advocated more particularly by Loewit, that these forms first arise in the blood after it has left the vessels, we may describe on the grounds of our own extensive observations as inaccurate.
The blood platelets, on the grounds of their small size and complete lack of nuclear substance, are generally regarded as not analogous to real cells. Whether they represent intravital precipitation of substances of the plasma, or whether they are budded off from the cells, cannot at the present be decided with certainty, though many facts seem to support the latter assumption. That they contain glycogen (see p. 45), marks them as descendants of the blood cells. Moreover, appearances are often met with in dry preparations that arouse the suspicion that the platelets arise from the red blood corpuscles (Koeppe). Arnold has further observed processes of budding in the red blood corpuscles not only extravascularly but also intravascularly in the mesentery of young guinea-pigs, and has seen the elements that were cut off change into forms free from haemoglobin.
Our knowledge too of the physiological function of the blood platelets still needs much amplification. The original view of Hayem, who regards the blood platelets as early stages of the red blood discs, and for this reason calls them "haematoblasts," is, according to the judgment of most haematologists, untenable.
Nearly all more recent papers, on the other hand (cp. Loewit's compilation), recognise the close connection of the blood platelets with coagulation, first observed by Bizzozero. Whether the substance of the platelets directly yields the material for fibrin formation, as Bizzozero holds, or whether according to the observations on thrombus production of Eberth and Schimmelbusch they play but a subordinate part, is not yet decided. To enter here into the chemical side of this complicated problem, would lead us much too far, and we will only refer to a few clinical observations which illustrate the relations between the clotting power of the blood and the number of platelets it contains.
Marked increase of the blood platelets occurs in chlorosis (Muir) and in posthaemorrhagic anaemia (Hayem). In both conditions there is a decided increase in the clotting power of the blood. In contrast, is the important observation of Denys, who found in two cases of purpura, where as is well-known the clotting power of the blood is always much lowered or may even be entirely destroyed, only one morphological blood change, a very marked diminution of the blood platelets. Ehrlich likewise had occasion to examine a similar case, in which the blood platelets were entirely absent.
* * * * *
H. F. Mueller has described a fourth formed constituent of the blood, and given it the name of "haemoconiae" or "blood atoms," "blood dust." It is found in the plasma of the blood as very small granule- or coccae-like colourless corpuscles, highly refractile, with a very active molecular movement, which keep their shape under observation for a very long time without any special precautions. According to Mueller these bodies are not blackened by osmic acid, and probably contain no fat; they seem to have no connection with fibrin formation, as they always lie outside the fibrin network. Mueller found them in every normal blood, in varying numbers however; much increased in a case of Morbus Addisonii; diminished in hunger and cachexias.
More detailed observations are necessary to determine the chemical nature of these forms. Experiments in this direction by extraction with ether, or by the use of fat staining substances, alkanna, Soudan dye, and comparative investigations on lipaemic blood should be successful.
FOOTNOTES:
[36] The physiological figures found by Brodie and Russell with the aid of this method exceed considerably those of earlier authors. They found a proportion of platelets to erythrocytes of 1:85 or an absolute number of about 635,000 per mm.{^3}
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Winternitz. Weitere Untersuchungen ueber Veraenderungen des Blutes unter thermischen Einwirkungen. Wiener klin. Woch. 1893, no. 47.
Wolff, F. und Koeppe. Ueber Blutuntersuchungen in Reiboldsgruen. Muench. med. Woch. 1893, no. 11.
Wright. Remarks on methods of increasing and diminishing the coagulability of the blood. Brit. Med. Journal, 1894.
Zangemeister. Ein Apparat fuer colorimetrische Messungen. Zeitschr. f. Biologie, 1896, vol. XXII.
Zappert, J. Ueber das Vorkommen der eosinophilen Zellen im anaemischen Blut. Zeitschr. f. klin. Med. vol. XXIII. (Literature.)
—— Neuerliche Beobachtungen ueber das Vorkommen des Ankylostomum duodenale bei den Bergleuten. Wiener klin. Woch. 1892, no. 24.
Zenoni, C. Ueber das Auftreten kernhaltiger roter Blutkoerperchen im circulierenden Blut. Virchow's Archiv, 1895, vol. CXX.
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FOOTNOTES:
[37] Owing to the enormous extent of haematological literature, we have been able to refer only to more recent publications. We have, however, indicated several papers, in which bibliographies of particular parts of the subject are to be found.
INDEX.
Active leucocytosis, 142
Acute lymphatic leukaemia, 170
—— —— —— marrow in, 118
Acute swelling of red corpuscles, 23
Administration of iron, 16
Agony leucocytosis, 146
Alexines, 139
Alkali distribution in blood, 47
—— test for in blood, 46
Anaemia, 1
—— bothriocephalus, 65
—— definition, 2
—— haemoglobin in, 49
—— iron in blood and organs in, 16
—— isotonic point of corpuscles in, 25
—— leukopenia in, 189
—— pernicious see Pernicious anaemia
—— platelets in, 193
—— posthaemorrhagic, 49, 51
—— —— erythroblasts in, 51
—— —— platelets in, 193
—— pseudoleukaemica infantum, 77
—— pulse in, 3
—— retinal vessels in, 3
—— specific gravity of blood in, 18
—— volume of corpuscles in, 23
Anaemic degeneration of corpuscles, 49-52
—— leucocytosis, 146
Arsenurietted hydrogen, leucocytosis from, 145
Asthma
—— eosinophilia in, 150, 158
—— sputum in, 157
—— suppuration in, 160
Atypical leucocytes, 77-80
—— in leukaemia, 179
Basic double staining, 38
Baths, leucocytosis from, 144
Bioblasts, theory of, 128
Birds, eosinophil cells of, 107, 130
Blood, quantity of, 2
—— —— in anaemias, 3
—— specific gravity of, 17
Blood corpuscles, enumeration of, 5, 6
—— —— enumeration of in anaemia, 12
Blood corpuscles, estimation of, 12
—— —— red see Red blood corpuscles
—— —— volume of, 13
—— —— white see Leucocytes
—— count, factors in, 11
—— crises, 62
—— dust, 193
—— platelets, 190
—— —— alkali in, 47
—— —— in chlorosis, 193
—— —— origin of, 192
—— poisons, leucocytosis from, 145
Bone-marrow, 105, 112
—— —— carcinoma of, 178
—— —— cells of, in various animals, 106
—— —— changes in anaemia, 117
—— —— changes in lymphatic leukaemia, 118
—— —— changes in pernicious anaemia, 117, 129
—— —— connection with leucocytosis, 155
—— —— connection with leukopenia, 189
—— —— development of leucocytes in, 108-110
—— —— giant cells in, 107
—— —— of dog, 114
—— —— protective organ, 111
—— —— tumours of, 115
Cachectic leucocytosis, 146
Camphor, eosinophilia from administration of, 154
Catarrhal jaundice, volume of corpuscles in, 23
Charcot's crystals, 151
Chemiotaxis, 139
Chemiotaxis, positive, 139
—— negative, 140
Chenzinsky's fluid, 43
Chloroform narcosis, leucocytosis from, 145
Chlorosis, platelets in, 193
Coagulation, rate of, 23
—— connection with platelets, 192, 193
—— in purpura, 193
Coagulometer, 23
Compensatory eosinophilia, 154
Congenital syphilis, leucocytosis in, 147
Corpuscles, at high altitudes, 8
—— enumeration of, 5
—— influences on, 7
—— red see Red corpuscles
—— volume of, 21
—— white see Leucocytes
Crisis, blood, 62
—— in infective fevers, 145
Diabetes, glycogen in blood in, 75
Differential count of corpuscles, 31
—— staining, theory of, 37
Digestion, leucocytosis of, 102
Diphtheria, myelocytes in, 78, 146
Dog, bone-marrow in, 114
Dry preparations, 32
—— substance of blood, 20
Duehring's disease, eosinophilia in, 156
Electricity, resistance to, of corpuscles, 25
Enumeration of corpuscles, 5, 31
—— —— —— in anaemia, 12
Eosine-methylene blue methods, 43
Eosinophil cells, 78, 185
Eosinophil cells after splenectomy, 89, 94
—— —— development of, 109
—— —— in birds, 130
—— —— in leukaemia, 176, 177
—— —— in malignant lymphoma, 163
—— —— in mammary glands, 163
—— —— origin of, 160, 161
—— —— secretion in, 134
—— leucocytosis, 148
—— —— causes of, 165
—— —— distinction from leukaemia, 178
—— —— occurrence, 150-154, 158
—— —— origin of, 154
—— myelocytes, 78
—— —— in leukaemia, 174
Erythroblasts, in leukaemia, 180
—— in spleen, 99
—— nuclei of, 57, 61
—— origin of, 55
—— varieties of, 55, 56
Exercise, leucocytosis from, 144
Ferrometer, 16
Fevers, complication of leukaemia, 177, 181
—— leucocytosis in, 144, 146
—— spleen in, 98
Fixation of films, 34
Formalin as fixative, 35
Giant cells in bone-marrow, 107
Gigantoblasts, 56
Glycogen in gonorrhoeal pus, 46
—— in platelets, 192
Glycogen in polynuclear leucocytes, 75
—— stain for, 45
Gonorrhoeal pus, glycogen in, 46
—— —— mast cells in, 160
Granulation, absence of, 118, 129, 182
—— chemical nature of, 134
—— ripening of, 108
Granules, 121
—— connection with emigration, 132
—— distribution of, 130
—— function of, 127
—— history of, 121-130
—— intravital staining of, 124
—— intravital staining of by neutral red, 125
—— reaction of, 126
—— secretory nature of, 134
—— specificity of, 133
—— survival staining of, 125
Guinea-pig, leucocytes in, 85, 112
Haematocrit, 21
Haematocytometer, 4
Haematoxylin-eosine mixture, 42
Haemoconiae, 193
Haemoglobin, amount of, 13
—— connection with specific gravity, 18
—— equivalent in anaemias, 49
—— estimation of, 14-17
Haemoglobinometer, 15
Haemorrhages, acute, 51
Haemorrhagic small-pox, pseudo-lymphocytes in, 79
Hayem's solution, 5
Heat as fixative agent, 34
Hedgehog, splenectomy in, 107
Helminthiasis, eosinophilia in, 150
High altitudes, erythrocytes at, 8-12
—— —— poikilocytosis at, 9
Hodgkin's disease (malignant lymphoma), 101, 102
—— —— eosinophil cells in, 165
Hyaline cells see Large mononuclear leucocytes
Hygraemometry, 20
Infectious diseases, leucocytosis in, 146, 147
—— —— myelocytes in, 77
—— —— splenic enlargement in, 99
Intestinal diseases, leucocytosis in, 102
Intravital staining, 124
Iron, administration of, 16
—— connection of, with haemoglobin, 16-18
—— in blood, 16
—— in eosinophil cells, 134
Isotonic point of corpuscles, 25
Jenner's stain, 44
Kresyl-violet-R, metachromatism with, 76
Kurloff's researches, 85
Lactation, eosinophil cells in, 163
—— mast cells in, 163
Large mononuclear leucocytes, 73, 112, 185 —— mononuclear leucocytes in measles, 113
Leucocytes, 71
Leucocytes, atypical forms, 77, 179
—— enumeration of, 5
—— in birds, 131
—— in guinea-pig, 85-87, 112
—— places of origin, 81
Leucocytosis, 138
—— active, 142
—— agony, 146
—— cachectic, 146
—— chemically produced, 189
—— classification of, 142
—— diagnostic importance of, 146
—— eosinophil see Eosinophil leucocytosis
—— function of bone-marrow, 110
—— in anaemia, 146; congenital syphilis, 147; measles, 113, 145, 189; parotitis, 144; pneumonia, 144, 174; rheumatism, 144; tumours of bone-marrow, 116; typhoid, 146, 189
—— mixed, 143, 167
—— of digestion, 102
—— origin of, 146
—— passive, 142
—— physiological, 144
—— polynuclear neutrophil, 143
—— theories of, 138
Leukaemia, acute lymphatic, 118, 170; chronic, 170; suppuration in, 105
—— myelogenic, 169
—— —— atypical cases, 182
Leukaemia, myelogenic, atypical leucocytes in, 179
—— —— characteristics of, 174-181
—— —— complicated with other diseases, 174, 181
—— —— contrasted with eosinophilia, 178
—— —— contrasted with pneumonia, 174
—— —— diagnosis from blood, 171
—— —— eosinophilia in, 176
—— —— mast cells in, 179
—— —— mitoses in, 180
—— —— mononuclear eosinophils in, 175
—— —— myelocytes in, 174
—— —— origin of blood condition, 183, 187
—— —— pleuritic exudation in, 186
—— —— polynuclear myelocytes in, 175
Leukopenia, 188-190
—— experimental, 140
—— in various diseases, 189
Liver, granules in, 127
Lymphaemia see Lymphocytosis
Lymphatic glands, 100
—— —— myelocytes in, 110
Lymphocytes, 71
—— in disease of lymphatic glands, 101; lymphatic tumours, 101; polynuclear leucocytosis, 143
Lymphocytosis, 101, 103, 144
—— after splenectomy, 90, 94
—— causes of, 101-103
—— in leukaemia, 170
—— origin of, 104
Lymphoma malignum (Hodgkin's disease), 101, 102
Malignant tumours, eosinophilia from, 153
Mast cells, 76, 160
—— —— halo round, 135
—— —— in gonorrhoea, 162; leukaemia, 179; purpura (horse), 136
—— —— in skin, 160
—— —— origin of, 162
—— —— secretion in, 135
Measles, leukopenia in, 145, 189
Medicinal eosinophilia, 154
Megaloblasts, 56-62
—— in bothriocephalus anaemia, 65; leukaemia, 180; pernicious anaemia, 62, 66; tumours of bone-marrow, 117
Megalocytes, 64
Metachromatism in mast cells, 76
Methylal method, 44
Microblasts, 57
Mitoses in leukaemic blood, 180
Mononuclear leucocytes, 73, 112, 116
—— —— origin of, 113
—— —— power of motion, 185
Mouse, polynuclear cells in, 131
—— spleen in, 99
Myelaemia, origin of, 183, 187
Myelocytes, 77, 110
—— importance in blood, 110; in diphtheria, 78
—— in anaemia pseudoleukaemica infantum, 77; bone-marrow tumours, 117; leukaemia, 174; lymphatic glands, 110; lymphatic leukaemia, 118; pneumonia, 78
Myelocytes, eosinophil, 78, 175
Myelogenic leukaemia see Leukaemia, myelogenic
Nasal polypi, eosinophil cells in, 159
Neutral red, 125
Neutrophil granulation, absence of, 118, 129
Neutrophil leucocytes see Polynuclear neutrophil leucocytes
Neutrophil pseudolymphocytes, 79
Normoblasts, 56, 57-62
—— in anaemias, 62; leukaemia, 180
Nose, diseases of, eosinophil cells in, 159
Nucleated red corpuscles see Erythroblasts
Old granulations, 109
Oligaemia, 2
Oligochromaemia, 2
Oligocythaemia, 2
Ozonophores, 129
Pacini's solution, 5
Paralysis, unilateral, corpuscles in, 6
Parotitis, leucocytosis in, 144
Passive leucocytosis, 142
Pemphigus bullae, 156
—— —— eosinophilia in, 150
Pernicious anaemia, bone-marrow in, 129
Pernicious anaemia, haemoglobin equivalent in, 49
—— —— megaloblasts in, 63, 65
—— —— prognosis, 66
Phagocytosis, 139
Phosphorus poisoning, spleen in, 98
Pilocarpine, lymphocytosis from, 103
Platelets see Blood platelets
Pleuritic exudations, in leukaemia, 186
—— —— pseudo-lymphocytes in, 79
Pneumonia, contrast with leukaemia, 174
—— glycogen reaction in, 75
—— leucocytosis in, 141, 146, 152
—— myelocytes in, 174
Poikilocytosis, 52
—— at high altitudes, 9
—— explanation of, 54
—— from heating, 54
Polychromatophil degeneration, 49
Polynuclear neutrophil leucocytes, 74, 112, 185
—— —— —— diminution of in lymphatic leukaemia, 118; in myelogenic leukaemia, 182
—— —— —— increase of see Leucocytosis
—— —— —— movement in, 184
—— —— —— secretion in, 137
Post-febrile eosinophilia, 152
Posthaemorrhagic anaemia, blood in, 51
—— —— —— platelets in, 193
Potassium chlorate, leucocytosis from, 155
Pregnancy, leucocytosis in, 144
Pseudo-eosinophil cells, 85, 133
—— —— —— secretion in, 137
Pseudo-lymphocytes, 79
Purpura, of horse, mast cells in, 136
—— platelets in, 193
Pyknosis, 61
Pyrodin, leucocytosis from, 145
Quadratic ocular diaphragm, 31
Quantity of blood, estimation of, 2
Red corpuscles, 48
—— —— acute swelling of, 21
—— —— at high altitudes, 8-12
—— —— connection with spleen, 99
—— —— in anaemia, 49-57
—— —— isotonic point of, 25
—— —— nucleated see Erythroblasts
—— —— number of, in health, 7
—— —— number of differences in age, 7; in sex, 7; food, 7; from vasomotor influences, 11
—— —— polychromatophil degeneration in, 49
—— —— size of, 12
—— —— volume of, 21
Retinal vessels in anaemia, 3
Rheumatic fever, leucocytosis in, 152
Scarlet fever, leucocytosis in, 146
—— —— lymphatic glands in, 110
Separation of serum, 24
Serum, specific gravity of, 20
Sex, influence on red corpuscles, 7
—— —— specific gravity of blood, 17
Shock, effect of, on specific gravity of blood, 18
Size of red corpuscles, 12
Skin diseases, eosinophilia in, 150
Small-celled infiltration, 105
Specific gravity of blood, 17
—— —— —— —— connection with haemoglobin, 18
—— —— —— —— in anaemias, 18
—— —— —— —— influences acting on, 18
—— —— —— —— of serum, 20
Spleen, 84
—— as blood forming organ, 84, 99
—— enlargement of, in fevers and phosphorus poisoning, 98
—— excision of see Splenectomy
—— functions of, 98
—— in guinea-pig, 91, 93, 99
—— tumours of, 97, 98
Splenectomy, effect of on blood in hedgehog, 107; in guinea-pig, 88; in man, 93, 95, 96, 113
Staining, theory of, 36
—— vital, 124
Stimulation forms of leucocytes, 79
Stroma of corpuscles, influence on specific gravity of blood, 19
Suppuration in lymphatic leukaemia, 104; in myelogenic, 177; in pemphigus, 157
Survival staining, 125
Thyroid, changes after splenectomy, 84
Time of life, influence of, on corpuscles, 7
Toxic leucocytosis, 145
Transitional forms of leucocytes, 74, 112
Triacid stain, 42, 131
Trichinosis, eosinophilia in, 152
Tropics, influence of, on red corpuscles, 12
Tuberculin injections, eosinophilia from, 152
—— —— lymphocytosis in, 103
Tumours of bone-marrow, 115
Typhoid fever, leukopenia in, 146, 189
Urticaria, eosinophilia in, 150
Vital staining, 124
Volume of corpuscles, 21
White blood corpuscles see Leucocytes
Whooping cough, lymphocytosis in, 103
Worms see Helminthiasis
Wright's coagulometer, 24
CAMBRIDGE: PRINTED BY J. AND C. F. CLAY, AT THE UNIVERSITY PRESS.
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