Part 9

A diminution in the hæmoglobin content can in this way be shewn in all anæmic conditions, especially in posthæmorrhagic, secondary and chlorotic cases. On the contrary, as Laache first observed, in the pernicious anæmias, the hæmoglobin equivalent of the individual discs is raised.

To appreciate correctly pathological conditions, it must always be borne in mind, that in normal blood the individual red blood corpuscles are by no means of the same value. Step by step some of the cells are used up and replaced by new. Every drop of blood contains, side by side, the most various stages of life of fully formed erythrocytes. For this reason influences which affect the blood--provided their intensity does not exceed a certain degree--cannot equally influence all red corpuscles. The least resistant elements, that is, the oldest, will succumb to the effect of influences, to which other and more vigorous cells adapt themselves.

To influences, of this moderate degree, belongs without doubt the anæmic constitution of the blood as such, the effect of which in this direction one can best investigate in cases of posthæmorrhagic anæmia.

In all anæmic conditions we observe characteristic changes in the blood discs.

A. =Anæmic or polychromatophil degeneration.=

This change in the red blood corpuscles, first described by Ehrlich, to which the second name was given later by Gabritschewski, is =only recognisable in stained preparations=. The red blood discs, which under normal circumstances stain in pure hæmoglobin colour, now take on a mixed colour. For instance, the red corpuscles are pure red in preparations of normal blood, stained with hæmatoxylin-eosine mixture. But in preparations of blood of a chromic anæmia stained with the same solution, in which possibly all stages of the degeneration in question are present, one sees red discs with a faint inclination to violet; others which are bluish red; and at the end of the series, forms stained a fairly intense blue, in which scarcely a trace of red can be seen, and which by their peculiar notched periphery are evidently to be regarded as dying elements.

Ehrlich put forward the theory, that this remarkable behaviour towards dyes indicates a gradual death of the red blood corpuscles, that is of the old forms, leading to a coagulation necrosis of the discoplasm. The latter takes up, as is the case in coagulation necrosis, the proteids of the blood, and acquires thereby the power of combining with nuclear stains. At the same time the discoplasm loses its power of retaining the hæmoglobin, and gives it up to the blood plasma in ever increasing quantity as the change proceeds. Hence the disc continues to lose the capacity for the specific hæmoglobin stain.

Objection has been raised to these views from many quarters, especially from Gabritschewski, and afterwards from Askanazy, Dunin and others. The polychromatophil discs are not, they say, dying forms, but on the contrary represent young individuals. The circumstance, that in certain anæmias the early stages of the nucleated red corpuscles are variously polychromatic, was evidence for this opinion.

In view of the great theoretical importance which attaches to this subject, the grounds for regarding this change as degenerative, may be here shortly brought forward.

1. The appearance of the erythrocytes which shew polychromatophilia in the highest degree. By the notching of their margins they appear to eyes practised in the judgment of morphological conditions, in a stage almost of dissolution, and as well-pronounced degeneration forms.

2. The fact that by animal experiment, for instance, in inanition, their appearance in large numbers in the blood can be produced. That is, precisely in conditions, where there can be least question of a fresh production of red blood corpuscles.

3. The clinical experience, that in acute losses of blood in man, these staining anomalies, can be observed in numerous cells, within so short a time as the first 24 hours. Whilst in our observations, which are very numerous upon this point, embracing several hundred cases, and carried out with particular care, no nucleated red blood corpuscles in this space of time can be found in man.

4. The polychromatophil degeneration can frequently be observed in nucleated red blood corpuscles, particularly in the megaloblasts. This fact can be so easily established that it can hardly escape even an unpractised observer, and it was sufficiently familiar to Ehrlich, who first directed attention to these conditions. The fact that the normoblasts, which are typical of normal regeneration, are as a rule free from polychromatophil degeneration, gave the key for the interpretation of this appearance. And similarly for the nucleated red blood corpuscles of lower animals. Askanazy asserts that the nucleated red blood corpuscles of the bone-marrow, which he was able to investigate in a case of empyema, shew, immediately after the resection of the ribs, complete polychromatophilia. This perhaps depends on the peculiarities of the case, or on the uncertainty of the staining method: eosine-methylene blue stain, which is for this purpose very unreliable, since slight overstaining towards blue readily occurs. (We expressly advise the use of the triacid solution or of the hæmatoxylin-eosine mixture for the study of the anæmic degenerations.)

After what has been adduced, we hold in agreement with the recent work of Pappenheim, and Maragliano, that the appearance of polychromatophilia is a sign of degeneration. To explain the presence of erythroblasts which have undergone these changes we must suppose that in severe injuries to the life of the blood these elements are not produced in the usual fashion, but from the very beginning are morbidly altered. Analogies from general pathology suggest themselves in sufficient number.

B. A second change that we find in the red blood corpuscles of the anæmias, is =poikilocytosis=.

By this name a change of the blood is denoted, where along with normal red blood corpuscles, larger, smaller and minute red elements are found in greater or less number. The excessively large cells are found in pernicious anæmia, as Laache first observed, and as has since been generally confirmed. On the contrary in all other severe or moderate anæmic conditions, the red corpuscles shew a diminution in volume, and in their amount of hæmoglobin. This contradiction, which Laache first mentioned, but was unable to explain, has found a satisfactory solution in Ehrlich's researches on the nucleated precursors of the myelocytes and normocytes (see below).

The blood picture of the anæmias is made still more complicated in that the diminutive cells do not preserve their normal shape, but assume the well-known irregular forms: pear-, balloon-, saucer-, canoe-shapes. Nevertheless in good dry preparations the smallest forms usually still shew the central depression. The so-called "microcytes" constitute an exception to this statement. These are small round forms, to which was allotted in the early days of the microscopic investigation of the blood, a special significance for the severe anæmias. They are however nothing but contraction forms of the poikilocytes, as the crenated are of the normal corpuscles. Consequently microcytes are but seldom found in dried specimens, whilst in wet preparations they are easily seen after some time. It is further of importance to know, that in fresh blood the poikilocytes exhibit certain movements, which have already given rise to mistakes in many ways. Thus at one time the poikilocytes were considered to be the cause of malaria. More recently the somewhat larger sizes were regarded by Klebs, Perles as amoebæ and similar organisms. In agreement with Hayem, who from the very first described these forms as =pseudo-parasites=, a warning must be given against attributing a parasitic character to them.

The origin of poikilocytosis, previously the subject of much discussion, is now generally explained in Ehrlich's way. For the mere fact, that by careful heating, poikilocytosis can be experimentally produced in any blood, forces one to the assumption that the poikilocytes are products of a fragmentation of the red blood corpuscles ("schistocytes," Ehrlich). And correspondingly the smallest fragments shew the biconcave form in the dry specimen; for they too contain the specific protoplasm of the disc "which possesses the inherent tendency to assume the typical biconcave form in a state of equilibrium."

Qualitative changes in the protoplasm of the poikilocytes are not to be observed, even by staining; and one may therefore ascribe to them complete functional power, and regard their production as a purposeful reaction to the diminished number of corpuscles. For by the division of a larger blood corpuscle into a series of homologous smaller ones, the respiratory surface is considerably increased.

C. A third morphological variation which anæmic blood may shew in the more severe degrees of the disease, is the appearance of =nucleated red blood corpuscles=.

Though we do not wish to enter here upon the latest questions concerning the origin of the blood elements, we must shortly indicate the present state of our knowledge of the nucleated red corpuscles.

Since the fundamental work of Neumann and Bizzozero, the nucleated forms have been generally recognised as the young stages of the normal red blood corpuscles. Hayem's theory, on the contrary, obstinately asserts the origin of the erythrocytes from blood-platelets, and has, excepting by the originator and his pupils, been generally allowed to drop.

Ehrlich had in the year 1880 pointed out the clinical importance of the nucleated red blood corpuscles, in as much as he demonstrated that in the so-called secondary anæmias, and in leukæmia, nucleated corpuscles of the normal size, "normoblasts"; in pernicious anæmia excessively large elements, "megaloblasts," "gigantoblasts" are present. At the same time Ehrlich mentioned that the megaloblasts also play a prominent part in embryonic blood formation.

In 1883 Hayem likewise proposed a similar division of the nucleated red blood corpuscles into two,

(1) the "globules nuclées géantes" which he found exclusively in the embryonic state, (2) the "globules nuclées de taille moyennes" which he found invariably present in the later stages of embryonic life, and in adults. Further, W. H. Howell (1890) found in cats' embryoes two kinds of erythrocytes, (1) very large, equivalent to the blood cells of reptiles and amphibia ("ancestor corpuscles"), and (2) of the usual size of the blood corpuscles of mammalia. And similarly more recent authors, H. F. Müller, C. S. Engel, Pappenheim and others, have adhered to the division of hæmatoblasts into normo- and megaloblasts. And it is on the whole recognised, that, physiologically, normoblasts are always present in the bone-marrow of adults, as the precursors of the non-nucleated erythrocytes; that the megaloblasts, however, are never found there under normal circumstances, but only in embryonic stages, and in the first years of extra-uterine life.

S. Askanazy on the contrary has expressed the view, that the normoblasts may arise from the megaloblasts, and thereby denies the principal distinction between them. Schaumann also holds that the separation of the two kinds rests on doubtful foundation, since occasionally it is questionable whether particular cells are the normoblasts or the megaloblasts.

We distinguish three kinds of nucleated red blood-corpuscles on the grounds of the following characters;

1. =The normoblasts.= These are red corpuscles of the size of the usual non-nucleated disc, whose protoplasm as a rule shews a pure hæmoglobin colour, and which possess a nucleus. Occasionally there may be 2-4 nuclei. The sharply defined nucleus lies generally in the centre, comprises the greater part of the cell, and is above all distinguished by its intense colour with nuclear stains, which exceeds that of the nuclei of the leucocytes, and indeed of all known nuclei. This property is so characteristic that the free nuclei, which occur occasionally in anæmias, and particularly often in leukæmia, may be recognised as nuclei of normoblasts, although surrounded by traces only of hæmoglobin, or by none at all.