Chapter M: B. Schmidt without making use of the principal distinction made by

Ehrlich, also concludes from his researches on sections of the bone-marrow of animals in extra-uterine life, that both kinds of erythrocyte formation occur.

Quite recently Pappenheim, partly in conjunction with O. Israel, has carried out very thorough researches on these particular points. As the subject for observation he chose the blood of embryonic mice. He was able in the first place, like Rindfleisch, to produce the exit of the nuclei from the cells by the addition of "physiological" salt solution to fresh blood, and is of the opinion that the exit of the nucleus from the erythroblasts only takes place artificially.

In embryonic blood the metamorphosis to erythrocytes occurs exclusively by nuclear destruction and solution within the cell, be it in the case of megalo- or gigantoblasts or of cells of the size of the normal red blood corpuscle.

The free nuclei that are observed, whose appearance Pappenheim explains by a preceding solution of the protoplasm (plasmolysis), he regards, in opposition to Rindfleisch and Neumann, not as the beginnings of a developmental series, but as the surviving remnants of the degenerated dying blood cells. Clinical observation, certainly, does not support this conception of Pappenheim's; in as much as in suitable cases with numerous free nuclei (leukæmia, blood crises) transitional forms, which according to Pappenheim must necessarily be present, are not to be found. Moreover, in alluding to a case of leukæmia of this kind, this author himself admits that the appearance of free nuclei can be explained in this instance by the exit of the nucleus.

Although Pappenheim, as above mentioned, recognises no difference between megaloblasts and normoblasts in embryonic blood as far as the fate of the nucleus is concerned, he nevertheless decidedly supports Ehrlich's separation of the erythroblasts into these two groups, as two hæmatogenetically distinct species of cells. He does not regard as distinguishing characteristics, the size and hæmoglobin content of the cells--although as we have described above, these are in general different in normo- and megaloblasts--for these two properties undergo such great variations as to increase considerably under certain circumstances the difficulty of diagnosis of individual cells. The chief characteristic is, as Ehrlich has always particularly insisted, the =constitution of the nucleus=. The nuclei of cells which are with certainty to be reckoned among the normoblasts are marked by the absence of structure, their sharply defined contour, their intense affinity for nuclear stains. That is by properties which histology sums up under the name =Pyknosis= (Pfitzner) and recognises as signs of old age. The nuclei of the megaloblasts are round, shew a good deal of structure, and stain far less deeply.

[beta]. The clinical differences. Normoblasts are found almost invariably in all severe anæmias that are the result of trauma, inanition or organic disease of some kind. They are however mostly rather scanty, so that a preparation must be searched for some time before an example is found. But occasionally, most often in acute, but also in chronic anæmias, and even in =cachectic= conditions, every field shews one or more normoblasts.

V. Noorden was the first to describe a case in which in the course of a hæmorrhagic anæmia normoblasts temporarily appeared in such overwhelming numbers in the circulating blood, that the microscopic picture, which at the same time comprised a marked hyperleucocytosis, was almost similar to that of a myelogenous leukæmia. And as in addition to this occurrence the number of blood corpuscles was nearly doubled, v. Noorden gave it the distinctive name "blood crisis."

The following procedure is to be recommended for the
investigation of the blood crisis:

1. Estimation of the absolute number of red blood corpuscles.

2. Estimation of the proportion of white to red corpuscles.

3. Estimation of the proportion of nucleated red to white
corpuscles by means of the quadratic ocular diaphragm (see page
31) in the dry preparation.

For instance if we find in a case of anæmia, 3-1/2 millions of
red blood corpuscles, the proportion of white to red corpuscles
= 1/100 and that of the nucleated red to the white = 1/10, then
in 1 cubic millimeter there are 3500 nucleated red corpuscles,
that is for 1000 ordinary there is 1 nucleated corpuscle.

=Megaloblasts= on the contrary are never found in traumatic anæmias. And in chronic anæmias of the severest degree, the result for example of old syphilis, carcinoma of the stomach and so forth, one looks for them almost always in vain, although they are sometimes to be found in leukæmia. On the contrary, the conditions, apparently much milder, in which from the clinical history, ætiology and general objective symptoms pernicious anæmia is suggested, are almost without exception characterised by the appearance of megaloblasts in the blood. Nevertheless in very late stages of the disease they are always scanty, and a very tedious search through one or more specimens is often required to demonstrate their presence. Hence follows the rule, that the investigation of a case of severe anæmia should never be considered closed, before three or four preparations at least have been minutely searched for megaloblasts under an oil immersion objective.

This clinical difference between the two kinds of hæmatoblasts admits of but one natural conclusion, which primarily leaves untouched the question, so much discussed at the present time, whether the megalo- or normoblasts can change one to the other. In all cases of anæmia, in which the fresh formation occurs according to the normal type, only in greater quantity and more energetically, we find normoblasts. Almost all anæmias resulting from known causes: acute hæmorrhages, chronic hæmorrhages, poverty of blood from inanition, cachexias, blood poisons, hæmaglobinæmia and so forth,--in short all conditions rightly called, secondary, symptomatic anæmias,--may shew this increase of normal blood production. In the conditions, which Biermer, on the grounds of their clinical peculiarities, has distinguished as "essential, pernicious anæmia" megaloblasts on the contrary occur, and represent an embryonic type of development. The extent to which this type participates in the blood formation in pernicious anæmia is most simply demonstrated by the fact that megaloblasts are present in all cases of pernicious anæmia, as Laache first shewed, and in some cases form the preponderating portion of the blood discs. Whilst, therefore, in the ordinary kinds of anæmia we find that the red corpuscles tend to produce small forms, in pernicious anæmia, on the other hand, and exclusively in this form, we find a tendency in the opposite direction. This constant difference cannot be a chance result, but must depend on some constant law: in pernicious anæmia excessively large blood corpuscles are produced. Ehrlich's demonstration of megaloblasts has sufficed for this logical advance. =All researches, which try to obscure or totally deny the distinction between megaloblasts and normoblasts are wrecked by the simple clinical fact that in pernicious anæmia the blood is megaloblastic.=

The appearance of megaloblasts and megalocytes is therefore evidence that the regeneration of the blood in the bone-marrow is not proceeding in the normal manner, but in a way which approximates to the embryonic type. The extreme cases are naturally seldom, such as that of Rindfleisch, in which the whole bone-marrow was found full of megaloblasts. It is sufficiently conclusive for the pernicious nature of the case, "if only considerable portions but not the whole marrow, have lapsed into megaloblastic degeneration." We can now say that the megaloblastic metamorphosis is not a purposeful process, and for the following reasons: 1. Since the fresh formation of red blood corpuscles by means of the megaloblastic method is clearly much slower. This is especially borne out by the fact that the megaloblasts are present in the blood always in small numbers only, whilst the normoblasts, as above mentioned, are often found in much larger quantities. In agreement with this, "blood crises" are not to be observed in the megaloblastic anæmias. 2. Since the megalocytes which are formed from the megaloblasts possess in proportion to their volume a relatively smaller respiratory surface, and so constitute a type disadvantageous for anæmic conditions[10]. This is still more evident when we remember that the production of poikilocytes is on the contrary a serviceable process.

The megaloblastic degeneration of the bone-marrow is no doubt due to chemical influences, which alter the type of regeneration in a disadvantageous manner. We do not for the most part yet know the exciting causes of the toxic process; consequently we are unable to put a stop to it, and its termination is lethal. The Bothriocephalus anæmias, which in general as is well-known offer a good prognosis, by no means contradict this view. They hold their privileged position amongst the anæmias of the megaloblastic type, only for the reason that their cause is known to us, and can be removed. As in many infectious diseases, individuals react quite differently to the presence of the Bothriocephalus. Some remain well; others show the signs of simple anæmia, ultimately with normoblasts; whilst a third group presents the typical picture of pernicious anæmia. For many years, so long as its ætiology was unknown, Bothriocephalus anæmia was not separated on clinical grounds from pernicious anæmia. Severe Bothriocephalus anæmia may be described as a pernicious anæmia, with a known and removable cause. Good evidence for this point of view is afforded by a case of Askanazy, who describes a severe pernicious anæmia, with typical megaloblasts, in which after the complete expulsion of the Bothriocephalus, the megaloblastic character of the blood formation quickly vanished, was replaced by the normoblastic, and the patient rapidly recovered. This observation is so unequivocal, that it is a matter of surprise that Askanazy chooses to deduce from it, the ready transition from megaloblasts to normoblasts; whereas it is clear and definite evidence that =megaloblasts are only produced under the influence of a specific intoxication=. And in this way the presence of megaloblasts in the pernicious anæmias is to be explained. The megaloblastic degeneration of the bone-marrow depends on the presence of certain injurious influences, of which unfortunately we are as yet ignorant. Were it possible to remove them, it is quite certain _à priori_ that the bone-marrow--if the disease were not too advanced--would resume its normal normoblastic type of regeneration. Clinical observation supports this contention in many cases. In megaloblastic anæmias apparent cures are by no means rare, but sooner or later a relapse occurs, and finally leads with certainty to a lethal issue. These cases, familiar to every observer, prove with certainty that the megaloblastic degeneration as such may pass away, and that in isolated cases the conventional treatment by arsenic suffices to bring about this result. A definite cure however under these conditions is not yet attained, since we do not know the ætiological agent, still less can we remove it. =For this reason, the prognosis of megaloblastic anæmia, apart from the group of Bothriocephalus anæmia, is exceedingly bad.=

FOOTNOTES:

[8] Dunin, on the contrary, designates the appearance of nucleated red blood corpuscles within the first 24 hours after the loss of blood as normal and regular. This view does not correspond with the facts. A single case on one occasion may exhibit a rarity of this kind.

[9] Probably the dot-like and granular enclosures in the red corpuscles, which stain with methylene blue, and which Askanzy and A. Lazarus have observed in numerous cases of pernicious anæmia are also products of a similar nuclear destruction.

[10] It does not seem superfluous in this place expressly to emphasise, that what has been said on the diagnostic importance of the megaloblasts only holds for the blood of adults. For the conditions of the blood in children, which vary in many respects from that of adults see "Die Anæmie," Ehrlich and Lazarus, Pt. II. (Anæmia pseudoleukæmica infantum).

THE WHITE BLOOD CORPUSCLES.

The physiological importance of the _white blood corpuscles_ is so many sided that they form the most interesting chapter of the subject. That the white corpuscles play a significant part in the physiology and pathology of man has been recognised but slowly, obviously because there was at first some hesitancy in ascribing important functions to elements that are present in the blood in such relatively small numbers. A place in pathology was first assured to them by Virchow's discovery of leukæmia. The interest in the question was increased by Cohnheim's discovery that inflammation and suppuration are due to an emigration of the white blood corpuscles, and these conditions were particularly suitable for throwing light on normal processes. The fact that in diffuse inflammations, large quantities of pus are often produced in a short time, without the blood being thereby made poorer in leucocytes,--that the opposite indeed occurs,--necessitated the supposition that the source of the leucocytes must be extraordinarily productive. Hence in contradistinction to the red blood corpuscles, their small number is fully compensated by their exceptional power of regeneration.

Nevertheless, a considerable time elapsed before the powerful impulse that started from Cohnheim, bore fruit for clinical histology. As we have mentioned this was due to the circumstance that an exact differentiation of the various forms of leucocytes was very difficult with the methods in use up to that time. Although such distinguished observers as Wharton Jones and Max Schultze had been able to distinguish different types of leucocytes, Cohnheim's work remained clinically fruitless since the criteria they assigned were far too subtle for investigation at the bedside. Virchow indeed, the discoverer of leucocytosis, interpreted it as an increase of the lymphocytes; whereas it is chiefly produced by the polynuclear cells. Only after the distinction was facilitated by the dry preparation and the use of stains, did interest in the white corpuscles increase, and continue progressively to the present day. This is borne out by the exceptionally exhaustive hæmatological literature, and particularly by that of leucocytosis.

In spite of these advances, a retrograde movement in the doctrine of the leucocytes has gained ground surprisingly, especially in the last few years. Ever since Virchow's description of the lymphocytes, observers have tried to separate the various forms of leucocytes one from another, and if possible to assign different places of origin to these different kinds. There now suddenly appears an endeavour to bring all the white blood corpuscles into one class, and to regard the different forms as different stages merely of the same kind of cells. The following sections will show that this tendency is unwarranted and unpractical.