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}
LITERATURE[37].
~Altmann.~ Ueber die Elementarorganismen und ihre Beziehungen zu den
Zellen. _Leipzig_, 1 Aufl. 1890. 2 Aufl. 1894.
~Arnold.~ Zur Morphologie und Biologie des Knochenmarks. _Virchow's
Archiv_, Bd. 140.
---- Ueber die Herkunft der Blutplaettchen. _Centralbl. f. allg.
Pathologie und path. Anat._ Bd. 8, 1897.
~Askanazy.~ Ueber einen interessanten Blutbefund bei rapid letal
verlaufender Anaemie. _Zeitschr. f. klin. Med._ 1893, Bd. 23.
---- Ueber Bothriocephalus-Anaemie, und die prognostische Bedeutung der
Megaloblasten in anaemischem Blut. _Zeitschr. f. klin. Med._ 1895, Bd.
27.
~Barker.~ On the presence of iron in the granules of the eosinophil
leucocytes. _Johns Hopkins Hosp. Bull._ no. 42, 1894.
~Baeumer.~ Beitraege zur Histologie der Urticaria simplex und pigmentosa,
mit besonderer Beruecksichtigung der Bedeutung der Mastzellen fuer die
Pathogenese der Urticaria pigmentosa. _Inaugural Dissertation._
_Berlin_, 1895.
~Beck.~ Ueber Quecksilber-Exantheme. _Charite Ann._ Bd. 20.
~v. Beck.~ Subcutane Milzruptur, Milzexstirpation, Heilung. _Muench. Med.
Woch._ 1897, no. 47.
~Benario.~ Noch einmal die Leucocytenschatten Klein's. _Deutsche Med.
Woch._ 1894, no. 27.
~Biernacki.~ Untersuchungen ueber die chemische Beschaffenheit bei
pathologischen, insbesondere bei anaemischen Zustaenden. _Zeitschr. f.
klin. Med._ 1894, vol. XXIV. (References to literature.)
~Bizzozero.~ Ueber die Bildung der roten Blutkoerperchen. _Virchow's
Archiv_, 1884, vol. XCV.
---- Ueber einen neuen Formbestandtheil des Blutes, und dessen Rolle bei
der Thrombose and der Blutgerinnung. _Virchow's Archiv_, 1882, vol. XC.
~Bleibtreu, L.~ Kritisches ueber den Haematokrit. _Berl. klin. Woch._ 1893,
nos. 30, 31.
~Bleibtreu, M. und L.~ Eine Methode zur Bestimmung des Volums der
koerperlichen Elemente im Blut. _Pflueger's Archiv_, 1892, vol. LI.
~Blix-Hedin.~ _Skandinavisches Archiv f. Path._ 1890 (quoted by Limbeck).
~Brodie and Russell.~ The enumeration of blood-platelets. _Journ. of
Physiology_, 1897, nos. 4 and 5.
~Brown, T. R.~ _Johns Hopkins Hosp. Bulletin_, 1897.
~Buchner.~ Untersuchungen ueber die bacterienfeindlichen Wirkungen des
Blutes and Blutserums. _Arch. f. Hygiene_, vol. X, 1890.