Studies in the Osteopathic
Cells of the Blood: Volume
Louisa Burns, M.S., D.O., D.Sc.O.
DEVELOPMENTAL RELATIONS OF THE BLOOD CELLS
The manner in which the cells of the blood have
been developed, both ontogenetically and phylogenetically, is of great
interest. Many problems presented by the cells of the blood in the
leukemias and in patients with abnormal inheritance are explained by a
knowledge of the biological relations of the blood.
An accurate understanding of the structure and the
function of the red bone marrow is especially desirable, and much work
has been done in the study of this important tissue. Unfortunately
we have only begun to pick up a few facts and these have not yet been properly
The importance of the red bone marrow in physiological
economy is indicated by the fact that this is one of the last of the tissues
of the body to lose its blood supply as a result of bleeding or of any
other cause of anemia.
Animals which have been bled to death retain a fairly
adequate blood supply to the bone marrow as well as to the heart, lungs,
digestive tract and respiratory muscles long after the muscles of locomotion,
the skin, spleen and omentum have become apparently completely bloodless.
In the anemias the bone marrow retains its blood supply long after other
tissues become very pale. Yet the marrow is affected by many abnormal
conditions and the effects of these may be very severe.
The marrow is seriously affected by vertebral and
costal lesions which affect the innervation of the blood vessels and the
cells of the hematopoietic tissues. Such lesions and their effects
have been studied in osteopathic institutions.
When vertebrae or ribs are lesioned there is a condition
of strain in and around the affected joints. The joint surfaces are
abundantly supplied with sensory nerve endings and these are subjected
to abnormal pressure due to this tension. The swelling and edema
which always follow any strain of joints increase the synovial fluid, and
this also irritates the sensory nerve endings.
The central relations of the sensory nerves distributed
to the joints are interesting. Normally sensations from the joint
surfaces are not carried to the cerebral centers, but they exert an important
influence upon the nerve centers of the spinal cord. Impulses derived
from any joint surface affect the spinal nerve centers which control the
skeletal muscles moving that joint and the viscera which were derived,
embryologically, from the same somites. When vertebrae or ribs are
lesioned the abnormal sensory impulses affect the centers which control
the small, deep spinal muscles and the intercostal muscles. These
muscles are stimulated constantly and are thrown into a condition of hypertonicity,
which is called contracture by several pathologists. This constant
hypertonicity of the spinal and intercostals muscles tends to perpetuate
the lesion. Several interesting changes occur in muscles subjected
to this abnormal form of stimulation and in time a condition of rigor is
present. Still later fibrosis occurs and after this time complete
recovery of the normal condition of the muscle is probably impossible.
The visceral centers affected at the same time by the abnormal sensory
impulses from lesioned articulations include the centers governing the
red bone marrow of the bones concerned in the lesion.
Again, when vertebrae or ribs are lesioned there
is some swelling or edema of the surrounding tissues. This edema
is not yet well understood, but the effects produced by a strained ankle
or a bunion are too well known for the facts of the case to be doubted.
This edema is always present around lesioned vertebrae or ribs. Edematous
fluids are not quite identical with normal tissue juices; in edema there
is some acidosis, some accumulation of carbonic acid and other katabolites
and other effects of the disturbed circulation through the affected area.
The tissues around the thoracic vertebrae and the ribs are so constructed
that in lesions of these bones the intervertebral nerves and the adjacent
sympathetic ganglia are subjected to considerable pressure, due to the
edema. The nerves passing through the intervertebral foramina to
and from the sympathetic ganglia upon the heads of the ribs pass through
the edematous tissues and are thus subjected to pressure and to the effects
of the abnormal tissue juices. Medullated nerves are not quite so
seriously injured as are the non-medullated nerves and the latter carry
impulses from the sympathetic ganglia to the blood vessels and to the viscera
innervated from the same spinal segment as that concerned in the lesion.
The nervous control of the red bone marrow is not
yet well understood. The nerve fibers entering the bone marrow in
any part of the skeleton include medullated fibers, which seem to be sensory,
and non-medullated fibers derived from the sympathetic system. Of
the sympathetic fibers at least two groups are present, vasomotor nerves
which terminate in plates upon the walls of the blood vessels, mostly the
arterioles, and other nerves which terminate in fine brush-like endings
which lie free among the intrinsic cells of the bone marrow. The
sensory nerves are distributed chiefly to the periosteum and to the region
of the red bone marrow nearest the bony walls.
In animals, a bony lesion affecting the circulation
through any area of red bone marrow is followed by atrophy of the marrow
cells of that area. Within two or three years after such a lesion
has been produced, the interior of the bone shows pale, hardened areas
in which bony spicules and connective tisssue are associated with only
a few pale areas of remaining marrow cells. These latter areas contain
little or no evidence of active blood development, but are made up chiefly
of blood vessels, connective tissue cells and a few atrophic remnants of
The effects of various diseases and poisons upon
the bone marrow have been studied in many laboratories, and the discussion
of the fats in this connection is best associated with the diseases in
which such marrow changes are of interest.
A brief review of the structure of the red bone marrow
may be of interest.
CELLS OF THE NORMAL ADULT BONE MARROW
The blood of adult marrow includes all the cells
present in fetal blood, but the proportion of younger cells is greater
in the marrow from younger individuals and in lower animals. Since
the bone marrow is the chief site for the manufacture of red cells and
the granular white cells, it is easy to find immature cells of the two
groups abundantly present in the red marrow.
Hyaline cells are abundant in the red bone marrow,
especially in younger subjects and fetuses.
Cells which cannot be differentiated from true lymphocytes
by any method of staining now in general use are abundant. Larger
cells which resemble large lymphocytes are present in about the same relative
proportions to the small hyaline cells as is the case in the blood.
There is much difference of opinion as to the origin, functions and destination
of these cells. (Plates V, VI.)
There are also hyaline cells which are definitely
myeloid in origin and which seem to be derived from the reticular cells.
These cells may or may not give the oxidase reaction. The hyaline
myeloblast (non-granular marrow cells; lymphoid mother cell; undifferentiated
leucoblast; hemocytoblast; lymphoid hemoblast; microlymphoidocyte; macrolymphoidocyte;
stem cell; indifferent lymphoid germinal cell) is a cell which is rounded,
occasionally somewhat irregular in form, with hyaline, basophilic protoplasm
and a nuclear structure which is characteristic. The myeloblast seems
soft and has relatively great protoplasm. There are no true granules
but the protoplasm is faintly and irregularly granular in structure.
Vacuoles are found within the protoplasm frequently. The nucleus
has a fine, delicate reticular appearance with one to several fairly large
nucleoli. The lymphoblast differs from the hyaline myeloblast in
being somewhat firmer in structure and in having a smaller nucleus with
coarser chromatin masses and a heavier nuclear membrane. Azur granules
are sometimes found within the protoplasm of the lymphoblast but not the
myeloblast. The oxidase reaction is of little or no value in distinguishing
these primordial cells, because immature forms do not always give the oxidase
reaction even though they are of the myelocytic group.
The nucleus of the myeloblast has a definite nuclear
membrane which is very delicate and very thin; it is sometimes difficult
to see this membrane but it can be shown by careful study in all cells
of this type. The chromatin is rather evenly distributed throughout
the nucleus, but may be somewhat denser around the nucleoli. The
parachromatin is abundant and the nucleus generally appears pale on this
account. Under pathological conditions the parachromatin is often
relatively diminished so that the nucleus appears much deeper in color.
The chromatin granules are distinctly demarcated from the parachromatin
(oxychromatin) in these myeloblasts, in which respect they are differentiated
from lymphocyte nuclei; in the latter the chromatin granules have indistinct
outline. In the myeloblasts which seem to be younger the chromatin
granules present a stippled appearance. With further development
the granules tend to arrange themselves in strands with node-like masses
at the intersections.
From two to five nucleoli are present within the
myeloblast nucleus. These nucleoli within the same nucleus present differences
in staining reactions, indicating that they have different chemical structure.
These are smaller than the nucleoli which may be found in sections
of lymphoid tissue.
Variations in the structure of the myeloblast are
found in the leukemias and under other pathological conditions. Such
cells may be found undergoing mitosis in the circulating blood, especially
in the leukemias. Cells with relatively more abundant protoplasm
are sometimes found in the circulating blood in splenomedullary leukemia.
Another cell found in this disease has its nucleus indented deeply in several
areas, thus producing a lobulated appearance; this is called a “Reider
cell.” These cells are occasionally found in the circulating blood
in sarcoma of the bone marrow. They are not found in normal bone
marrow at any time. The myeloblastic nature of the Reider cell has
been called in question, chiefly on account of the presence of fine granules
in its protoplasm. In two of our fulminating cases of leukemia we
have found two different cells of this type. In one fine azure granules
were present and the chromatin was arranged in coarser masses; no doubt
these were immature monocytes. In the other type no azur granules
were present and the chromatin was arranged in extremely fine and delicate
granules; these Reider cells were certainly properly included with the
myeloblasts though the nucleus was deeply lobulated.
From the hyaline myeloblast all the cells of the
bone marrow, and perhaps the lymphocytes are, or may be, derived.
From the myeloblast are developed myelocytes, from
which are developed the adult neutrophiles, eosinophiles and basophiles
of the circulating blood; megaloblasts, from which are developed the normoblasts
and the erythrocytes and also the plasma cells, Turck cells and monocytes.
They are increased under abnormal conditions. Under very abnormal
conditions de-differentiation seems to occur; leucocytes appear to become
transformed into myelocytes or myeloblasts. In one of our cases of
aplastic anemia the cell-structure indicated this type of anaplasia.
Lymphocytes which are apparently of normal adult type, sometimes dividing,
are found in the circulating blood and the daughter cells are morphologically
identical with the microlymphoidocytes, or smaller myeloblasts This
relation was noted very plainly in one of our cases of sarcoma of the bone
marrow associated with marked anemia.
Whether the cells from which lymphocytes arise are
identical with the myeloblasts or not has not yet been definitely determined.
One group of hematologists, called Unitarians or monophyletists, emphasizes
the identity of the stem cell which is the progenitor of lymphocytes and
other blood cells. The other group, called polyphyletists, recognizes
the marked similarity of the primordial cell of the lymphocytes and the
primordial cell of the myeloytic series but denies their identity.
According to the latter group the cells derived from bone marrow elaborate
oxidizing and, perhaps, other ferments, and these cells can be recognized
by the oxidase reaction and by other specific methods of staining.
Inasmuch as the argument is based on a study of acute or fulminating forms
of the leukemias and other seriously abnormal conditions it is evident
that the actual facts can be determined only with great difficulty.
More spherical than the microlymphoidocyte in the
stained smear and somewhat more deeply staining, are other cells not more
than five microns in diameter. The protoplasm of these cells may
be so thin as to be invisible; possibly it may be absent. These have
been supposed to develop into normoblasts. Cells which resemble these,
but which have a thicker rim of protoplasm, with a nucleus which is eccentrically
placed and occasionally lobulated, are present also. These differ
from ordinary lymphocytes in the eccentricity of the nuclear positon and
in the finer chromatin structure.
Megakaryocytes are hyaline cells with basophilic
protoplasm. These have a single, long, ribbon-like, coiled nucleus
of characteristic form. They may form red cells by budding off fragments
of their peripheral protoplasm; probably this is not a normal source of
red cells. There is much reason for believing that they form platelets
by budding off very small masses of their protoplasm.
Osteoblasts are usually found in the bone marrow.
They do not seem to be concerned in blood formation.
Large phagocytic cells are sometimes found.
They disappear very quickly during the process of preparing the slides
for examination. They ingest large numbers of senile or abnormal
red cells and other debris. These phagocytic cells are especially
over-filled in pernicious and in sickle-cell anemias. They have a
single round nucleus and are not readily distinguishable from other monocytes
unless they contain fragments of red cells. Similar cells contain
droplets resembling myelin glycogen or some related carbohydrate substance,
and various other granules which seem to be deutoplasmic. These cells
are supposed by Osler and others to develop into normoblasts.
Erythroblast is a term applied to several types of
cell by different hematologists, but always with the understanding that
the cell so named is intermediate between megaloblast and normoblast.
These cells may be eight to twelve microns in diameter. The protoplasm
stains rather feebly and the nucleus shows a small amount of chromatin
which has a typical wheel-like arrangement. The protoplasm contains
no granules and scanty or much hemoglobin. Intermediate forms are
found in series between any type of cell described as an erythroblast and
the cells which are commonly called normoblasts. (Plates VII, VIII.)
Normoblasts are nucleated red cells. They are
very abundant in the red bone marrow. The protoplasm contains hemoglobin
in varying amount; the less the amount of hemoglobin the greater is the
basophilia of the protoplasm: with increasing hemoglobin concentration
the cells show increasing avidity for eosin. The nuclei of the normoblasts
vary greatly. Extrusion of the nuleus is common; so also is gradual
dissolution of the nucleus. Intermediate forms are abundant between
normoblasts and adult erythrocytes. Normal erythrocytes are also
found within the red bone marrow.
Normoblasts have been divided by Howell into mature
and immature forms. The immature forms are a little larger than normal
adult erythrocytes; they stain variably according to their degree of maturity,
from basophilic to acidophilic; the chromatin fibers are arranged radially,
and they divide by karyokinesis, very rapidly. Mature forms are eosinophilic,
as are adult red cells; they are of the same size as adult cells; the nucleus
is very small, is deeply staining, often vacuolated, without chromatin
structure. Other cells present a peculiar rosette-like arrangement
of chromatin within the nuleus. These nuclei are recognizable as
erythrocytic even when they seem to have no protoplasm.
The bone marrow is very abundantly supplied with
granular white blood cells in various stages of development. Eosinophilic
forms are not very abundant except under pathological conditions.
Eosinophilic myelocytes are larger than adult eosinophiles. They
have a basophilic, hyaline, intergranular protoplasm with large round granules
which are deeply eosinophilic. The large, round, pale nulei are placed
near the periphery of the cells and may be bare for half their circumference.
Cells smaller than those with nulei which present indented, saddle-shaped
and polymorphic shapes, are present in series leading to the normal adult
eosinophiles which appear in the circulating blood. The basophilic,
intergranular, hyaline protoplasm gradually diminishes with increasing
maturity and is barely visible in the eosinophiles of normal adult human
Basophilic granular cells are scanty in normal marrow.
Cells which resemble polymorphonuclear neutrophiles except that the fine
granules are definitely basophilic are present. Typical mast cells
are rare; they may be mononuclear or polymorphonuclear.
Amphophilic myelocytes are present in small numbers.
Atypical granules in any of the younger forms of basophiles, eosinophiles
and neutrophiles are occasionally found even in normal marrow, and they
may be so abundant under certain abnormal conditions as to render the differential
count of the various forms almost or quite impossible.
Neutrophiles of adult forms, younger neutrophiles
which are approximately of adult type, neutrophiles with larger and merely
indented nuclei and all intermediate gradations are present in the bone
marrow. The typical neutrophilic myelocytes are large, sixteen microns
or more in diameter when fresh, and they may reach twenty microns when
spread out in a thin smear. Their nulei are very large, pale, without
marked chromatin structure and they often appear naked because of the thinness
of the protoplasm around them. The protoplasm is scanty, filled with
very fine granules which do not take any stain with avidity but are feebly
neutrophilic. The very early and young myelocyte (Cornil’s marrow
cell) disappears quickly and it is rather difficult to find good stained
specimens of this form. Many names have been applied to the intermediate
stages of development of the neutrophiles, (metamyelocyte, promyelocytes,)
but intermediate gradations between every stage and the next are present;
there is no logical demarcation between the types. The mononuclear
neutrophile with its round or slightly indented nucleus is often called,
incorrectly, a “transitional’ cell. It is more abundant in the normal
bone marrow than in the normal blood, no matter at what age of the subject
enumerations are made. These cells, which are usually included with
the monocytes of the circulating blood, include several types which differ
only slightly in their nuclear structure and which probably have somewhat
different lines of development. Among these are cells which have
a very fine and delicate arrangement of chromatin in a perfectly round,
pale nucleus; other cells with larger masses of chromatin, a nucleus which
is sometimes indented or even saddle-shaped, and still other cells in which
the chromatin is in large masses connected with delicate fibrillae.
Much further study must be made of the cells of normal human adult bone
marrow before the relations of the different cell types can be accurately
ATAVISM IN HUMAN BLOOD
Human adult blood cells show very peculiar and puzzling
changes under abnormal conditions. Some of these changes suggest
very strongly a condition of atavism or reversion to earlier forms.
Atavistic traits are those qualities not normally present in an individual
of a certain race or family, but present normally in some distant ancestor.
For example, oval blood cells are not present in normal human blood at
any stage of development, nor in normal human bone marrow. Oval non-nucleated
blood cells are normally present in the blood of the camel and certain
related animals and are found, though rarely, in the blood of human beings.
When they are so found in human blood, this is considered atavism.
This condition of atavism, that is, reversion of
human tissues to some ancestral form, is very puzzling. It was formerly
supposed that atavism proved direct inheritance, -- that is, that the occurrence
of oval non-nucleated cells in human blood, for example, proved that the
human race descended from some ancestor whose blood contained cells of
this type. It is now supposed that this is not necessarily the case
but that the presence of oval red blood ells indicates an ancestry from
a race in whose hematopoietic tissues a potentiality of oval forms existed.
In other words, the reversion is to some primordial cell structure in which
were present the possibilities of development of red cells of different
forms, and for some unknown reason in certain human beings whose development
has been adversely affected in some way the blood-forming tissues followed
the line of development leading to oval red cells rather than the line
leading to round red cells. While oval red cells are rare in human
blood, several cases have been reported in which they are present, apparently
as a developmental anomaly.
The ontogenetic development of the mass of the blood
cells, as well as of the individual cells, follows the phylogenetic development
in many respects. This statement applies to the relationships of
the various classes of leucocytes, as well as to their absolute numbers,
and it applies also to the variations in the blood cells under physiological
or pathological conditions.
Under abnormal conditions of the circulation, the
nutrition, or the metabolism of the body, the blood, as a mass, tends to
revert to its primeval appearances. It is not possible to determine
whether the cells themselves actually assume primeval appearances, or whether
the formation of new cells, under the abnormal conditions, becomes imperfect
and of a more or less embryonic type, and thus the cells found on examination
present the characteristics of phylogenetically and ontogenetically immature
cells. The latter view is inherently more probable, and it is further
supported by the fact that certain irritants in the circulating blood seem
to being about first an increase in the relative numbers of cells showing
the characteristics of old age, while the continued presence of the irritant
is associated with increasing numbers of phylogenetically younger cells.
In one of our cases, a young woman apparently healthy,
though not robust, had blood with oval cells. The first blood examination
was made as a routine procedure in the clinic of The Pacific College of
Osteopathy. The oval cells were recognized immediately. During
the three years following the first examination her blood was examined
many times and the cells always included a large proportion of oval forms.
During most of that time she was in ordinarily good health. The oval
blood cells showed no changes, and the condition was evidently one of a
developmental peculiarity; an instance of atavism. Other cases of
oval red cells in human blood have been reported in various periodicals.
Developmental anomalies in the blood cells are often
associated with developmental anomalies of several other parts of the body,
especially those of the nervous system. The recognition of atavistic
blood cells may differentiate a developmental and therefore an essentially
incurable nervous or mental condition from an acquired neurosis or insanity
with similar symptoms. Atavistic cells are present in the blood of
paranoiacs, morons, idiots, feeble-minded children, and in various developmental
or inherited abnormal states These cells are not present in the blood
of persons suffering from nervous or mental symptoms which are due to trauma,
acquired diseases or bad training. It is to be remembered in this
connection that even those neuroses based on abnormal development may be
greatly improved by suitable methods of treatment.
Embryonic but not usually atavistic cells are present
in the blood after extremely serious demands have been made upon the hematopoietic
tissues, as, for example, after repeated hemorrhage, or long infection
with virulent pathogenic organisms. Atavistic cells are often present
in the leukemias and in erythremia, chlorosis, pernicious anemia and malignancy
of the bone marrow. They are rare in aplastic anemia and are not
commonly found in ordinary infections nor in ordinary secondary anemias,
though these may be extremely serious.
A very brief review of some of the cells characteristic
of the blood of certain lower animals, together with the conditions under
which such cells are found in human blood, is interesting, though the relationships
which are concerned in these instances of atavism cannot be explained at
ANALOGUES OF HEMOGLOBIN
Most invertebrates carry their oxygen-bearing chemicals
in the blood plasma. Certain mollusks and tunicates have colorless
globulin-like substances which hold oxygen in a loose combination and carry
it to the tissues; these are called achroglobins. Other mollusks
and certain crustaceans use copper instead of iron in a pigment called
hemocyanin; this also carries the oxygen, feebly bound, to the tissues.
Hemocyanin is blue in tint, in arterial blood, and is almost or quite colorless
in venous blood. Certain worms carry oxygen by means of an iron-containing
green pigment (colorless when reduced) which is called chlorocruorin.
Echinoderms and certain other marine animals have a red pigment, also iron-containing,
called echinochrom; this is colorless when reduced.
The hemoglobin percentage varies rather irregularly.
In general, among all animals the hemoglobin increases in ascending scale
of vertebrates and from infancy to maturity. In most diseases affecting
the blood the hemoglobin is decreased, though in certain diseases in which
the amount of water in the blood is diminished, the hemoglobin is relatively
The color index is high in lower vertebrates, since
these have extremely large erythrocytes. Among mammals, the color
index increases generally from the lower to the higher forms, and from
infancy to maturity. In most diseases the color index is lower than
normal; in pernicious anemia the color index is high, because of the presence
of many abnormally large red cells. The saturation index is never
increased by any abnormal condition.
RED BLOOD CELLS
The power of the erythrocyte cytoplasm to carry
a relatively large amount of hemoglobin is thus one charateristic of the
higher development, the more nearly perfect specialization.
Vertebrates carry hemoglobin in red blood corpuscles,
and all carry small amounts of oxygen free in the plasma. The efficiency
of the red cell as an oxygen-carrying structure increases with a fair degree
of regularity, though many diversions from the direct line of ascent are
found. Vertebrates below mammals have their red cells usually nucleated,
though non-nucleated red cells are occasionally found in the blood of all
those examined in our laboratories.
In all vertebrates below mammals the red cells have
either a cell wall or a definite external limiting layer which can be demonstrated
by careful staining. This cell wall is not present in normal adult
mammalian blood though a delicate peripheral condensation of the stroma
is present. In severe anemias, such as may be due to intestinal parasites,
gastric ulcers or old, severe, chronic infections with some hemolytic bacteria,
human red cells show a marked thickening of the stroma at the periphery
and this may somewhat resemble a cell wall.
Erythrocytes in the blood of fishes are usually round
or roundish, though long ovals are characteristic of some species.
Except for occasional cells all are nucleated. The nuclei vary from
round to rod-shaped, but are never polymorphic and are rarely lobate.
The cells vary greatly in form and in size, and may be as much as five
times the diameter of the normal human red cell. The counts are low
and the oxygen-carrying efficiency is always far below that of human blood.
Cells apparently identical with the megaloblasts
of human blood in pernicious anemia are abundant in certain normal fishes,
such as the minnow and the cod, but in other fishes, such as the perch,
these large red cells are absent or very scanty. The hemoglobin is
often present as granules within the red cell protoplasm, in the blood
The development of the red cells in the fish is of
interest. The first stage is a small round cell resembling a lymphocyte
but with characteristic wheel-like nucleus. Between this and the
large nucleated hemoglobin-carrying erythrocyte there are all intermediate
forms, including hyaline cells with more abundant protoplasm than that
of lymphocytes, then basophilic granules or basophilic reticulation with
thickenings at the intersections appear, then hemoglobin appears, at first
very scantily, then more and more abundantly until the adult form is reached.
The nucleus grows progressively smaller but remains present and apparently
active throughout the life of the red cell.
Amphibian blood contains erythrocytes which are oval
in nearly all genera and in other genera are round or roundish.
In some species the red cells are large enough to be visible to the naked
eye. They are nucleated in all species though non-nucleated individual
cells may occasionally be found in any blood. Irregular non-nucleated
masses of hemoglobin-containing protoplasm are occasionally found.
Nuclei are usually oval, occasionally irregular in outline, usually deeply
staining. The nuclear structure of all amphibian erythrocytes presents
one peculiarity,--the linin network arises from the nuclear membrane in
masses somewhat resembling feet. Threads from these masses form the
linin network of the nucleus with meshes rather regular in size and form
except where the nucleoli and chromatin masses interrupt the continuity
of the netlike arrangement.
This peculiarity is rarely found in human blood.
In our laboratory two cases have been found,—both during pernicious anemia—occurring
in men between forty and fifty years of age, both of whom presented rather
plentiful stigmata of degeneracy and both of whom had been of subnormal
mentality always. Cells resembling the megaloblasts of human blood
in pernicious anemia and related conditions are extremely rare in amphibian
blood. Polychromasia is almost universal.
Seasonal variations in blood formation are more marked
in amphibia than in other animals. Blood counts taken from the same
animal at different seasons varies more widely than does blood from different
genera at the same season.
Reptiles have only oval red cells, biconvex and nucleated.
They are smaller than amphibian cells, generally. Their nuclei show
a linin network which touches the nuclear membrane in slender, rather pointed
processes. They carry the hemoglobin chiefly around the edges of
the red cells, and in masses near the ends of the ovals. Cells resembling
human megaloblasts are scanty and usually have nuclei which stain less
avidly than do human megaloblasts. Seasonal variations in blood formation
are generally less marked than in amphibia.
Birds have oval, biconvex, nucleated red cells.
Rarely round or roundish, non-nucleated red cells may be found. Birds
have much larger red cells than do reptiles, and, generally speaking, their
erythrocyte protoplasm is more efficient as an oxygen-carrying mechanism.
The hemoglobin is carried mostly at the periphery of the cell.
Cells with very scanty hemoglobin located mostly
in the periphery of the cell were found in one of our cases of aplastic
anemia, a baby seven months old. None of the red cells was nucleated,
and no immature or myelocytoid cells, either red or white, were found in
The red cells of birds present rather long ovals
and the nuclei are oval of about the same general form as the cells.
The cells are more uniform in size, form and staining than is the case
with lower vertebrates. The genesis of avian red cells differs somewhat
from that of red cells in other vertebrates. In the red bone marrow
of nearly all species of birds the capillary walls are entire, and the
capillaries are greatly dilated into sinus-like spaces. In these
spaces the red cells are formed from mother-cells which lie next to the
capillary walls. As the cells assume progressively more nearly adult
traits they are pushed toward the lumen of the sinus and are washed out
into the blood stream. In the red bone marrow outside the sinus walls
there also are active masses of marrow cells, and from these masses the
cells enter the sinuses by diapedesis between the endothelial cells.
The endothelial cells themselves seem to form red cells by dividing into
daughter cells of two different characters,--one is an endothelial cell,
the other develops into a typical red cell.
The tendency of endothelial cells to form red blood
cells is not present in normal mammalian tissues, but after repeated hemorrhages
in experimental animals this form of red-cell development has been reported,
denied an again reported. We have found no evidence of this form
of development in our cases of abnormal blood.
Normal adult mammalian blood has only round, non-nucleated
red cells, except that in the case of the camel and related species the
red cells are oval and non-nucleated The finding of oval cells in
human blood has already been discussed in this chapter. Oval nucleated
red cells have been described in human embryoni blood, but these have not
been found in any of the human embryos studied in our laboratories.
Among mammals, the lower forms generally show the
more distinct stroma, with greater irregularities in size, shape, and staining,
and of greater instability under slightly abnormal conditions, as well
as after removal from the vessels. Cabot’s rings and other structures
abnormal to human blood are often found in the blood of lower mammals.
The erythrocytes of the lower mammals become distorted
more easily after removal from the vessels than do those of the higher
forms, and the erythrocytes of the younger individuals, both human and
animal, are more easily distorted. Under abnormal conditions affecting
the nutrition of the human body, the erythrocytes become more fragile.
The remarkable variations of form found in sickle-cell anemia (a peculiar
developmental anomaly of blood cells found especially in negroes or in
persons with some negro inheritance) should be considered in this connection.
Among the lower animals also and among the young
in any genus, slighter nutritional variations, such as fatigue, poor nutrition
and starvation, affect the appearance of the erythroytes more seriously
than is the case in older individuals. In human children comparatively
slight metabolic disturbances produce very marked changes in the appearance
of the erythrocytes; conversely, in the presence of anemias appearing severe,
even slight improvement in nutrition is followed by very speedy improvement
in the blood picture.
Spindle cells are peculiar structures not found
in the blood of mammals. They are very abundant in the blood of birds
and are present in small numbers in the blood of reptiles, amphibia and
fishes. They seem to function in much the same manner as do the platelets
of mammalian blood.
A spindle cell, as its name indicates, has a spindle,
almond, or elliptical form, with the ends often rounded. It is four
or five microns in length by two or three microns in width, and it has
usually a thickened area near its center around its nucleus. The
protoplasm is faintly fibrillar with the fibrillae arranged in irregularly
concentric rings around the nuleus. In some animals a faintly granular
appearance is visible. The protoplasm contains no hemoglobin.
The nucleus stains feebly and contains chromatin in fine masses.
The network is delicate and has slight thickenings at the intersections.
After the blood leaves the vessels the spindle cells tend to become rounded,
to throw out fibrin threads and to form net-like masses. Their development
is still uncertain, though they are known to be formed in the bone marrow.
These cells have not been reported for any human
blood. In our laboratories they have never been found in any mammalian
1. Eosinophiles from blood
of rabbit, normal.
2. Eosinophiles from blood
of guinea pig, normal.
3. Eosinophiles from blood
of patient with many stigmata of degeneracy and mentality of imbecile.
4. Eosinophiles form blood
of horned toad.
5. Basophiles from blood
6. Basophiles from blood
of human fetus of three months’ development.
The total number of leucocytes per cubic millimeter
of blood varies more for different individuals, and for the same individual
at different times, among lower mammals than among members of the human
race. Seasonal variations and daily variations are more marked among
lower mammals. The same environmental and pathological conditions
cause the same general changes in the total leucocyte count among lower
mammals, and these changes are more pronounced than in adult human subjects.
Children’s blood shows more extravagant reactions
to pathological and environmental changes in both the leucocyte and the
erythrocyte counts than is the case with adults. The maintenance
of a fairly constant level of leucocyte count under varying pathological
conditions cause the same general changes in the total leucocyte count
among lower mammals, and these changes are more pronounced than in adult
Variations in the cells themselves and in the relative
numbers of different cell groups present many peculiarities which suggest
The earliest form of blood cell is a hyaline, basophilic,
mononuclear cell bearing some resemblance to the small lymphocyte of normal
adult human blood. It does not give the oxidase reaction. This
has been called a primordial cell or a stem cell. It has been found
in the blood or the tissues of nearly all forms of metazoa. Even
such highly developed invertebrates as crabs and caterpillars have only
this form of blood cell though it occurs in varying sizes. The bone
marrow of marsupials contains only this type of cell, and from it other
forms of blood ells are developed. Wandering cells capable of differentiating
into these hyaline cells and also into tissue cells are present in the
tissues of nearly all metazoa, even those as low as sponges.
Crustaceans have a mass of cells near the stomach
in which large hyaline cells are abundant, and are rapidly dividing.
This mass seems to be the chief hematopoietic tissue of animals of this
In all vertebrate blood are found plasma cells, large
and small hyaline cells resembling human lymphocytes, and large mononuclear
cells resembling human endothelial cells.
In fishes the small hyaline cells have a delicate
spongioplasm which is more finely meshed at the periphery of the cells,
so that the cell often seems to have a cell wall. The protoplasm
is scanty, the nucleus relatively large, but it is practically always possible
to find some enveloping cytoplasm. Cells with extremely thin cytoplasmic
covering of the nucleus, so often seen in human lymphocytes, are not found
among the small hyaline cells of fishes. Granules which vary somewhat
in staining are sometimes found, very scantily, in the hyaline protoplasm.
The nucleus is always round or oval, and never shows any marked irregularity
Large, mononuclear, basophilic, hyaline cells which
are phagocytic are mportant in the blood of fishes. They surround
foreign objects and they digest and utilize as food suitable foreign substances
within the body. These cells often contain scanty granules which
are feebly basophilic, feebly eosinophilic or amblychromatic. These
cells sometimes contain lobed nulei and are probably the precursors of
the granular phagoytes of higher forms of life.
Both large and small hyaline cells are occasionally
spindle-shaped or oval in certain genera of fishes and in these cells the
nucleus also is oval. In the cod, the triton and certain related
forms a large mononuclear cell is present which is irregularly triangular,
with well rounded angles. The nuleus is relatively small and occupies
one corner of the cell. The cytoplasm shows a web-like structure
which presents some faint resemblance to granulations. This cell
is very feebly basophilic and does not contain true granules. Cells
presenting identical structure are occasionally found in human blood as
a developmental anomaly.
In ganoid fishes the hyaline cells resemble human
lymphocytes but they possess a very distinct nuclear membrane. Lymphocytes
, or similar cells, with distinct nuclear membranes were found in one of
our cases of late lymphatic leukemia, a few days before death.
Amphibian blood contains several types of hyaline
basophilic cells, and these are generally rather more primitive in type
than is the case in the blood of fishes. Azur granules are occasionally
found in the cytoplasm, sometimes arranged at the periphery, sometimes
near the nucleus. Amphibian blood also contains extremely large hyaline
cells with deeply basophilic protoplasm and feebly staining nuleus which
almost entirely fills the cell. The chromatin is in peculiar radiating
masses. Cells of this type are often found in the blood of human
beings as a developmental anomaly.
A rather small hyaline cell shows unusually eccentric
nuclear site; this permits half or two-thirds of the nuclear outline to
be perfectly naked while there is an amount of cytoplasm almost or quite
equal to the nuclear area upon the opposite side of the nucleus.
This cytoplasm is feebly basophilic and it does not contain granules.
This cell is not found in normal human blood or marrow at any stage of
development, but it does occasionally appear in human blood after long
and severe infectious processes.
Amphibians react to infectious processes by producing
abundant large and small hyaline cells. This reaction is often present
in human children, especially those poorly nourished. The peculiar
disease of adults called agranulytic angina is characterized by a similar
type of reaction to infection, except that the cells are never as abundant
as is the case with amphibians.
Reptilian blood contains many small and large hyaline
cells, and also the extremely large cells with very large nuclei which
have been mentioned for amphibian blood; they may be thirty or even forty
microns in diameter. The large hyaline cells are the most important
phagocytes of reptilian blood.
The blood of birds includes all three sizes of hyaline
cells described for reptiles and amphibia, and also a large cell with scanty,
deeply basophilic protoplasm and a large round nucleus with large masses
of chromatin which show marked avidity for stains; these resemble the Turck
cells of human blood. These large hyaline cells are the most important
phagocytes of avian blood. Birds also carry large mononuclear cells
resembling the endothelial cells of human blood, especially during the
active stage of some inflammatory process. Birds possess very little
lymphoid tissue in their bodies and the hyaline cells are chiefly produced
in the red bone marrow and in the spleen.
All mammalian blood contains hyaline cells very like
those of human normal blood, except that very large hyaline cells with
large round nuclei, such as are present in the blood of birds and lower
vertebrates, are present in some of the lower mammals. (Plates V,
Progressive differentiation is more marked among
granular cells than among hyaline cells. Reversionary traits are,
for this reason, somewhat more easily recognizable. Basophiles (mast
cells) are not found at all in the blood of invertebrates or of fishes.
In amphibia and in higher vertebrates several varieties of basophilic granular
cells are found. One type, especially, seems to be a precursor of
the human neutrophile. The granules are abundant and are very fine,
and they are sometimes only feebly basophilic. The nucleus of this
type of basophile may have two lobes though usually a single nucleus is
round or roundish. These cells are especially abundant in amphibian
blood. Another type of basophile has a rather small nucleus, deeply
staining, and a scanty, basophilic, hyaline, intergranular protoplasm.
The granules are very large, very deeply basophilic and are arranged mostly
around the periphery of the cell. The granules of this type of cell
are so large, so deeply stained and so brilliant that they present an unusual
and vivid picture. Other types of basophile show different forms
of nucleus and different arrangement of granules; many intermediate forms
are present. These forms appear in the leukemias of human beings.
Reptilian blood contains a basophile with a large
nucleus which occupies at least two-thirds the area of the cell, abundant,
deeply staining basophilic granules of moderate size, and scanty, hyaline,
intergranular, feebly staining basophilic protoplasm. The nucleus
of this cell stains rather feebly with ordinary dyes. This type of
cell is rarely found in the blood of birds, and is never found in normal
embryonic or adult human blood or bone marrow. It occurs in human
subjects with late lymphatic leukemia, though rather rarely. In our
records such cells have been three times reported,--one man with very late
lymphatic leukemia, one woman with an atypical leukemia following typical
Hodgkins disease, and one late myeloid leukemia in which reversionary traits
were unusually abundant.
Basophiles of the type found in normal, adult, human
blood are not found in the blood of lower mammals, and are scanty in any
blood except human.
Eosinophiles are not found in typical form in the
blood of invertebrates. The blood of fishes contains a few atypical
eosinophiles. The granules are usually round, they stain feebly and
are most abundant near the center of the cell.
Reptilian blood contains eosinophiles abundantly.
The granules vary considerably in size and in form in different species,
and are sometimes definitely polygonal. Extremely large nuclei which
stain feebly are present in many eosinophiles. In others there are
smaller and sometimes bi-lobed nuclei containing definite chromatin masses
which take stain with avidity. Rather smaller round nulei with indistinct
chromatin are found in other species. Polymorphonuclear forms are
also present; these cells are phagocytic and ameboid, and they behave much
as human neutrophiles do. In certain snakes eosinophiles occur which
have rather scanty, rod-like granules and very noticeable large nuclei
in which the chromatin material is arranged in tigroid masses. The
nucleus is placed at one side of the cell and often is completely bare
of protoplasm for almost half its periphery. It has an abundant,
intergranular, basophilic, hyaline cytoplasm. This cell has not been
found in any human blood or marrow. The blood of certain other reptiles
contains eosinophile granules which are quite long and rod-shaped, and
these rods are arranged in the basophilic cytoplasm in radiating lines
forming a star-like structure. The nucleus is smaller and tigroid
markings are less marked than is the case with the cells just described.
Similar star-like arrangement of rod-shaped eosinophile granules has been
found in one case of aplastic anemia, in our records Many other stigmata
of degeneracy were present in that case.
In the blood of birds eosinophiles are less abundant.
Two forms are rather common. The type most abundant contains granules
somewhat finer than human eosinophile granules, and the nucleus is often
bi-lobed. These cells divide by mitosis while circulating.
Another form is less abundant. The granules are rod-shaped and are
closely and densely packed together; no hyaline protoplasm is visible.
The granules are intensely eosinophilic and the nucleus varies from round,
notched and bilobate to polymorphonuclear. Thse cells are ameboid
and phagocytic, and they seem to be rather closely related to the neutrophiles
of human blood. They increase during inflammatory conditions, as
do human neutrophiles, and they surround foreign bodies.
Among mammals the eosinophiles are often very large
or very small, oval and rod-shaped granules are frequently found.
These oval granules are never found in normal embryonic or adult human
blood or marrow, but sometimes in human blood after long and severe infectious
processes with evidences of exhaustion of the hematopoietic tissues the
granules of the eosinophile become rod-shaped.
PRECURSORS OF NEUTROPHILES
Really typical polymorphonuclear neutrophiles are
found only in human blood. Very similar cells are found in the blood
of primates, and cells which are polymorphonuclear but whose granules are
feebly basophilic, feebly eosinophilic or feebly amblochromatic are present
in the blood of nearly all vertebrates. Amphophilic cells which are
phagocytic and ameboid, which are developed from the small hyaline cells
previously mentioned, are found in many of the lower metazoa and are present
in the blood of many vertebrates.
Fishes have peculiar granular cells which are spindle-shaped
or round. The granules seem to be concerned in the coagulation of
the blood. They are acidophilic and stain deep red with Giemsa’s
stain. The granules are much smaller than eosinophile granules of
human blood. Granular cells in the blood of fishes often show vacuoles,
and there is much reason to believe that these cells have some sort of
secretory function. The granules are formed within the cell in increasing
numbers so that the nucleus may be crowded into a very eccentric position.
The granules then seem to dissolve, leaving vacuoles, and these seem to
discharge their contents into the blood plasma. The cell again fills
with granules, and the process is again repeated. In some fishes
the cells of the lymphoid tissue form granules very abundantly during the
digestion of food, and these are lost during sleep. These cells do
not seem related to any human cells and have not been reported for any
human blood or marrow.
Amphibians have many amphophilic, basophilic
and eosinophilic cells. All three forms of granular cells are ameboid
and phagocytic, and they ingest many forms of pathogenic bacteria.
These cells include both mononuclear and polymorphonuclear types
In these cells the granules are often rod-like or oval rather than round.
Birds have also eosinophilic, basophilic and amphophilic
ameboid and phagocytic cells. True neutrophilic granules are not
present in their blood.
Among mammals fairly definitely neutrophilic granules
are occasionally found. Apes’ blood contains neutrophiles something
like those of human blood. With certain stains neutrophilic granules
of varying sizes are found in the polymorphonuclear leucocytes of the goat,
dog, mouse and a few other animals, though with other stains these granules
are eosinophilic or amphophilic. The polymorphonuclear leucocytes
of the rabbit have amphophilic granules which include a few rather large
neutrophilic granules. The granules of the polymorphonuclear leucocytes
of the guinea pig are very fine and are faintly eosinophilic. The
granules of certain polymorphonuclear cells of the horse are neutrophilic
and are extremely fine. The polymorphonuclear cells of the cow, pig,
rat and sheep contain faintly eosinophilic granules.
Under many conditions of exhaustion of the hematopoietic
tissues and in the leukemias, the neutrophilic granules diminish or disappear
and amphophilic, feebly eosinophilic or feebly basophilic granules appear
in the polymorphonuclear cells of human adult blood.
SPECIAL STUDY OF THE BLOOD OF MONKEYS
Differences in the numerical relations of the different
classes of blood cells of mammals are of interest in this connection.
In the laboratory of The A. T Still Research Institute in Chicago the blood
of normal monkeys (macacus rhesus) was studied during the autumn and early
winter months. Ten examinations were made of the blood of each of
ten monkeys, all in good health, all about two years old. The hemoglobin
was determined by means of Dare’s hemoglobinometer, and this was checked
with the Meisner modification of Fleischl’s instrument. For the differential
count a modification of Wright’s stain was used and for each count 1,000
cells examined. The actual counts were based on cells found in 200
small squares, for the red cells, and 4,000 small squares, for the white
cells. The blood was taken about four hours after the last meal,
in each case, and at about ten ‘clock in the morning. The following
findings were thus secured:
Instances of atavism are often noted in connection
with various deformities and developmental anomalies, in many tissues of
the body. The blood cells share in this tendency of abnormal development
to follow the line indicated by some remote progenitor. When atavistic
cells occur in the blood of a human being during the course of some disease
it may safely be concluded that the hematopoietic tissues of that individual
were not quite properly developed during his embryonic life. Immature
forms may appear in the circulating blood of any person as a result of
disease affecting the bone marrow, but true instances of atavism occur
only in human blood when other tissues of the body also show evidences
of abnormal embryological development.
The presence of these reversionary forms is to be included
with other stigmata of degeneracy. The frequent occurrence of atavistic
forms of white blood cells during the course of the leukemias suggests the possibility
that these diseases have a developmental origin. In pernicious anemia
atavistic forms are fairly common. The developmental abnormalities associated
with pernicious anemia are discussed elsewhere. The study of the atavistic
cells occurring during the course of other diseases may show that abnormal developmental
conditions may be important factors in lowering immunity and in delaying or
preventing recovery from accidental injuries or poisonings.