Man 4,000,000 to 5,000,000 per cub. mm.
Goat 9,000,000 to 10,000,000 " "
Sheep 13,000,000 to 14,000,000 " "
Birds 1,000,000 to 4,000,000 " "
Fish 250,000 to 2,000,000 " "
Frog 500,000 per cub. mm.
Proteus 36,000 " "
In mammals they are apparently homogeneous in structure, have no
nucleus, but possess a thin envelope. Their specific gravity is
distinctly higher than that of the plasma (1.088), so that if clotting
has been prevented, blood on standing yields a large deposit which may
form as much as half the total volume of the blood.
_Chemical Composition._--On destruction the red corpuscles yield two
chief proteins, haemoglobin and a nucleo-protein, and a number of other
substances similar to those usually obtained on the break-down of any
cellular tissue, such for instance as lecithin, cholesterin and
inorganic salts. The most important protein is the haemoglobin. To it
the corpuscle owes its distinctive property of acting as an oxygen
carrier, for it possesses the power of combining chemically with oxygen
and of yielding up that same oxygen whenever there is a decrease in the
concentration of the oxygen in the solvent. Thus in a given solution of
haemoglobin the amount of it which is combined with oxygen depends
absolutely on the oxygen concentration. The greatest dissociation of
oxyhaemoglobin occurs as the oxygen tension falls from about 40 to 20
mm. of mercury. That the oxygen forms a definite compound with the
haemoglobin is proved by the fact that haemoglobin thoroughly saturated
with oxygen (oxyhaemoglobin) has a definite absorption spectrum showing
two bands between the D and E lines, whilst haemoglobin from which the
oxygen has been completely removed only gives one band between those
lines. In association with this, oxyhaemoglobin has a typical bright red
colour, whereas haemoglobin is dark purple. A further striking
characteristic of haemoglobin is that it contains iron in its molecule.
The amount present, though small bears a perfectly definite quantitative
relation to the amount of oxygen with which the haemoglobin is capable
of combining (two atoms of oxygen to one of iron). One gram of
haemoglobin crystals can combine with 1.34 cc. of oxygen. On destruction
with an acid or alkali, haemoglobin yields a pigment portion, haematin,
and a protein portion, globin, the latter belonging to the group of the
histones (Gr. [Greek: istos], web, tissue). In this cleavage the iron
is found in the pigment. By the use of a strong acid, it may be made to
yield iron-free pigment, the remainder of the molecule being much
further decomposed.
_Destruction and Formation._--In the performance of their work the
corpuscles gradually deteriorate. They are then destroyed, chiefly in
the liver, but whether the whole of this process is effected by the
liver alone is not decided. It is proved, however, that the destruction
of the haemoglobin is entirely effected there. It was for a long time
considered to be one of the functions of the spleen to examine the red
corpuscles and to destroy or in some way to mark those no longer fitted
for the performance of their work. It is proved that the destruction of
the haemoglobin is entirely effected in the liver, since both the main
cleavage products may be traced to this organ, which discharges the
pigmentary portion as the bile pigment, but retains the iron-protein
moiety at any rate for a time. The amount of bile pigment eliminated
during the day indicates that the destruction must be considerable, and
since the number of corpuscles does not vary there must be an equivalent
formation of new ones. This takes place in the red bone-marrow, where
special cells are provided for their continuous production. In embryonic
life their formation is effected in another way. Certain mesodermic
cells, resembling those of the connective tissue, collect masses of
haemoglobin, and from these elaborate red blood corpuscles which thus
come to lie in the fluid part of the cell. By a canalization of the
branches of these cells which unite with branches of other cells the
precursors of the blood capillaries are formed.
_White Blood Corpuscles._--These constitute the second important group
of formed elements in the blood, and number about 12,000 to 20,000 per
cubic mm. They are typical wandering cells carried to all parts of the
body by the blood stream, but often leave that stream and gain the
tissue spaces by passing through the capillary wall. They exist in many
varieties and were first classified according as, under the microscope,
they presented a granular appearance or appeared clear. The cells were
also distinguished from one another according as they possessed fine or
coarse granules. The granules are confined to the protoplasm of the
cell, and it has been shown that they differ chemically, because their
staining properties vary. Thus, some granules select an acid stain, and
the cells containing them are then designated _acidophile_ or
_eosinophile_;[1] other granules select a basic stain and are called
_basophile_, while yet others prefer a neutral stain (_neutrophile_).
In human blood the following varieties of leucocytes may be
distinguished:--
1. _The Polymorphonuclear Cell._--This possesses a nucleus of very
complicated outline and a fair amount of protoplasm filled with numbers
of fine granules which stain with eosin. They vary in size but are
usually about 0.01 mm. in diameter. They are highly amoeboid and
phagocytic, and form about 70% of the total number of leucocytes.
2. _The Coarsely Granular Eosinophile Cell._--These large cells contain
a number of well-defined granules which stain deeply with acid dyes. The
nucleus is crescentic. The cells amount to about 2% of the total number
of leucocytes, though the proportion varies considerably. They are
actively amoeboid.
3. _The Lymphocyte._--This is the smallest leucocyte, being only about
0.0065 mm. in diameter. It has a large spherical nucleus with a small
rim of clear protoplasm surrounding it. It forms from 15 to 40% of the
number of leucocytes, and is less markedly amoeboid than the other
varieties.
4. _The Hyaline_ (Gr. [Greek: hualinos], glassy, crystalline, [Greek:
ualos], glass) _cell or macrocyte_ (Gr. [Greek: makros], long or
large).--This is a cell similar to the last with a spherical, oval or
indented nucleus, but it has much more protoplasm. It constitutes about
4% of all the leucocytes and is highly amoeboid and phagocytic.
5. _The Basophile Cell_.--This possesses a spherical nucleus and the
protoplasm contains a small number of granules staining deeply with
basic dyes. It is rarely found in the blood of adults except in certain
diseases.
_Functions._--These cells act as scavengers or as destroyers of living
organisms that may have gained access to the tissue spaces. They play an
important part in the chemical processes underlying the phenomena of
immunity, and some at least are of importance in starting the process of
clotting.
They are constantly suffering destruction in the performance of their
work. Many, too, are lost to the body by their passage through the
different mucous surfaces. Their origin is still obscure in many points.
The lymphocytes are derived from lymphoid tissue, wherever it exists in
the different parts of the body. The polymorphonuclear and eosinophile
cells are derived from the bone-marrow, each by division of specific
mother cells located in that tissue. The macrocyte is believed by many
to represent a further stage in the development of the lymphocyte. Their
rate of formation may be influenced by a variety of conditions--for
instance, they are found to vary in number according to the diet and
also, to a considerable extent, in disease.
_Platelets._--The platelets or thrombocytes (Gr. [Greek: thrombos],
clot) are the third class of formed elements occurring in mammalian
blood. There are still, however, many observers who consider that
platelets are not present in the normal circulating blood, but only make
their appearance after it has been shed or otherwise injured. They are
minute lens-shaped structures, and may amount to as many as 800,000 per
cubic mm. Under certain conditions, examination has shown that they are
protoplasmic and amoeboid, and that each one contains a central body of
different staining properties from the remainder of the structure. This
has been regarded by some as a nucleus. On being brought into contact
with a foreign surface they adhere to it firmly, very rapidly passing
through a number of phases resulting ultimately in the formation of
granular debris. In shed blood they tend to collect into groups, and
during clotting, fibrin filaments may be observed to shoot out from
these clumps.
_Variations in the Blood of different Animals._--If we contrast the
blood of different animals of the vertebrate class we find striking
differences both in microscopic appearances and in chemical properties.
In the first place, the corpuscles vary in amount and in kind. Thus,
whilst in a mammal the corpuscles form 40 to 50% of the total volume of
the blood, in the lower vertebrates the volume is much less, e.g. in
frogs as low as 25% and in fishes even lower. The deficiency is chiefly
in the red corpuscles, the ratio of white to red increasing as we
examine the blood from animals lower in the scale. The corpuscles
themselves are also found to vary, especially the red ones. In the
mammal they are biconcave disks with bevelled edges, they do not contain
a nucleus so that they are not cells. In the bird they are larger,
ellipsoidal in shape and have a large nucleus in the centre of the cell.
In reptiles and amphibia the red corpuscles are also nucleated, but the
_stroma_ portion containing the haemoglobin is arranged in a thickened
annular part encircling the nucleus. When seen from the flat they are
oval in section. In fishes the corpuscles show very much the same
structure. A further very significant difference to be observed between
the bloods of different vertebrates is in the amount of haemoglobin they
contain; thus in the lower classes, fishes and amphibia, not only is the
number of red corpuscles small but the amount of haemoglobin each
corpuscle contains is relatively low. The concentration of the
haemoglobin in the corpuscles attains its maximum in the mammal and the
bird. Since the haemoglobin is practically the same from whatever animal
it is obtained and can only combine with the same amount of oxygen, the
oxygen-capacity of the blood of any vertebrate is in direct proportion
to the amount of haemoglobin it contains. Therefore we see that as we
ascend the scale in the vertebrate series the oxygen-carrying capacity
of the blood rises. This increase was a natural preliminary condition
for the progress of evolution. In order that a more active animal might
be developed the main essential was that the chemical processes of the
cell should be carried out more rapidly, and as these processes are
fundamentally oxidative, increased activity entails an increased rate
of supply of oxygen. This latter has been brought about in the animal
kingdom in two ways, first by an increase in the concentration of the
haemoglobin of the blood effected by an increase both in the number of
corpuscles and in the amount of haemoglobin contained in each, and
secondly by an increase in the rate at which the blood has been made to
pass through the tissues. In the lower vertebrates the blood pressure is
low and the haemoglobin content of the blood is low, consequently both
rate of blood-flow and oxygen-content are low. In contrast with this, in
higher vertebrates the blood pressure is high and the haemoglobin
content of the blood is high, consequently both rate of blood-flow and
oxygen-content are high. We must associate with this important step in
evolution the means employed for the more rapid absorption of oxygen and
for its increased rate of discharge to the tissues, the most important
features of which are a diminution in the size of the corpuscle and the
attainment of its peculiar shape, both resulting in the production of a
relatively enormous corpuscular surface in a unit volume of blood.
Variations are also found in the white corpuscles as well as in the red,
but these differences are not so striking and lie chiefly in unimportant
details of structure of individual cells. Enormous variations are to be
found in different species of mammals, but the cells generally conform
to the types of secreting cells or phagocytes.
The platelets also differ in the different species. In the frog, for
instance, many are spindle-shaped and contain a nucleus-like structure.
Birds' blood is stated to contain no platelets. The variations in number
of these bodies have not been satisfactorily ascertained on account of
the difficulties involved in any attempt to preserve them and to render
them visible under the microscope.
Differences are also found in the chemical composition of the plasma.
The chief variation is in the amount of protein present, which attains
its maximum concentration in birds and mammals, while in reptiles,
amphibia and fishes it is much less. The bloods of the latter two
classes are much more watery than that of the mammal. Moreover, it has
been proved that there are specific differences in the chemical nature
of the various proteins present even between different varieties of
mammals. Thus the ratio of the globulin fraction to the albumin fraction
may vary considerably, and again, one or other of the proteins may be
quite specific for the animal from which it is derived.
_Clotting._--If a sample of blood be withdrawn from an animal, within a
short time it undergoes a series of changes and becomes converted into a
stiff jelly. It is said to _clot_. If the process is watched it is seen
to start first from the surfaces where it is in contact with any foreign
body; thence it extends through the blood until the whole mass sets
solid. A short time elapses before this process commences--a time
dependent upon two chief conditions, viz. the temperature at which the
blood is kept and the extent of foreign surface with which it is brought
into contact. Thus in a mammal the blood clots most quickly at a
temperature a little above body temperature, while if the blood be
cooled quickly the clotting is considerably delayed and in the case of
some animals altogether prevented. For example, human blood kept at body
temperature clots in three minutes, while if allowed to cool to room
temperature the first sign of clotting may not make its appearance until
eight minutes after its removal from the body. The process of clotting
is also considerably accelerated by making the blood flow in a thin
stream over a wide surface. The full completion of the process occupies
some time if the blood be kept quiet, but ultimately the whole mass of
the blood becomes converted into a solid. At this stage the containing
vessel may be inverted without any drop of fluid escaping. A short time
after this stage has been reached drops of a yellow fluid appear upon
the surface and, increasing in size and number, run together to form a
layer of fluid separated from the clot. This fluid is termed _serum_;
its appearance is due to the contraction of the clot, which thus
squeezes out the fluid from between its solid constituents. Contraction
continues for about twenty-four hours, at the end of which time a large
quantity (one-third or more of the total volume) of serum may have been
separated. The clot contracts uniformly, thus preserving throughout the
same general shape as that of the vessel in which the blood has been
collected. Finally the clot swims freely in the serum which it has
expressed.
The cause of the clot formation has been found to be the precipitation
of a solid from the liquid plasma of the blood. This solid is in the
form of very minute threads and hence is termed _fibrin_. The threads
traverse the mass of blood in every possible direction, interlacing and
thus confining in their meshes all the solid elements of the blood. Soon
after their deposition they begin to contract, and as the meshwork they
form is very minute they carry with them all the corpuscles of the
blood. These with the fibrin form the shrunken clot.
If the rate at which blood clots be retarded either by cooling or by
some other process the corpuscles may have time to settle, partially or
completely, in which case distinct layers may form. The lowermost of
these contains chiefly the red corpuscles, the second layer may be grey
owing to the high percentage of leucocytes present, while a third,
marked by opalescence only, may be very rich in platelets. Above these a
clear layer of fluid may be found. This is _plasma_. The formation of
these layers depends solely upon the rate of sedimentation of these
elements, the rate depending partly upon differences in specific
gravity, and partly upon the tendency the corpuscles have to run into
clumps. Horse's blood offers one of the best instances of the clumping
of red corpuscles, and in this animal sedimentation of the red
corpuscles is most rapid.
If now such a sedimented blood is allowed to clot the process is found
to start in the middle two layers, i.e. in those containing the white
corpuscles and platelets. From these layers it spreads through the rest
of the liquid, being most retarded, however, in the red corpuscle layer,
and particularly so if the sedimentation has been very complete. Not
only does the clotting process start from the layers containing the
leucocytes and platelets, but in them it also proceeds more quickly.
These observations clearly indicate that the clotting process is
initiated by some change starting from these elements.
The object of the clotting of the blood is quite clear. It is to
prevent, as far as possible, any loss of blood when there is an injury
to an animal's vessels. The shed blood becomes converted into a solid,
and this, extending into the interior of the ruptured vessel, forms a
plug and thus arrests the bleeding. It is found that clotting is
especially accelerated whenever the blood touches a foreign tissue, for
instance, the outer layers of a torn blood-vessel wall, muscle tissue,
&c., i.e. in exactly those conditions in which rapid clotting becomes
of the greatest importance. Yet another very pregnant fact in connexion
with clotting is that if an animal be bled rapidly and the blood
collected in successive samples it is found that those collected last
clot most quickly. Hence the more excessive the haemorrhage in any case,
the greater becomes the onset of the natural cure for the bleeding, viz.
clotting.
When we begin to inquire into the nature of clotting we have to
determine in the first place whence the fibrin is derived. It has long
been known that two chemical substances at least are requisite for its
production. Thus certain fluids are known, e.g. some samples of
hydrocele or pericardial fluid, which will not clot spontaneously, but
will clot rapidly when a small quantity of serum or of an old blood-clot
is added to it. The constituent substance which is present in the
first-named fluids is known as fibrinogen, and that present in the serum
or the clot is known as fibrin-ferment or _thrombin_.
Fibrinogen is present in living blood dissolved in the plasma; it is
also present in such fluids as hydrocele or pericardial effusions,
which, though capable of clotting, do not clot spontaneously. Thrombin,
on the other hand, does not exist in living blood, but only makes its
appearance there after blood is shed. It is not yet certain what is the
nature of the final reaction between fibrinogen and thrombin. The
possibilities are, that thrombin may act--(1) by acting upon fibrinogen,
which it in some way converts into fibrin, (2) by uniting with
fibrinogen to form fibrin, or (3) by yielding part of itself to the
fibrinogen which thus becomes converted into fibrin. The experimental
study of the rate of fibrin formation, when different strengths of
thrombin solutions are allowed to act upon a fibrinogen solution, leads
us to the probable conclusion that the first of these three
possibilities is the correct one, and that thrombin therefore exerts a
true ferment action upon fibrinogen. It is known that in the reaction,
in addition to the formation of fibrin, yet another protein makes its
appearance. This is known as fibrinoglobulin, and apparently it arises
from the fibrinogen, so that the change would be one of cleavage into
fibrin and fibrinoglobulin. It is very noteworthy that although the
amount of fibrin formed during the clotting appears very bulky, yet the
actual weight is extremely small, not more than 0.4 grms. from 100 cc.
of blood.
Having ascertained that the clotting is due to the action of thrombin
upon fibrinogen, we now see that the next step to be explained is the
origin of thrombin. It has been shown that the final step in its
formation consists in the combination of another substance, termed
prothrombin, with calcium. Any soluble calcium salt is found to be
effective in this respect, and conversely the removal of soluble calcium
(e.g. by sodium oxalate) will prevent the formation of thrombin and
therefore of clotting.
In the next place it can be proved that prothrombin does not exist as
such in circulating blood, so that the problem becomes an inquiry as to
the origin of prothrombin. Experiment has shown that in its turn
prothrombin arises from yet another precursor, which is named
thrombogen, and that thrombogen also is not to be found in circulating
blood but only makes its appearance after the blood is shed. The
conversion of thrombogen into prothrombin has been proved to be due to
the action of a second ferment which has been named thrombokinase, and
this latter is again absent from living blood. Hence the question
arises, whence are derived thrombogen and thrombokinase? In the study of
this question it has been found that if the blood of birds be collected
direct from an artery through a perfectly clean cannula into a clean and
dust-free glass vessel, it does not clot spontaneously. The plasma
collected from such blood is found to contain thrombogen but no
thrombokinase. A somewhat similar plasma may be prepared from a mammal's
blood by collecting samples of blood from an artery into vessels which
have been thoroughly coated with paraffin, though in this instance
thrombogen may be absent as well as thrombokinase. If plasma containing
thrombogen but no thrombokinase be treated with a saline extract of any
tissues it will soon clot. The saline extract contains thrombokinase.
This ferment can therefore be derived from most tissues, including also
the white blood corpuscles and the platelets. Thrombogen is produced
from the leucocytes, but it is not yet certain whether it is also formed
from the platelets. The discovery of the origin of the thrombokinase
from tissue cells explains a fact that has long been known, namely, that
if in collecting blood, it is allowed to flow over cut tissues, clotting
is most markedly accelerated. The fact that birds' blood if very
carefully collected will not clot spontaneously tends to prove that
thrombokinase is not derived from the leucocytes, and makes probable its
origin from the platelets, for it is known that birds' blood apparently
does not contain platelets, at any rate in the form in which they are
found in mammalian blood. When examining the general properties of
platelets, attention was drawn to the remarkably rapid manner in which
they undergo change on coming into contact with a foreign surface. It is
apparently the actual contact which initiates these changes, changes
which are fundamentally chemical in character, resulting in the
production of thrombokinase and possibly also of thrombogen.
Thus as our knowledge at present stands the following statement gives a
recapitulated account of the changes which constitute the many phases of
clotting. When blood escapes from a blood-vessel it comes into contact
with a foreign surface, either a tissue or the damaged walls of the cut
vessel. Very speedily this contact results in the discharge of
thrombogen and thrombokinase, the former from the white blood corpuscles
and also possibly from the platelets, the latter from the platelets or
from the tissue with which the blood comes in contact. The interaction
of these two bodies next results in the formation of prothrombin, which,
combining with the calcium of any soluble lime salt present, forms
thrombin or fibrin-ferment. The last step in the change is the action of
thrombin upon fibrinogen to form fibrin, and the clot is complete.
The intrinsic value to the animal of these changes is quite plain. The
power of clotting and thus stopping haemorrhage is of essential
importance, and yet this clotting must not occur within the living
blood-vessels, or it would speedily result in death. That the tissues
should be able to accelerate the process is of very obvious value. That
the inner lining of the blood-vessels does not act as a foreign tissue
is possibly due to the extreme smoothness of their surface.
Further, an animal must always be exposed to a possible danger in the
absorption of some thrombin from a mass of clotted blood still retained
within the body, and we know that if a quantity of active ferment be
injected into the blood-stream intravascular clotting does result. Under
all usual conditions this is obviated, the protective mechanism being of
a twofold character. First, it is found that thrombin becomes converted
very quickly into an inactive modification. Serum, for instance, very
quickly loses its power of inducing clotting in fibrinogen solutions.
Secondly, the body has been found to possess the power of making a
substance, antithrombin, which can combine with thrombin forming a
substance which is quite inactive as far as clotting is concerned.
Finally, there is evidence that normal blood contains a small quantity
of this substance, antithrombin, and that under certain conditions the
amount present may be enormously increased. (T. G. Br.)
_Pathology of the Blood._
The changes in the blood in disease are probably as numerous and varied
as the diseases which attack the body, for the blood is not only the
medium of respiration, but also of nutrition, of defence against
organisms and of many other functions, none of which can be affected
without corresponding alterations occurring in the circulating fluid.
The immense majority of these changes are, however, so subtle that they
escape detection by our present methods. But in certain directions,
notably in regard to the relations with micro-organisms, changes in the
blood-plasma can be made out, though they are not associated in all
cases with changes in the formed elements which float in it, nor with
any obvious microscopical or chemical alterations.
Immunity.
The phenomena of immunity to the attacks of bacteria or their toxins, of
agglutinative action, of opsonic action, of the precipitin tests, and of
haemolysis, are all largely dependent on the inherent or acquired
characters of the blood serum. It is a commonplace that different people
vary in their susceptibility to the attacks of different organisms, and
different species of animals also vary greatly. This "natural immunity"
is due partly to the power possessed by the leucocytes or white blood
corpuscles of taking into their bodies and digesting or holding in an
inert state organisms which reach the blood--phagocytosis,--partly to
certain bodies in the blood serum which have a bactericidal action, or
whose presence enables the phagocytes to deal more easily with the
organisms. This natural immunity can be heightened when it exists, or an
artificial immunity can be produced in various ways. Doses of organisms
or their toxins can be injected on one or several occasions, and
provided that the lethal dose be not reached, in most cases an increased
power of resistance is produced. The organisms may be injected alive in
a virulent condition, or with their virulence lessened by heat or cold,
by antiseptics, by cultivation in the presence of oxygen, or by passage
through other animals, or they may first be killed, or their toxins
alone injected. The method chosen in each case depends on the organism
dealt with. The result of this treatment is that in the animal treated
protective substances appear in the serum, and these substances can be
transferred to the serum of another animal or of man; in other words the
active immunity of the experimental animal can be translated into the
passive immunity of man. According to the nature of the substances
injected into the former, its serum may be antitoxic, if it has been
immunized against any particular toxin, or antibacterial, if against an
organism. Familiar examples of these are, of the former diphtheria
antitoxin, of the latter anti-plague and anti-typhoid sera. An antitoxin
exerts its effects by actual combination with the respective toxin, the
combination being inert. It is probable that the ultimate source of the
antitoxin is to be found in the living cells of the tissues and that it
passes from them into the blood. The action of an antibacterial serum
depends on the presence in it of a substance known as "immune-body,"
which has a special affinity and power of combining with the bacterium
used. In order that it may exert this power it requires the presence of
a substance normally present in the serum known as "complement." The
development of these "anti-bodies," though it has been studied mainly in
connexion with bacteria and their toxins, is not confined to their
action, but can be demonstrated in regard to many other substances, such
as ferments, tissue cells, red corpuscles, &c. In some animals, for
example, the blood serum has the power of dissolving the red corpuscles
of an animal of different species; e.g. the guinea-pig's serum is
"haemolytic" to the red corpuscles of the ox. This haemolytic power
(haemolysis) can be increased by repeated injections of red corpuscles
from the other animal, in this case also, as in the bacterial case, by
the production and action of immune-body and complement. The antiserum
produced in the case of the red corpuscles may sometimes, if injected
into the first animal, whose red corpuscles were used, cause extensive
destruction of its red corpuscles, with haemoglobinuria, and sometimes a
fatal result.
Opsonic action depends on the presence of a substance, the "opsonin," in
the serum of an immunized animal, which makes the organism in question
more easily taken up by the phagocytes (leucocytes) of the blood. The
opsonin becomes fixed to the organisms. It is present to a certain
extent in normal serum, but can be greatly increased by the process of
immunization; and the "opsonic index," or relation between the number of
organisms taken up by leucocytes when treated with the serum of a
healthy person or "control," and with the serum of a person affected
with any bacterial disease and under treatment by immunization, is
regarded by some as representing the degree of immunity produced.
Agglutinative action is evidence of the presence in a serum of a
somewhat similar set of substances, known as "agglutinins." When a
portion of an antiserum is added to an emulsion of the corresponding
organism, the organisms, if they are motile, cease to move, and in any
case become gathered together into clumps. In all probability several
different bodies are concerned in this process. This reaction, in its
practical applications at least, may be regarded as a reaction of
infection rather than of immunization as ordinarily understood, for it
is found that the blood serum of patients suffering from typhoid, Malta
fever, cholera, and many other bacterial diseases, agglutinates the
corresponding organisms. This fact has come to be of great importance in
diagnosis.
The precipitin test depends on a somewhat analogous reaction. If the
serum of an animal be injected repeatedly into another animal of
different species, a "precipitin" appears in the serum of the animal
treated, which causes a precipitate when added to the serum of the first
animal. The special importance of this fact is that it can be utilized
as a method of distinguishing between human blood and that of animals,
which is often of importance in medical jurisprudence.
In this summary the facts adduced are practically all biological, and
are due to the extraordinary activity with which the study of
bacteriology (q.v.) has been pursued in recent years. The chemistry of
the blood has not hitherto been found to give information of clinical or
diagnostic importance, and nothing need here be added to what is said
above on the physiology of the blood. Enough has been said, however, to
show the extraordinary complexity of the apparently simple blood serum.
The methods at present employed in examining the blood clinically are:
the enumeration of the red and white corpuscles per cubic millimetre;
the estimation of the percentage of haemoglobin and of the specific
gravity of the blood; the microscopic examination of freshly-drawn blood
and of blood films made upon cover-glasses, fixed and stained. In
special cases the alkalinity and the rapidity of coagulation may be
ascertained, or the blood may be examined bacteriologically. We have no
universally accepted means of estimating, during life, the total amount
of blood in the body, though the method of J.S. Haldane and J. Lorrain
Smith, in which the total oxygen capacity of the blood is estimated, and
its total volume worked out from that datum, has seemed to promise
important results (_Journ. of Physiol_. vol. xxv. p. 331, 1900). After
death the amount of blood sometimes seems to be increased, and
sometimes, as in "pernicious anaemia," it is certainly diminished. But
the high counts of red corpuscles which are occasionally reported as
evidence of plethora or increase of the total blood are really only
indications of concentration of the fluid except in certain rare cases.
It is necessary, therefore, in examining blood diseases, to confine
ourselves to the study of the blood-unit, which is always taken as the
cubic millimetre, without reference to the number of units in the body.
Anaemia.
_Anaemia_ is often used as a generic term for all blood diseases, for in
almost all of them the haemoglobin is diminished, either as a result of
diminution in the number of the red corpuscles in which it is contained,
or because the individual red corpuscles contain a smaller amount of
haemoglobin than the normal. As haemoglobin is the medium of respiratory
interchange, its diminution causes obvious symptoms, which are much more
easily appreciated by the patient than those caused by alterations in
the plasma or the leucocytes. It is customary to divide anaemias into
"primary" and "secondary": the primary are those for which no adequate
cause has as yet been discovered; the secondary, those whose cause is
known. Among the former are usually included chlorosis, pernicious
anaemia, and sometimes the leucocythaemias; among the latter, the
anaemias due to such agencies as malignant disease, malaria, chronic
metallic poisoning, chronic haemorrhage, tubercle, Bright's disease,
infective processes, intestinal parasites, &c. As our knowledge
advances, however, this distinction will probably be given up, for the
causes of several of the primary anaemias have been discovered. For
example, the anaemia due to _bothriocephalus_, an intestinal parasite,
is clinically indistinguishable from the other forms of pernicious
anaemia with which it used to be included, and leucocythaemia has been
declared by Lowit, though probably erroneously, to be due to a blood
parasite closely related to that of malaria. In all these conditions
there is a considerable similarity in the symptoms produced and in the
pathological anatomy. The general symptoms are pallor of the skin and
mucous membranes, weakness and lassitude, shortness of breath,
palpitation, a tendency to fainting, and usually also gastro-intestinal
disturbance, headache and neuralgia. The heart is often dilated, and on
auscultation the systolic murmurs associated with that condition are
heard. In fatal cases the internal organs are found to be pale, and very
often their cells contain an excessive amount of fat. In many anaemias
there is a special tendency to haemorrhage. Most of the above symptoms
and organic changes are directly due to diminished respiratory
interchange from the loss of haemoglobin, and to its effect on the
various organs involved. The diagnosis depends ultimately in all cases
upon the examination of the blood.
Though the relative proportions of the leucocytes are probably
continually undergoing change even in health, especially as the result
of taking food, the number of red corpuscles remains much more constant.
Through the agency of some unknown mechanism, the supply of fresh red
corpuscles from the bone-marrow keeps pace with the destruction of
effete corpuscles, and in health each corpuscle contains a definite and
constant amount of haemoglobin. The disturbance of this arrangement in
anaemia may be due to loss or to increased destruction of corpuscles, to
the supply of a smaller number of new ones, to a diminution of the
amount of haemoglobin in the individual new corpuscles, or to a
combination of these causes. It is most easy to illustrate this by
describing what happens after a haemorrhage. If this is small, the loss
is replaced by the fully-formed corpuscles held in reserve in the
marrow, and there is no disturbance. If it is larger, the amount of
fluid lost is first made up by fluid drawn from the tissues, so that the
number of corpuscles is apparently diminished by dilution of the blood;
the erythroblasts, or formative red corpuscles, of the bone-marrow are
stimulated to proliferation, and new corpuscles are quickly thrown into
the circulation. These are apt, however, to be small and to contain a
subnormal amount of haemoglobin, and it is only after some time that
they are destroyed and their place taken by normal corpuscles. If the
loss has been very great, nucleated red corpuscles may even be carried
into the blood-stream. The blood possesses a great power of recovery, if
time be given it, because the organ (bone-marrow) which forms so many of
its elements never, in health, works at high pressure. Only a part of
the marrow, the so-called red marrow, is normally occupied by
erythroblastic tissue, the rest of the medullary cavity of the bones
being taken up by fat. If any long-continued demand for red corpuscles
is made, the fat is absorbed, and its place gradually taken by red
marrow. This compensatory change is found in all chronic anaemias, no
matter what their cause may be, except in some rare cases in which the
marrow does not react.
It is often very difficult, especially in "secondary" anaemias, to say
which of the above processes is mainly at work. In acute anaemias, such
as those associated with septicaemia, there is no doubt that blood
destruction plays the principal part. But if the cause of anaemia is a
chronic one, a gastric cancer, for instance, though there may possibly
be an increased amount of destruction of corpuscles in some cases, and
though there is often loss by haemorrhage, the cancer interferes with
nutrition, the blood is impoverished and does not nourish the
erythroblasts in the marrow sufficiently, and the new corpuscles which
are turned out are few and poor in haemoglobin. In chronic anaemias,
regeneration always goes on side by side with destruction, and it is
important to remember that the state of the blood in these conditions
gives the measure, not of the amount of destruction which is taking
place so much as of the amount of regeneration of which the organism is
capable. The evidence of destruction has often to be sought for in other
organs, or in secretions or excretions.
Of the so-called primary anaemias the most common is _chlorosis_, an
anaemia which occurs only in the female sex, between the ages of fifteen
and twenty-five as a rule. Its symptoms are those caused by a diminution
of haemoglobin, and though it is never directly fatal, and is extremely
amenable to treatment with iron preparations, its subjects very
frequently suffer from relapses at varying intervals after the first
attack. Its causation is probably complex. Bad hygienic conditions,
over-fatigue, want of proper food, especially of the iron-containing
proteids of meat, the strain put upon the blood and blood-forming organs
by the accession of puberty and the occurrence of menstruation, all
probably play a part in it. It has also been suggested that internal
secretions may be concerned in stimulating the bone-marrow, and that in
the female sex in particular the genital organs may act in this way.
Imperfect assumption of function by these organs at puberty, caused
perhaps by some of the above-mentioned conditions, might lead to
sluggishness in the bone-marrow, and to the supply to the blood of the
poorly-formed corpuscles deficient in haemoglobin which are
characteristic of the disease. Chlorosis is the type of anaemias from
imperfect blood-formation. Lorrain Smith has produced evidence to show
that the total amount of haemoglobin in the body is not diminished in
this disease, but that the blood-plasma is greatly increased in amount,
so that the haemoglobin is diluted and the amount in each blood-unit
greatly lessened.
_Pernicious anaemia_ is a rarer disease than chlorosis, occurs usually
later in life, and is distributed nearly equally between the two sexes.
But it is of great importance because of its almost uniformly fatal
termination, though its downward course is generally broken by
temporary improvement on one or more occasions. The symptoms are those
of a progressive anaemia, in which gastro-intestinal disturbance usually
plays a large part, and nervous symptoms are common, and they become at
last much more severe than those of any secondary anaemia. The patient
may die in the first attack, but more usually, when things seem to be at
their worst, improvement sets in, either spontaneously or as the result
of treatment, and the patient slowly regains apparent health. This
remission may be followed by a relapse, that again by a remission, and
so on, but as a rule the disease is fatal within, at the outside, two or
three years.
The prime cause of the disease is not known. It seems probable indeed
that the causal factors are numerous. Severe malarial infection,
syphilis, pregnancy, chronic gastro-intestinal disease, chronic
gas-poisoning, are all, in different cases, known to have been causally
associated with it, and it is probable that a congenital weakness of the
bone-marrow has often to do with its production, as in many cases a
family or hereditary history of the disease can be obtained. The
condition is now regarded as a chronic toxaemia, partly because of the
clinical symptoms and pathological appearances, partly because analogous
conditions can be produced experimentally by such poisons as saponin and
toluylendiamin, and partly because of the facts of _bothriocephalus_
anaemia. The site of production of the toxin, or toxins, for it is
possible that several may have the same effect on the blood, is possibly
not always the same, but must often be the alimentary canal, as
_bothriocephalus_ anaemia proves. Not all persons affected with this
intestinal tapeworm contract the disease, but only those in whose
intestines the worm is dead and decomposing or sometimes only "sick."
The expulsion of the worm puts an end to the absorption of the toxin and
the patients recover. No adequate explanation of the formation of the
toxin in the immense majority of the cases, in which there is no
tapeworm, has yet been given. It is certain that no organism as yet
known is concerned.
This toxaemia affects the marrow and through it the blood, the
gastro-intestinal apparatus and the nervous system, especially the
spinal cord, in different proportions in different cases. The effect
upon the marrow is to alter the type of red corpuscle formation, causing
a reversion to the embryonic condition, in which the nucleated red
corpuscles are large (megaloblasts), and the corpuscles in the blood
formed from them are also large, are apparently ill suited to the needs
of the adult, and easily break down, as the deposits of iron in the
liver, spleen, kidneys and marrow prove. Whether this reversion is due
to an exhaustion of the normal process or to an inhibition of it is not
definitely known. The result is that the circulating red corpuscles are
enormously diminished; it is usual to find 1,000,000 or less in the
cubic millimetre instead of the normal 5,000,000. Though the haemoglobin
is of course absolutely diminished, it is always, in severe cases,
present in relatively higher percentage than the red corpuscles, because
the average red corpuscle is larger and contains more haemoglobin than
the normal. The large nucleated red corpuscles (megaloblasts) with which
the marrow is crowded, often appear in the blood.
Other anaemias, such as those known as _lymphadenoma_, or Hodgkin's
disease, _splenic anaemia_, _chloroma_, _leucanaemia_ and the _anaemia
pseudo-leucaemica_ of children, need not be described here, as they are
either rare or their occurrence or nature is still too much under
discussion.
Leucocytosis.
The number and nature of the leucocytes in the blood bears no constant
or necessary relation to the number or condition of the red corpuscles,
and their variations depend on entirely different conditions. The number
in the cubic millimetre is usually about 7000, but may vary in health
from 5000 to 10,000. A diminution in their number is known as
_leucopenia_, and is found in starvation, in some infective diseases, as
for example in typhoid fever, in malaria and Malta fever, and in
pernicious anaemia. An increase is very much more frequent, and is known
as _leucocytosis_, though in this term is usually connoted a relative
increase in the proportion of the polymorphonuclear neutrophile
leucocytes. Leucocytosis occurs under a great variety of conditions,
normally to a slight extent during digestion, during pregnancy, and
after violent exercise, and abnormally after haemorrhage, in the course
of inflammations and many infective diseases, in malignant disease, in
such toxic states as uraemia, and after the ingestion of nuclein and
other substances. It does not occur in some infective diseases, the most
important of which are typhoid fever, malaria, influenza, measles and
uncomplicated tuberculosis. In all cases where it is sufficiently severe
and long continued, the reserve space in the bone-marrow is filled up by
the active proliferation of the leucocytes normally found there, and is
used as a nursery for the leucocytes required in the blood. In many
cases leucocytosis is known to be associated with the defence of the
organism from injurious influences, and its amount depends on the
relation between the severity of the attack and the power of resistance.
There may be an increase in the proportions present in the blood of
lymphocytes (_lymphocytosis_), and of eosinophile cells
(_eosinophilia_). This latter change is associated specially with some
forms of asthma, with certain skin diseases, and with the presence of
animal parasites in the body, such as ankylostoma and filaria.
Leucaemia.
The disease in which the number of leucocytes in the blood is greatest
is _leucocythaemia_ or leucaemia. There are two main forms of this
disease, in both of which there are anaemia, enlargement of the spleen
and lymphatic glands, or of either of them, leucocytic hypertrophy of
the bone-marrow, and deposits of leucocytes in the liver, kidney and
other organs. The difference lies in the kind of leucocytes present in
excess in the blood, blood-forming organs and deposits in the tissues.
In the one form these are lymphocytes, which are found in health mainly
in the marrow, the blood itself, the lymph glands and in the lymphatic
tissue round the alimentary canal; in the other they are the kinds of
leucocytes normally found in the bone-marrow-myelocytes, neutrophile,
basophile and eosinophile, and polymorphonuclear cells, also
neutrophile, basophile and eosinophile. The clinical course of the two
forms may differ. The first, known as lymphatic leucaemia or
_lymphaemia_, may be acute, and prove fatal in a few weeks or even days
with rapidly advancing anaemia, or may be chronic and last for one or
two years or longer. The second, known as spleno-myelogenous leucaemia
or _myelaemia_, is almost always chronic, and may last for several
years. Recovery does not take place, though remissions may occur. The
use of the X-rays has been found to influence the course of this disease
very favourably. The most recent view of the pathology of the disease is
that it is due to an overgrowth of the bone-marrow leucocytes, analogous
in some respects to tumour growth and caused by the removal of some
controlling mechanism rather than by stimulation. The anaemia
accompanying the disease is due partly to the leucocyte overgrowth,
which takes up the space in the marrow belonging of right to red
corpuscle formation and interferes with it. (G. L. G.)