DANGERS OF BLOOD TRANSFUSION
Appreciation of the dangers attending the practice of blood
transfusion has varied greatly at different times. In the seventeenth
century a happy ignorance took no account of them whatever. In the
eighteenth century they were so greatly feared that transfusion fell
into abeyance. In the nineteenth century it was realized that dangers
existed, but they were imperfectly understood; when fatalities
occurred, a partial knowledge explained them away more easily than
our fuller knowledge can to-day, so that transfusion was practised in
spite of them. At the beginning of the twentieth century, with the
discovery of “blood groups,” it was thought that all danger had been
eliminated. At the present time the pendulum is swinging back again,
and the problem of the complete elimination of danger is proving more
complex than it was thought to be a few years ago.
The chief dangers of blood transfusion are two-fold--that of
introducing into the recipient a disease carried by the donor, and
that due to the inherent properties of the donor’s blood which may
interact in a serious manner with the blood of the recipient. The
first of these dangers is obvious, and common sense will suggest what
steps should be taken to avoid it. Danger of communicating disease
is almost restricted to conditions in which an infective agent is
actually circulating in some form in the blood. Inquiry will usually
be enough to establish the possible presence in the prospective
donor’s blood of an organism such as the malaria parasite.
Nevertheless, a case has been recorded by van Dijk, in which malaria
was transmitted by injecting into a patient suffering from influenza
some serum obtained from another patient who was supposed to be
convalescent from influenza, but had been treated for malaria a few
months earlier. Another case is reported by Bernheim, who transmitted
a double infection of malaria--tertian and æstivo-autumnal--by means
of a blood transfusion. Blood infections, such as those due to the
exanthemata, may be avoided by the precaution of never employing a
blood donor who shows any signs of present illness, even though a
raised temperature be the only symptom. In certain cases, when, for
instance, the prospective donor may be suffering from tuberculosis in
some form or from gonorrhœa, the organism is extremely unlikely to be
present in the blood in numbers sufficient to communicate disease.
Nevertheless, on general principles, such donors should be eliminated
if circumstances permit. The most subtle form of infection, the most
dangerous, and the most difficult to eliminate, is syphilis. Definite
cases have been recorded in which syphilis has been communicated by
blood transfusion. In one instance recorded by Sydenstricker and
by Bernheim a father was infected by blood taken from his son, who
had refused beforehand to allow himself to be tested. Fortunately
such occurrences are rare. Still rarer and still more curious is the
transmission of horse asthma recorded by Ramirez. In this instance,
in which the disease is to be regarded as a form of anaphylaxis, the
patient had received an amount of serum sensitive to horse protein
great enough to provide him with the corresponding symptoms for some
time afterwards.
If the transfusion is being done at leisure, the donor’s blood
must be tested for a positive Wassermann reaction. Even this test,
however, has been known to fail, and since, in an emergency, the
most careful inquiry, aided by a desire on the part of the donor to
arrive at the truth, may reach an erroneous conclusion, the risk of
infection with syphilis can never be completely eliminated. Since
reasonable care can make the danger a remote one, it need not hinder
the performance of a transfusion any more than an occasional death
under anæsthesia prevents the frequent use of general anæsthetics.
The mere existence of such a danger is, however, an argument in
favour of the general use of the “professional blood donor,” whose
Wassermann reaction, personal history, and mode of life are well
known to the practitioner; the previous use of his blood on perhaps
more than one occasion, if unattended by any ill results, will give
an added confidence. The tragedy of such a misfortune is so great
that no precaution which can possibly be taken should be regarded as
absurd.
The second danger present in the inherent qualities of the donor’s
blood has been already alluded to in the historical sketch of the
subject. Before the existence of the “blood groups” was realized, a
number of fatalities due to an unexplained cause had occurred. Even
after the existence of the groups had been demonstrated, the warning
that resulted was apt to be disregarded, and it was not until still
further fatalities due to this incompatibility of bloods had taken
place that the very important nature of the discovery came to be
understood. The chances are, on the whole, that the blood of any
donor chosen at random will not prove fatal to a given recipient;
nevertheless, it must frequently happen that the transfusion
without being fatal will be wasted, or to some degree detrimental.
It is therefore evident that the existence of blood groups must be
seriously regarded, and it is necessary to enter into a detailed
consideration of their relations to one another and the symptoms
which they may produce. In the next chapters will be found a further
description of their physiology and pathology and of the methods of
testing for them.
It has long been known that if the blood of one species of animal
is injected into the circulation of another species, the corpuscles
of the foreign blood are at once destroyed, their contained
hæmoglobin being set free. This process of hæmolysis is under such
circumstances rapid and complete, and hæmoglobin may appear in the
urine in a short time. The precise nature of the reaction is obscure
and need not be discussed here in detail. The present bearing of
the phenomenon is the fact that a similar, or analogous, reaction
may occur when the bloods of certain individuals are mixed with
the bloods of certain others even of the same species. It was the
observation of this fact that first led to the discovery of the
so-called “blood groups” among human beings, and so to the partial
elucidation of the cause of the previously unexplained fatalities
following blood transfusion. In 1901 Landsteiner had detected the
presence of hæmolysins and iso-hæmolysins in blood and classified
three groups in human beings. In 1907 it was shown by Jansky that
human beings may be divided into four groups, the blood of the
members of each group having a certain definite relation to the blood
of the other groups as determined by the manner of their interaction.
The work was repeated and confirmed by Moss in 1910. The reaction
takes place between the serum of one group and the corpuscles of the
other groups, and is evidenced by the agglutination or hæmolysis
of the corpuscles that are being acted upon. In the course of his
researches Moss showed that hæmolysis, or the breaking up of the
corpuscles, is always preceded by agglutination or the clumping
together of the corpuscles. The process does not necessarily go as
far as the destruction of the corpuscles, but may be arrested at the
stage of agglutination. It may, on the other hand, be as rapid and
complete as if the bloods belonged to different species, and the
appearance of hæmoglobin in the urine may quickly give evidence of
this.
The groups have been arbitrarily numbered, and it is now usual to
refer to them by the Roman numerals I, II, III, and IV. According to
the accepted convention, the reactions of these four groups are as
follows:[5]
The corpuscles of Group I are agglutinated by the sera of II, III,
IV. The corpuscles of Group II are agglutinated by the sera of III,
IV. The corpuscles of Group III are agglutinated by the sera of II,
IV. The corpuscles of Group IV are not agglutinated by any of the
other groups.
On the other hand:
The serum of Group I agglutinates no other corpuscles. The serum of
Group II agglutinates the corpuscles of Groups I, III. The serum of
Group III agglutinates the corpuscles of Groups I, II. The serum of
Group IV agglutinates the corpuscles of Groups I, II, III.
This may be represented more graphically by the following table, a +
indicating agglutination, a - indicating no reaction:
-------------------+-----------------------+
| Serum |
+-----------------------+
| I | II | III | IV |
------------+------+-----+-----+-----+-----+
Corpuscles | I | - | + | + | + |
+------+-----+-----+-----+-----+
| II | - | - | + | + |
+------+-----+-----+-----+-----+
| III | - | + | - | + |
+------+-----+-----+-----+-----+
| IV | - | - | - | - |
------------+------+-----+-----+-----+-----+
The active principle in the serum is called “agglutinin” or
“hæmolysin,” according to the degree of the reaction, and the
corpuscles are rendered sensitive to this by the possession of
an “iso-agglutinin” or “iso-hæmolysin.” Sometimes the corpuscles
are said to have “agglutinophilic” properties. It may be stated,
therefore, that the serum of Group I entirely lacks agglutinins,
whereas the corpuscles of Group IV lack iso-agglutinins. All these
terms, like the “amboceptors,” “receptors,” and “haptophores” of
Ehrlich, are used to conceal ignorance rather than as an expression
of knowledge, but, until more light has been shed upon the nature of
the reactions, ignorance must be abbreviated.
It is now clear that the blood as a whole contains two sets of
reactions which are independent. These properties reside in the
serum and in the corpuscles respectively, and the reactions are
complementary between Groups II and III, that is to say, the serum of
each group agglutinates the corpuscles of the other. It will be seen
from the table that the serum of Group I blood does not agglutinate
the corpuscles of any of the other groups, and conversely the
corpuscles of Group IV are not agglutinated by the serum of any of
the other groups. Individuals of Groups I and IV have therefore been
named “universal recipients” and “universal donors” respectively.
This implies that if the recipient be found to belong to Group I,
the blood of any donor may be transfused into his veins irrespective
of his group, and that if the donor be of Group IV, his blood may
be used for transfusion irrespective of the group of the recipient.
These statements may be accepted as true in an emergency, but
important reservations may have to be made under certain conditions.
It was at one time believed that the group reactions were clear-cut
and absolute rather than relative. At the present time, however,
the view is gaining ground that there may be some “over-lapping” of
groups, that is to say, a serum may contain agglutinins which give a
gross reaction with the corpuscles of one group and a reaction with
another group so slight that it can be detected only with difficulty,
or alternatively the recipient’s corpuscles may give a definite and
limited group reaction, while his serum may cause some agglutination
in the blood of a theoretically compatible group. These properties
have recently been termed “major” and “minor agglutinins” by Unger,
who claims that the possible presence of minor agglutinins makes it
advisable to test the recipient’s blood directly against the donor’s
in every case. The term “universal donor” commonly applied to Group
IV is, in fact, misleading. The blood of Group IV cannot be used
indiscriminately with complete impunity. The groups are determined by
the major agglutinins, and by these the ordinary gross reactions may
be eliminated. Everyone who has used blood transfusions extensively
has observed that slight reactions may occur after transfusion with a
compatible blood, irrespective of the methods employed. Usually these
reactions are slight, and do not in any way prejudice the benefits
conferred by the transfusion, but they may become greatly accentuated
in the later transfusions of a series, and it is probable that minor
agglutinins may be developed in certain pathological conditions.
Further reference to these phenomena will be made elsewhere (p. 93).
In addition to this, it has been commonly observed that the intensity
of the reaction varies greatly with the sera of different individuals
of the same group. It has also been stated by Stansfeld that the
agglutinating power of the serum of an individual may vary from time
to time. As a rule the corpuscles of a person belonging to Group I
are not agglutinated with equal rapidity or intensity by the sera of
Groups II and III, but the meaning of this phenomenon has not been
fully investigated.
A possible source of trouble will occur to anyone looking
critically at the table of reactions, for it will be noticed
that the serum of Group IV, the so-called “universal donors,”
agglutinates the corpuscles of all the other groups. How does it
come about, therefore, that the blood of this group may be given
indiscriminately? The answer is to be found in the fact that though
the reaction takes place as shown in the table _outside the body_,
nevertheless the serum of the transfused blood does not exert its
agglutinating power in the body of the recipient. Several hypotheses
have been advanced to account for this discrepancy, though no
final explanation has yet been arrived at. In the first place it
is possible that the agglutinating power of the serum is rendered
ineffective by the dilution which it undergoes when it is mixed with
the blood of the recipient. It has been shown, however, by Culpepper
that agglutination takes place outside the body with serum diluted up
to 1 : 150, a degree of dilution far greater than is ever obtained
in a transfusion where the dilution in the patient’s circulation
is usually no greater than 1 : 7. Secondly, it has been suggested
that the transfused plasma meets with an excess of plasma containing
protective or antihæmolytic properties. The evidence on this point
is conflicting. Hektoen in 1907 was unable to demonstrate any such
property in serum or plasma. Brem and Minot in 1916 both claimed
to have demonstrated antihæmolytic properties in serum, and Minot
added the observation that its concentration varies. Karsner in 1921
reported that he had failed to demonstrate anti-agglutinins in the
blood. For the present, therefore, the point must remain undecided.
Finally, it is possible that the agglutinins of the transfused
plasma, meeting with an excess of agglutinable cells, are all
absorbed without actually producing any agglutination. Whichever of
these hypotheses be true, the fact remains that the blood of Group
IV individuals may be given without serious effects in most ordinary
cases in which transfusion is indicated.
It must not be inferred from the tabulated reactions that a
transfusion with the blood of an incompatible group necessarily
produces a fatal, or even a serious, result. If, for instance,
an individual of Group II be transfused with blood of Group III,
the corpuscles of the donor’s blood will certainly be rendered
ineffective, being destroyed either at once or in the course of a
short time. But beyond this wastage of the transfused blood there
may be no effects as shown by morbid symptoms in the recipient; he
will merely not be benefited. There may, on the other hand, be an
evident reaction in the recipient, the symptoms varying from slight
discomfort to almost immediate death. It appears, therefore, that
there is a gradation of toxicity between the bloods of incompatible
groups, so that it may be justifiable owing to extreme urgency in
certain cases to perform a transfusion without doing any preliminary
tests on the bloods of donor and recipient. There is a good
chance that the groups will be compatible; if, however, they be
incompatible, there is still a good chance that the recipient will be
no worse off than he was before the transfusion.
Even when the tests have been performed, it may still happen
that through various causes a mistake has arisen. Owing to the
inexperience of the operator or to staleness of the sera used
in performing the test, an incompatible group may appear to be
compatible. It is necessary, therefore, that everyone who performs a
transfusion should be able to recognize the symptoms of a reaction
as soon as it begins to appear, so that the transfusion may be at
once discontinued. Sometimes the reaction between incompatible
groups is so immediate and severe that death takes place almost at
once. I did not myself perform any transfusions until after the
period when blood-grouping tests had become a routine procedure, so
that I have no personal experience of such unfortunate results. The
symptoms may therefore best be described in the words of one who
has several times witnessed the effects of an incompatible blood:
“The clinical picture of these reactions is typical. They occur
early, after the introduction of 50 cc. or 100 cc. of blood; the
patient first complains of tingling pains shooting over the body, a
fullness in the head, an oppressive feeling about the precordium,
and, later, excruciating pain localized in the lumbar region. Slowly
but perceptibly the face becomes suffused a dark red to a cyanotic
hue; respirations become somewhat laboured, and the pulse rate,
at first slow, sometimes suddenly drops as many as from twenty to
thirty beats a minute. The patient may lose consciousness for a few
minutes. In one-half of our cases an urticarial eruption, generalized
over the body, or limited to the face, appeared with these symptoms.
Later the pulse may become very rapid and thready; the skin becomes
cold and clammy, and the patient’s condition is indeed grave. In
from fifteen minutes to an hour a chill occurs, followed by high
fever, a temperature of 103° to 105°, and the patient may become
delirious. Jaundice may appear later. The macroscopic appearance of
hæmoglobinuria is almost constant.” (Peterson.)
In a fatal case recorded by other writers the chief symptom was
hæmoglobinuria, which progressively increased until the functions of
the kidney became so much interfered with by deposits of hæmoglobin
or damaged corpuscles that the patient died with suppression of urine
and all the signs of uræmia (25).
In other cases a slighter and transient hæmoglobinuria has been
noticed, showing that some destruction of red cells has taken place
without producing any further effects. This symptom is, of course,
due to hæmolysis following reactions between the serum and corpuscles
as explained above. The variation in degree of the reaction is to be
partly explained by the fact that there are three possibilities: (1)
The donor’s corpuscles may be hæmolysed by the recipient’s serum;
this will result in the transient hæmoglobinuria and wastage of the
transfused blood; (2) the recipient’s corpuscles may be hæmolysed
by the donor’s serum, or (3) serum of each may hæmolyse the other’s
corpuscles. Either of the latter events will be extremely serious.
As already mentioned, hæmolysis is always preceded by agglutination,
and it seems that the agglutination may be the more rapidly fatal of
the two. It was probably this that was chiefly responsible for the
suppression of urine in the case referred to, and a case has been
recorded in which it appeared to be the only cause of immediate death
or, as an American writer expresses it, “sudden exitus took out, out
of a clear sky,” owing to the presence of multiple emboli.
In addition to the evidence of hæmolysis the patient may exhibit
the symptoms described above. Sometimes the urticarial rash has
been accompanied by vomiting and headache. This group of symptoms
suggests that the condition is analogous to the anaphylactic shock
which may follow the intravenous injection of any foreign protein.
The symptoms in a mild degree do occasionally follow the transfusion
of blood which has been shown to belong to a compatible group, and it
had been found to develop even to an alarming extent after the later
transfusions, when a series was being given for a condition such
as pernicious anæmia (34). In such cases, however, as is suggested
elsewhere, this may, perhaps, be regarded as true anaphylactic shock.
The symptoms which may accompany a first transfusion cannot be
identical with this since true anaphylaxis must have been preceded by
sensitization with a minimal dose of foreign protein introduced into
the circulation.
It was formerly thought that possibly the products of hæmolysis were
themselves toxic and capable of producing the symptoms described.
This seems, however, to have been disproved by Bayliss, who has shown
that in the dog and cat the hæmolysed blood of the same species is,
with extremely rare exceptions, innocuous.
Another possible cause of similar symptoms is the sodium citrate used
as an anticoagulant in one of the methods of transfusion subsequently
to be described. But the symptoms, if due to this cause, will not be
accompanied by any signs of hæmolysis, are usually not severe, and
are always very transient. This will be referred to again later on.
The symptoms of incompatibility begin to be apparent so quickly that
the worst results can be avoided by the exercise of caution. If for
any reason it has been necessary to use an untested blood donor, the
first 100 cc. of blood should be injected very slowly. If no untoward
symptoms result, the remainder of the blood can be injected with
greater confidence. Little can be said as to the treatment of this
condition, for prevention is far better than cure. When the symptoms
have developed, the damage has been done, and cannot be undone. The
ordinary measures for combating severe collapse may be used.
A lesser danger of transfusion is that of administering the blood
too rapidly. Sometimes during a transfusion the patient complains of
difficulty in breathing and a sensation of tightness in the chest;
this should always be regarded as a warning that the blood must be
given more slowly or perhaps that enough has been given and that
the transfusion should be discontinued. Usually the symptom amounts
to nothing more than discomfort, and will disappear if caution be
exercised. The explanation is to be found in the too rapid filling
of the venous side of an impaired circulation with overloading, and
perhaps temporary dilatation, of the right side of the heart. I have
never seen these symptoms occur to an alarming degree, but actual
loss of consciousness with a very rapid and feeble pulse has been
recorded by other writers. Directions as to the amount of blood which
should be given and the rate at which it should be injected so that
these symptoms may be avoided will be found under the description of
methods given in a later chapter.