DANGERS OF BLOOD TRANSFUSION (It should be remembered that this chapter was written before the discovery of the Rhesus Factor).

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 he 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 estivo-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 gonorrhoea, 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, lids 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 anaesthesia prevents the frequent use of general anaesthetics. 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 haemoglobin being set free. This process of haemolysis is under such circumstances rapid and complete, and haemoglobin 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 blood 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 haemolysins and iso-haemolysins 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 haemolysis of the corpuscles that are being acted upon. In the course of his researches Moss showed that haemolysis, 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 corpuseles, 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 haemoglobin 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 1, 11, III, and IV. According to the acetpted convention, the reactions of these four groups are as follows. ( The notation used here is that initiated by Moss in 1910. This does not agree with the notation introduced three years previously by Jansky.)

The corpuscles of Group 1 are agglutinated by the serum of II, III, IV. The corpuscles of Group 11 are agglutinated by the sera of III, IV. The corpuscles of Group III are agglutinated by the sera of 11, 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:

+ indicating agglutination, a - indicating no reaction: The present day ABO equivalents are in brackets:

The active principle in the serum is called "agglutinin" or "haemolysin" according to the degree of the reaction, and the corpuscles are rendered sensitive to this by possession of an "iso-agglutinin" or "iso-haemolysin". Sometimes the corpuscles are said to have 'agglutinophilic" properties. it may be stated, therefore, that the serum of Group 1 entirely lacks agglutinins, whereas the corpusclesof 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 scrum and in the corpuscles, respectively, and the reactions are complementary between Groups 11 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 1 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 1 and IV have therefore been named "universal recipients " and universal donors " respectively. This implies that if the recipient be found to belong to Group 1, 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. 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 1 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 maybe 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 anti-haemolytic 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 antihaemolytic 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 haemoglobinuria is almost constant." (Peterson.)

In a fatal case recorded by other writers the chief symptom was haemoglobinuria, which progressively increased until the functions of the kidney became so much interfered with by deposits of haemoglobin or damaged corpuscles that the patient died with suppression of urine and all the signs of uraemia.In other cases a slighter and transient haemoglobinuria 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 haemolysis 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 haemolysed by the recipient's serum; this will result in the transient haemoglobinuria and wastage of the transfused blood;

(2) the recipient's corpuscles may be haemolysed by the donor's serum, or

(3) serum of each may haemolyse the other's corpuscles.

Either of the latter events will be extremely serious. As already mentioned, haemolysis 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 haemolysis 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 anaemia. 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 haemolysis 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 haemolysed 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 haemolysis, 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.

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