Blood Transfusion

by Geoffrey Keynes

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.