Blood Diseases

Pernicious Anæmia.—Blood transfusion has been advocated for several conditions characterized by alterations in the cells of the patient’s blood. It has been used in the treatment of aplastic anæmia, splenic anæmia, chlorosis, and leukæmia, but in none of these diseases has it been of much avail. In pernicious anæmia, however, transfusion has proved to be of very great service.

It is, indeed, now a recognized form of treatment for this disease, though the numerous reports upon results that have been published have not pronounced unanimously in its favour. Variability in results probably depends to some extent upon the difficulty of distinguishing true pernicious anæmia from some forms of secondary anæmia. It is hardly to be expected that much benefit would follow blood transfusion in the undiagnosed secondary type, since the destruction or loss of corpuscles is continuous until the cause has been removed. In true pernicious anæmia, on the other hand, there may be remissions in the disease, and it is quite clear that these may be initiated or prolonged by blood transfusion. The largest number of consecutive cases that has been recorded was treated in the Mayo Clinic in the years 1915 to 1918 (Archibald, Pemberton, Hunt). It was estimated that in about 60 per cent. of the patients with pernicious anæmia a definite improvement followed transfusion. It is generally agreed that the best results are seen in those who have not yet reached the last stages of the disease, though sometimes patients who are actually in extremis will also show great improvement. A remarkable instance of this has been reported in Norway (261). A man, aged thirty-three, was dyspnœic, semi-conscious, and moribund when admitted to hospital. His red cells numbered 850,000 per cmm., and his hæmoglobin percentage was 19. Immediate improvement followed the transfusion of 900 cc. of citrated blood, the red cells rising quickly to 2,000,000 and later to 3,000,000. Twelve days after admission he was walking about. No case must therefore be regarded as hopeless, though disappointments must be expected.

As a general rule blood transfusion should be given before the more serious secondary manifestations of the disease have shown themselves, that is to say, some time before the condition has become dangerous to life. Probably the disappointing results of this treatment have partly been due to the fact that it has been regarded as a last resort and has often been given at too late a stage. No rule can be laid down as to when transfusion should be given, but common sense suggests that it should be tried as soon as it is evident that the disease is progressing in spite of other methods of treatment. One authority (Anders) even advises that transfusions should be given as soon as an assured diagnosis has been made, but he weakens his case by adding that other methods of treatment should be used at the same time. If the patient is already seriously ill when first seen, the blood transfusion should be tried at once, as its effect, if beneficial, is likely to be more rapid than that of any other form of treatment.

The amounts of blood given in pernicious anæmia have varied. Massive doses have occasionally been given (179), but the general opinion seems to favour smaller amounts, 300-500 cc., the dose being repeated at intervals of two or three weeks. Repeated transfusions have been an outstanding feature of the treatment, and as many as thirty-five transfusions of 500 cc. or more have been given to one patient, extending over a period of thirty months. This is in itself a demonstration of the fact that blood transfusion does not cure the disease; the beneficial effect of each transfusion may wear off in a short time, but by repeating the treatment the patient’s life can be prolonged for months or even years beyond the time when it would otherwise have ended.

Although the effect of transfusion is apt to be transient yet it is certain that its good effects are due not merely to the addition of a certain number of healthy corpuscles to the circulation, but, in addition, to an obscurer factor. This can best be expressed by saying that the transfused blood appears to have a stimulating effect upon the blood-forming tissues of the patient, so that more red corpuscles are discharged into the circulation. One observer believes that enumeration of the reticulated red cells may be used as an indication of the hæmopoietic powers of the bone marrow (289). The reticulated appearance is assumed to be characteristic of cells which have recently entered the circulation. The mode in which this stimulus acts is unknown, and the whole subject calls for further investigation. That this does take place is well illustrated by the following details of three cases from Dr. Drysdale’s wards at St. Bartholomew’s Hospital. The transfusions were given by Dr. Joekes, who was also responsible for the estimations of the corpuscles.

Fig. 3.—Pernicious Anæmia, Case I

I. A woman, aged 51, had been treated for four years for pernicious anæmia, and when admitted to hospital was becoming steadily worse. The red corpuscles numbered 1,470,000 per cmm., and her hæmoglobin percentage was 32 on October 21, 1918, and by November 19 they had fallen to 750,000 and 25. On November 22 she was transfused with 500 cc. of citrated blood, and a blood count made immediately afterwards showed that she then had 1,410,000 red cells per cmm. On December 12 the number had risen to over 3,000,000, and on January 28 of the following year it was over 4,000,000. This was still maintained in May, 1919, and on the last occasion on which a blood count was made she was found to have 4,400,000, with a hæmoglobin percentage of 90. Since then she has been lost sight of, but would certainly have returned had she relapsed. This case shows what remarkable results sometimes follow a single transfusion and the progressive improvement which follows the initial rise. The diagram shows the results more graphically.

Fig. 4.—Pernicious Anæmia, Case II

II. A similar result, even more striking, was obtained in a woman aged 42. She was treated medicinally for four months, during which time her red cells steadily decreased from 1,250,000 to 429,000 per cmm. She was then transfused with 400 cc. of blood, and her blood count rose immediately to 967,000. The rise continued steadily, and three months later her blood count was 3,690,000 per cmm. Two very small additional transfusions were given during this period, but to what extent these helped in the treatment cannot be estimated. The results in this case also are represented graphically by the diagram above.

Fig. 5.—Pernicious Anæmia, Case III

III. A less favourable result is illustrated by the following history: A stores assistant, aged 47, had been ill for two years, and was first treated for pernicious anæmia in April, 1920. He was medicinally treated with arsenic, but no improvement followed. On June 18, 1920, his corpuscles numbered 1,060,000 per cmm. He was transfused with 600 cc. of blood, and his corpuscles increased at once to 1,840,000 per cmm. A month later there had been a further increase to 2,520,000, but this was not maintained, and nine months afterwards he was given a second transfusion of 500 cc. of blood. Immediately after this his red cells numbered 1,800,000 per cmm. (April 14, 1921). There was a further slight rise and then another rapid fall, so that on June 4, 1921, he had only 830,000 red cells per cmm. He was then given a third transfusion of 700 cc. The effect of this was a steady rise, and on June 17 he had 2,112,000 red cells per cmm. A fourth transfusion of 500 cc. was given at this point, and thereafter the improvement was maintained, with slight variations, until, on August 4, 1921, his corpuscles numbered 3,450,000 per cmm.

In this case the effect of the two first transfusions was short-lived, but perseverance with the treatment brought him in the course of two months from an extremely serious condition to a state of comparatively good health, in which he could again for a time go about his business. The diagram illustrates well the rise which followed each of the later transfusions. He had again relapsed four months later, but, unless each transfusion had chanced to coincide with the remissions which may occur spontaneously in this disease, it seems clear that the treatment greatly relieved him for a time.

There is no objection to the use of citrated blood for pernicious anæmia, so that the transfusion can be carried out in the ordinary way described in Chapter VII. It is necessary, however, to utter a warning as to the choice of a blood donor. It is quite clear that in some patients, whose disease has been diagnosed as pernicious anæmia, there is an alteration in the reactions of the serum. The corpuscles may show an agglutination which conforms to one of the group tests described in Chapter VI; nevertheless, it is essential in addition that the patient’s serum should be tested directly against the corpuscles of the proposed donor, even if he belongs to Group IV, whose corpuscles are not agglutinated by the serum of any normal person. I was recently asked to transfuse a patient whose disease had been diagnosed as pernicious anæmia. Her red blood cells had fallen to 600,000 per cmm., so that she was probably in the last stages. Her corpuscles were agglutinated only by serum of Group III, so that she apparently belonged to Group II. Only two donors were available, both of whom belonged to Group IV. Nevertheless, the patient’s serum strongly agglutinated the corpuscles of both of them, so that I considered it inadvisable to carry out the treatment. Similar abnormalities have been noticed by others. It seems to be a universal experience that slight reactions are more commonly met with after transfusion for pernicious anæmia than when it is done for other conditions, although these do not in any way prejudice the results that are obtained. These reactions are possibly to be explained by abnormalities, though of slight degree, in the patient’s serum. In a case such as I have described the reaction would probably be very severe, if not fatal. It is possible also that a well-marked alteration in the serum reaction is not characteristic of the clinical entity constituting true pernicious anæmia, but in reality indicates that there is another underlying cause for the anæmia, such as an undiagnosed carcinoma. Dr. Joekes has recently (August 1921) told me that he believes from his own observations that this is actually the case, but it needs to be established by further investigation. The connexion between malignant disease and abnormal serum reactions is referred to elsewhere (p. 93).

Another possible complication is introduced into the treatment by the necessity for giving repeated transfusions. It has been noticed that sometimes a serious reaction follows one or more of the later transfusions of a series, even when the blood is taken from the same donor who had been used before without ill effects. A report on several such cases shows that this form of reaction cannot be predicted or eliminated by the most careful testing beforehand for reactions between the patient’s serum and the donor’s corpuscles, though it has occasionally been so severe as actually to hasten the patient’s death (34). This fact suggests that the reaction is not due to the presence of agglutinins, but is rather of the nature of an anaphylactic shock, the patient having been sensitized by a trace of foreign protein introduced in the blood on the earlier occasions. Possibly it may be to some extent avoided by not using the same donor if another is available. It also emphasizes the necessity for giving the blood slowly and cautiously, so that the transfusion may be stopped at the first sign of a reaction in the patient.

Very large numbers of transfusions for pernicious anæmia have been given in the past, yet a reaction of a dangerous severity has occurred in but few of them. This need not, therefore, be regarded as a contra-indication for transfusion, but rather as an indication for circumspection in giving it. Transfusion is clearly a therapeutic measure of great value.

Very recently it has been claimed by Waag that excellent results have been obtained by the repeated subcutaneous injection of small doses (5 cc.) of whole blood. In an actual case which he reports, nine injections were given twice weekly. If the claim be substantiated by further successes, this method of treatment may eventually supplant the more elaborate process of actual transfusion.

Toxæmias
Bacterial Infections

Pyogenic.—The value of vaccines and bactericidal sera in pyogenic infections, though not in universal favour, is strongly advocated by many competent authorities, and the transfusion of blood from an immunized donor suggests itself as a natural corollary. A quantity of blood taken from a vigorously reacting man and given to a debilitated patient should theoretically supply him with a large amount of the antibodies of which he stands in need. During the war it was found that transfusion enabled an exsanguinated patient better to withstand the attacks of pyogenic and putrefactive organisms in his wounds, but this was probably due to the improvement in the general circulation which resulted rather than to any bactericidal properties in the transfused blood. It is known that outside the body blood has considerable powers of inhibiting the growth of bacteria, but ordinarily it does not possess bactericidal properties. It has been claimed, on the other hand, that the best criterion of the degree of immunity in an immunized animal is the measurement of the bactericidal power of its blood. There is justification therefore for attempting to combat a pyogenic infection by the transfusion of immunized blood.

This method has at present not progressed beyond the stage of preliminary trials. I have attempted it in one case, but without any obvious benefit. The patient was a middle-aged man suffering from a chronic staphylococcal septicæmia and a secondary anæmia. He received a transfusion of 650 cc. of blood from a donor who had himself just recovered from a severe infection with staphylococcus aureus. The patient’s red blood cells underwent a temporary increase in number, but no other result was observed. One series of nine cases has been recorded by Fry, and in these the results leave some doubt as to the efficacy of the treatment. Six of these patients were almost hopelessly ill with streptococcal (five) or staphylococcal (one) septicæmia, and only one of these responded to treatment. He received transfusion from an ordinary donor and two from immunized donors, who had been given five or six injections of a mixed vaccine, the maximum dose of which contained 120,000,000 streptococci. Improvement definitely followed the transfusions, and his recovery was afterwards encouraged by injections of an autogenous vaccine. The other five patients received similar treatment, but all died. The remaining three patients had chronic suppuration, one following a streptococcal arthritis of the knee, but no septicæmia, and all recovered. It cannot be assumed that these recoveries were due to the transfusions.

It is stated by Waugh that he transfused nineteen cases of pyæmia of whom twelve recovered, and in these cases an ordinary donor was used. No details, however, are given, so that it is not possible to make any inferences from this.

Greater success is claimed by Hooker, who reported that in five cases of pyogenic infection the results were distinctly favourable. He used immunized blood, but has formed the impression that the transfusion even of normal blood is of value in septicæmia by correcting the anæmia and helping to restore the normal resistance. He recommends that if the patient has a good blood volume and a high bacterial content in the blood, he should be bled by venesection before transfusion. A striking case of staphylococcal septicæmia has been recorded by Little, who believed that the patient’s recovery was directly due to the treatment. Four transfusions were given, the blood for three of these being taken from donors who had each received, four days previously, an injection of vaccine made from the patient’s own infection. Ottenberg and Libmann have treated ten cases of pyogenic infections with transfusions. All the patients were extremely ill and six died. It is stated that the four who recovered “probably owe their lives to the transfusion,” but obviously it is difficult to control the results. The same observers have used transfusion in the treatment of infective endocarditis, but unsuccessfully.

Some experimental work on this subject has been carried out by Kahn. A bacterial infection was introduced into the peritoneal cavities of several dogs. Continuous transfusion between an infected dog and a healthy dog was then performed, the blood passing to and fro between the animals, sometimes for over an hour. It was found that all the transfused animals fared better than those that were not. The experiment suggests that resistance to infection is heightened if two bodies can combat the infection present in one; but continuous transfusion is scarcely practicable in man.

Diphtheria.—In the later stages of some acute diseases due to a bacterial infection, the patient falls into a condition of acute toxæmia, the symptoms of which resemble in some ways those of shock. Harding has drawn attention to this condition in diphtheria; he has produced it experimentally in animals and has treated it by blood transfusion. The toxæmic stage was found to occur on the fourth to the eleventh day. It was characterized by a reduction of the output of the heart with a corresponding fall in blood pressure, an exudation of lymph into the tissues, and an increased specific gravity of the blood. In all these respects it resembled the collapse due to trauma or to hæmorrhage, and it was shown by experiment that the treatment must be directed towards increasing the amount of effective fluid in the circulation and to decreasing its viscosity. It was found that normal saline solution failed to do this; gum-saline solution also failed, and tended to produce a pronounced agglutination of the red blood cells. Blood transfusion, on the other hand, resulted in a considerable number of recoveries. In the aggregate more than twice as many animals survived after transfusion as survived without it, the same amount of toxin being given in each case.

These experimental findings are exceedingly suggestive, but the clinical efficacy of the treatment still remains to be proved. Harding found that the amount of blood that should be transfused was one-fifth of the total blood volume; the following amounts are, therefore, recommended for the treatment of children in the toxæmia stage of diphtheria:

Age.Weight.Amount.
1½ years.21 lbs.160 ccm.
2 ”28 ”200 ”
4 ”35 ”300 ”
6 ”42 ”400 ”

Pneumonia.—A condition of toxæmia similar to that seen in diphtheria was also observed in some of the cases of pneumonia which complicated the influenza epidemic of 1918-19. In the United States, among a large number of cases admitted to an emergency hospital, a series of 28 patients, some of whom were moribund, was treated by blood transfusion by Rose and Hund. The results were compared with those in 21 similar cases which were not transfused. The figures seemed to show that transfusion was of some value. Of the 28 who were transfused, 6, or 22·4 per cent., died, and the rest recovered; of the 21 who were not transfused, 9, or 47·7 per cent., died, and 12 recovered. The numbers treated are not large enough to afford statistical evidence that can be relied upon, but the results were at least encouraging.

Typhoid, Measles, Tuberculosis.—Transfusion has been tried for several other bacterial infections with varying results. McClure has administered immunized blood to a typhoid patient with a remarkably good result. Ottenberg and Libmann have transfused five typhoid patients, all of whom were desperately ill; two of them recovered. Transfusion has also been used for intestinal hæmorrhage in typhoid, but this is chiefly with the object of combating anæmia. Subcutaneous injection of blood has been successfully used by Terrien in a case of malignant measles; the donor had had measles six months previously. Freilich has recently transfused six patients suffering from tuberculosis, but without benefit. He is at present testing the use of blood from donors who show a positive complement fixation test for the tubercle bacillus.

It is evident that treatment with immunized blood is still in an experimental stage, but it merits further trials, all the circumstances of which should be carefully recorded.

Toxæmias of Pregnancy.—The treatment of eclampsia by blood transfusion was first employed by Kimpton, who speaks favourably of the results obtained. Later it was independently suggested to Blair Bell, who was the first to employ it in this country, by certain investigations into the facts of immunology. It had been found that symptoms resembling those of eclampsia could be produced in mice by injecting into them an extract of placenta, whether from a healthy or an eclamptic woman; the same results were obtained by injecting fresh serum from similar individuals. Further, if the placental extract was mixed with serum from a normal person of either sex, the effects were not obtained, and it was inferred that the placental toxin had been neutralized by antibodies in the serum. If, however, the placental extract was mixed with serum obtained from the blood of an eclamptic patient, then the toxic symptoms were obtained as before. Apparently, therefore, the serum in eclampsia lacks certain antibodies which are present in the serum of normal individuals. If these observations had been correctly interpreted, it seemed reasonable to suppose that blood from a normal person would supply an eclamptic patient with the antibodies which she lacks. The patient treated by Blair Bell was already comatose and apparently dying. She was given 500 cc. of citrated blood and rapidly recovered; her convalescence was uninterrupted. It would be unwise to found great hopes on a single case, but the treatment undoubtedly merits further trial.

Transfusion has also been used by Keator in treating the toxæmia of early pregnancy, and Morel has successfully used the blood of a healthy pregnant woman for the same purpose. Gettler recommends the use of alkalinized blood for “acidosis” in pregnancy. At present, however, little evidence can be adduced in favour of this form of treatment.

Nephritis.—A single case of nephritis successfully treated by blood transfusion has been recorded by Ramsay. The patient, a man aged 22, had been ill for ten days. He was slightly drowsy and had a furred tongue. His systolic blood pressure was 100 mm. and diastolic 60. His urine had a specific gravity of 1010, and contained much albumin and many granular casts, but no blood cells. Vomiting was incessant. On the second day after admission he passed 2 ozs. of urine and his systolic blood pressure fell to 90 mm., his diastolic to 40 mm. His low blood pressure and the evident imminence of suppression of urine suggested the administration of blood; he was accordingly given 1,140 cc. of fresh blood. His blood pressure immediately rose to 100 mm. systolic, and 50 mm. diastolic, and the other symptoms abated. He passed 24 ozs. of urine during the ensuing twenty-four hours. He was afterwards treated with alkalies, intravenously and by the mouth, and his condition steadily improved. It cannot be inferred from the evidence that his recovery is to be attributed entirely to the transfusion, but it appears to have been initiated by this treatment, which was a reasonable one in view of the symptoms. No other similar cases have as yet been recorded.

Carbon Monoxide Poisoning.—In any condition in which the function of a large proportion of the red blood cells as oxygen carriers has been temporarily destroyed or impaired, it is a rational procedure to replace as many of them as possible with normal red cells. The evidence that transfused blood cells can carry out their functions in their new host has been given on another page. In carbon monoxide poisoning the oxyhæmoglobin has been converted into carboxyhæmoglobin, which is more stable than the oxygen compound, and therefore useless for purposes of respiratory exchange. Undoubtedly the ideal treatment for carbon monoxide poisoning is by putting the patient in a specially constructed chamber in which he can breathe oxygen under a pressure of about three atmospheres. By this means the carboxyhæmoglobin is dissociated and replaced by oxyhæmoglobin. An oxygen chamber is usually not available, though a very useful substitute may be tried in the shape of a Haldane’s oxygen mask. Failing this, there is evidence to show that a blood transfusion is an effective form of treatment. Nevertheless, although poisoning with coal gas is by no means a rare event, this treatment does not seem to have had the attention it undoubtedly deserves. Transfusion was first used for carbon monoxide poisoning by Hüter in 1870, who was able to record a case in which recovery appeared to have been due to the treatment. It was also advocated by Lauder Brunton in 1873. After this date recorded cases are few, but in 1916 Burmeister put this form of treatment on a more scientific basis by direct experiment. Using rabbits and dogs he showed that if the animals treated with coal gas were transfused without a venesection, 75 per cent. of them recovered. Of a series of control animals, which were not transfused, nearly all died.

Most writers on the subject have recommended that as much blood be taken from the patient by venesection as is to be replaced by transfusion. On theoretical grounds this seems to be sound, though it is not supported by the results of Burmeister’s experiments. Nevertheless, in a recent series of seven cases reported by Bruce Robertson, in which 1,000 cc. of blood were removed and the same amount given by transfusion, satisfactory results were obtained. If no venesection is done, there is some risk that the transfusion may put an additional load upon an already over-strained right heart, so that a preliminary venesection is certainly a wise precaution. Transfusion should not be withheld until the patient is in extremis; if no oxygen chamber is available, it should be given at once. A minimum amount of 750 cc. of blood should be taken by venesection, and 1,000 cc. of blood should be given. If the patient’s condition does not then show enough improvement, this should be repeated.

Nitrobenzol and Benzol Poisoning.—Blood transfusion for poisoning with nitro-benzol (C6H5NO2) has been recommended by Hindse-Nielsen, who records a case in which it was successfully employed. The patient, a girl of 19, had taken a tablespoonful of the poison several hours before, and her condition appeared to be hopeless. She was deeply cyanosed, the mucous membranes being of a dark blue colour. Washing out the stomach and inhalation of oxygen were tried without effect. Finally she was bled to the extent of 600 cc., and 1,000 cc. of citrated blood were injected. Her colour at once became more normal and recovery followed. The literature does not contain records of any other cases treated in this way, but the condition is analogous to coal-gas poisoning referred to in the last paragraph, oxyhæmoglobin being in this case replaced by methhæmoglobin, and its treatment by transfusion has, therefore, a rational basis.

A somewhat similar condition is seen in benzol poisoning, though there is an additional destruction of red blood cells. Three cases treated by transfusion have been reported by McClure. One patient, whose red blood cells had been reduced to 1,460,000 per cmm., was extremely ill, but recovered after five transfusions up to a total amount of 1,500 cc.

Diabetes.—Blood transfusion has been used in treating diabetes mellitus, but there is no evidence to show that it is of any service. Ottenberg and Libmann transfused four patients who were already in diabetic coma, but no improvement resulted. Another patient who was transfused by Raulston was actually made worse, as was indicated by an increased output of sugar, acetone, and ammonia compounds.

Pellagra.—The precise ætiology of pellagra being still unknown, treatment of the disease can only be empirical. From this point of view blood transfusion has been tried by Cole, who began using it in 1908. The results in twenty cases have been reported, and are distinctly encouraging. All the transfused patients were in the last stages of the disease, but nevertheless a recovery rate of 60 per cent. was obtained, the usual rate being 10 to 20 per cent. In the present state of knowledge comment is scarcely possible, but if pellagra is, as some observers have suggested, a “deficiency disease,” it may be supposed that the transfused blood provides a temporary supply of the substance that is lacking; the patient is thus enabled to start along the road to recovery.

CHAPTER IV
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
IIIIIIIV
CorpusclesI–+++
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.

CHAPTER V
PHYSIOLOGY AND PATHOLOGY OF BLOOD GROUPS

In the foregoing chapter the reactions between the blood groups and the morbid symptoms which may follow the injection of incompatible blood have been described. In the present chapter some account will be given of the more general physiology and pathology of the groups.

It seems to be clear that iso-agglutinins and iso-hæmolysins, that is to say, serum reactions among the individuals of a species, are to be found distributed widely through the animal kingdom. The phenomenon is, however, weak in operation compared with that found among human beings, and it is very much more difficult to demonstrate. The facts have not been investigated for very many species of animals.

Some of the earliest attempts to investigate the distribution of iso-agglutinins among animals were made by Hektoen in 1907. He tested the blood of rabbits, guinea-pigs, dogs, horses, and cattle; his results were negative in every case, but probably his technique was imperfect or an insufficient number of animals was tested. Grouping has been found among goats by Ehrlich. Ottenberg and others believe that they have demonstrated the existence of three groups among steers, and of four groups among rabbits. Von Dungern has shown that there are four groups among dogs. Agglutination reactions were found by Ingebrigtsen and by Ottenberg among cats, but they were not constant, and it was not found possible to distinguish any grouping. The same was found to be true of rats. I have not been able to discover any record of research upon iso-agglutinins in birds or reptiles. The phenomenon of blood groups has a possible bearing on the success or failure of experimental transplantations of tissue, whether healthy or diseased, from one animal to another of the same species. From this point of view an investigation of the blood reactions among mice was carried out by B. R. G. Russell in the laboratories of the Imperial Cancer Research Fund, but he was unable to find any sort of grouping. Ingebrigtsen has made an attempt to correlate the results of the transplantation of arteries in cats with their serum reactions, but he was unable to do so. His results were equally bad whether iso-agglutinins were present or not. Nevertheless, it is highly probable that the success of tissue transplantation in man will be found to be largely dependent upon compatibility of blood groups in donor and recipient. The problem is one that cannot easily be investigated by experiment on animals, among which natural incompatibility is evidently much less well marked than it is in man. A method of overcoming this unsuitability is suggested by the experiments of Ottenberg and Thalimer. These observers, as already mentioned, found that in cats iso-agglutinins were present, though inconstant; on the other hand, iso-hæmolysins were seldom if ever found in normal cats, though they often appeared in the recipients of transfusions. Grafting experiments might therefore be preceded by transfusions designed to stimulate artificially incompatibility of the tissue fluids.

The incompatibility of blood is essentially a phenomenon which distinguishes different species of animals, since in no case can the blood of one species circulate unaltered in the blood-vessels of another kind of animal. This serological specificity may be in some way related to the sterility of one kind of animal with another, though not actually causing it, and so be merely an incidental phenomenon. It cannot be in any sense protective, since it never happens in the course of nature that blood is transferred from one animal to another. In the same way it is difficult to see how there can be any biological “purpose” in similar differences between individuals of the same species, and, so far as is at present known, the possession of a particular group does not confer upon its owner any advantage over the individuals of other groups, such as a relatively greater immunity from disease, longevity, or fertility. It is quite clear that there is no connexion between incompatible blood groups and sterility between individuals.

An investigation of a possible relation between blood groups and disease has been begun by W. Alexander at St. Andrews University. In a preliminary communication concerning the blood groups found among fifty patients suffering from “malignant disease” of all forms, including leukæmia, he has found that there is a considerably higher proportion of Groups I and III than among healthy people. On the other hand, the groups are found in the normal proportions among people suffering from tuberculosis, syphilis, and tetanus. It would, however, be premature to assume that individuals of Groups I and III are more liable to suffer from “malignant disease” than other people, as the numbers tested are, at present, too small for definite conclusions to be formulated. Also it remains to be proved that the presence of malignant disease does not produce an alteration in the agglutinating reactions by which the groups are determined.

It seems probable that the differences between the groups have arisen incidentally in the evolution of mankind, possibly as the result of the parallel descent of two or more original stocks from different sources, which afterwards converged and mingled, with the production of serological hybrids. In view of this it is of interest to find that some investigation of the racial incidence of blood groups has already been carried out. On the Macedonian front during the war a large number of men of many different races were gathered together, and scientific advantage of this opportunity was taken by L. and H. Hirschfeld. The blood groups were determined in approximately 8,000 individuals, including French, English, Italians, Germans, Austrians, Serbs, Greeks, Bulgarians, Arabs, Turks, Russians, Jews, Malagasies, Senegal Negroes, Annamese, and Indians. According to the results obtained by the Hirschfelds, the groups designated II and III show a definite variation in their distribution among different races. As will be seen hereafter, Group I is compounded of the two factors producing Groups II and III, while Group IV results from their absence. It is therefore necessary only to consider the incidence of Groups II and III in calculating the racial differences. For the statistical tables and diagrams the reader must be referred to the original paper published in 1919, but the results may be roughly summarized as follows. It was found that the factor producing Group II is prevalent among European peoples, whereas the factor producing Group III is characteristic of men from Asia and Africa. Thus the Group II factor was found in not less than 45 per cent. among most European peoples. It gradually diminishes in the countries lying between Asia and Central Europe, being present in Arabs 37 per cent., in Russians 37 per cent., in Jews 38 per cent. In Asiatics and Africans it falls considerably, being in Malagasies 30 per cent., in Negroes 27 per cent., in Annamese 29 per cent., in Indians 27 per cent. On the other hand, the factor producing Group III shows exactly the opposite variation. Among the English, the most Western people of Europe, it is rare, being found by these observers to be present in only 10 per cent.; it rises to 14 per cent. in French and Italians, to 18 per cent. in German Austrians, and to 20 per cent. in the Balkan peoples. In Africa and Asia the Group III factor rises considerably, being present in Malagasies 28 per cent., in Negroes 34 per cent., in Annamese 35 per cent., and in Indians 49 per cent.

We may still be far from elucidating the anthropological meaning of these facts, for the mingling of the hypothetical stocks of which mankind is made no doubt began in a remote antiquity, and it is possible that a serologically pure race does not exist. The investigation, however, of the more isolated peoples might throw much light on the problems of anthropology.

Interesting as the wider questions may be, we are here more immediately concerned with the distribution of the blood groups amongst our own population. The percentages in which the four groups occur have been estimated by various observers, and, as will be readily understood from the foregoing remarks, the numbers show some variation. The approximate figures as worked out by three observers in America are as follows:

BernheimMossCulpepper
(1,600 tests)(5,000 tests)
I 2103per cent.
II404038 ” ”
III15 718 ” ”
IV434341 ” ”

The percentages found among the first hundred men whom I tested in the British Army in 1917 conformed almost exactly to the first of these series of figures, and they may be taken as an average result for Western peoples. It will now be seen upon what grounds it was stated in the last chapter that the chances were in favour of the blood of a donor chosen at random being compatible with that of the recipient. If the patient belong to Group II, then 83 per cent. of other bloods will be compatible. If he belong to Group III, 58 per cent. will be compatible. Only if he belong to Group IV will the chance in favour of compatibility fall below 50 per cent.

This statement of the facts concerning distribution of the blood groups will serve to emphasize the absolute necessity for the careful testing of a donor before his blood is used for transfusion. But, further than this, it is necessary to clear away several widely spread misapprehensions as to the group relations between an infant and its mother and between the various members of a family. It has several times been stated in print that a mother’s blood must be compatible with that of her child, or sometimes that a baby has no blood group, so that it may be safely transfused with blood taken from its mother or its father without preliminary testing. On other occasions the statement has been made that the brother or sister of a patient is more likely than other people to belong to the same or a compatible blood group, so that untested blood may be transfused from one member of a family to another with little risk. Knowledge of the existence of blood groups has become somehow mixed up with vague popular beliefs concerning “affinities” and “blood relations.” Such confusions must, however, be dissipated, for none of these statements are more than partially true, and they may lead to a false sense of security and to disaster.

The assertion that an infant has no blood group was tested by the writer some time ago and shown to be false. On several occasions a newly born infant was tested and found to show well-marked agglutination reactions indicating Groups II or III as the case might be. Even in 1905 it had been shown by Martin that reactions could often be demonstrated between an infant’s corpuscles and the maternal serum, and sometimes between the infant’s serum and the maternal corpuscles. More recently (March 1920) the results of a full investigation into the reactions found in infants and children have been published by W. M. Happ in America. These researches began with the testing of blood from the umbilical cord, and this was seldom found to show the blood reactions as given by the adult. So far the statement quoted above was justified. It is even true that the serum of an infant’s blood will usually not give any reaction at birth or during the first month. The percentage in which it does give a reaction increases with the age of the child; after one year it is usually, and after two years always, established. On the other hand, the agglutination reaction in the corpuscles appears before that in the serum, so that the grouping tested in this way may be present immediately after birth, as I found to be the case. It is possible that the grouping which first appears may afterwards be modified, but any change which occurs is always by the addition of factors and not by their subtraction; thus an apparent Group IV may become a Group II or III, or an apparent Group II or III may become a Group I. It is found that when a reaction is present in both the corpuscles and the serum, the group does not afterwards change. Happ’s conclusion, based on his investigations, was that it is unsafe to transfuse an infant with its mother’s blood without first making the usual tests, and the reasons for this will now be evident. In the first place an infant may be possessed of its final blood reactions very shortly after birth, and should therefore be treated in the same way as if it were an adult. In the second place, although its serum may be without agglutinating powers, so that transfused corpuscles will not be attacked, yet its corpuscles may be possessed of pronounced agglutinophilic properties, so that they may be seriously affected by the serum of transfused blood from an incompatible group. In the third place, as will presently be seen, it is by no means the rule that an infant should belong to the same group as its mother, whatever its blood reactions may be.

Another set of observations, leading to precisely the same conclusions, have been made by F. B. Chavasse of Liverpool. He terms the potential agglutination of the fœtal corpuscles by the mother’s serum, and of the maternal corpuscles by the serum of the fœtus, the “maternal threat” and the “fœtal threat” respectively, and states that there is no obvious relationship between the “fœtal threat” and eclampsia or the toxæmias of pregnancy. The inference is therefore justified that there is no transference of the agglutinating substances in either direction across the placental membranes. No chemical “immunity” is acquired, therefore, on either side, since the protection is mechanical. This agrees with the fact observed by Happ that the mother’s milk contains the same agglutinins as the serum of her blood; but these do not have any deleterious effect upon the infant, and are therefore either not absorbed at all or are destroyed in the process of digestion.

The statement that the blood group of an infant is not necessarily the same as that of its mother can be amplified, for it has been found that blood groups are inherited on a definite plan, so that if the groups of the parents be known, certain predictions can be made as to the possible groups that may be found among their offspring. Many characters in animals and plants have been shown during the last twenty years to be transmitted according to the Mendelian plan of inheritance, but up to the present time very few normal characters in man have been isolated, and their manner of inheritance demonstrated, though a number of pathological conditions have been shown to conform to the theory. It is therefore of much interest to find that the inheritance of blood groups in man can be quite satisfactorily and consistently explained in Mendelian terms.

According to this theory, each quality in an organism which can be isolated and investigated independently of other qualities, is termed a “unit character,” and the appearance of each such unit character is determined by the presence of something called a “factor” in the sexual cells or “gametes,” male and female, by the union of which the individual is formed. Further, these unit characters are believed to occur in alternative pairs, and at first it was supposed that each alternative pair consisted of “dominant” and “recessive” characters, the second of which could only make its presence apparent in the individual if the dominant character were absent. Subsequently it was seen that the dominant and recessive characters need not necessarily consist of two positive, though opposite, qualities, but might better be regarded as consisting of the presence of a character and its absence. To use a classical illustration of this view, sweet peas may be classified into tall peas and dwarf peas. At first the unit characters were taken to be tallness (dominant) and dwarfness (recessive). Later this idea was modified, and it was said that potentially all peas are dwarf, but to some is added a factor producing tallness, this factor being absent in those that are dwarf. To represent this idea more simply a conventional notation has been used, according to which the large letters of the alphabet indicate the presence, and the small letters the absence, of each factor.

In order to apply this theory to the case under consideration, it has been suggested that two pairs of factors are concerned:

A the presence of the character producing Group II.
a the absence of the character producing Group II.
B the presence of the character producing Group III.
b the absence of the character producing Group III.

Each pair of factors is transmitted independently of the other. Both A and B may be absent, in which case the individual belongs to Group IV; or both may be present, and in this case the individual gives the reactions of Group I.

It must be understood that the term “character producing Group II” is here used as a convenient way of expressing the obscure and probably complicated set of properties responsible for the reactions manifested by individuals of Group II. It includes not only the agglutinin or hæmolysin of the serum which reacts with corpuscles of Group III, but also the complementary iso-agglutinin or iso-hæmolysin by virtue of which the corpuscles react with serum of Group III.

The appearance of the different groups can now be further explained in terms of the Mendelian theory. According to the conception of the individual formulated by Mendel, each cell of the body contains an ingredient derived from each of the sexual cells or gametes which united at the moment of fertilization of the ovum by the spermatozoon to form the individual. But when the adult in his or her turn forms sexual cells or gametes, these ingredients separate again, half the gametes containing one of the pair of factors, half containing the other. This process certainly takes place during the rearrangement of the nuclear substance or chromosomes at the cell divisions which result in the formation of the ripe sexual cells. It is called the “segregation of the gametes.”

In the present case the unit character producing Group II will be first considered. As already explained, the factors concerned may be called A and a, and the individual of Group II may be constituted by AA or Aa, and the gametes, therefore, may contain either A or a, but not both. The individuals resulting from the union of the gametes derived from Aa adults may then be constituted in three ways—AA, Aa, or aa. Similarly for the unit character producing Group III, the factors concerned may be called B and b, and the individual of this group may contain BB or Bb. The gametes then contain either B or b, and the individual resulting from their union may again be constituted in three ways—BB, Bb, or bb.

In computing the results, however, it must be remembered that most, or perhaps all, people are hybrids, so that both unit characters are present simultaneously, and all the factors must be taken into account. It is easily seen that the gametes derived from a hybrid individual must contain one of the following combinations:

AB, Ab, aB, or ab,

and consequently the individuals formed from them must have one of the following constitutions:

AB—Ab, Ab—aB, aB—ab, ab—ab, AB—AB,
AB—aB, Ab—ab, aB—aB,
AB—ab, Ab—Ab.

This includes all the possible combinations that can result from the chance union of the gametes, and it is now clear which blood groups result from which combinations, if it be remembered that

Ais dominant toa,
B ” ” ”b,

and that

Group Iresults from the presence ofboth A and B.
” II” ” ” ” ” A only.
” III” ” ” ” ” B ”
” IV” ” ” absence ”both A and B.
Thus Group Imay be constituted byAB—AB.
AB—aB.
AB—Ab.
AB—ab.
Ab—aB.
Group IImay be constituted byAb—Ab.
Ab—ab.
” III ” ” ” ”ab—aB.
aB—aB.
” IV ” ” ” ”ab—ab.

It now becomes evident what offspring may result from the union of parents who have any of the above constitutions. Thus parents both of Group I may have offspring belonging to any group according to which of the five possible constitutions they possess. If the union be represented by

AB—AB × AB—AB,

then only offspring of Group I can result, since every gamete contains both A and B. The other possibilities may be worked out by the reader if he desire.

Similarly, a union of Groups I × II, I × III, or II × III may produce any of the groups, definite limitations being imposed by the detailed constitution of the parents. On the other hand, the remaining group unions that are possible can only produce a more limited variety of offspring. Thus II × II or II × IV can only produce Groups II or IV; III × III or III × IV can only produce Groups III or IV; IV × IV can only produce Group IV.

The Mendelian theory of inheritance in general has been subjected to a prolonged and widely ramifying series of tests, and it seems in the present state of knowledge to present a satisfactory and consistent explanation of the facts. For a more extended account of it the reader must be referred to the standard works on the subject.[6] As regards its application to the present case, the test of actual experiment has not yet been carried out on a large scale. A series of observations has, however, been published by J. R. Learmonth, who, taking forty families at random, determined the blood groups of both parents and the children in each family. In this way he tested most of the possible group matings, and, with a single exception, the group inheritance conformed to the theory as set out above. Additional confirmation of the truth of the theory is afforded by the pedigree given on the [page opposite]. I have recently collected this pedigree, which includes fifty-nine individuals belonging to four generations, and it has not been published before. It will give, perhaps, a more graphic representation of the facts than has been conveyed by the brief summary contained in the foregoing pages. It does not show any variation from the results that were to be anticipated according to the theory.

The exceptional result obtained by Learmonth in one of his forty families serves to emphasize the clarity of the theoretical considerations. In this family parents both belonging to Group IV had a child showing the reactions of Group I. There are three possible explanations of this:

(1) The observations were at fault.

(2) The putative father was not the real father.

(3) The Mendelian theory of inheritance is wrong.

The Mendelian theory is established on so firm a basis that, in the absence of more numerous exceptions, (3) may be rejected. There is no reason for supposing that the observations were inaccurate, and we are therefore brought to the conclusion that in such a case the child is illegitimate.

Fig. 6.—Pedigree showing Inheritance of Blood Groups through Four Generations. The Group of each Individual is indicated by a Numeral. Those who were not available are represented by a O

The conclusions which emerge from this structure of theory and fact are obviously of very great clinical importance. It is now clearly demonstrated that a mother belonging, say, to Group I, may give birth to a child belonging to any one of Groups I, II, III, or IV; her blood may not be used for transfusing her child without a grave risk that the “maternal threat” may culminate in the death of the child. The same applies to the possible relations between a father and his child. Two brothers, again, may belong to Groups II and III respectively. Even the blood of twins may be mutually incompatible, except in the rare case of “identical twins,” who, it may be supposed on theoretical grounds, would certainly belong to the same group, though I am not aware of a case in which this has been put to the test. As much care, therefore, must be exercised in testing the blood groups of members of the same family before performing a transfusion as would be taken before using a donor who is not related to the patient.

The medico-legal importance of the facts concerning the inheritance of blood groups is also evident, and, although this test has not yet been used as a test of legitimacy, there can be little doubt but that it will be so used in the near future. The information to be derived from it is of a negative rather than a positive character. Thus the occurrence of Group III blood in a child whose mother is of Group II and putative father of Group I cannot be taken as a proof either of legitimacy or the reverse. But if, as in Learmonth’s case, parents both of Group IV have a child of Group I, or if parents both of Group II have a child of Group I or III, then this may be taken as a proof of illegitimacy.

There is not much experimental evidence concerning the effect of various pathological conditions on the agglutination reactions of the blood and serum. It has already been mentioned that there is no proof that the possession of any particular blood group confers upon its owner any special immunity from, or liability to, disease. The numbers, investigated by Alexander in the communication referred to on p. 81, are too small for the observation to be of much value; it is also necessary, as a preliminary to any such research, to demonstrate that there is no abnormal alteration in the reactions of the blood of these patients. It is probable, indeed, that evidence of this alteration in malignant disease already exists, for a reference to it is to be found in Kolmer’s work on serum-therapy,[7] but I have been unable to find a record of the investigation.

I possess, on the other hand, evidence that an alteration may take place in some other diseases, such as pernicious anæmia and familial, or acholuric, jaundice. Evidence for the former was provided recently by a patient whose condition was typical, clinically, of the last stages of the disease. Her corpuscles, tested with stock sera, belonged to Group II, but her serum, tested directly with the corpuscles of prospective donors known to belong to Group IV, agglutinated these vigorously, so that a transfusion could not safely be performed. The same phenomenon has been found by other observers. In acholuric jaundice there is a progressive destruction of red corpuscles in the patient’s circulation. This appears to be connected in some way with an abnormal functioning of the greatly enlarged spleen, since the destruction of corpuscles ceases almost at once when this organ is removed. There seems to be, in addition, an alteration in the blood reactions. In a case which I tested recently, the patient’s corpuscles were quickly agglutinated by serum of Group III, and he therefore nominally belonged to Group II. His serum, however, when separated and tested against other bloods of known groups gave, in addition to a rapid agglutination of corpuscles belonging to Group III, a definite, though slower, agglutination of corpuscles belonging to Groups II and IV, showing that it had acquired abnormal properties.

It is possible that there are similar alterations of reactions in other pathological conditions. The instances mentioned above suggest that the serum is affected rather than the corpuscles, but further investigations are needed. It is an observed fact that blood outside the body soon develops the property of auto-hæmolysis. If blood is drawn from a vein, put into a test-tube, and allowed to clot, then after twenty-four hours or more the serum which has separated from the clot begins to be tinged with hæmoglobin, even though it has remained absolutely sterile. It appears, therefore, that the serum develops a hæmolysin and the corpuscles the corresponding iso-hæmolysin, the interaction of which results in the breaking up of corpuscles. If this process takes place in normal blood outside the body, it would not be surprising to find that it may also occur abnormally inside the body. This actually happens in the condition known as paroxysmal hæmoglobinuria. The pathology of the disease is obscure, but it seems that a hæmolysin develops in the serum as the result of cooling in the extremities and hæmolysis takes place when the cooled serum is again warmed by being restored to the general circulation. The presence of this hæmolysin in addition to the normal hæmolysins has been demonstrated by Moss. It is possible that a similar though less acute change takes place in acholuric jaundice. Blood transfusion, therefore, is not likely to be efficacious in such conditions, since the transfused corpuscles may be destroyed whatever the apparent blood group of the patient. Some of the facts of auto-hæmolysis have been recently investigated by Bond, but it is not necessary to give the details here. He concludes that the development of auto-hæmolysins, which are non-specific and independent of the specific hæmolysins of the blood groups, has a biological significance in the history of the red corpuscle, and is a product of ageing. The biochemistry, however, of the process remains at present entirely unknown.

The necessity for careful blood grouping in every case before performing a transfusion has now been sufficiently emphasized, but before proceeding to the description of the methods of choosing a donor and of grouping, a possible danger must be mentioned which may arise even when the blood groups are known. In the preceding chapters references were made to the effects which have been observed to follow repeated transfusions given in the treatment of a condition such as pernicious anæmia. In such cases, although the groups were ascertained, and the bloods were also tested directly against one another without any incompatibility being detected, yet when the third or fourth transfusion was given, symptoms of toxæmia followed, sometimes with hæmolysis. The death of the patient has even been hastened in this way. A very striking instance of this phenomenon, which has been recently reported (278), will serve to bring home the reality of the danger. A boy was transfused by the citrate method with blood from his father, and this was followed only by a mild febrile reaction such as is often observed. Eighteen days later a second transfusion with blood from the same donor was performed, and after 150 cc. had been given, a severe reaction resulted, which was followed later by pronounced hæmoglobinuria. In this case the bloods of donor and recipient had been tested against one another directly, but this was not repeated, and the groups were not ascertained until afterwards. Probably there was some error in the original test, for it afterwards appeared that the boy belonged to Group I and his father to Group III, so that there should have been agglutination of the boy’s corpuscles by his father’s serum outside the body. Nevertheless, Group I individuals have been called the “universal recipients,” and no ill effects are usually observed whatever blood be used for transfusing them. In the other cases already mentioned a reaction followed the later transfusions, even when the donor and recipient belonged to the same group. It appears that by repeated transfusions the recipient becomes as it were sensitized to the blood of another individual even of the same group, and consequently great caution must be used in giving the later transfusions of a series. Some light is thrown on this question by the observations of Ottenberg, already referred to, concerning the artificial production of iso-hæmolysins in cats. In these animals iso-agglutinins are found, but iso-hæmolysins seldom or never. The reaction is, however, found to become hæmolytic in the recipients of transfusions, and it is then selective. It seems, therefore, that the group reactions may not be as clearly defined as was at one time supposed. Probably there are slight incompatibilities of an unknown nature between individuals of the same or compatible groups. These are very seldom of any consequence in a first transfusion, but become accentuated as the result of “sensitization,” and in later transfusions have a pronounced influence. This “over-lapping” of groups has been mentioned on another page. It must not be supposed that any untoward results follow repeated transfusions as a general rule, for usually no such effect is observed. In order, however, to minimize the risk, it may be suggested that the following precautions should be taken: (1) The donor should be actually of the same group as the recipient, and not merely of a theoretically compatible group; a patient, for instance, of Group II should receive blood of Group II rather than of Group IV. (2) The same donor should not be used for the later transfusions of a series, on the grounds that the sensitization appears to be an individual rather than a group phenomenon. (3) In performing the later transfusions, the blood should be given at first very slowly, so that it may be discontinued at the first appearance of any signs of a reaction.

CHAPTER VI
THE CHOICE OF BLOOD DONOR

The physiology of blood groups having been examined, the principles governing the choice of a blood donor can be more readily understood. It is evident that this choice is determined largely by blood groups, and in the present chapter therefore the clinical methods of testing for the groups will be described.

Before, however, the bloods can be tested, a willing donor must be found, and this is not always an easy matter. During the war, even when transfusion was being practised on a large scale, there was never any difficulty in finding volunteers among the men that were more lightly wounded. In addition to the genuine and ready response which many men would make at once to a call for help in a matter of life and death, there was the glamour of novelty and the feeling of satisfaction following an act of conscious heroism—for such the sacrifice of blood was held to be, the days having long been forgotten when as much blood was “let” in the treatment of almost any ailment. In the Expeditionary Force, too, the unofficial reward of a fortnight’s leave in England proved a potent inducement, and the rejection of a volunteer on the ground of incompatibility was regarded almost as an injustice or as a reflection upon the physical condition of the candidate. In civilian life, however, such inducements cannot be held out, and it will be found that many a man “does not like the idea” of parting with a pint of blood, even though the sacrifice may save another’s life. Often, however, a near relative of the patient may happen to be willing and suitable, or, failing this, in a hospital ward there will usually be some young man who has been admitted for a slight operation, such as the radical cure of a hernia, and will accede to a request for blood if the procedure, its object, and its harmlessness to himself be briefly explained. Notoriety is fortunately seldom a motive for volunteering, and though paragraphs have occasionally appeared in the daily press with headings such as “Police Inspector’s Sacrifice,” this has probably not been done by the donor’s own wish. It is, after all, natural that to the mind of a layman the giving to another of so personal a possession as his blood should seem to be an act of heroism, and it is also natural that occasionally a man should feel some repugnance to taking part in a strange performance which he but dimly understands. To the young, on the other hand, the procedure may appeal by its faint flavour of adventure.

Occasionally during the last two years advertisements for blood donors have appeared in newspapers, probably not in vain. If the demand for blood donors becomes greater than it has been as yet, it will certainly result in the creation of a class of “professional blood donors,” who already exist in some numbers in the United States of America, where blood transfusion is a more widely recognized form of therapeutics than it is in this country. These professionals have even formed a Trade Union, so that as high a fee as possible may be obtained from those who need their blood. Apart from this, some of the advantages of having these professionals available have already been explained in the chapter on the dangers of blood transfusion. It is evident that certain sources of danger can be eliminated in advance, and in an emergency it is obviously better to have donors of known groups available, so that no time is lost in testing the prospective donors of whom several in succession may be found unsuitable. Probably it will be easier for practitioners to arrange for such professionals to be available at the shortest notice than for necessary arrangements to be made in a hospital. Even in large institutions it is usually difficult for any of the men employed in them to be spared from their work for twenty-four hours, so that, although suitable men of known groups are always within call, it may be impossible to use them. This, however, is not the place to discuss the organization that is necessary to make a blood transfusion a really efficient form of emergency treatment in a hospital. It may merely be observed that in every hospital it should be possible to give a blood transfusion to a patient suffering from urgent hæmorrhage within fifteen minutes of his arrival on the premises.

Whether the donor be a “professional” or an “amateur,” it may be useful to mention a few points to be observed in choosing him. There can be no doubt that the most satisfactory individuals for the purpose are young men between the ages of eighteen and twenty-five. The younger the donor, the less likely is he to be suffering from certain of the diseases mentioned in the chapter on the dangers, the less will be the immediate effect of the withdrawal of circulating fluid, and the more quickly will he recuperate from the loss of blood.

It must not be supposed, however, that the withdrawal of even 1,000 cc. of blood will usually have an appreciable effect upon a healthy man. It is impossible to predict from the donor’s appearance what immediate effect the loss of blood will have upon him. It sometimes happens that the most robust-looking individual becomes faint after losing a few hundred cubic centimetres, whereas another, to all appearances pallid and much less satisfactory, will not evince the slightest discomfort from the loss of 750 cc. or even more. Normally a man should be able, by his physiological mechanisms, to compensate reflexly and at once for the removal of this amount of fluid from his circulation. In any case, the worst effect that is seen in a well-chosen donor is a transient faintness; it is usually wise to keep him on his back for two or three hours after the operation, and he should not, if it can be avoided, return to his work on the same day. During the late war a medical officer of my own acquaintance gave 750 cc. of blood for a severely wounded friend and continued his arduous duties as Surgical Specialist in a Casualty Clearing Station immediately afterwards. In this case, however, the donor was solely responsible for his own welfare; usually this responsibility rests upon another, and greater care must be exercised. The effect, indeed, of a transfusion upon the donor seems to depend more upon psychological than upon physiological factors. A nervous and excitable donor is more likely to suffer than one who approaches the operation without apprehension. This is another point in favour of employing a professional donor, who soon becomes familiar with the whole procedure and will lose all symptoms of fear.

The same considerations may be applied to the use of women as blood donors. In them the spirit of self-sacrifice is commonly more highly developed than it is in men, and some of the most eager donors will be found among them. The disability of nervousness will, however, occur more often in women, and another consideration of importance is that the veins of a woman are usually much less easily accessible than those of a man. Not only is the abundant subcutaneous fat an impediment in women, but usually the superficial veins are all of small size. The method of choice for performing a blood transfusion will be presently described, and it will then be seen that the operation is easier and that much less damage is inflicted on the donor if a large superficial vein can be tapped. In women this will very often be difficult or even impossible. In general, therefore, it may be stated that the use of women as blood donors is to be avoided. The fallacies concerning the indiscriminate transfusion of an infant with its mother’s blood and of any patient with the blood of a near relation have already been explained.