The immune haemolytic anaemias: a century of exciting progress in understandingстатья из журнала
Аннотация: The growth in knowledge of the scientific basis of disease and consequent advances in the practice of medicine that have taken place in the past century have been truly remarkable. This is certainly true of the haemolytic anaemias, which have been a main interest of the author since the mid-1930s. At that time, the cause and mechanism of important disorders such as the acquired antibody-determined (immune) haemolytic anaemias, haemolytic disease of the newborn, hereditary spherocytosis and paroxysmal nocturnal haemoglobinuria were unknown or but partially understood. The purpose of this short review is to record and highlight some of the most significant advances in knowledge of the acquired immune haemolytic anaemias that have been made between the first decade and the end of the twentieth century. First, however, a diversion. According to Crosby (1952), William Hunter of London, in an article on pernicious anaemia published in 1888, was the first to use the term 'haemolytic' to denote an anaemia caused by excessive blood destruction. By the turn of the century, the term was being widely used in clinical literature, e.g. by Widal et al (1908a,b) and Micheli (1911), and in experimental studies, e.g. by Cantacuzène (1900). At that time, however, and for a decade or so later, no reliable data were available as to the life-span of the erythrocyte in health. Peyton Rous, in his comprehensive review 'Destruction of the red blood corpuscles in health and disease' (Rous, 1923), concluded that the generally held view in the early 1930s was that about one-fifteenth of the erythrocyte mass was destroyed daily. Rous was aware of the pioneer work of Winifred Ashby (1919a,b), who, by following the survival of serologically distinct but compatible transfused erythrocytes, had found that normal erythrocytes might live for up to 100 d in the recipients' circulation. The difficulty in accepting Ashby's conclusions without question was that she was unable, using her technique, to measure the life-span of the experimental subjects' cells in their own environment. Subsequent work using radioactive chromium (51Cr) as an erythrocyte label, showed that Ashby's data and conclusions were in fact correct, i.e. that normal erythrocytes in health circulate in the peripheral blood for approximately 110 d. Both Asby's differential agglutination method and 51Cr labelling have been used with brilliant effect in the investigation of patients suffering from many types of increased haemolysis. Thus, in contrast to the finding in hereditary haemolytic anaemias, e.g. hereditary spherocytosis (HS), that the life-span of transfused normal erythrocytes is normal, that of normal erythrocytes transfused to patients with an acquired immune haemolytic anaemia is characteristically shortened (Brown et al, 1944; Mollison, 1947). Erythrocyte labelling with 51Cr also had a further advantage over the Ashby method in addition to enabling the life-span of the patients' erythrocytes to be assessed in his or her own circulation, namely, that it was possible, by surface counting, to detect and measure the accumulation of radioactivity in the spleen and liver, i.e. the presence in the organ of the labelled erythrocytes, and thereby assess the organs' role in haemolysis (Szur, 1970). It was in France in the first decade of the twentieth century that Widal et al (1908a) and Le Gendre & Brulé (1909) reported that autohaemoagglutination was a striking finding in some cases of ictère hémolytique acquis. At about the same time, Chauffard & Trosier (1908) and Chauffard & Vincent (1909) had described the presence of haemolysins in the serum of patients suffering from intense haemolysis. These observations suggested that abnormal immune processes, i.e. the development of auto-antibodies damaging the patients' own erythrocytes, might play a part in the genesis of some cases of acquired haemolytic anaemia. That this might be so had in fact been antedated by the classic observations of Donath & Landsteiner (1904) and Eason (1906) on the mechanism of haemolysis in paroxysmal cold haemoglobinuria, the clinical aspects of which had been well described in the 19th century. That blood might auto-agglutinate when chilled had been described by Landsteiner (1903) and that an unusual degree of the phenomenon might complicate some types of respiratory disease was reported by Clough & Richter (1918) and later by Wheeler et al (1939). It was not until a few years later, however, that it was reported by Peterson et al (1943) and Horstmann & Tatlock (1943) that cold auto-agglutinins at high titres were frequently to be found in the serum of patients who had suffered from the then so-called primary atypical pneumonia. Significantly, two of their patients had developed acute haemolytic anaemia. Earlier, in the 1930s, a chronic syndrome of unknown origin, not associated with respiratory disease, had been recognized in which a markedly raised titre of cold agglutinins associated with intravascular haemolysis and haemoglobinuria were prominent features (Ernstene & Gardner, 1935; Roth, 1935; Salén, 1935). Stats & Wasserman's (1943) review on cold haemagglutination was a valuable contribution to contemporary knowledge. They listed in a table as many as 94 references to papers published between 1890 and 1943 in which cold haemagglutination had been described. In 32 of the papers the patients referred to had suffered from increased haemolysis. Recognition that cold auto-antibodies played an important role in the pathogenesis of some cases of haemolytic anaemia led to the concept that auto-immune haemolytic anaemia (AIMA) might usefully be classified into warm-antibody or cold-antibody types, according to whether the patient is forming (warm) antibodies which react (perhaps optimally) at body temperature or (cold) antibodies which react strongly at low temperatures (e.g. 4°C) but progressively less well as the temperature is raised and are perhaps inactive at 37°C. The clinical syndrome suffered by the patient would depend not only on the amount of antibody produced but also on its temperature requirement. Another important advance in understanding has been the realization that both types of AIHA could develop in association with a wide range of underlying disorders (secondary AIHA) as well as 'idiopathically', i.e. for no obvious cause (primary AIHA). Published data on the relative proportion of primary to secondary cases, based on large numbers of patients, date from the 1950s. For instance, Lal & Speiser (1957) reported that 48 out of 97 cases of warm-antibody AIHA had been secondary cases and van Loghem et al (1958) reported 60 out of 122 cases. Subsequently, somewhat higher proportions of secondary cases were reported, e.g. by Videbaek (1962a), 36 out of 41 cases, Homberg et al (1967), 60 out of 95 cases, and Pirofsky (1969), 190 out of 234 cases. The author's own experience was summarized in a review (Dacie & Worlledge, 1969): 99 out of 210 cases of warm AIHA were judged to be secondary as were 39 out of 85 cases of cold AIHA. Petz & Garratty (1980), summarized the data from six centres: 55% out of a total of 656 cases had been reported as secondary. They listed the disorders with which warm-antibody AIHA had been associated as chronic lymphocytic leukaemia, Hodgkin's disease, non-Hodgkin's lymphomas, thymomas, multiple myeloma, Waldenström's macroglobulinaemia, systemic lupus erythematosus, scleroderma, rheumatoid arthritis, infectious disease/childhood viral disorders, hypogammaglobulinaemia, dysglobulinaemias, other immune deficiency syndromes, ulcerative colitis and ovarian dermoid cysts. Conley (1981), in an interesting review of warm-antibody AIHA patients seen at the Johns Hopkins Hospital, emphasized how important it was to carry out a careful enquiry into the patient's past history and also to undertake a prolonged follow-up. He stated that a retrospective review of 33 patients whose illnesses 'in the past have been designated 'idiopathic'' had revealed an associated immunologically related disorder in 19 of them. An additional three patients had developed a lymphoma 2–10 years after they had developed AIHA. As already referred to, warm-antibody AIHA is now known to complicate a wide range of underlying diseases, particularly malignant lymphoproliferative disorders, other auto-immune disorders and immune deficiency syndromes. There is an extensive literature. Reports of the occurrence of haemolytic anaemia in chronic lymphocytic leukaemia (CLL) and Hodgkin's disease date from the 1920s and 1930s (Netousěk, 1922–23; Holler & Paschkis, 1927; Paschkis, 1927), but whether auto-antibodies played a part in the haemolysis in their patients is unknown. Reports of patients in whom the direct antiglobulin test (DAT) had been carried out and found to be positive date from the early 1950s (Hutt, 1950; Dameshek et al, 1951). It was not long before it was reported that in some patients the haemolytic anaemia had appeared to antedate the development of the lymphoma; in other patients, however, the reverse appeared to be true (Rosenthal et al, 1955). Most of the patients who had developed AIHA appear to have suffered from CLL. Pirofsky (1968a, 1969) reported that, of 113 personally observed patients, 48 had had CLL, 10 acute lymphocytic leukaemia (ALL), 13 Hodgkin's disease, seven lymphosarcoma, one giant-follicle lymphoma and four reticulum-cell sarcoma. What proportion of patients suffering from a lymphoproliferative disorder develop AIHA is an interesting question. Dührsen et al (1987) stated that this had occurred in 12 out of 637 patients. It has also been reported (D. Catovsky, personal communication) that the DAT had been positive in 57 out of 788 CLL patients at the time their leukaemia was diagnosed. AIHA is well known to develop in a minority of patients suffering from SLE. The first reports date from the late 1940s and early 1950s (Aegerter & Long, 1949; Zoutendyk & Gear, 1950). Occasionally, haemolytic anaemia dominates the clinical picture; it may even antedate the development of overt SLE by many months or even years (Michael et al, 1951; Wasserman et al, 1955; Videbaek, 1962b). Early data on the incidence of a positive DAT in SLE were provided by Harvey et al (1954)– in six out of 34 patients tested the DAT had been positive. Later, Mongan et al (1967), who had studied a large number of patients suffering from a variety of connective tissue disorders, reported that the DAT had been positive in 15 out of 23 patients with SLE, none of whom, however, had suffered from overt haemolytic anaemia. AIHA has been recorded; the incidence, however, is low. de Gruchy (1954) and Evans & Weiser (1957) recorded single cases of the association. The author (Dacie, 1967) reported that two out of 250 patients with AIHA had given a history of rheumatoid arthritis and Pirofsky (1969) reported five out of 234 patients. Rather rarely, AIHA complicates ulcerative colitis. Lorber et al (1955) referred to four such patients. The author (Dacie, 1967) reported that two out of about 250 patients with AIHA he had seen between 1947 and 1965 had ulcerative colitis and that the DAT had been positive in the absence of clear evidence of haemolysis in a third patient. It has been realized since the 1960s that warm-antibody AIHA may develop in patients suffering from a variety of immune deficiency syndromes, both congenital and acquired. The author (Dacie, 1992) listed 25 papers published between 1961 and 1988 in which 33 such patients were described. Earlier reports of splenomegaly and hypersplenism in association with agammaglobulinaemia had been reviewed by Citron (1957) and Prasad et al (1957). The rare occurrence of generally severe haemolytic anaemia in patients with ovarian dermoid cysts or teratomata has been recognized since the late 1930s (West-Watson & Young, 1938; Singer & Dameshek, 1941). A remarkable feature of these early reports was that haemolysis had subsided following removal of the tumour. This has been true in similar patients described in later reports. The DAT has been found to be positive in almost all the patients in which the test has been carried out; typically, the test has become negative 3–6 months after surgery. The haematological and serological findings have been indistinguishable from those of 'idiopathic' AIHA. It was in the mid-1960s that it was realized that, in a significant proportion of patients thought to have 'idiopathic' warm-antibody AIHA, the development of the causal auto-antibodies had been triggered in some way by a drug the patient was taking. The first drug implicated was the antihypertensive drug α-methyldopa (Aldomet) (Carstairs et al, 1966a,b). According to Worlledge et al (1966), who had investigated 40 patients, the clinical, haematological and serological findings were indistinguishable from those of 'idiopathic' AIHA. An interesting question was the proportion of hypertensive patients being treated with α-methyldopa (who were not suffering from overt haemolytic anaemia) in whom the DAT was positive. The author (Dacie, 1999) listed 22 reports published between 1966 and 1972. Remarkably, the incidence of positive DATS varied widely – from 0% to 27%. There were hints of a possible genetic influence, for the lowest percentages (0–4%) were found in African, coloured, Indian and Chinese patients (it is possible, however, that these patients had been treated with lower doses of the drug or had failed to take their medicine regularly). Following the finding that treating hypertensive patients with α-methyldopa led to the formation of anti-erythrocyte auto-antibodies in a significant percentage of patients, renewed interest was taken in the possibility that other drugs might have the same effect. Case histories had in fact been reported earlier that supported the possibility, e.g. Snapper et al (1953) in the case of mesantoin and Schwartz & Costea (1966) in the case of dilantoin. Mefenamic acid (Ponstan) and levodopa (l-dopa) were the next drugs to be implicated. Scott et al (1968) reported that three patients being treated with mefenamic acid had developed severe AIHA and Cotzias & Papavasiliou (1969) reported that the DAT of four out of 43 patients receiving levodopa had been positive. The author (Dacie, 1999) listed 15 other drugs the use of which had been reported as being, rarely, the apparent cause of AIHA or a positive DAT. Two main hypotheses have been advanced in relation to how certain drugs in some patients appear to have caused the development of anti-erythrocyte auto-antibodies. One hypothesis was that the drug or its metabolites act on the immune system so as to impair immune tolerance; the other was that the drug affects antigens at the erythrocyte surface in such a way that a normally active immune system responds by developing anti-erythrocyte antibodies. Clearly, too, the patient's individuality must be an important factor, for only a proportion of patients receiving the same dosage of the offending drug for the same period of time develop a positive DAT and only a small percentage develop overt AIHA. These interesting questions have been discussed in detail in numerous reviews, e.g. Worlledge (1969, 1973) and Garratty (1989, 1994). An interesting development in the history of the immune haemolytic anaemias was the realization in the mid-1950s that, rather rarely, haemolysis was brought about by the patient developing antibodies that were directed against a drug the patient had been taking and that the erythrocytes were in some way secondarily involved. The first drug to be implicated was Fuadin (stibophen), which had been used to treat a patient with schistosomiasis (Harris, 1954, 1956). The patient's serum contained an antibody that agglutinated his own or normal erythrocytes and/or sensitized them to agglutination by antiglobulin sera; however, this occurred only in the presence of the drug. Other drugs, e.g. quinidine, phenacetin and penicillin, were later reported to be a cause of haemolytic anaemia by a similar mechanism. The author (Dacie, 1999) listed 12 drugs that had been implicated between 1954 and 1961. It is now realized in fact that a wide range of drugs are capable of causing the DAT to be positive in susceptible recipients and, occasionally, causing clinically significant haemolysis. Habibi (1987) listed as many as 78 drugs and Garratty (1994) lists 71 drugs. Remarkably, some patients have been reported to have formed both drug-induced auto-antibodies and drug-dependant antibodies (Habibi, 1985). The importance of patient individuality, i.e. genetic factors, has been repeatedly referred to in the foregoing brief descriptions of the clinical syndromes associated with AIHA. The occurrence of more than one case of AIHA in the same family is, however, most unusual, but it has happened. The author (Dacie, 1969) reported that he had encountered only one example – a sister and brother – out of more than 100 cases of AIHA seen up to that time. Writing in 1992, he was, however, able to list 20 published descriptions of the occurrence of AIHA in more than one family member, included in the relationships were four pairs of twins. The reported occurrence of an immune-mediated disorder, other than AIHA, in the family of a patient with AIHA is, however, not rare. Dreyfus (1964), in an important review, mentioned the occurrence of thrombocytopenia, polyarteritis nodusa, rheumatoid arthritis, pernicious anaemia and hypogammaglobulinaemia. Pirofsky (1968b, 1969) stated that one or more relatives of eight out of 43 patients had suffered from a wide range of possible or probable auto-immune disorders. Conley (1981) reported an even higher incidence – 14 out of 33 patients. In the late 1940s, several accounts of patients with AIHA who had persistently low platelet counts were published, e.g. Fisher (1947) and Evans & Duane (1949); and it was suggested that the patients might have been forming auto-antibodies directed against platelets. This concept was further developed by Evans et al (1951). Eight out of their 18 patients with AIHA were thrombocytopenic; four had clinically obvious purpura. Evans et al (1951) suggested that there exists 'a spectrum-like relationship between acquired haemolytic anaemia and thrombocytopenic purpura'; also that 'on the one hand, acquired haemolytic anaemia with sensitization of the red cells is often accompanied with thrombocytopenia, while, on the other hand, primary thrombocytopenic purpura is frequently accompanied with red cell sensitization with or without haemolytic anaemia'. Many further case reports of AIHA accompanied by severe thrombocytopenia have since been published, e.g. in the later 1950s by Crosby & Rappaport (1957) and Dausset & Colombani (1959). AIHA was even reported to have developed in patients who had previously undergone splenectomy for thrombocytopenic purpura. Earlier, Waugh (1932), had described a possible example. The author (Dacie, 1954, 1962) described two similar occurrences. Some patients, too, have suffered from granulocytopenia as well as thrombocytopenia and haemolytic anaemia, e.g. as reported by Fisher (1947) and Evans et al (1951). Later descriptions include reports of the presence of antibodies against platelets and leucocytes in such cases, e.g. in patients described by Baumgartner (1956) and Müller & Weinreich (1956) (who coined the descriptive term 'Immunopancytopenien'). There are two features in the blood film of a patient with an acquired haemolytic anaemia which indicate that he or she is suffering from AIHA; one is auto-agglutination, the other is erythrophagocytosis. Spherocytosis, although often present to a marked degree, is of course found in other types of haemolytic anaemia. The early descriptions by French authors published in the first decade of the century have already been referred to. Noteworthy descriptions published in the 1940s of patients suffering from acute haemolysis in which auto-agglutination was conspicuous include those of Reisner & Kalkstein (1942), Evans (1943), Renner & McShane (1947) and Hahn & Lüttgens (1949). Phagocytosis by monocytes circulating in the peripheral blood has been frequently reported. It is most easily seen in buffy-coat preparations (Zinkham & Diamond, 1952; de Gruchy, 1954). Hargraves et al (1941) had earlier described a patient suffering from acute haemolysis in whom both monocytes and neutrophils were acting as erythrophages. It was not until the late 1930s that spherocytosis was recognized to be a common phenomenon in acquired haemolytic anaemias, in addition to being a characteristic finding in congenital acholuric jaundice (hereditary spherocytosis). Small darkly staining round microcytes had, however, been noticed much earlier than this as a feature of the blood picture in experimental antibody-produced haemolytic anaemia in animals, e.g. by Christophers & Bentley (1908, 1909) who described the cells as spherocytes, and Muir & McNee (1912). The 'rediscovery' of spherocytes by Dameshek & Schwartz (1938a, 1940) in the blood of animals (guinea-pigs) to which immune sera had been administered and their report of similar cells in the blood of human patients suffering from acute haemolytic anaemia proved to be a most important contribution to knowledge (Dameshek & Schwartz, 1938a,b; 1940). Up to that time, the current teaching, in the United Kingdom at least, was that many, perhaps most, of the cases of acquired haemolytic anaemia with spherocytes in the peripheral blood were in reality cases of previously symptomless congenital acholuric jaundice (Dawson, 1931; Vaughan, 1936; Israëls & Wilkinson, 1938). The pioneer French observations on auto-agglutination already referred to were generally overlooked until the late 1930s, and serological studies seem seldom to have been undertaken until the publication of Dameshek & Schwartz's (1938b) report in which they described the presence of 'haemolysins' in cases of acute apparently acquired haemolytic anaemia. Dameshek & Schwartz (1940) summarized contemporary knowledge in an extensive review. They concluded that it was not improbable that haemolysins of various types and 'dosages' were in fact responsible for many cases of human haemolytic anaemias, including congenital haemolytic anaemia, which they suggested might be caused by the 'more or less continued action of an haemolysin'. Dameshek and Schwartz's concept of the important role of haemolysins in haemolytic anaemia was viewed with some scepticism by their contemporaries, a major difficulty in its acceptance being that, in the great majority of cases, the presence of a haemolysin could not be demonstrated by techniques that were then available. Six years were to pass before the concept that an abnormal immune mechanism played a decisive role in some cases of acquired haemolytic anaemia was clearly demonstrated by Boorman et al (1946), who reported that the erythrocytes of five patients with acquired acholuric jaundice had been agglutinated by an antiglobulin serum, i.e. that the newly described antiglobulin reaction or Coombs test (Coombs et al, 1945) was positive, while the test had been negative in 28 patients suffering from congenital acholuric jaundice. This work aroused great interest and was soon confirmed and extended by other workers throughout the world. Early reports included those of Denys & van den Broucke (1947), who demonstrated the presence of free antibody globulin in their patients' sera by means of an indirect Coombs test and also that normal cells varied in their sensitivity to the antibody. Sturgeon (1947) reported that direct and indirect tests were positive in three patients and that antibody could be eluted from washed patients' erythrocytes. Evans et al (1947) also showed that globulin could be eluted from washed suspensions of patients' cells by heating at 56°C and that the eluted material could be transferred to normal cells. They showed, too, that their patients' cells auto-agglutinated when suspended in 30% bovine albumin, and they drew attention to the similarity in behaviour between the presumed antibody of haemolytic anaemia and that of Rh 'blocking' antibody. Much subsequent work was directed to elucidating the nature of the positive antiglobulin reactions and on the specificity of the antibodies involved. Coombs & Mourant (1947) demonstrated that the component in antiglobulin sera that reacted with Rh antibody coating erythrocytes was in all probability an anti-γ-globulin. van Loghem et al (1950) reported that, in AIHA, when various concentrations of antiglobulin serum were used, the reaction might be inhibited in the strongest concentrations of antiglobulin serum, i.e. there was a so-called prozone reaction. In 1951, the author had reported that the effect on the agglutination of erythrocytes from patients with AIHA of adding human γ-globulin to antiglobulin sera was inconstant (Dacie, 1951). When the test was carried out with the erythrocytes of two patients with warm-antibody AIHA, the reaction was inhibited by very small amounts of γ-globulin; in contrast, much more γ-globulin was required to inhibit the reaction in two patients whose serum contained high-titre cold agglutinins. These findings aroused considerable interest. In particular, interest was focused on the nature of the material coating erythrocytes that were agglutinated by antiglobulin sera to which large amounts of γ-globulin had been added – a so-called non-γ reaction. Were the cells coated by antibody globulins other than γ-globulin, or was the reaction between absorbed complement components and anticomplement antibodies in the antiglobulin serum, or were proteins being adsorbed non-specifically to antibody-damaged cells? Subsequent work established that the non-γ reaction depended upon the adsorption of sublytic amounts of complement components (Dacie et al, 1957; Rosenfield et al, 1960). Much subsequent work has been devoted to identifying the complement components involved. According to Lachmann et al (1983), using monoclonal antibodies, the erythrocytes of patients with the cold-haemagglutinin disease (CHAD), which give a strong non-γantiglobulin reaction, are coated with C3d, g (an α-2D globulin). Voak et al (1983) also demonstrated that CHAD erythrocytes were agglutinated by both anti-C3g and anti-C3d sera. Until the 1950s, the auto-antibodies responsible for AIHA were generally concluded to be 'non-specific'. According to Wiener et al (1953), 'Red cell auto-antibodies react not only with the individual's own red cells but also with the erythrocytes of all other human beings. The substances on the red blood cell envelope with which the auto-antibodies combine are agglutinogens like the A–B–O, M–N and Rh–Hr systems, except that, in the former case, the blood factors with which the auto-antibodies react are not type specific but are shared by all human beings.' They suggested that the auto-antibodies might be directed to the 'nucleus of the Rh–Hr substance'. Earlier work had, however, indicated that the sensitivity of normal group-compatible erythrocytes to a patient's auto-antibody might vary considerably (Denys & van den Broucke, 1947; Kuhns & Wagley, 1949). That auto-antibodies might have a clearly defined Rh specificity, e.g. anti-e, was described by Race & Sanger (1954) in the second edition of their book. Referring to Wiener et al (1953), they wrote: 'This beautifully clear investigation made the present authors realize that a curious result obtained by one of them (Ruth Sanger) in 1953 in Australia had after all been true; the serum of a man who had died of a haemolytic anaemia 3000 miles away contained anti-e; his cells were clearly CDe-cde'. A similar finding, i.e. an auto-anti-e, was described by Weiner et al (1953). Holländer (1953), too, reported that he had identified a specific auto-antibody in a case of AIHA: the patient's probable genotype was CDe/cde; anti-c was identified in serum and anti-c and a 'non-specific' component in erythrocyte eluates. Dacie (1953) and Dacie & Cutbush (1954) were able to report on the specificity of the auto-antibodies formed by 10 patients with warm-antibody AIHA. Nine of the patients had developed antibodies that appeared to be 'non-specific'. However, three of them were also forming specific Rh antibodies, namely anti-e, and one further patient had formed anti-e and anti-D at different times. As the probable genotype of these patients was CDe/cde, it was clear that the specific antibodies were acting as auto-antibodies. The 'non-specific' antibodies were interesting too: in three patients the antibodies appeared to have two components – a component reacting with all the cells tested and a component reacting with all the cells tested except those of –D–/–D– genotype. The results of studies carried out by van Loghem & van der Hart (1954a, b) were equally interesting. Specific auto-antibodies were identified in five out of six patients: namely, anti-D, anti-c, anti-C + e (two patients) and anti-Jka. The reports summarized above established without doubt that many of the auto-antibodies demonstrable in warm-antibody AIHA were reacting with specific antigens, in nearly all cases within the Rh system. The relative proportions of specific to apparently 'non-specific' antibodies was, however, uncertain, as cases in which a definite specificity had been demonstrated were more likely to be recorded that those in which no specificity had been established. The data available up to 1960 suggested, in fact, that auto-antibodies of demonstrable specificity were being formed by almost one-third of patients. The studies referred to above were greatly expanded and elaborated. A complicated picture emerged. It has been established, for instance, in relation to Rh antigens that several antibodies of different specificities may be present at the same time and that some antibodies, while reacting with normal eryt
Год издания: 2001
Авторы: Sir John Dacie
Издательство: Wiley
Источник: British Journal of Haematology
Ключевые слова: Blood groups and transfusion, Erythrocyte Function and Pathophysiology, Blood disorders and treatments
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Том: 114
Выпуск: 4
Страницы: 770–785