1515
31. Violette SM, Shashikant CS, Salbaum JM, Belting HG, Wang JCH, Ruddle FH. Repression of the beta-amyloid gene in a Hox-3.1producing cell line. Proc Natl Acad Sci USA 1992; 89: 3805-09. 32. Shier AF, Gehring WJ. Direct homeodomaine-DNA interaction in the autoregulation of the fushi tarazu gene. Nature 1992; 356: 804-07. 33. Hardy J, Mullan M. In search of the soluble. Nature 1992; 359: 268-69. 34. Mayer RJ, Landon M, Laszlo L, Lennox G. Lowe J. Protein processing in lysosomes: the new therapeutic target in neurodegenerative disease. Lancet 1992; 340: 156-59. 35. Golde TE, Estus S, Younkin LH, Selkoe DJ, Younkin SG. Processing of the amyloid protein precursor to prtentially amyloidogenic derivatives. Science 1992; 255: 728-30.
C, Koo EH, Mellon A, Hung AY, Selkoe DJ. Targeting of cell-surface beta-amyloid precursor protein to lysosomes: alternative processing into amyloid-bearing fragments. Nature 1992; 357: 500-03.
36. Haass
AM, Paskevich PA, Kominami E, Nixon RA. Lysosomal hydrolases of different classes are abnormally distributed in brains of patients with Alzheimer disease. Proc Natl Acad Sci USA 1991; 88:
37. Cataldo
10998-1002. 38. Hsaio
K, Scott M, Foster D, et al. Spontaneous neurodegeneration in transgenic mice with mutant prion protein. Science 1990; 250: 1557-60. 39. Van Nostrand WE, Wagner SL, Shankle WR, et al. Decreased levels of soluble amyloid beta-protein precursor in cerebrospinal fluid of live Alzheimer disease patients. Proc Natl Acad Sci USA 1991; 89: 2551-55.
40. Farlow M, Ghetti B, Benson Mb, Farrow JS, van Nostrand WE, Wagner SL. Low cerebrospinal-fluid concentrations of soluble amyloid &bgr;-protein precursor in hereditary Alzheimer’s disease. Lancet 1992; 340: 453-54. 41. Nieto A, Montejo de Garcini E, Correas I, Avila J. Characterization of tau protein present in microtubules and paired helical filaments of Alzheimer’s disease patient’s brain. Neuroscience 1990; 37: 163-70. 42. Lee VM, Balin BJ, Otvos L Jr, Trojanowski JQ. A68: a major subunit of paired helical filaments and derivatized forms of normal tau. Science 1991; 251: 675-78. 43. Hanger DP, Brion JP, Gallo JM, et al. Tau in Alzheimer’s disease and Down’s syndrome is insoluble and abnormally phosphorylated. Biochem J 1991; 275: 99-104. 44. Steiner B, Mandelkow EM, Biernat J, et al. Phosphorylation of microtubule-associated protein tau: identification of the site for Ca++ -calmodulin dependent kinase and relationship with tau phosphorylation in Alzheimer tangles. EMBO J 1990; 9: 3539-44. 45. Goedert M, Spillantino MG, Cairns NJ, Crowther RA. Tau proteins of Alzheimer paired helical filaments: abnormal phosphorylation of all six brain isoforms. Neuron 1992; 8: 159-68. 46. Vincent IJ, Davies P. A protein kinase associated with paired helical filaments in Alzheimer disease. Proc Natl Acad Sci USA 1992; 89: 2878-82. 47. Refolo LM, Wittenberg IS, Friedrich VL, Robakis NK. The Alzheimer amyloid precursor is associated with the detergent insoluble cytoskeleton. J Neurosci 1991; 11: 3888-97.
CLINICAL PRACTICE Red blood cell transfusion in warm-type autoimmune haemolytic anaemia
Blood transfusions are regarded as hazardous in patients with warm-type autoimmune haemolytic anaemia (AIHA) because of potential intensification of haemolysis and a presumed high incidence of alloimmunisation. We have retrospectively analysed data of 79 multitransfused patients (74 adults, 5 children) with detectable warm autoantibodies and transitory or persisting haemolytic anaemia. All patients had received blood transfusions on at least two occasions. Patients were reexamined at least twice within the first 6 months of transfusion (duration of follow-up 6 months-12 years). 53 patients had received blood transfusions because of decompensated AIHA, all of whom presented with detectable autoantibodies against red blood cells. None of these patients had transfusion-related alloimmunisation or a definite increase in haemolysis, even when the transfused red cells were serologically incompatible because of free serum autoantibodies. The other 26 patients had no signs of AIHA at presentation (negative direct and indirect antiglobulin test), but received blood transfusions for anaemia due to various other causes. 23 of these 26 patients went on to develop alloantibodies as well as autoantibodies upon transfusion, and 3 patients developed autoantibodies alone. Our findings do not support the generally accepted notion that transfusion therapy should be
avoided in AIHA patients. Rather, they indicate that the incidence of alloimmunisation as well as adverse haemolytic transfusion reactions are less common in AIHA patients than in other multitransfused patients. Lancet 1992; 340: 1515-17.
Introduction The notion that blood transfusion may lead to intensification of haemolysis in patients with warm-type autoimmune haemolytic anaemia (AIHA) and that these patients are highly susceptible to alloimmunisation has repeatedly been emphasised.1-4 However, most studies have dealt only with serological findings, or have not provided detailed transfusion histories.5-9 Additionally, the number of subjects studied is not representative of the numerous transfused (but unpublished) cases of AIHA. Our experience of transfusion therapy in patients with classical AIHA does not accord with the unanimous recommendation to strictly avoid red cell transfusions. We therefore have reassessed this problem in multitransfused patients with detectable warm autoantibodies and transitory or
persisting haemolytic anaemia.
ADDRESSES: Institute for Clinical Immunology and Transfusion Medicine (A Salama, MD, H. Berghofer, MTA, Prof C. Mueller-Eckhardt. MD), and Department of Internal Medicine (A. Salama), Justus Liebig University, Giessen, Germany. Correspondence to Prof C. Mueller-Eckhardt, Institute of Clinical Immunology and Transfusion Medicine, Justus Liebig University, Langhansstrasse 7, D-6300 Giessen,
Germany.
1516
TABLE I-CLINICAL DATA AT FIRST PRESENTATION
I
TABLE II-NUMBER OF TRANSFUSIONS AND DURATION OF OBSERVATION TIME AFTER FIRST TRANSFUSION
I
lymphocytic leukaemia, MDS=myelodysplastic syndrome. AIHA autoimmune haemolytic anaemia associated with *All adults and 2 women with systemic lupus erythematosus and 1 woman with
CLL=chronic assoc =
t1 man rheumatoid arthritis t1 woman, 3 men with leukaemia, 1 woman, 1 man with solid carcinomas. §Disorders unrelated to immune system (see text).
Patients and methods From 1981
1992, about 3000 patients with suspected AIHA institutions or blood specimens were referred to us for serological investigations. 79 of these patients were eligible for study on the following criteria: positive direct antiglobulin test (AGT) and the presence of elutable warm autoantibodies from autologous red blood cells; transfusion of red cells on at least two different occasions; serological re-evaluation at least twice within the first 6 months of the start of transfusion therapy; and availability of complete clinical and serological data before and after to
*All adults, tDlsorders unrelated to the
immune
(see text).
system
were seen at our
TABLE III-ANTIBODIES AT FIRST PRESENTATION (AFP) AND DURING POST-TRANSFUSION OBSERVATION TIME (POST) I
I
transfusions. Blood transfusions were given to all patients. Patients with classical and active AIHA had already been on immunosuppressive therapy (prednisone and/or azathioprine, in a few cases cyclophosphamide); otherwise, corticosteroid therapy (1-2 mg/kg per day) was started immediately before transfusion. When crossmatched cells were incompatible because of free serum autoantibodies, the attending physicians were informed by a sticker attached to each blood unit. Serological assays (identification of serum antibodies, direct and indirect AGT, antibody adsorption and elution) were done as previously described.1o,1l
Results Clinical features of all patients at the time of first presentation are shown in table I. Most patients were adults (37 female, 42 male; age range 17-86 years). Only 5 children were included (2 girls, 3 boys; age range 2-13). AIHA was the only underlying disease (idiopathic form) in 32 patients (27 adults, 5 children). The remaining cases were associated with various disease conditions (table I). Table II shows the transfusion regimens and observation time after the first transfusion, and serological findings are given in table III. In 27 of 32 patients with idiopathic AIHA, direct AGT remained positive. Free red cell autoantibodies were initially detectable in 18 of the 32 patients and in later stages in 4; none of them developed alloantibodies or showed signs of augmented haemolysis after red cell transfusions, even if transfused cells were serologically incompatible because of free serum autoantibodies (table ill). This was also the case in 4 patients with AIHA associated with other immune disorders (table ill). Similarly, increased haemolysis or alloimmunisation was not seen in any of the patients with secondary AIHA and recognisable red cell autoantibodies (ie, positive direct AGT) before red cell transfusion (7 of 13 patients with chronic lymphocytic leukaemia [CLL]; 7 of 11I patients with lymphoma; 3 of 6 patients with other malignant disorders).
AGT= antiglobulin test: autoantibodies elutable m all cases. *Autoantibodies A FP/a utoa nti bodies during entire observation time. tThese patients had already been on immunosuppressive therapy, or corticosteroid therapy was started immediately before red cell transfusion AFP. tDlsorders unrelated to immune system (see text).
By contrast, of the remaining 26 patients who initially presented with a negative direct AGT, 3 developed warm autoantibodies alone, and 23 patients developed both alloantibodies and autoantibodies after red cell transfusions (table III). Immunisation coincided with the first transfusion in about half the patients and with subsequent transfusions in the remaining patients (table IV). Whereas the "transfusion-induced" autoantibodies in patients with CLL and lymphoma persisted for long periods and caused AIHA indistinguishable from its classical form (strongly positive direct IgG-AGT and clinically relevant haemolysis), the autoantibodies in the other cases were usually weak and vanished within 6 months to 1 year without steroid treatment (table iv). In all cases, IgG autoantibodies were elutable from circulating red cells while the direct AGT remained positive.
Discussion It is generally believed that in patients with AIHA, blood transfusions are associated with a high risk of
1517
TABLE IV-NUMBER OF PATIENTS IN RELATION TO BLOOD TRANSFUSION ASSOCIATED WITH ANTIBODY PRODUCTION, DURATION OF TIME OF AUTOANTIBODY DETECTABILITY, AND SPECIFICITY OF ALLOANTIBODIES
I
I I
I
No of patients
I
I
I
AAB=autoantibodies. BT= blood transfusion. *Patient developed alloantibodies after first and autoantibodies after second BT. tPatient developed first anti-Kalloantibodies plus autoantibodies and later anti -C+ D+E alloantibodies. tOne patient developed only autoantibodies and did not require further BT §Disorders unrelated to the immune system (see text)
alloimmunisation and/or increase in haemolysis. In this study, all patients at some time developed detectable warm autoantibodies against red cells and required transfusion therapy for anaemia, and 23 patients developed alloantibodies secondary to blood transfusion. At first glance, these findings could easily be interpreted as presenting the so-called typical constellation of AIHA. However, a careful analysis of the history and the serological course of each individual clearly indicated that patients with classical AIHA seem to be less susceptible to alloimmunisation than has previously been thought. At first presentation, only 53 of the 79 patients had AIHA associated with detectable autoantibodies. Transfusions were well tolerated in these 53 patients, but even more surprising was that there was not one case of alloimmunisation. Although the increase in haemoglobin concentrations by red cell transfusions was usually inadequate, as expected, there was no increase in haemolysis. The reasons for this are not clear. Could it be related to the underlying disease itself, in as much as autologous red cells which are already coated with autoantibodies are destroyed at maximum rates? If so, the transfused red cells should survive at least as long as autologous cells. Another reason for the lack of a haemolytic transfusion reaction may be that after transfusion the concentration of antibody molecules per cell is reduced owing to the increased number of circulating red cells. Whether the immune response in these patients is generally downregulated by increased red-cell destruction, or whether the immune system has become depressed by the administration of corticosteroids and/or by red cell transfusions,12 requires further studies. The pathogenesis of autoimmunisation by blood transfusion in the other patients is obscure. The possibility that these patients were already autoimmunised before transfusion with undetectable autoantibodies at first investigation (the so-called Coombs-negative AIHA) is unlikely, since the patients did not show signs of haemolytic anaemia before transfusion therapy. This viewpoint is further supported by the fact that the development of autoantibodies after transfusion is not uncommon in patients with delayed haemolytic transfusion reactions.lO,13 Likewise, the clinical course of patients who were not affected by CLL or lymphoma was typical for a haemolytic transfusion reaction rather than for classical AIHA. But the reasons why the resultant autoantibodies in patients with CLL or lymphoma persisted whereas those in the other patients did not, remain unresolved. It is also unclear why
red cell transfusions led to the production of autoantibodies alone in 3 patients. Our data clearly indicate that transfusion therapy in patients with classical AIHA is not associated either with a high risk of alloimmunisation or with a tendency to aggravate haemolysis. Therefore, we see no reason why transfusion therapy should be withheld for correction of anaemia in AIHA patients. We have often seen patients with haemoglobin concentrations as low as 3 g/dl who were denied blood transfusions solely because of apparent in-vitro serological incompatibility due to free serum autoantibodies. Even when the transfused red cells in these instances survive only for a few days, transfusions should be given until other forms of therapy become effective. Supported by the Deutsche Forschungsgemeinschaft (Sa 405/1-3).
REFERENCES B. Immune haemolytic disease: the autoimmune haemolytic anaemias. Clin Haematol 1975; 4: 167-80. 2. Rosenfield RE. Transfusion therapy for autoimmune hemolytic anemia. Semin Hematol 1976; 13: 311-21. 3. Petz LD, Garratty G. Acquired immune hemolytic anemias. New York: Churchill Livingstone, 1980. 4. Issitt PD. Applied blood group serology; 3rd ed. (Montgomery Scientific Publication, Miami, Florida 1985.) 5. Habibi B, Homberg J-C, Schaison G, Salmon C. Autoimmune hemolytic anemia in children: a review of 80 cases. Am J Med 1974; 56: 61-69. 6. Leddy JP, Peterson P, Yeaw MA, Bakemeier RF. Patterns of serologic specificity of human alpha-G erythrocyte autoantibodies. Correlation of antibody specificity with complement-fixing behaviour. J Immunol 1970; 105: 677-86. 7. Bell CA, Zwicker H, Sacks HJ. Autoimmune hemolytic anemia: routine serologic evaluation in a general hospital population. Am J Clin Pathol 1973; 60: 903-11. 8. Crookston JH. Hemolytic anemia with IgG and IgM autoantibodies and alloantibodies. Arch Intern Med 1975; 135: 1314-15. 9. Wallhermfechtel MA, Pohl BA, Chaplin H. Alloimmunization in patients with warm autoantibodies: a retrospective study employing three donor alloabsorptions to aid in antibody detection. Transfusion 1984; 24: 482-85. 10. Salama A, Mueller-Eckhardt C. Delayed hemolytic transfusion reactions: evidence for complement activation involving allogeneic and autologous red cells. Transfusion 1984; 24: 188-93. 11. Salama A, Mueller-Eckhardt C. Autoimmune haemolytic anaemia in childhood associated with non-complement binding IgM autoantibodies. Br J Haematol 1987; 65: 67-71. 12. Brunson ME, Alexander JW. Mechanisms of transfusion-induced immunosuppression. Transfusion 1990; 30: 651-58. 13. Ness PM, Shirey RS, Thoman SK, Buck SA. The differentiation of delayed serologic and delayed hemolytic transfusion reactions: incidence, long-term serologic findings and clinical significance. Transfusion 1990; 30: 688-93. 1.
Pirofsky
31. Violette SM, Shashikant CS, Salbaum JM, Belting HG, Wang JCH, Ruddle FH. Repression of the beta-amyloid gene in a Hox-3.1producing cell line. Proc Natl Acad Sci USA 1992; 89: 3805-09. 32. Shier AF, Gehring WJ. Direct homeodomaine-DNA interaction in the autoregulation of the fushi tarazu gene. Nature 1992; 356: 804-07. 33. Hardy J, Mullan M. In search of the soluble. Nature 1992; 359: 268-69. 34. Mayer RJ, Landon M, Laszlo L, Lennox G. Lowe J. Protein processing in lysosomes: the new therapeutic target in neurodegenerative disease. Lancet 1992; 340: 156-59. 35. Golde TE, Estus S, Younkin LH, Selkoe DJ, Younkin SG. Processing of the amyloid protein precursor to prtentially amyloidogenic derivatives. Science 1992; 255: 728-30.
C, Koo EH, Mellon A, Hung AY, Selkoe DJ. Targeting of cell-surface beta-amyloid precursor protein to lysosomes: alternative processing into amyloid-bearing fragments. Nature 1992; 357: 500-03.
36. Haass
AM, Paskevich PA, Kominami E, Nixon RA. Lysosomal hydrolases of different classes are abnormally distributed in brains of patients with Alzheimer disease. Proc Natl Acad Sci USA 1991; 88:
37. Cataldo
10998-1002. 38. Hsaio
K, Scott M, Foster D, et al. Spontaneous neurodegeneration in transgenic mice with mutant prion protein. Science 1990; 250: 1557-60. 39. Van Nostrand WE, Wagner SL, Shankle WR, et al. Decreased levels of soluble amyloid beta-protein precursor in cerebrospinal fluid of live Alzheimer disease patients. Proc Natl Acad Sci USA 1991; 89: 2551-55.
40. Farlow M, Ghetti B, Benson Mb, Farrow JS, van Nostrand WE, Wagner SL. Low cerebrospinal-fluid concentrations of soluble amyloid &bgr;-protein precursor in hereditary Alzheimer’s disease. Lancet 1992; 340: 453-54. 41. Nieto A, Montejo de Garcini E, Correas I, Avila J. Characterization of tau protein present in microtubules and paired helical filaments of Alzheimer’s disease patient’s brain. Neuroscience 1990; 37: 163-70. 42. Lee VM, Balin BJ, Otvos L Jr, Trojanowski JQ. A68: a major subunit of paired helical filaments and derivatized forms of normal tau. Science 1991; 251: 675-78. 43. Hanger DP, Brion JP, Gallo JM, et al. Tau in Alzheimer’s disease and Down’s syndrome is insoluble and abnormally phosphorylated. Biochem J 1991; 275: 99-104. 44. Steiner B, Mandelkow EM, Biernat J, et al. Phosphorylation of microtubule-associated protein tau: identification of the site for Ca++ -calmodulin dependent kinase and relationship with tau phosphorylation in Alzheimer tangles. EMBO J 1990; 9: 3539-44. 45. Goedert M, Spillantino MG, Cairns NJ, Crowther RA. Tau proteins of Alzheimer paired helical filaments: abnormal phosphorylation of all six brain isoforms. Neuron 1992; 8: 159-68. 46. Vincent IJ, Davies P. A protein kinase associated with paired helical filaments in Alzheimer disease. Proc Natl Acad Sci USA 1992; 89: 2878-82. 47. Refolo LM, Wittenberg IS, Friedrich VL, Robakis NK. The Alzheimer amyloid precursor is associated with the detergent insoluble cytoskeleton. J Neurosci 1991; 11: 3888-97.
CLINICAL PRACTICE Red blood cell transfusion in warm-type autoimmune haemolytic anaemia
Blood transfusions are regarded as hazardous in patients with warm-type autoimmune haemolytic anaemia (AIHA) because of potential intensification of haemolysis and a presumed high incidence of alloimmunisation. We have retrospectively analysed data of 79 multitransfused patients (74 adults, 5 children) with detectable warm autoantibodies and transitory or persisting haemolytic anaemia. All patients had received blood transfusions on at least two occasions. Patients were reexamined at least twice within the first 6 months of transfusion (duration of follow-up 6 months-12 years). 53 patients had received blood transfusions because of decompensated AIHA, all of whom presented with detectable autoantibodies against red blood cells. None of these patients had transfusion-related alloimmunisation or a definite increase in haemolysis, even when the transfused red cells were serologically incompatible because of free serum autoantibodies. The other 26 patients had no signs of AIHA at presentation (negative direct and indirect antiglobulin test), but received blood transfusions for anaemia due to various other causes. 23 of these 26 patients went on to develop alloantibodies as well as autoantibodies upon transfusion, and 3 patients developed autoantibodies alone. Our findings do not support the generally accepted notion that transfusion therapy should be
avoided in AIHA patients. Rather, they indicate that the incidence of alloimmunisation as well as adverse haemolytic transfusion reactions are less common in AIHA patients than in other multitransfused patients. Lancet 1992; 340: 1515-17.
Introduction The notion that blood transfusion may lead to intensification of haemolysis in patients with warm-type autoimmune haemolytic anaemia (AIHA) and that these patients are highly susceptible to alloimmunisation has repeatedly been emphasised.1-4 However, most studies have dealt only with serological findings, or have not provided detailed transfusion histories.5-9 Additionally, the number of subjects studied is not representative of the numerous transfused (but unpublished) cases of AIHA. Our experience of transfusion therapy in patients with classical AIHA does not accord with the unanimous recommendation to strictly avoid red cell transfusions. We therefore have reassessed this problem in multitransfused patients with detectable warm autoantibodies and transitory or
persisting haemolytic anaemia.
ADDRESSES: Institute for Clinical Immunology and Transfusion Medicine (A Salama, MD, H. Berghofer, MTA, Prof C. Mueller-Eckhardt. MD), and Department of Internal Medicine (A. Salama), Justus Liebig University, Giessen, Germany. Correspondence to Prof C. Mueller-Eckhardt, Institute of Clinical Immunology and Transfusion Medicine, Justus Liebig University, Langhansstrasse 7, D-6300 Giessen,
Germany.
1516
TABLE I-CLINICAL DATA AT FIRST PRESENTATION
I
TABLE II-NUMBER OF TRANSFUSIONS AND DURATION OF OBSERVATION TIME AFTER FIRST TRANSFUSION
I
lymphocytic leukaemia, MDS=myelodysplastic syndrome. AIHA autoimmune haemolytic anaemia associated with *All adults and 2 women with systemic lupus erythematosus and 1 woman with
CLL=chronic assoc =
t1 man rheumatoid arthritis t1 woman, 3 men with leukaemia, 1 woman, 1 man with solid carcinomas. §Disorders unrelated to immune system (see text).
Patients and methods From 1981
1992, about 3000 patients with suspected AIHA institutions or blood specimens were referred to us for serological investigations. 79 of these patients were eligible for study on the following criteria: positive direct antiglobulin test (AGT) and the presence of elutable warm autoantibodies from autologous red blood cells; transfusion of red cells on at least two different occasions; serological re-evaluation at least twice within the first 6 months of the start of transfusion therapy; and availability of complete clinical and serological data before and after to
*All adults, tDlsorders unrelated to the
immune
(see text).
system
were seen at our
TABLE III-ANTIBODIES AT FIRST PRESENTATION (AFP) AND DURING POST-TRANSFUSION OBSERVATION TIME (POST) I
I
transfusions. Blood transfusions were given to all patients. Patients with classical and active AIHA had already been on immunosuppressive therapy (prednisone and/or azathioprine, in a few cases cyclophosphamide); otherwise, corticosteroid therapy (1-2 mg/kg per day) was started immediately before transfusion. When crossmatched cells were incompatible because of free serum autoantibodies, the attending physicians were informed by a sticker attached to each blood unit. Serological assays (identification of serum antibodies, direct and indirect AGT, antibody adsorption and elution) were done as previously described.1o,1l
Results Clinical features of all patients at the time of first presentation are shown in table I. Most patients were adults (37 female, 42 male; age range 17-86 years). Only 5 children were included (2 girls, 3 boys; age range 2-13). AIHA was the only underlying disease (idiopathic form) in 32 patients (27 adults, 5 children). The remaining cases were associated with various disease conditions (table I). Table II shows the transfusion regimens and observation time after the first transfusion, and serological findings are given in table III. In 27 of 32 patients with idiopathic AIHA, direct AGT remained positive. Free red cell autoantibodies were initially detectable in 18 of the 32 patients and in later stages in 4; none of them developed alloantibodies or showed signs of augmented haemolysis after red cell transfusions, even if transfused cells were serologically incompatible because of free serum autoantibodies (table ill). This was also the case in 4 patients with AIHA associated with other immune disorders (table ill). Similarly, increased haemolysis or alloimmunisation was not seen in any of the patients with secondary AIHA and recognisable red cell autoantibodies (ie, positive direct AGT) before red cell transfusion (7 of 13 patients with chronic lymphocytic leukaemia [CLL]; 7 of 11I patients with lymphoma; 3 of 6 patients with other malignant disorders).
AGT= antiglobulin test: autoantibodies elutable m all cases. *Autoantibodies A FP/a utoa nti bodies during entire observation time. tThese patients had already been on immunosuppressive therapy, or corticosteroid therapy was started immediately before red cell transfusion AFP. tDlsorders unrelated to immune system (see text).
By contrast, of the remaining 26 patients who initially presented with a negative direct AGT, 3 developed warm autoantibodies alone, and 23 patients developed both alloantibodies and autoantibodies after red cell transfusions (table III). Immunisation coincided with the first transfusion in about half the patients and with subsequent transfusions in the remaining patients (table IV). Whereas the "transfusion-induced" autoantibodies in patients with CLL and lymphoma persisted for long periods and caused AIHA indistinguishable from its classical form (strongly positive direct IgG-AGT and clinically relevant haemolysis), the autoantibodies in the other cases were usually weak and vanished within 6 months to 1 year without steroid treatment (table iv). In all cases, IgG autoantibodies were elutable from circulating red cells while the direct AGT remained positive.
Discussion It is generally believed that in patients with AIHA, blood transfusions are associated with a high risk of
1517
TABLE IV-NUMBER OF PATIENTS IN RELATION TO BLOOD TRANSFUSION ASSOCIATED WITH ANTIBODY PRODUCTION, DURATION OF TIME OF AUTOANTIBODY DETECTABILITY, AND SPECIFICITY OF ALLOANTIBODIES
I
I I
I
No of patients
I
I
I
AAB=autoantibodies. BT= blood transfusion. *Patient developed alloantibodies after first and autoantibodies after second BT. tPatient developed first anti-Kalloantibodies plus autoantibodies and later anti -C+ D+E alloantibodies. tOne patient developed only autoantibodies and did not require further BT §Disorders unrelated to the immune system (see text)
alloimmunisation and/or increase in haemolysis. In this study, all patients at some time developed detectable warm autoantibodies against red cells and required transfusion therapy for anaemia, and 23 patients developed alloantibodies secondary to blood transfusion. At first glance, these findings could easily be interpreted as presenting the so-called typical constellation of AIHA. However, a careful analysis of the history and the serological course of each individual clearly indicated that patients with classical AIHA seem to be less susceptible to alloimmunisation than has previously been thought. At first presentation, only 53 of the 79 patients had AIHA associated with detectable autoantibodies. Transfusions were well tolerated in these 53 patients, but even more surprising was that there was not one case of alloimmunisation. Although the increase in haemoglobin concentrations by red cell transfusions was usually inadequate, as expected, there was no increase in haemolysis. The reasons for this are not clear. Could it be related to the underlying disease itself, in as much as autologous red cells which are already coated with autoantibodies are destroyed at maximum rates? If so, the transfused red cells should survive at least as long as autologous cells. Another reason for the lack of a haemolytic transfusion reaction may be that after transfusion the concentration of antibody molecules per cell is reduced owing to the increased number of circulating red cells. Whether the immune response in these patients is generally downregulated by increased red-cell destruction, or whether the immune system has become depressed by the administration of corticosteroids and/or by red cell transfusions,12 requires further studies. The pathogenesis of autoimmunisation by blood transfusion in the other patients is obscure. The possibility that these patients were already autoimmunised before transfusion with undetectable autoantibodies at first investigation (the so-called Coombs-negative AIHA) is unlikely, since the patients did not show signs of haemolytic anaemia before transfusion therapy. This viewpoint is further supported by the fact that the development of autoantibodies after transfusion is not uncommon in patients with delayed haemolytic transfusion reactions.lO,13 Likewise, the clinical course of patients who were not affected by CLL or lymphoma was typical for a haemolytic transfusion reaction rather than for classical AIHA. But the reasons why the resultant autoantibodies in patients with CLL or lymphoma persisted whereas those in the other patients did not, remain unresolved. It is also unclear why
red cell transfusions led to the production of autoantibodies alone in 3 patients. Our data clearly indicate that transfusion therapy in patients with classical AIHA is not associated either with a high risk of alloimmunisation or with a tendency to aggravate haemolysis. Therefore, we see no reason why transfusion therapy should be withheld for correction of anaemia in AIHA patients. We have often seen patients with haemoglobin concentrations as low as 3 g/dl who were denied blood transfusions solely because of apparent in-vitro serological incompatibility due to free serum autoantibodies. Even when the transfused red cells in these instances survive only for a few days, transfusions should be given until other forms of therapy become effective. Supported by the Deutsche Forschungsgemeinschaft (Sa 405/1-3).
REFERENCES B. Immune haemolytic disease: the autoimmune haemolytic anaemias. Clin Haematol 1975; 4: 167-80. 2. Rosenfield RE. Transfusion therapy for autoimmune hemolytic anemia. Semin Hematol 1976; 13: 311-21. 3. Petz LD, Garratty G. Acquired immune hemolytic anemias. New York: Churchill Livingstone, 1980. 4. Issitt PD. Applied blood group serology; 3rd ed. (Montgomery Scientific Publication, Miami, Florida 1985.) 5. Habibi B, Homberg J-C, Schaison G, Salmon C. Autoimmune hemolytic anemia in children: a review of 80 cases. Am J Med 1974; 56: 61-69. 6. Leddy JP, Peterson P, Yeaw MA, Bakemeier RF. Patterns of serologic specificity of human alpha-G erythrocyte autoantibodies. Correlation of antibody specificity with complement-fixing behaviour. J Immunol 1970; 105: 677-86. 7. Bell CA, Zwicker H, Sacks HJ. Autoimmune hemolytic anemia: routine serologic evaluation in a general hospital population. Am J Clin Pathol 1973; 60: 903-11. 8. Crookston JH. Hemolytic anemia with IgG and IgM autoantibodies and alloantibodies. Arch Intern Med 1975; 135: 1314-15. 9. Wallhermfechtel MA, Pohl BA, Chaplin H. Alloimmunization in patients with warm autoantibodies: a retrospective study employing three donor alloabsorptions to aid in antibody detection. Transfusion 1984; 24: 482-85. 10. Salama A, Mueller-Eckhardt C. Delayed hemolytic transfusion reactions: evidence for complement activation involving allogeneic and autologous red cells. Transfusion 1984; 24: 188-93. 11. Salama A, Mueller-Eckhardt C. Autoimmune haemolytic anaemia in childhood associated with non-complement binding IgM autoantibodies. Br J Haematol 1987; 65: 67-71. 12. Brunson ME, Alexander JW. Mechanisms of transfusion-induced immunosuppression. Transfusion 1990; 30: 651-58. 13. Ness PM, Shirey RS, Thoman SK, Buck SA. The differentiation of delayed serologic and delayed hemolytic transfusion reactions: incidence, long-term serologic findings and clinical significance. Transfusion 1990; 30: 688-93. 1.
Pirofsky
