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Transfusion requirements and splenectomy in thalassemia major
10 0
Brief clinical and laboratory observations
cific for IgG, IgM, and IgA.S'9 Only small numbers of plasma ceils were stained positive for IgG, which closely corresponded to the low level of IgG in the serum. Most plasma cells were stained positive for IgM. Some plasma cells were IgA positive (Figure). DISCUSSION The clinical manifestations of isolated lgG deficiency are similar to those observed in patients with agammaglobulinemia. However, histologic examination of the lymph nodes shows a striking difference between these two diseases: The lymph nodes of isolated IgG deficiency contain a normal number of plasma cells? ~ 11 In order to diagnose our patient as having isolated IgG defciency, it was very important to distinguish his disease from other conditions such as protein-losing or hypercatabolic states. Immunodeficiency associated with proteinlosing entheropathy is recognized by relatively low serum levels of all classes of immunoglobulin. However, our patient had no episodes of diarrhea, proteinuria, and hypoproteinemia, and his serum concentrations of IgM and IgA were elevated. In addition, only a small number of plasma cells were IgG positive despite the presence of a considerable number of plasma cells in the lymphoid tissues. Furthermore, a lesser number of plasma cells stained for cytoplasmic IgG were detected than in the control following pokeweed mitogen. From these findings, it is suggested that the possible pathogenesis of this disorder would be a disturbance in the development of IgG producing plasma cells from IgG committed B-lymphocytes.
The Journal of Pediatrics July 1980 REFERENCES
1. Schur PH, Borel H, Gelfand EW, Alper CA, and Rosen FS: Selective gamma-G globulin deficiencies in patients with recurrent pyogenic infections, N Engl J Med 283:631, 1970. 2. Van der Giessen M, Reerink-Brongers EE, and Veen TA: Quantitation of Ig classes and IgG sub classes in sera of patients with a variety of immunoglobulin deficiencies and their relatives, Clin Immunol Immunopathol 5:388, 1976. 3. Kumagai K, Abo T, Sekisawa T, and Sasaki M.: Studies of surface immunoglobulins on human B lymphocytes. I. Dissociation of cell-bound immunoglobulins with acid pH or at 37oc, J Immunol 115:982, 1975. 4. Froland SS, Wisloff F, and Michelsen TE: Human lymphocytes with receptor IgG, Int Arch Allergy Appl Immunol 47:124, 1974: 5. Shevach EM, Herberman R, and Frank MM: Receptor for complement and immunoglobulin on human leukemic cells and human lymphoblastoid cell lines, J Clin Invest 51:1933, 1972. 6. Jondal M, Holm G, and Wigzell H.: Surface markers on human T and B lymphocytes forming non-immune rosettes with sheep red blood cells, J Exp Med 136:207, 1972. 7. Wu LYF, Lawton AR, and Cooper MD: Differentiation capacity of cultured B lymphocytes from immunodeficient patients, J Clin Invest 52:3180, 1973. 8. Sternberger LA: Immunocytochemistry, Englewood Cliffs, N.J., 1974, Prentice-Hall, Inc. 9. Taylor CR: Immunocytochemical methods in the study of lymphomas and related conditions, J Histochem Cytochem 26:496, 1978. 10. Rosen FS, and Janeway CA: The gamma globulins. III. The antibody deficiency syndromes, N Engl J Med 275:709, 1966. 11. Rosen FS, and Janeway CA: The gamma globulins. III. The antibody deficiency syndromes (concluded), N Engl J Med 275:769, 1966.
Transfusion requirements and splenectomy in thalassemia major Alan Cohen, M.D.,* Alicejane L. Markenson, M.D., and Elias Schwartz, M.D., Philadelphia, Pa., and New York, N.Y.
From the Department of Pediatrics, University of Pennsylvania School of Medicine and the Children's Hospital of Philadelphia and the Department of Pediatrics, Cornell University Medical College and New York Hospital/Cornell Medical Center. Supported-in part by a grant (AM 16691) and a research training award (HL 07150) from the National Institutes of Health, a contract from the Commonwealth of Pennsylvania, and the Children's Blood Foundation. *Reprint address: Division of Hematology, The Children's Hospital of Philadelphia, 34th St. & Civic Center Blvd., Philadelphia. PA 19104.
THE MAJOR INDICATION for splenectomy in children with thalassemia major is an increasing requirement for red cell transfusions to maintain an appropriate hemoglobin level? Accurate prediction of the postsplenectomy blood requirement would be of importance in determining the potential benefits of the operation, including diminution in need for transfusion and, therefore, decrease in the rate of iron loading which would occur following surgery. Previously, a transfusion index based on body weight, mean hemoglobin level and volume of whole blood used was found to be helpful in predicting 0022-3476/80/070100+03500.30/0 9 1980 The C. V. Mosby Co.
Volume 97 Number I
Brief clinical and laboratory observations
the response to splenectomy in Cypriot patients with fl + -thalassemia in Great Britain. ~ In the present study we have modified this index to make it readily applicable to transfusion practices in the United States. In addition, we have analyzed a large and diverse group of patients with homozygous fl?thalassemia to determine the reliability o f predicting the reduction in transfusion requirements after splenectomy. PATIENTS
AND METHODS
Patients with homozygous fl-thalassemia who ranged in age from 3 to 28 years and who were of Italian, Greek, or Sicilian background were studied. The thalassemia disorders included /3~ and fl+-thalassemia. Transfusion requirements were evaluated in 42 patients with intact spleens and in 23 patients at least six months after splenectomy. Eleven of the patients were studied at least six months before and after splenectomy. Age and sex distribution were similar in the patients with and without spleens. Transfusion requirements are expressed as the volume of packed red blood cells used for transfusion in one year, divided by the weight of the patient at midyear. Based upon measurements of 30 units, each unit of packed red cells was assumed to have a volume of 220 ml. Mean pretransfusion hemoglobin levels were calculated from values obtained prior to each transfusion during the year of study. With only occasional exceptions, hemoglobin levels prior to transfusion were 8 to 10 gm/dl in accordance with standard hypertransfusion programs. Statistical analyses were performed using the Student t test for independent samples and paired samples, and standard methods for analysis of correlation. RESULTS In patients with intact spleens the requirement for packed cells was 131 to 382 ml/kg/year (mean 230 +_ 56). In contrast, patients who had undergone splenectomy required 80 to 155 ml/kg/year (mean 129 _+ 21), a lower value with a much narrower range (P < 0.001). Only two patients with intact spleens had transfusion, requirements which fell within the range for patients after splenectomy. The transfusion requirements of 11 patients studied at least six months before and after splenectomy decreased 24 to 74%. The range prior to splenectomy was 193 to 382 ml/kg/year (mean 272 _+ 62). After splenectomy the range was 95 to 149 ml/kg/year (mean 127 __ 16), all values being within the limits of the total group of splenectomized patients (P < 0.001). Mean pretransfusion hemoglobin levels were 7.8 to 9.8 gm/dt for patients with intact spleens and 8.3 to 10.6 gm/dl for splenectomized patients. However, within these
10 1
ranges, no correlation was found between mean pretransfusion hemoglobin level and transfusion requirement (r = 0.22). Use of the mean pretransfusion hemoglobin level did not improve the value of the transfusion requirement in predicting the response to splenectomy. DISCUSSION The spleen may offer partial protection against transfusional hemochromatosis for patients with thalassemia major, by providing a relatively safe site for the storage of excessive iron. ~ However, rising transfusion requirements due to hypersplenism may dramatically increase the rate of iron loading. British investigators have suggested that when the transfusion requirement in the nonsplenectomized patient is more than twice the predicted requirement following splenectomy, the damaging effects of total iron accumulation outweigh the beneficial effects of maximal reticuloendothelial storage; therefore, the spleen should be removed? For patients receiving iron chelation therapy, a smaller reduction in the transfusion requirement may be an indication for splenectomy, since negative iron balance diminishes the value of the spleen as a storage site. A transfusion index using the yearly amount of transfused whole blood and the mean hemoglobin level (average of pre- and post-transfusion values) has been shown to be highly predictive of the change in transfusion requirement following splenectomy.'-' However, in most American centers treating patients with thalassemia major only packed red cells are administered and post-transfusion hemoglobin levels are infrequently measured. Using a modified index incorporating the volume of packed red cells administered yearly and the weight of the patient, a narrow range of postsplenectomy transfusion requirements has been established. Within the range of pretransfusion hemoglobin levels which are commonly maintained, the response to splenectomy has been shown to be independent of the mean pretransfusion hemoglobin concentration, in contrast to the British study. Besed upon readily available data, the reduction in blood requirement and iron loading after splenectomy can be predicted with e a s e for patients with thalassemia major. Splenectomy should be considered when the transfusion requirement exceeds 200 ml/kg/year since a minimum reduction in the need for blood of more than 20% can be expected. However, in determining the appropriate time for removal of the spleen in each patient, one must also consider the age of the patient and possible dangers of bacterial sepsis following splenectomy,' and the benefit of decrease in amount of iron acquired by transfusion in achieving negative iron balance with chelation therapy. With these considerations, splenectomy becomes an important element in a total program aimed at reduction of iron stores
10 2
Brief clinical and laboratory observations
The Journal of Pediatrics July 1980
b y chelation, dietary modification, a n d m i n i m i z i n g the n e e d for transfusion. The authors thank Carol Way for assistance in data collection and Judith Ann Williams for assistance in the preparation of the manuscript.
2.
Modell B: Total management of thalassemia major, Arch Dis Child 52:489, 1977. 3. l~erry CL, and Marshall WC: Iron distribution in the liver of patients with thalassemia major, Lancet 1:1031, 1967. 4. Smith CH, Erlandson ME, Stern G, and Hilgartner MW: Postsplenectomy infection in Cooley's anemia, N Engl J Med 266:737, 1962.
REFERENCES
I.
Pearson HA, and O'Brien RT: The management of thalassemia major, Semin Hematol 12:255, 1975.
Information for authors
Most of the provisions of the Copyright Act of 1976 became effective on January 1, 1978. Therefore, all manuscripts must be accompanied by the following written statement, signed by one author: "'The undersigned author transfers all copyright ownership of the manuscript (title of article) to The C. V. Mosby Company in the event the work is published. The undersigned author Warrants that the article is original, is not under consideration by another journal, and has not been previously published. I sign for and accept responsibility for releasing this material on behalf of any and all co-authors." Authors will be consulted, when possible, regarding republication of their material.
Brief clinical and laboratory observations
cific for IgG, IgM, and IgA.S'9 Only small numbers of plasma ceils were stained positive for IgG, which closely corresponded to the low level of IgG in the serum. Most plasma cells were stained positive for IgM. Some plasma cells were IgA positive (Figure). DISCUSSION The clinical manifestations of isolated lgG deficiency are similar to those observed in patients with agammaglobulinemia. However, histologic examination of the lymph nodes shows a striking difference between these two diseases: The lymph nodes of isolated IgG deficiency contain a normal number of plasma cells? ~ 11 In order to diagnose our patient as having isolated IgG defciency, it was very important to distinguish his disease from other conditions such as protein-losing or hypercatabolic states. Immunodeficiency associated with proteinlosing entheropathy is recognized by relatively low serum levels of all classes of immunoglobulin. However, our patient had no episodes of diarrhea, proteinuria, and hypoproteinemia, and his serum concentrations of IgM and IgA were elevated. In addition, only a small number of plasma cells were IgG positive despite the presence of a considerable number of plasma cells in the lymphoid tissues. Furthermore, a lesser number of plasma cells stained for cytoplasmic IgG were detected than in the control following pokeweed mitogen. From these findings, it is suggested that the possible pathogenesis of this disorder would be a disturbance in the development of IgG producing plasma cells from IgG committed B-lymphocytes.
The Journal of Pediatrics July 1980 REFERENCES
1. Schur PH, Borel H, Gelfand EW, Alper CA, and Rosen FS: Selective gamma-G globulin deficiencies in patients with recurrent pyogenic infections, N Engl J Med 283:631, 1970. 2. Van der Giessen M, Reerink-Brongers EE, and Veen TA: Quantitation of Ig classes and IgG sub classes in sera of patients with a variety of immunoglobulin deficiencies and their relatives, Clin Immunol Immunopathol 5:388, 1976. 3. Kumagai K, Abo T, Sekisawa T, and Sasaki M.: Studies of surface immunoglobulins on human B lymphocytes. I. Dissociation of cell-bound immunoglobulins with acid pH or at 37oc, J Immunol 115:982, 1975. 4. Froland SS, Wisloff F, and Michelsen TE: Human lymphocytes with receptor IgG, Int Arch Allergy Appl Immunol 47:124, 1974: 5. Shevach EM, Herberman R, and Frank MM: Receptor for complement and immunoglobulin on human leukemic cells and human lymphoblastoid cell lines, J Clin Invest 51:1933, 1972. 6. Jondal M, Holm G, and Wigzell H.: Surface markers on human T and B lymphocytes forming non-immune rosettes with sheep red blood cells, J Exp Med 136:207, 1972. 7. Wu LYF, Lawton AR, and Cooper MD: Differentiation capacity of cultured B lymphocytes from immunodeficient patients, J Clin Invest 52:3180, 1973. 8. Sternberger LA: Immunocytochemistry, Englewood Cliffs, N.J., 1974, Prentice-Hall, Inc. 9. Taylor CR: Immunocytochemical methods in the study of lymphomas and related conditions, J Histochem Cytochem 26:496, 1978. 10. Rosen FS, and Janeway CA: The gamma globulins. III. The antibody deficiency syndromes, N Engl J Med 275:709, 1966. 11. Rosen FS, and Janeway CA: The gamma globulins. III. The antibody deficiency syndromes (concluded), N Engl J Med 275:769, 1966.
Transfusion requirements and splenectomy in thalassemia major Alan Cohen, M.D.,* Alicejane L. Markenson, M.D., and Elias Schwartz, M.D., Philadelphia, Pa., and New York, N.Y.
From the Department of Pediatrics, University of Pennsylvania School of Medicine and the Children's Hospital of Philadelphia and the Department of Pediatrics, Cornell University Medical College and New York Hospital/Cornell Medical Center. Supported-in part by a grant (AM 16691) and a research training award (HL 07150) from the National Institutes of Health, a contract from the Commonwealth of Pennsylvania, and the Children's Blood Foundation. *Reprint address: Division of Hematology, The Children's Hospital of Philadelphia, 34th St. & Civic Center Blvd., Philadelphia. PA 19104.
THE MAJOR INDICATION for splenectomy in children with thalassemia major is an increasing requirement for red cell transfusions to maintain an appropriate hemoglobin level? Accurate prediction of the postsplenectomy blood requirement would be of importance in determining the potential benefits of the operation, including diminution in need for transfusion and, therefore, decrease in the rate of iron loading which would occur following surgery. Previously, a transfusion index based on body weight, mean hemoglobin level and volume of whole blood used was found to be helpful in predicting 0022-3476/80/070100+03500.30/0 9 1980 The C. V. Mosby Co.
Volume 97 Number I
Brief clinical and laboratory observations
the response to splenectomy in Cypriot patients with fl + -thalassemia in Great Britain. ~ In the present study we have modified this index to make it readily applicable to transfusion practices in the United States. In addition, we have analyzed a large and diverse group of patients with homozygous fl?thalassemia to determine the reliability o f predicting the reduction in transfusion requirements after splenectomy. PATIENTS
AND METHODS
Patients with homozygous fl-thalassemia who ranged in age from 3 to 28 years and who were of Italian, Greek, or Sicilian background were studied. The thalassemia disorders included /3~ and fl+-thalassemia. Transfusion requirements were evaluated in 42 patients with intact spleens and in 23 patients at least six months after splenectomy. Eleven of the patients were studied at least six months before and after splenectomy. Age and sex distribution were similar in the patients with and without spleens. Transfusion requirements are expressed as the volume of packed red blood cells used for transfusion in one year, divided by the weight of the patient at midyear. Based upon measurements of 30 units, each unit of packed red cells was assumed to have a volume of 220 ml. Mean pretransfusion hemoglobin levels were calculated from values obtained prior to each transfusion during the year of study. With only occasional exceptions, hemoglobin levels prior to transfusion were 8 to 10 gm/dl in accordance with standard hypertransfusion programs. Statistical analyses were performed using the Student t test for independent samples and paired samples, and standard methods for analysis of correlation. RESULTS In patients with intact spleens the requirement for packed cells was 131 to 382 ml/kg/year (mean 230 +_ 56). In contrast, patients who had undergone splenectomy required 80 to 155 ml/kg/year (mean 129 _+ 21), a lower value with a much narrower range (P < 0.001). Only two patients with intact spleens had transfusion, requirements which fell within the range for patients after splenectomy. The transfusion requirements of 11 patients studied at least six months before and after splenectomy decreased 24 to 74%. The range prior to splenectomy was 193 to 382 ml/kg/year (mean 272 _+ 62). After splenectomy the range was 95 to 149 ml/kg/year (mean 127 __ 16), all values being within the limits of the total group of splenectomized patients (P < 0.001). Mean pretransfusion hemoglobin levels were 7.8 to 9.8 gm/dt for patients with intact spleens and 8.3 to 10.6 gm/dl for splenectomized patients. However, within these
10 1
ranges, no correlation was found between mean pretransfusion hemoglobin level and transfusion requirement (r = 0.22). Use of the mean pretransfusion hemoglobin level did not improve the value of the transfusion requirement in predicting the response to splenectomy. DISCUSSION The spleen may offer partial protection against transfusional hemochromatosis for patients with thalassemia major, by providing a relatively safe site for the storage of excessive iron. ~ However, rising transfusion requirements due to hypersplenism may dramatically increase the rate of iron loading. British investigators have suggested that when the transfusion requirement in the nonsplenectomized patient is more than twice the predicted requirement following splenectomy, the damaging effects of total iron accumulation outweigh the beneficial effects of maximal reticuloendothelial storage; therefore, the spleen should be removed? For patients receiving iron chelation therapy, a smaller reduction in the transfusion requirement may be an indication for splenectomy, since negative iron balance diminishes the value of the spleen as a storage site. A transfusion index using the yearly amount of transfused whole blood and the mean hemoglobin level (average of pre- and post-transfusion values) has been shown to be highly predictive of the change in transfusion requirement following splenectomy.'-' However, in most American centers treating patients with thalassemia major only packed red cells are administered and post-transfusion hemoglobin levels are infrequently measured. Using a modified index incorporating the volume of packed red cells administered yearly and the weight of the patient, a narrow range of postsplenectomy transfusion requirements has been established. Within the range of pretransfusion hemoglobin levels which are commonly maintained, the response to splenectomy has been shown to be independent of the mean pretransfusion hemoglobin concentration, in contrast to the British study. Besed upon readily available data, the reduction in blood requirement and iron loading after splenectomy can be predicted with e a s e for patients with thalassemia major. Splenectomy should be considered when the transfusion requirement exceeds 200 ml/kg/year since a minimum reduction in the need for blood of more than 20% can be expected. However, in determining the appropriate time for removal of the spleen in each patient, one must also consider the age of the patient and possible dangers of bacterial sepsis following splenectomy,' and the benefit of decrease in amount of iron acquired by transfusion in achieving negative iron balance with chelation therapy. With these considerations, splenectomy becomes an important element in a total program aimed at reduction of iron stores
10 2
Brief clinical and laboratory observations
The Journal of Pediatrics July 1980
b y chelation, dietary modification, a n d m i n i m i z i n g the n e e d for transfusion. The authors thank Carol Way for assistance in data collection and Judith Ann Williams for assistance in the preparation of the manuscript.
2.
Modell B: Total management of thalassemia major, Arch Dis Child 52:489, 1977. 3. l~erry CL, and Marshall WC: Iron distribution in the liver of patients with thalassemia major, Lancet 1:1031, 1967. 4. Smith CH, Erlandson ME, Stern G, and Hilgartner MW: Postsplenectomy infection in Cooley's anemia, N Engl J Med 266:737, 1962.
REFERENCES
I.
Pearson HA, and O'Brien RT: The management of thalassemia major, Semin Hematol 12:255, 1975.
Information for authors
Most of the provisions of the Copyright Act of 1976 became effective on January 1, 1978. Therefore, all manuscripts must be accompanied by the following written statement, signed by one author: "'The undersigned author transfers all copyright ownership of the manuscript (title of article) to The C. V. Mosby Company in the event the work is published. The undersigned author Warrants that the article is original, is not under consideration by another journal, and has not been previously published. I sign for and accept responsibility for releasing this material on behalf of any and all co-authors." Authors will be consulted, when possible, regarding republication of their material.