Delayed Overt Hemolytic Transfusion Reaction Due to Anti-U Antibody 1. K. ROTHMAN,H. J. ALTER,AND G. J. STREWLER From the Clinical Center Blood Bonk Deportment and from the Loboratory of Kidney and Electrolyte Metabolism, Notional Institutes of Heolth. Bethesdo. Morylond
A patient i s described who developed a delayed hemolytic transfusion reaction, 11 days posttransfusion, caused by anti-U. This case illustrates the difficulty that can occur in distinguishing a delayed transfusion reaction from autoimmune hemolytic disease when the antibody involved is directed against a high incidence blood group antigen.
A DELAYED HEMOLYTIC transfusion reaction ,represents an infrequent, but potentially hazardous complication of blood transfusion.' This phenomenon usually originates with exposure to a blood group antigen by prior transfusion or pregnancy. The antibody resulting from this primary sensitization is not detected during compatibility testing at the time of the next transfusion. Reexposure to the same blood group antigen causes an anamnestic response with the rapid appearance of an isoantibody after a latent period of up to 14 days. Clinical manifestations range from minimal to severe and the latter may be accompanied by renal failure. The following report describes a delayed hemolytic transfusion reaction of moderate severity caused by the antibody, anti-U. Case Report
J. P. is a 39-year-old black female with the syndrome of insulin-resistant diabetes mellitus and acanthosis nigrican~.'*~ She has been shown to have a high titer of circulating antibody which inhibits in vifro insulin binding to cell membrane^.^ Laboratory evidence of potential autoimmune phenomena consisted of a strongly positive antinuclear antibody, anti-DNA of 54.1 per cent (normal 0 to 36%), hypergammaglobulinemia, and a slightly depressed level (88) of complement Received for publication September 8, 1975; accepted October 21. 1975.
component C , (normal, 119 to 175). Tests for LE cells were negative. The patient was known to have a chronic, mild hypochromic anemia and leukopenia. She was transfused on two occasions prior to the present admission: in 1956, she received blood transfusion because of hemoptysis associated with pulmonary tuberculosis, and in 1968 blood was administered during a hysterectomy. These transfusions were not accompanied by an apparent reaction. The patient also had one pregnancy terminating in an early spontaneous abortion. The present admission, in April 1975, was for evaluation of a rectal prolapse. A cystic pelvic mass was noted necessitating abdominal exploration. Transfusion was requested and pretransfusion evaluation by the blood bank showed the patient to be group B, Rho (D) positive and to have a negative direct antiglobulin test. Antibody screen in saline including antiglobulin test against two reagent red blood cells was negative a t 22 C and at 37 C. Antibody screen with enzyme was also negative. N o incompatibility was demonstrated in the crossmatch using an albumin to indirect antiglobulin technique. On the day prior to surgery, two units of red blood cells were administered without difficulty and the hematocrit rose from 31.6 to 38 per cent. At laparotomy, bilateral, benign, ovarian cystadenomas were found and removed. The postoperative course was complicated by a wound infection which was treated with penicillin, cephalothin, gentamicin, and clindamycin. On the sixth postoperative day, the hematocrit was relatively unchanged a t 36.1 per cent. By this time, all antibiotics had been discontinued with the exception of gentamicin. On the tenth postoperative day, I 1 days after receiving the blood transfusions, the patient developed a fever of 40.2 C and grossly red urine; urine sediment showed no red blood cells. Evaluation disclosed hemoglobinemia (70 mg/dl), and hemoglobinuria. Prothrombin time, partial thromboplastin time, platelet count, and fibrinogen level were normal. The blood showed minimal abnormalities with only a few schistocytes, target cells, and microspherocytes. There
357 Transfusion July-Aug. 1976
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Number4
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ROTHMAN, ET AL.
was no clinical or laboratory evidence of sepsis or of clostridial wound infection. Fluid and bicarbonate therapy was given and the renal function remained normal. Over the following 48 hours, her hematocrit fell to 23.8 per cent without evidence of blood loss. A blood sample obtained a t the onset of the acute hemolytic episode (the tenth postoperative day) showed a weakly positive direct antiglobulin test ( I to 2 + with four different antiglobulin reagents). A serum antibody was detected for the first time which reacted strongly against all eight panel red blood cells tested giving 3 + agglutination in the indirect antiglobulin test; in the auto control, in which the patient’s own red blood cells were incubated with her serum antibody, only a 1 + reaction was noted. The serologic finding of a panagglutinin in a patient with other evidence of autoimmune disease suggested a diagnosis of a u t o i m m u n e hemolytic anemia and steroid therapy was initially considered. However, it was then noted that the patient had been previously phenotyped and found to be negative for the high frequency U antigen. This was confirmed by performing a phenotype on the patient’s pretransfusion blood sample. The antibody detected in the patient’s postreaction serum sample was then further tested against U-negative red blood cells from eight donors and found to be nonreactive with each; it reacted strongly with all U-positive red blood cells tested. A heat eluate performed on the patient’s postreaction red blood cells revealed antibody with anti-U specificity. The pretransfusion serum sample was retested and anti-U could not be detected (by indirect antiglobulin o r enzyme) even after fivefold concentration. The two units of blood received by the patient were both U-positive. One day following the reaction (12 days postoperative), t h e patient’s temperature had returned to normal, gross hemoglobinuria had disappeared and the plasma hemoglobin level returned to zero. The patient had normal levels of direct and indirect reacting bilirubin in her pretransfusion sample which did not rise following the hemolytic episode. By the fifth postreaction day the direct antiglobulin test had become negative and the patient’s serum, containing anti-U, no longer reacted with her own cells indicating the disappearance of transfused U-positive red blood cells. The patient’s reticulocyte count peaked a t 6 per cent and by the sixth postreaction day the hematocrit had risen to 32.6 per cent. A blood sample obtained on the seventh postreaction day continued to show strongly reactive (3+) antibody in the indirect antiglobulin test. The patient was discharged and later samples were not available.
Transfusion July-Aug. 1976
Discussion
An acute hemolytic episode occurring during the first or second week following a blood transfusion should suggest the possibility of a delayed transfusion reaction. In most cases, this diagnosis is easily established by the development of a positive direct and/or indirect antiglobulin test due to an antibody directed against a specific and easily identifiable blood group antigen. The antigens most frequently implicated belong to the Kidd or Rh blood group^.^ However, the formation of multiple antibodies is not uncommon and when this occurs the laboratory findings may suggest a panagglutinin and lead to the incorrect diagnosis of autoimmune hemolytic anemia.3 The unusual occurrence of an antibody against a high incidence antigen can also be misleading, as illustrated by the case reported herein. In this patient, the antibody responsible for the delayed hemolytic transfusion reaction, anti-U, reacts with the red blood cells of virtually all Caucasians and 99 per cent of all Blacks.’* An antibody of this nature, when tested against a routine panel of cells, may appear to be a panagglutinin and, thus, falsely suggest a diagnosis of idiopathic autoimmune hemolytic disease. It is most important to be able to differentiate between a delayed transfusion reaction and an acute onset of autoimmune hemolytic disease because of the differences in treatment and in prognosis. In the present case, the initial laboratory evaluation suggested the presence of a panagglutinin, and a diagnosis of autoimmune hemolytic anemia seemed to be all the more plausible because of this patient’s known propensity for developing autoimmune phenomena. The initiation of high dose prednisone therapy was strongly considered at that time. However, several observations weighed against the diagnosis of autoimmune hemolytic anemia. At the height of the clinical episode, blood smear morphology showed little evidence of the ongoing erythrocyte destruction (spherocytes, schistocytes) that would be expected with a
Volume 16 Number 4
DELAYED HEMOLYSIS DUE TO ANTI-U
fulminant autoimmune hemolytic anemia. This suggested that most of the susceptible cells had by this time been cleared from the circulation. In addition, the patient’s direct antiglobulin test was only weakly positive and her serum antibody produced a strong reaction with all of the U-positive panel red blood cells, but only a weak reaction with the patient’s own red blood cells. This combination of findings suggested that only a portion of the patient’s red blood cell population was subject to immunologic destruction. Such limited destruction was more consistent with a delayed hemolytic transfusion reaction than with acute autoimmune hemolytic anemia. Subsequent evaluation confirmed the presence of a specific isoantibody, anti-U, which had destroyed most of the previously transfused red blood cells, but had no effect on the patient’s own U-negative erythrocy t es. Identification of the antibody in this patient was aided by the knowledge that she was U-negative. This illustrates the importance of determining the blood group phenotype on a pretransfusion sample when trying to characterize an unusual antibody. The demonstration of a specific antibody confirmed the relationship to transfusion therapy and avoided the multiple hazards of steroid therapy which might otherwise have been administered. In addition, because of the self-limited hemolysis associated with incompatible t ran sfusion, steroids ad min istered at that time would have given the false impression of a therapeutic response. This might have resulted in the unwarranted continued use of predisone to prevent a hemolytic recurrence. Evidence for an antibody-mediated hemolytic episode in this patient appears to be unequivocal. However, the fall i n hematocrit from 36.1 to 23.8 per cent was more than could be accounted for by destruction of the two units of U-positive red blood cells she had received. This excessive fall in hematocrit may have been due, in part, to frequent phlebotomy for laboratory tests or
359
unrecognized occult blood loss in a patient who was chronically/ill and presumably could not rapidly replace blood loss. At the time of the hemolytic reaction, she was not receiving any drug known to be associated with a Coombs’-positive hemolytic anemia. The latent period between the time of transfusion and the onset of overt hemolysis was 1 1 days, a relatively long interval for an anamnestic response. Delayed transfusion reactions normally occur within ten dayslo but there have been reports of a delay up to 14 days.s The patient described here had almost certainly been exposed to U-positive blood at the time of her previous transfusions and the reaction therefore probably represented an anamnestic rather than a primary antibody response. Nonetheless, anti: U antibody could not be demonstrated in the pretransfusion sample even when employing enzyme enhancement and serum concentration techniques. There has been one previous report of antiU causing a delayed hemolytic transfusion r e a c t i ~ n .In~ that case, the latent period was five days and the hemolytic episode was accompanied by acute renal failure. Anti-U has been implicated in several cases of maternal isoimmunization and can be a cause of erythroblastosis fetalis.1*2Auto-anti-U has been reported in the sera of patients with autoimmune hemolytic anemia,” but in the present case the hemolytic episode was clearly that of a delayed transfusion reaction, due to iso-anti-U directed against transfused U-positive red blood cells and not the patient’s own U-negative red blood cells. The patient has been notified that she is Unegative and that she has anti-U antibody. She has been told that she should never again receive U-positive blood whether or not detectable antibody persists in her blood; a subsequent hemolytic reaction could be potentially more severe. The patient has been advised to carry a card defining the nature of her antibody. The possibility of maintaining several units of her own blood in frozen storage for emergency use has been
360
ROTHMAN, ET AL.
discussed and, in addition, family members will be phenotyped to see if any could serve as potential donors should the need arise. Acknowledgment We wish to express our thanks to Mr. Wallace Mook for his technical assistance in evaluating this case and to Ms. Mary Ann Gralnick for having maintained the repository of frozen U-negative cells which helped to establish the diagnosis. We would also like to thank Dr. Ronald Khan of the Diabetes Branch of the National Institutes of Arthritis, Metabolism and Digestive Diseases for having provided theopportunity to study this patient.
References 1. Afonso, J. F., and R. R. de Alvarez: Maternal isosensitization to the red cell antigen U. Am. J. Obstet. Gynecol. 81:45, 1961. 2. Burki, U., T. J. Degnan, and R. E. Rosenfield: Stillbirth due to anti-U. Vox Sang. 9:209, 1964. 3. Croucher, B. E., M. C. Crookston, and J. H. Crookston: Delayed hemolytic transfusion reactions simulating autoimmune hemolytic anemia. Vox Sang. 12:32, 1967. 4. Field, J. B., P. Johnson, and B.-Herring: Insulinresistant diabetes associated with increased endogenous plasma insulin followed by complete remission. J. Clin. Invest. 40:1672, 1961. 5 . Flier, J. S., C. R. Kahn, J. Roth, and R. S. Bar: Circulating antibodies that impair insulin receptor binding in patients with an unusual diabetic syndrome and extreme insulin resistance. Science (in press).
Transfusion July-Aug. 1976
6. Holland, P. V., and R. 0. Wallerstein: Delayed hemolytic transfusion reaction with acute renal failure. JAMA 204:1007, 1968. 7. Howard, P. L.: Delayed hemolytic transfusion reactions. Ann. Clin. Lab. Sci. 3:13, 1973. 8. Kahn, C. R., R. S. Bar, P. Gorden, and J. Roth: The syndrome of extreme insulin resistance and acanthosis nigricans: a primary insulin receptor defect in man. Clin. Res. 23:324a, 1975. 9. Meltz, D. J., D. S. David, J. F. Bertles, and A. C. De Ciutiis: Delayed hemolytic transfusion reaction with renal failure. Lancet II:1348, 1971. 10. Mollison, P. L.: Blood Transfusion in Clinical Medicine, 5th ed. Oxford, Blackwell, 1972, p. 559. 11. Nugent M. E., K. I. Colledge, and W. L. Marsh: Autoimmune hemolytic anemia caused by antiU. Vox Sang. 20:519, 1971. 12. Weiner, A. S., L. J. Unger, and L. Cohen: Distribution and heredity of blood factor U. Science 119:734, 1954.
I. K. Rothman, Clinical Associate, Blood Bank Department, National Institutes of Health, Bethesda, Maryland 20014 (Current address: Department of Hematology, New York University Medical Center, 550 First Avenue, New York, N.Y. 10016). H. J. Alter, Chief Immunology Section, Clinical Center Blood Bank, National Institutes of Health (Reprint requests). G. J. Strewler, Clinical Associate, Laboratory of Kidney and Electrolyte Metabolism, National Institutes of Health.
A patient i s described who developed a delayed hemolytic transfusion reaction, 11 days posttransfusion, caused by anti-U. This case illustrates the difficulty that can occur in distinguishing a delayed transfusion reaction from autoimmune hemolytic disease when the antibody involved is directed against a high incidence blood group antigen.
A DELAYED HEMOLYTIC transfusion reaction ,represents an infrequent, but potentially hazardous complication of blood transfusion.' This phenomenon usually originates with exposure to a blood group antigen by prior transfusion or pregnancy. The antibody resulting from this primary sensitization is not detected during compatibility testing at the time of the next transfusion. Reexposure to the same blood group antigen causes an anamnestic response with the rapid appearance of an isoantibody after a latent period of up to 14 days. Clinical manifestations range from minimal to severe and the latter may be accompanied by renal failure. The following report describes a delayed hemolytic transfusion reaction of moderate severity caused by the antibody, anti-U. Case Report
J. P. is a 39-year-old black female with the syndrome of insulin-resistant diabetes mellitus and acanthosis nigrican~.'*~ She has been shown to have a high titer of circulating antibody which inhibits in vifro insulin binding to cell membrane^.^ Laboratory evidence of potential autoimmune phenomena consisted of a strongly positive antinuclear antibody, anti-DNA of 54.1 per cent (normal 0 to 36%), hypergammaglobulinemia, and a slightly depressed level (88) of complement Received for publication September 8, 1975; accepted October 21. 1975.
component C , (normal, 119 to 175). Tests for LE cells were negative. The patient was known to have a chronic, mild hypochromic anemia and leukopenia. She was transfused on two occasions prior to the present admission: in 1956, she received blood transfusion because of hemoptysis associated with pulmonary tuberculosis, and in 1968 blood was administered during a hysterectomy. These transfusions were not accompanied by an apparent reaction. The patient also had one pregnancy terminating in an early spontaneous abortion. The present admission, in April 1975, was for evaluation of a rectal prolapse. A cystic pelvic mass was noted necessitating abdominal exploration. Transfusion was requested and pretransfusion evaluation by the blood bank showed the patient to be group B, Rho (D) positive and to have a negative direct antiglobulin test. Antibody screen in saline including antiglobulin test against two reagent red blood cells was negative a t 22 C and at 37 C. Antibody screen with enzyme was also negative. N o incompatibility was demonstrated in the crossmatch using an albumin to indirect antiglobulin technique. On the day prior to surgery, two units of red blood cells were administered without difficulty and the hematocrit rose from 31.6 to 38 per cent. At laparotomy, bilateral, benign, ovarian cystadenomas were found and removed. The postoperative course was complicated by a wound infection which was treated with penicillin, cephalothin, gentamicin, and clindamycin. On the sixth postoperative day, the hematocrit was relatively unchanged a t 36.1 per cent. By this time, all antibiotics had been discontinued with the exception of gentamicin. On the tenth postoperative day, I 1 days after receiving the blood transfusions, the patient developed a fever of 40.2 C and grossly red urine; urine sediment showed no red blood cells. Evaluation disclosed hemoglobinemia (70 mg/dl), and hemoglobinuria. Prothrombin time, partial thromboplastin time, platelet count, and fibrinogen level were normal. The blood showed minimal abnormalities with only a few schistocytes, target cells, and microspherocytes. There
357 Transfusion July-Aug. 1976
Volume 16
Number4
358
ROTHMAN, ET AL.
was no clinical or laboratory evidence of sepsis or of clostridial wound infection. Fluid and bicarbonate therapy was given and the renal function remained normal. Over the following 48 hours, her hematocrit fell to 23.8 per cent without evidence of blood loss. A blood sample obtained a t the onset of the acute hemolytic episode (the tenth postoperative day) showed a weakly positive direct antiglobulin test ( I to 2 + with four different antiglobulin reagents). A serum antibody was detected for the first time which reacted strongly against all eight panel red blood cells tested giving 3 + agglutination in the indirect antiglobulin test; in the auto control, in which the patient’s own red blood cells were incubated with her serum antibody, only a 1 + reaction was noted. The serologic finding of a panagglutinin in a patient with other evidence of autoimmune disease suggested a diagnosis of a u t o i m m u n e hemolytic anemia and steroid therapy was initially considered. However, it was then noted that the patient had been previously phenotyped and found to be negative for the high frequency U antigen. This was confirmed by performing a phenotype on the patient’s pretransfusion blood sample. The antibody detected in the patient’s postreaction serum sample was then further tested against U-negative red blood cells from eight donors and found to be nonreactive with each; it reacted strongly with all U-positive red blood cells tested. A heat eluate performed on the patient’s postreaction red blood cells revealed antibody with anti-U specificity. The pretransfusion serum sample was retested and anti-U could not be detected (by indirect antiglobulin o r enzyme) even after fivefold concentration. The two units of blood received by the patient were both U-positive. One day following the reaction (12 days postoperative), t h e patient’s temperature had returned to normal, gross hemoglobinuria had disappeared and the plasma hemoglobin level returned to zero. The patient had normal levels of direct and indirect reacting bilirubin in her pretransfusion sample which did not rise following the hemolytic episode. By the fifth postreaction day the direct antiglobulin test had become negative and the patient’s serum, containing anti-U, no longer reacted with her own cells indicating the disappearance of transfused U-positive red blood cells. The patient’s reticulocyte count peaked a t 6 per cent and by the sixth postreaction day the hematocrit had risen to 32.6 per cent. A blood sample obtained on the seventh postreaction day continued to show strongly reactive (3+) antibody in the indirect antiglobulin test. The patient was discharged and later samples were not available.
Transfusion July-Aug. 1976
Discussion
An acute hemolytic episode occurring during the first or second week following a blood transfusion should suggest the possibility of a delayed transfusion reaction. In most cases, this diagnosis is easily established by the development of a positive direct and/or indirect antiglobulin test due to an antibody directed against a specific and easily identifiable blood group antigen. The antigens most frequently implicated belong to the Kidd or Rh blood group^.^ However, the formation of multiple antibodies is not uncommon and when this occurs the laboratory findings may suggest a panagglutinin and lead to the incorrect diagnosis of autoimmune hemolytic anemia.3 The unusual occurrence of an antibody against a high incidence antigen can also be misleading, as illustrated by the case reported herein. In this patient, the antibody responsible for the delayed hemolytic transfusion reaction, anti-U, reacts with the red blood cells of virtually all Caucasians and 99 per cent of all Blacks.’* An antibody of this nature, when tested against a routine panel of cells, may appear to be a panagglutinin and, thus, falsely suggest a diagnosis of idiopathic autoimmune hemolytic disease. It is most important to be able to differentiate between a delayed transfusion reaction and an acute onset of autoimmune hemolytic disease because of the differences in treatment and in prognosis. In the present case, the initial laboratory evaluation suggested the presence of a panagglutinin, and a diagnosis of autoimmune hemolytic anemia seemed to be all the more plausible because of this patient’s known propensity for developing autoimmune phenomena. The initiation of high dose prednisone therapy was strongly considered at that time. However, several observations weighed against the diagnosis of autoimmune hemolytic anemia. At the height of the clinical episode, blood smear morphology showed little evidence of the ongoing erythrocyte destruction (spherocytes, schistocytes) that would be expected with a
Volume 16 Number 4
DELAYED HEMOLYSIS DUE TO ANTI-U
fulminant autoimmune hemolytic anemia. This suggested that most of the susceptible cells had by this time been cleared from the circulation. In addition, the patient’s direct antiglobulin test was only weakly positive and her serum antibody produced a strong reaction with all of the U-positive panel red blood cells, but only a weak reaction with the patient’s own red blood cells. This combination of findings suggested that only a portion of the patient’s red blood cell population was subject to immunologic destruction. Such limited destruction was more consistent with a delayed hemolytic transfusion reaction than with acute autoimmune hemolytic anemia. Subsequent evaluation confirmed the presence of a specific isoantibody, anti-U, which had destroyed most of the previously transfused red blood cells, but had no effect on the patient’s own U-negative erythrocy t es. Identification of the antibody in this patient was aided by the knowledge that she was U-negative. This illustrates the importance of determining the blood group phenotype on a pretransfusion sample when trying to characterize an unusual antibody. The demonstration of a specific antibody confirmed the relationship to transfusion therapy and avoided the multiple hazards of steroid therapy which might otherwise have been administered. In addition, because of the self-limited hemolysis associated with incompatible t ran sfusion, steroids ad min istered at that time would have given the false impression of a therapeutic response. This might have resulted in the unwarranted continued use of predisone to prevent a hemolytic recurrence. Evidence for an antibody-mediated hemolytic episode in this patient appears to be unequivocal. However, the fall i n hematocrit from 36.1 to 23.8 per cent was more than could be accounted for by destruction of the two units of U-positive red blood cells she had received. This excessive fall in hematocrit may have been due, in part, to frequent phlebotomy for laboratory tests or
359
unrecognized occult blood loss in a patient who was chronically/ill and presumably could not rapidly replace blood loss. At the time of the hemolytic reaction, she was not receiving any drug known to be associated with a Coombs’-positive hemolytic anemia. The latent period between the time of transfusion and the onset of overt hemolysis was 1 1 days, a relatively long interval for an anamnestic response. Delayed transfusion reactions normally occur within ten dayslo but there have been reports of a delay up to 14 days.s The patient described here had almost certainly been exposed to U-positive blood at the time of her previous transfusions and the reaction therefore probably represented an anamnestic rather than a primary antibody response. Nonetheless, anti: U antibody could not be demonstrated in the pretransfusion sample even when employing enzyme enhancement and serum concentration techniques. There has been one previous report of antiU causing a delayed hemolytic transfusion r e a c t i ~ n .In~ that case, the latent period was five days and the hemolytic episode was accompanied by acute renal failure. Anti-U has been implicated in several cases of maternal isoimmunization and can be a cause of erythroblastosis fetalis.1*2Auto-anti-U has been reported in the sera of patients with autoimmune hemolytic anemia,” but in the present case the hemolytic episode was clearly that of a delayed transfusion reaction, due to iso-anti-U directed against transfused U-positive red blood cells and not the patient’s own U-negative red blood cells. The patient has been notified that she is Unegative and that she has anti-U antibody. She has been told that she should never again receive U-positive blood whether or not detectable antibody persists in her blood; a subsequent hemolytic reaction could be potentially more severe. The patient has been advised to carry a card defining the nature of her antibody. The possibility of maintaining several units of her own blood in frozen storage for emergency use has been
360
ROTHMAN, ET AL.
discussed and, in addition, family members will be phenotyped to see if any could serve as potential donors should the need arise. Acknowledgment We wish to express our thanks to Mr. Wallace Mook for his technical assistance in evaluating this case and to Ms. Mary Ann Gralnick for having maintained the repository of frozen U-negative cells which helped to establish the diagnosis. We would also like to thank Dr. Ronald Khan of the Diabetes Branch of the National Institutes of Arthritis, Metabolism and Digestive Diseases for having provided theopportunity to study this patient.
References 1. Afonso, J. F., and R. R. de Alvarez: Maternal isosensitization to the red cell antigen U. Am. J. Obstet. Gynecol. 81:45, 1961. 2. Burki, U., T. J. Degnan, and R. E. Rosenfield: Stillbirth due to anti-U. Vox Sang. 9:209, 1964. 3. Croucher, B. E., M. C. Crookston, and J. H. Crookston: Delayed hemolytic transfusion reactions simulating autoimmune hemolytic anemia. Vox Sang. 12:32, 1967. 4. Field, J. B., P. Johnson, and B.-Herring: Insulinresistant diabetes associated with increased endogenous plasma insulin followed by complete remission. J. Clin. Invest. 40:1672, 1961. 5 . Flier, J. S., C. R. Kahn, J. Roth, and R. S. Bar: Circulating antibodies that impair insulin receptor binding in patients with an unusual diabetic syndrome and extreme insulin resistance. Science (in press).
Transfusion July-Aug. 1976
6. Holland, P. V., and R. 0. Wallerstein: Delayed hemolytic transfusion reaction with acute renal failure. JAMA 204:1007, 1968. 7. Howard, P. L.: Delayed hemolytic transfusion reactions. Ann. Clin. Lab. Sci. 3:13, 1973. 8. Kahn, C. R., R. S. Bar, P. Gorden, and J. Roth: The syndrome of extreme insulin resistance and acanthosis nigricans: a primary insulin receptor defect in man. Clin. Res. 23:324a, 1975. 9. Meltz, D. J., D. S. David, J. F. Bertles, and A. C. De Ciutiis: Delayed hemolytic transfusion reaction with renal failure. Lancet II:1348, 1971. 10. Mollison, P. L.: Blood Transfusion in Clinical Medicine, 5th ed. Oxford, Blackwell, 1972, p. 559. 11. Nugent M. E., K. I. Colledge, and W. L. Marsh: Autoimmune hemolytic anemia caused by antiU. Vox Sang. 20:519, 1971. 12. Weiner, A. S., L. J. Unger, and L. Cohen: Distribution and heredity of blood factor U. Science 119:734, 1954.
I. K. Rothman, Clinical Associate, Blood Bank Department, National Institutes of Health, Bethesda, Maryland 20014 (Current address: Department of Hematology, New York University Medical Center, 550 First Avenue, New York, N.Y. 10016). H. J. Alter, Chief Immunology Section, Clinical Center Blood Bank, National Institutes of Health (Reprint requests). G. J. Strewler, Clinical Associate, Laboratory of Kidney and Electrolyte Metabolism, National Institutes of Health.
