Fatal Delayed Hemolytic Transfusion Reaction due to Anti-c
+E
N . M. HILLMAN From the Deparimeni of Pathology, Mount Sinai School of Medicine of the City University of New York and City Hospital Center at Elmhurst, Depariment of Pathology, Elmhursi, New York
A 'IZyear-old man with a peptic ulcer received seven units of apparently compatible red blood cells. Six days after the last unit, be had a hemolytic transfusion reaction manifested by high fever, marked fall in hematocrlt, hemoglobinemln, hemoglobinuria, severe bllirublnemb and oliguria. He went on to become uremk, hyperkalemk, anuric and died five days later. Serologic studies showed that the donor and recipient bloods were completely compatible prior to the transfusions and that unexpected antibodies were not detected. The anamnestic response fiom donor antigens was precipitous even after a latent period of six days.
DELAYED hemolytic transfusion reaction is the result of delayed anamnestic alloantibody response four to 14 days after transfusion of apparently compatible Most delayed hemolytic transfusion reactions are very mild and may not be recognized clinically.'*'* Some are manifested only by anemia.'P6 Only a few are severe enough to induce a massive hemolytic reaction followed by frank renal fail~re.~"O The case to be reported is the first fatal delayed hemolytic transfusion reaction, with acute renal failure, due to anti-c(hr') and antiE(rh"). Case Report
A 72-year-old white man with a duodenal ulcer was brought to the emergency room because of massive upper gastrointestinal bleeding. He had a similar episode 20 years previously, at which time several units of blood were required. He probably received blood when he underwent splenectomy 14 years previously for ruptured spleen following abdominal trauma. Except for mild emphysema and congestive heart failure, he had been in reasonably good health. At the time of admission he was pale and restless, but alert and cooperative. His hemoglobin was 6.9 g/dl, but his blood urea nitrogen (BUN) was 81 mg/dl. Endoscopy disclosed an actively bleeding prepyloric ulcer. His blood type was 0 Received for publication May IS, 1978; accepted August 22, 1978.
Rh positive, and his serum was negative for unexpected antibodies when tested against two different panels of commercial reagent red blood cells by saline, albumin, enzyme and indirect antiglobulin tests. Nine units of blood were matched by saline, albumin, and indirect antiglobulin tests, and all were found to be fully compatible. One unit of red blood cells was given before an operation during which the ulcer was ligated and a truncal vagotomy and pyloroplasty were performed. He received four units of blood during surgery, and two units immediately postoperative. N o immediate or early reactions were noted from this blood. The immediate postoperative period was uneventful. The patient's hemoglobin was 10.3 g/dl and his blood urea nitrogen was now only 15 mg/dl. The elevated BUN at the time of admission was assumed to have been prerenal. On the sixth postoperative day, he developed a sudden fever 104.8 F and became cyanotic with acute respiratory distress. Chest x-ray showed pulmonary congestion, but his electrocardiogram was unchanged. Blood pH was 7.4, and Po, was 52. The patient was intubated, placed in a respirator, and treatment with sodium cephalothin (2 g every 6 hours) was started. He was also treated with aminophyllin and digoxin. Later in the day he became deeply jaundiced and his urine was found to be dark red. His hemoglobin was now 7 g/dl, plasma haptoglobin 26 mg/dl, plasma hemoglobin 90 mg/dl, and his total bilirubin was 32 mg/dl. Plasma myoglobin was found in only a trace amount. Blood smear contained many nucleated red blood cells, numerous microspherocytes, marked polychromasia, and a few schistocytes. Reticulocytes were 2.1 per cent. Urine was strongly positive for hemoglobin with a small amount of bile and urobilinogen, but the urinary sediment was devoid of red blood cells. A fresh blood sample was obtained and was typed as 0 Rh positive, but had a positive direct antiglobulin test. There was no convincing evidence of significant disseminated intravascular coagulation or fibrinolysis. The patient did not respond to intravenous fluids and lasix (furosemide) so peritoneal dialysis was done.
0041-1 132/79/0900/0548 $00.70 0 J. B. Lippincott Co. Transfusion September-October 1979
548
Volume 19 Number 5
549
FATALDELAYEDREACTION
Volume 19
Number 5
-
FIG. 1 . Patient's course detailing the effect of delayed hemolytic transfusion reaction on the sixth post-transfusion d a y . Hemoglobin (right axis) rose in response to compatible transfusion on day nine, but anuria occurred on day eight, followed by death on the eleventh day.
E
I3
a
I3
LI
0
o
-
Unitc+€neo
I I
I
W
z U
3
DAYS The next day the patient was afebrile, but moderate wheezing continued. He was anuric, and his hemoglobin had fallen to 4.8 ddl. At this time he received three units of compatible deglycerolized red blood cells that elevated his hemoglobin to 7.2 ddl. He was in poor condition, acidotic, in pulmonary edema, and stuporous. Finally he became hypotensive and died. The patient's course is summarized in Figure 1 and Table 1. Postmortem examination showed a sutured chronic peptic ulcer, pyloroplasty and gastrostomy. There was evidence of emphysema and microscopic bronchopneumonia. The liver was fatty with focal hepatic cell necrosis; bile thrombi were in canaliculi, but there was no obstruction of the major and common bile ducts. Mild left
ventricular hypertrophy and generalized arteriosclerosis were noted. In the kidneys, mild arteriolosclerosis was found and the distal tubules contained pigmented benzidine positive, hemoglobin casts. The Bureau of Biologics and FDA were notified of the fatal outcome of this delayed hemolytic transfusion reaction.
Serologic Studies A specimen of blood from this patient obtained eight days after the last unit of transfused blood, was typed as 0 Rh positive, and strong agglutination was noticed when his serum was tested against two different panels of reagent red blood cells. Anti-E (1: 16) and anti-c ( 1 5 4 ) were identified in the patient's serum. Both antibodies were
Table 1. Laboratory Data Not Shown in Figure 1
1' 6t 7 8 9 10 11
-
-
32
2 2.2 4.9 6.1 6.1 6.1
50 55
53
-
Transfusion of seven units of apparently compatible blood.
4.1 3.5 4.6 5.1 5.4 5.1
81 15 25 44 56 74
4.2 3.9
a4 109
t Delayed hemolytic episode.
HILLMAN
550
active by saline, albumin, enzyme and indirect antiglobulin techniques. No other unexpected antibodies were detected. The direct antiglobulin test was strongly positive with specific IgG reagent, but not all of the cells were agglutinated. An ether eluate16was prepared and found to contain anti-E and anti-c agglutinins reactive by saline, enzyme and indirect antiglobulin tests. The patient's red blood cells were Kell negative and Jk(a-). The three units of deglycerolized red blood cells, all RIRl, Kell negative, and Jk(a-), were compatible and were administered. The pretransfusion specimen of this patient was no longer available having been discarded on the seventh day. Samples of all donor bloods administered were available. All were c positive and three were E positive. Discussion Delayed hemolytic transfusion reactions, although infrequent, are hazardous complications of blood transfusion therapy. Many different kinds of antibodies have been reAnti-Jka has acsponsible. 1A-7.1OJ1J3-15 counted for more than one-third of the reported rea~ti0ns.I~ Multiple antibodies have been observed in 38 per cent of cases.17 Serologic incompatibility was not demonstrated prior to transfusion. In some cases, no antibodies were identified although shortened life span of the transfused red blood cells could be demonstrated by 51Crtagging., Acute hemolytic transfusion reactions may occur soon after the transfusion of incompatible blood. ABO incompatibility is the commonest ~ a u s e ~ *and - ' ~ this type of reaction is alleged to carry a mortality rate of 50 per cent in spite of major advances in management and therapy.3*4*12*17 Acute renal failure with tubular necrosis usually complicates these fatal reactions. Although acute tubular necrosis is reversible, patients with this complication require prolonged treatment and the mortality rate remains at 50 per cent.3 Complexes of antibody with erythrocytic membrane blood group antigens have been reported to induce renal failure." A current hypothesise suggests that persistant renal vascular constriction may be secondary to actual tubular necrosis.
Transfusion September-October 1979
Acute renal failure with tubular necrosis may complicate delayed hemolytic transfusion r e a c t i o n ~ . ~Death ~ , ' ~ due solely to delayed hemolytic transfusion reaction has not been reported, but death has been associated in three patients with serious underlying disease.I3 The delayed hemolytic reaction in these patients seems to have complicated an underlying disease.13 In one of these three patients acute renal failure occurred and the antibody involved was antiKell.13 Delayed hemolytic transfusion reaction due to combination of anti-c + E has been reported, but was unrelated to either renal failure or death.13 Low Po, seen as one of the early manifestations of this patient's delayed transfusion reaction is probably due to his pre-existing mild emphysema. A peculiar feature of the case now reported was severe hyperbilirubinemia (55 mg/dl) in which 90per cent of the serum bilirubin was conjugated. Elevated unconjugated bilirubinemia has been reported in certain adults with apparently normal hepatic function following acute hemolytic reaction to blood transfusion,* but conjugated bilirubinemia this high is unusual. Acknowledgment The author is indebted to Dr. Richard E. Rosenfield for his interest and helpful suggestions and review of the manuscript. The author is also grateful to Miss Gloria Ffolkes for technical assistance, Mrs. Haniet Goldfarb for administrative assistance, Miss Julia Mann of Diagnostic Division of Ptizer. Connecticut for confirmation of antibody specificity, and in particular, to Mr. W. L. Marsh and his staffof the New York Blood Center, for their serological help both in diagnosis and in providing compatible blood.
1.
References Croucher. B. E. E., M. C. Crookston, and J. H.
Crookston: Delayed hemolytic transfusion reactions simulating auto-immune hemolytic anemia. Vox Sang. 12:32, 1%7. 2. Fudenberg, H., and F. H. Allen, Jr.: Transfusion reactions in the absence of demonstrable incompatibility. N. Engl. J. Med. 2561180, 1957. 3. Goldfinger. D.: Acute hemolytic transfusion reactions-a fresh look at pathogenesis and
Volume 19
Number 5
FATAL DELAYED REACTION
considerations regarding therapy. Transfusion 17:85, 1977. 4. Greenwalt, T. J.: General Principles of Blood Transfusions. Chicago, American Medical Association, 1973,p. 11. 5. Holland, P. V., and R. 0. Wallerstein: Delayed hemolytic transfusion reaction with acute renal failure. JAMA u)I:1007, 1968. 6. Howard, P. L.: Delayed hemolytic transfusion reactions. Ann. Clin. Lab. Sci. 3:13, 1973. 7. Issitt, P. D.,and C. H.Issitt: Applied Blood Group Serology, 2nd ed. Oxnard, Spectra Biologicals, 1975,p. 287. 8. Lester, R.: Causes of postoperative jaundice. Am. J. Surg. 116342, 1968. 9. Levinsky. N. G.: Pathophysiology of acute renal failure. N. Engl. J. Med. 2%:1453, 1977. 10. Meltz, D. J., D. S. David, J. F. Bertles, and A. C. DeCiutiis: Delayed hemolytic transfusion reaction with renal failure. Lancet 11: 1348,1971. 11. Mollison, P. L.: Blood Transfusion in Clinical Medicine, 5th ed. Oxford, Blackwell Scientific, 1972,p. 559. 12. Myhre, B., and W. Worthen: Untoward response to blood transfusion. In: Blood Banking for
55 1
the Hospital Laboratory. Chicago, Am. SOC. Clin. Pathol. 1977,p. 73. 13. Pineda, A. A.. H. F. Taswell, and S. M.Brzic, Jr.: Delayed hemolytic transfusion reaction: An immunologic hazard of blood transfusion. Transfusion 181, 1978. 14. Rosenfield, R. E.: Immunohematology Syllabus. New York, Intercontinental Medical Book Corp., 1974,p. 99. 15. Rothman, I. K.,H. J. Alter and G. J. Strewlew: Delayed overt hemolytic transfusion reaction due toanti-U antibody. Transfusion 16357,1976. 16. Rubin, H.: Antibody elution from red blood cells. J. Clin. Pathol. 1670, 1963. 17. Schmidt, P. J., and P. V. Holland: Pathogenesis of the acute renal failure associated with incompatible transfusion. Lancet 1k1169, 1%7. 18. Solanki, D., and P. R. McCurdy: Delayed hemolytic transfusion reactions, an often-missed entity. JAMA 239:729, 1978.
Nosrat M. Hillman, M.D., Director of Blood Bank, City Hospital Center at Elmhurst, 79-01 Broadway, Elmhurst, New York 11373.
+E
N . M. HILLMAN From the Deparimeni of Pathology, Mount Sinai School of Medicine of the City University of New York and City Hospital Center at Elmhurst, Depariment of Pathology, Elmhursi, New York
A 'IZyear-old man with a peptic ulcer received seven units of apparently compatible red blood cells. Six days after the last unit, be had a hemolytic transfusion reaction manifested by high fever, marked fall in hematocrlt, hemoglobinemln, hemoglobinuria, severe bllirublnemb and oliguria. He went on to become uremk, hyperkalemk, anuric and died five days later. Serologic studies showed that the donor and recipient bloods were completely compatible prior to the transfusions and that unexpected antibodies were not detected. The anamnestic response fiom donor antigens was precipitous even after a latent period of six days.
DELAYED hemolytic transfusion reaction is the result of delayed anamnestic alloantibody response four to 14 days after transfusion of apparently compatible Most delayed hemolytic transfusion reactions are very mild and may not be recognized clinically.'*'* Some are manifested only by anemia.'P6 Only a few are severe enough to induce a massive hemolytic reaction followed by frank renal fail~re.~"O The case to be reported is the first fatal delayed hemolytic transfusion reaction, with acute renal failure, due to anti-c(hr') and antiE(rh"). Case Report
A 72-year-old white man with a duodenal ulcer was brought to the emergency room because of massive upper gastrointestinal bleeding. He had a similar episode 20 years previously, at which time several units of blood were required. He probably received blood when he underwent splenectomy 14 years previously for ruptured spleen following abdominal trauma. Except for mild emphysema and congestive heart failure, he had been in reasonably good health. At the time of admission he was pale and restless, but alert and cooperative. His hemoglobin was 6.9 g/dl, but his blood urea nitrogen (BUN) was 81 mg/dl. Endoscopy disclosed an actively bleeding prepyloric ulcer. His blood type was 0 Received for publication May IS, 1978; accepted August 22, 1978.
Rh positive, and his serum was negative for unexpected antibodies when tested against two different panels of commercial reagent red blood cells by saline, albumin, enzyme and indirect antiglobulin tests. Nine units of blood were matched by saline, albumin, and indirect antiglobulin tests, and all were found to be fully compatible. One unit of red blood cells was given before an operation during which the ulcer was ligated and a truncal vagotomy and pyloroplasty were performed. He received four units of blood during surgery, and two units immediately postoperative. N o immediate or early reactions were noted from this blood. The immediate postoperative period was uneventful. The patient's hemoglobin was 10.3 g/dl and his blood urea nitrogen was now only 15 mg/dl. The elevated BUN at the time of admission was assumed to have been prerenal. On the sixth postoperative day, he developed a sudden fever 104.8 F and became cyanotic with acute respiratory distress. Chest x-ray showed pulmonary congestion, but his electrocardiogram was unchanged. Blood pH was 7.4, and Po, was 52. The patient was intubated, placed in a respirator, and treatment with sodium cephalothin (2 g every 6 hours) was started. He was also treated with aminophyllin and digoxin. Later in the day he became deeply jaundiced and his urine was found to be dark red. His hemoglobin was now 7 g/dl, plasma haptoglobin 26 mg/dl, plasma hemoglobin 90 mg/dl, and his total bilirubin was 32 mg/dl. Plasma myoglobin was found in only a trace amount. Blood smear contained many nucleated red blood cells, numerous microspherocytes, marked polychromasia, and a few schistocytes. Reticulocytes were 2.1 per cent. Urine was strongly positive for hemoglobin with a small amount of bile and urobilinogen, but the urinary sediment was devoid of red blood cells. A fresh blood sample was obtained and was typed as 0 Rh positive, but had a positive direct antiglobulin test. There was no convincing evidence of significant disseminated intravascular coagulation or fibrinolysis. The patient did not respond to intravenous fluids and lasix (furosemide) so peritoneal dialysis was done.
0041-1 132/79/0900/0548 $00.70 0 J. B. Lippincott Co. Transfusion September-October 1979
548
Volume 19 Number 5
549
FATALDELAYEDREACTION
Volume 19
Number 5
-
FIG. 1 . Patient's course detailing the effect of delayed hemolytic transfusion reaction on the sixth post-transfusion d a y . Hemoglobin (right axis) rose in response to compatible transfusion on day nine, but anuria occurred on day eight, followed by death on the eleventh day.
E
I3
a
I3
LI
0
o
-
Unitc+€neo
I I
I
W
z U
3
DAYS The next day the patient was afebrile, but moderate wheezing continued. He was anuric, and his hemoglobin had fallen to 4.8 ddl. At this time he received three units of compatible deglycerolized red blood cells that elevated his hemoglobin to 7.2 ddl. He was in poor condition, acidotic, in pulmonary edema, and stuporous. Finally he became hypotensive and died. The patient's course is summarized in Figure 1 and Table 1. Postmortem examination showed a sutured chronic peptic ulcer, pyloroplasty and gastrostomy. There was evidence of emphysema and microscopic bronchopneumonia. The liver was fatty with focal hepatic cell necrosis; bile thrombi were in canaliculi, but there was no obstruction of the major and common bile ducts. Mild left
ventricular hypertrophy and generalized arteriosclerosis were noted. In the kidneys, mild arteriolosclerosis was found and the distal tubules contained pigmented benzidine positive, hemoglobin casts. The Bureau of Biologics and FDA were notified of the fatal outcome of this delayed hemolytic transfusion reaction.
Serologic Studies A specimen of blood from this patient obtained eight days after the last unit of transfused blood, was typed as 0 Rh positive, and strong agglutination was noticed when his serum was tested against two different panels of reagent red blood cells. Anti-E (1: 16) and anti-c ( 1 5 4 ) were identified in the patient's serum. Both antibodies were
Table 1. Laboratory Data Not Shown in Figure 1
1' 6t 7 8 9 10 11
-
-
32
2 2.2 4.9 6.1 6.1 6.1
50 55
53
-
Transfusion of seven units of apparently compatible blood.
4.1 3.5 4.6 5.1 5.4 5.1
81 15 25 44 56 74
4.2 3.9
a4 109
t Delayed hemolytic episode.
HILLMAN
550
active by saline, albumin, enzyme and indirect antiglobulin techniques. No other unexpected antibodies were detected. The direct antiglobulin test was strongly positive with specific IgG reagent, but not all of the cells were agglutinated. An ether eluate16was prepared and found to contain anti-E and anti-c agglutinins reactive by saline, enzyme and indirect antiglobulin tests. The patient's red blood cells were Kell negative and Jk(a-). The three units of deglycerolized red blood cells, all RIRl, Kell negative, and Jk(a-), were compatible and were administered. The pretransfusion specimen of this patient was no longer available having been discarded on the seventh day. Samples of all donor bloods administered were available. All were c positive and three were E positive. Discussion Delayed hemolytic transfusion reactions, although infrequent, are hazardous complications of blood transfusion therapy. Many different kinds of antibodies have been reAnti-Jka has acsponsible. 1A-7.1OJ1J3-15 counted for more than one-third of the reported rea~ti0ns.I~ Multiple antibodies have been observed in 38 per cent of cases.17 Serologic incompatibility was not demonstrated prior to transfusion. In some cases, no antibodies were identified although shortened life span of the transfused red blood cells could be demonstrated by 51Crtagging., Acute hemolytic transfusion reactions may occur soon after the transfusion of incompatible blood. ABO incompatibility is the commonest ~ a u s e ~ *and - ' ~ this type of reaction is alleged to carry a mortality rate of 50 per cent in spite of major advances in management and therapy.3*4*12*17 Acute renal failure with tubular necrosis usually complicates these fatal reactions. Although acute tubular necrosis is reversible, patients with this complication require prolonged treatment and the mortality rate remains at 50 per cent.3 Complexes of antibody with erythrocytic membrane blood group antigens have been reported to induce renal failure." A current hypothesise suggests that persistant renal vascular constriction may be secondary to actual tubular necrosis.
Transfusion September-October 1979
Acute renal failure with tubular necrosis may complicate delayed hemolytic transfusion r e a c t i o n ~ . ~Death ~ , ' ~ due solely to delayed hemolytic transfusion reaction has not been reported, but death has been associated in three patients with serious underlying disease.I3 The delayed hemolytic reaction in these patients seems to have complicated an underlying disease.13 In one of these three patients acute renal failure occurred and the antibody involved was antiKell.13 Delayed hemolytic transfusion reaction due to combination of anti-c + E has been reported, but was unrelated to either renal failure or death.13 Low Po, seen as one of the early manifestations of this patient's delayed transfusion reaction is probably due to his pre-existing mild emphysema. A peculiar feature of the case now reported was severe hyperbilirubinemia (55 mg/dl) in which 90per cent of the serum bilirubin was conjugated. Elevated unconjugated bilirubinemia has been reported in certain adults with apparently normal hepatic function following acute hemolytic reaction to blood transfusion,* but conjugated bilirubinemia this high is unusual. Acknowledgment The author is indebted to Dr. Richard E. Rosenfield for his interest and helpful suggestions and review of the manuscript. The author is also grateful to Miss Gloria Ffolkes for technical assistance, Mrs. Haniet Goldfarb for administrative assistance, Miss Julia Mann of Diagnostic Division of Ptizer. Connecticut for confirmation of antibody specificity, and in particular, to Mr. W. L. Marsh and his staffof the New York Blood Center, for their serological help both in diagnosis and in providing compatible blood.
1.
References Croucher. B. E. E., M. C. Crookston, and J. H.
Crookston: Delayed hemolytic transfusion reactions simulating auto-immune hemolytic anemia. Vox Sang. 12:32, 1%7. 2. Fudenberg, H., and F. H. Allen, Jr.: Transfusion reactions in the absence of demonstrable incompatibility. N. Engl. J. Med. 2561180, 1957. 3. Goldfinger. D.: Acute hemolytic transfusion reactions-a fresh look at pathogenesis and
Volume 19
Number 5
FATAL DELAYED REACTION
considerations regarding therapy. Transfusion 17:85, 1977. 4. Greenwalt, T. J.: General Principles of Blood Transfusions. Chicago, American Medical Association, 1973,p. 11. 5. Holland, P. V., and R. 0. Wallerstein: Delayed hemolytic transfusion reaction with acute renal failure. JAMA u)I:1007, 1968. 6. Howard, P. L.: Delayed hemolytic transfusion reactions. Ann. Clin. Lab. Sci. 3:13, 1973. 7. Issitt, P. D.,and C. H.Issitt: Applied Blood Group Serology, 2nd ed. Oxnard, Spectra Biologicals, 1975,p. 287. 8. Lester, R.: Causes of postoperative jaundice. Am. J. Surg. 116342, 1968. 9. Levinsky. N. G.: Pathophysiology of acute renal failure. N. Engl. J. Med. 2%:1453, 1977. 10. Meltz, D. J., D. S. David, J. F. Bertles, and A. C. DeCiutiis: Delayed hemolytic transfusion reaction with renal failure. Lancet 11: 1348,1971. 11. Mollison, P. L.: Blood Transfusion in Clinical Medicine, 5th ed. Oxford, Blackwell Scientific, 1972,p. 559. 12. Myhre, B., and W. Worthen: Untoward response to blood transfusion. In: Blood Banking for
55 1
the Hospital Laboratory. Chicago, Am. SOC. Clin. Pathol. 1977,p. 73. 13. Pineda, A. A.. H. F. Taswell, and S. M.Brzic, Jr.: Delayed hemolytic transfusion reaction: An immunologic hazard of blood transfusion. Transfusion 181, 1978. 14. Rosenfield, R. E.: Immunohematology Syllabus. New York, Intercontinental Medical Book Corp., 1974,p. 99. 15. Rothman, I. K.,H. J. Alter and G. J. Strewlew: Delayed overt hemolytic transfusion reaction due toanti-U antibody. Transfusion 16357,1976. 16. Rubin, H.: Antibody elution from red blood cells. J. Clin. Pathol. 1670, 1963. 17. Schmidt, P. J., and P. V. Holland: Pathogenesis of the acute renal failure associated with incompatible transfusion. Lancet 1k1169, 1%7. 18. Solanki, D., and P. R. McCurdy: Delayed hemolytic transfusion reactions, an often-missed entity. JAMA 239:729, 1978.
Nosrat M. Hillman, M.D., Director of Blood Bank, City Hospital Center at Elmhurst, 79-01 Broadway, Elmhurst, New York 11373.
