Intravascular
Haemolysis in Association Enterocolitis
With Necrotising
By R. Squire, E. Kiely, D. Drake, and A. Lander London, England l Severe haemolysis tion with necrotising Thomsen-Freidenriech
is an unusual occurrence in associaenterocolitis (NEC). Activation of the (T) antigen on the neonatal erythro-
cytes is proposed as the mechanism. This haemolytic process is precipitated by transfusion with serum-containing blood products, which should therefore be avoided. Once haemolysis has become established
the outcome is usually fatal. This
report describes the management of four neonates who had established haemolysis complicating severe NEC. T activation was confirmed in two infants, but could not be tested for in the other two. Exchange transfusion abolished the haemolysis in two patients,
who survived.
Despite reduced use of
blood products the other two infants died. We believe that exchange transfusion was essential in the successful management of the infants who survived, and recommend early exchange transfusion when haemolysis complicates Copyright
6 1992 by WA
NEC.
Saunders Company
INDEX WORDS: Haemolysis; necrotising antigen; T activation; exchange transfusion.
enterocolitis;
T
I
N 1979, SEGER ET AL drew attention to the risk of haemolysis following transfusion in infants with necrotising enterocolitis (NEC),’ and suggested that the haemolysis was due to activation of the ThomsenFriedenreich antigen (T antigen) on the neonatal erythrocytes. T antigen is present on all human erythrocytes, although not normally expressed.2 Neuraminidase, which removes N-ace@ neuraminic acid residues from the antigen, can cause T antigen expression. This T activation can occur in vivo due to neuraminidase secreted by a number of microorganisms, most commonly clostridia.3 Anti-T antibody is present in adult serum, although not in the serum of infants under the age of 6 months.4 If an infant with T activation secondary to clostridial infection were to be transfused with adult donor blood products containing anti-T, haemolysis might be anticipated. Seger et al reported T activation in the blood of a neonate with
From the Hospital for Sick Children and Queen Elizabeth Hospital for Children, London, England. Presented at the 38th Annual International Congress of the British Association of Paediatrii Surgeons, Budapest, Hungary, July 24-26, 1991. Address reprint requests to R. Squire, FRCS, Department of Paediahic Surgery, Hospital for Sick Children, Great Orrnond St, London WCIN 3JH, England. Copyright Q 1992 by WB. Saunders Company 0022-3468/92/2707-00000/0 808
UMridiumperj?ingens bacteraemia secondary to NEC, in whom blood transfusion caused haemolysis. This association has been reported sporadically, and its pathogenesis apparently confirmed.5-7 T activation has been identified surprisingly frequently, especially in neonates with severe NEC.8 However, haemolysis complicating NEC has proved difficult to treat. We describe four infants with haemolysis complicating severe NEC, and report the successful use of exchange transfusion in their management. CASE REPORTS Case 1 A full-term female infant was born with bladder exstrophy, which was closed during the first day of life. Two days later she developed NEC, with early intestinal perforation. Following resuscitation with blood and plasma protein fraction (PPF), a laparotomy was performed, with resection of the most severely affected bowel. Massive intravascular haemolysis ensued, and T activation was suspected, but the laboratory test for confirmation was not available. Despite avoidance of further plasma-containing transfusions, the haemolysis continued unabated and the infant died within 24 hours.
Case 2 A full-term male infant developed perforated NEC at 4 days of age. Following resuscitation with blood and fresh frozen plasma (FFP), he developed signs of haemolysis. Confirmation of T activation was still unavailable. Despite the severe haemolysis a higher priority was given to treatment of the perforated bowel. An emergency laparotomy was performed, with intestinal resection and primary anastomosis. Postoperatively exchange transfusions were commenced, using standard plasma-reduced blood. The haemolytic process stopped immediately, without subsequent relapse. A total exchange volume of 1,420 mL was required to bring the serum bilirubin to below 300 umol/L (peak level, 546 umol/L). The infant recovered, but at 1 year of age he has athetoid cerebral palsy and is deaf, almost certainly secondary to kernicterus. Case
3
A full-term male infant presented with severe NEC at 36 hours of age. He developed haemoglobinuria during transfer to our unit. There was no record of blood product administration, but T activation was confirmed by the peanut lectin agglutination test.g As he was becoming increasingly jaundiced, an exchange transfusion was performed prior to surgery. A 400-mL exchange was carried out, using packed cells resuspended in saline-adenineglucose-mannitol (SAGM blood). During the exchange the haemolysis stopped, and the serum bilirubin fell from 410 to 318 umol/L. A laparotomy confirmed perforated NEC and two resections with primary anastomoses were carried out. An intraoperative platelet transfusion did not cause further haemolysis and the serum bilirubin continued to fall. The infant made a complete recovery. Peritoneal cultures grew clostridia and Enterococcus. JournalofPediafric Surgery, Vol27, No
7
(July), 1992: pp 808-810
HAEMOLYTIC
NECROTISING
ENTEROCOLITIS
Case 4 A 30-day-old infant boy who had been born at 30 weeks’ gestation was transferred with perforated NEC. Blood and FFP were administered prior to transfer. Upon arrival, T activation was identified, and mild haemolysis was observed on laboratory blood specimens. Further resuscitation was therefore carried out using only human albumin solution. A laparotomy showed extensive NEC, which was treated by resection and stoma formation. Intraoperative transfusion with maximally plasma-reduced (hardpacked) blood was without complication. Postoperatively he developed a severe coagulopathy, with major haemorrhage, requiring treatment with FFP and cryoprecipitate. Though the bleeding stopped, severe haemolysis ensued, the haemoglobin decreasing from 10.9 g/dL to 4.4 g/dL in a few hours. The infant died before an exchange transfusion could be effected. DISCUSSION The four cases we report reflect a learning process in the management of intravascular haemolysis complicating NEC. Infant 1 died rapidly following the onset of the haemolysis. In case 2 the haemolysis was recognised early, but surgical intervention to treat the perforation was given higher priority. Despite a successful surgical outcome, the infant progressed to develop kernicterus. In the third case previous experience indicated that exchange transfusion should precede the surgery. The exchange was associated with an immediate reduction in the haemolytic process, and this improvement persisted despite the continued presence of gangrenous, perforated bowel. The sustained remission of the haemolysis in infant 3 suggests that preoperative exchange in case 2 might have stopped the haemolysis earlier. Case 4 presented a different situation. In this infant there was proven T activation, but only mild haemolysis. The aim of management in this child was to treat the NEC without precipitating further haemolysis. Successful management of these cases has been accomplished by limiting transfusions to washed cells, human albumin solution, or low anti-T titre blood products*; maximally plasma-reduced (‘hard-packed’) blood products may be used as a last resort. In this patient the perioperative period was successfully negotiated using “hard-packed” blood, without increasing the haemolysis. The development of a severe coagulopathy introduced a dilemma, since the required infusions contained the anti-T antibody. The best alternative, low anti-T titre FFP (taken from low anti-T donors), requires special preparation, and is seldom available at short notice. The administration of FFP and cryoprecipitate stopped the bleeding, but caused lethal haemolysis. In retrospect, we suggest that the clotting agents should have been given as part of an exchange transfusion. In a recent large prospective trial of admissions to a neonatal intensive care unit, 11% of those with NEC
809
showed T activation, increasing to 28% in the subgroup that required surgical treatment. This compared with 0.1% having T activation out of all other neonatal admissions.* Prevention is better than cure, and a policy of early detection of T activation, followed by measures to avoid haemoiysis is reported to reduce the risks. Therefore, the peanut lectin agglutination test should be performed on all infants with a diagnosis of NEC,9 or when there is a strong suspicion of this diagnosis. It is cheap, effective, simple, rapid, and easily available. Although no recommendations have been made for the treatment of established haemolysis, the theoretical use of exchange transfusion has been discussed.’ Three cases have been reported in which exchange transfusion has been carried out for haemolysis complicating severe NEC. 6,8 On two occasions this was late in the course of the disease, and the infants died. In the third case the exchange was performed early, for hyperbilirubinaemia. The high level of T activation identified in this infant was reduced following exchange transfusion, and the infant survived. Including the cases in this report, exchange transfusion has now been performed early in the course of this disease in three infants, of whom two had confirmed T activation. On each occasion the haemolysis was controlled and the infant survived. The mechanism by which exchange transfusion works is not entirely certain. The transfusion may simply replace T activated erythrocytes with donor cells not expressing the antigen. This would reduce the percentage of cells showing T activation, though would not be expected to remove them completely. Also, the exchange may reduce the anti-T levels in the serum. It is unlikely that this alone is responsible, since the exchange in our second case was carried out using standard packed cells, which almost certainly contained significant quantities of anti-T. Our experience suggests that early exchange transfusion should be considered in the treatment of haemolysis complicating severe NEC, using washed cells resuspended in 4.5% human albumin, or SAGM blood. If these products are not rapidly available, we would recommend exchanging with packed cells. It may be appropriate to perform the exchange transfusion before operation. In the rare circumstance in which FFP or cryoprecipitate is essential, in the presence of activation, we suggest that these agents should be given as part of an exchange transfusion. The value of blood products from selected low anti-T donors may be paramount in this situation. Consideration should be given to keeping a limited store of low titre FFP in all centres where a substantial number of cases of severe NEC are treated.
810
SQUIRE
ET AL
REFERENCES 1. Seger R, Joller P, Kenny A, et al: Potential hazards of blood transfusion in clostridia-associated necrotising enterocolitis. Lancet 1:48-49,1979 2. Friedenreich V: The Thomsen Hemagglutination Phenomenon. Copenhagen, Denmark, Levin and Munksgaard, 1930 3. Seger R, Joller P, Bird GWG, et al: Necrotising enterocolitis and neuraminidase-producing bacteria. Helv Paediatr Acta 35:121128,198O 4. Kim YD, Prakash U, Weber GF, et al: Nature of human serum blood group T antibodies. Immunol Commun 8:397-406, 1979
5. Seger RA, Kenny A, Bird GWG, et al: Pediatric surgical patients with severe anaerobic infection: Report of 16 T-antigen positive cases and possible hazards of blood transfusion. J Pediatr Surg 16905910,198l 6. Novak RW: Bacterial-induced rbc alterations complicating necrotizing enterocolitis. Am J Dis Child 138:183-185,1984 7. Placzek MM, Gorst DW: T activation haemolysis and death after blood transfusion. Arch Dis Child 62743-744, 1987 8. Williams RA, Brown EF, Hurst D, et al: Transfusion of infants with activation of erythrocyte T antigen. J Pediatr 115:949953,1989 9. Bird GWG: Anti-T in peanuts. VOXSang 9:748-749,1964
Haemolysis in Association Enterocolitis
With Necrotising
By R. Squire, E. Kiely, D. Drake, and A. Lander London, England l Severe haemolysis tion with necrotising Thomsen-Freidenriech
is an unusual occurrence in associaenterocolitis (NEC). Activation of the (T) antigen on the neonatal erythro-
cytes is proposed as the mechanism. This haemolytic process is precipitated by transfusion with serum-containing blood products, which should therefore be avoided. Once haemolysis has become established
the outcome is usually fatal. This
report describes the management of four neonates who had established haemolysis complicating severe NEC. T activation was confirmed in two infants, but could not be tested for in the other two. Exchange transfusion abolished the haemolysis in two patients,
who survived.
Despite reduced use of
blood products the other two infants died. We believe that exchange transfusion was essential in the successful management of the infants who survived, and recommend early exchange transfusion when haemolysis complicates Copyright
6 1992 by WA
NEC.
Saunders Company
INDEX WORDS: Haemolysis; necrotising antigen; T activation; exchange transfusion.
enterocolitis;
T
I
N 1979, SEGER ET AL drew attention to the risk of haemolysis following transfusion in infants with necrotising enterocolitis (NEC),’ and suggested that the haemolysis was due to activation of the ThomsenFriedenreich antigen (T antigen) on the neonatal erythrocytes. T antigen is present on all human erythrocytes, although not normally expressed.2 Neuraminidase, which removes N-ace@ neuraminic acid residues from the antigen, can cause T antigen expression. This T activation can occur in vivo due to neuraminidase secreted by a number of microorganisms, most commonly clostridia.3 Anti-T antibody is present in adult serum, although not in the serum of infants under the age of 6 months.4 If an infant with T activation secondary to clostridial infection were to be transfused with adult donor blood products containing anti-T, haemolysis might be anticipated. Seger et al reported T activation in the blood of a neonate with
From the Hospital for Sick Children and Queen Elizabeth Hospital for Children, London, England. Presented at the 38th Annual International Congress of the British Association of Paediatrii Surgeons, Budapest, Hungary, July 24-26, 1991. Address reprint requests to R. Squire, FRCS, Department of Paediahic Surgery, Hospital for Sick Children, Great Orrnond St, London WCIN 3JH, England. Copyright Q 1992 by WB. Saunders Company 0022-3468/92/2707-00000/0 808
UMridiumperj?ingens bacteraemia secondary to NEC, in whom blood transfusion caused haemolysis. This association has been reported sporadically, and its pathogenesis apparently confirmed.5-7 T activation has been identified surprisingly frequently, especially in neonates with severe NEC.8 However, haemolysis complicating NEC has proved difficult to treat. We describe four infants with haemolysis complicating severe NEC, and report the successful use of exchange transfusion in their management. CASE REPORTS Case 1 A full-term female infant was born with bladder exstrophy, which was closed during the first day of life. Two days later she developed NEC, with early intestinal perforation. Following resuscitation with blood and plasma protein fraction (PPF), a laparotomy was performed, with resection of the most severely affected bowel. Massive intravascular haemolysis ensued, and T activation was suspected, but the laboratory test for confirmation was not available. Despite avoidance of further plasma-containing transfusions, the haemolysis continued unabated and the infant died within 24 hours.
Case 2 A full-term male infant developed perforated NEC at 4 days of age. Following resuscitation with blood and fresh frozen plasma (FFP), he developed signs of haemolysis. Confirmation of T activation was still unavailable. Despite the severe haemolysis a higher priority was given to treatment of the perforated bowel. An emergency laparotomy was performed, with intestinal resection and primary anastomosis. Postoperatively exchange transfusions were commenced, using standard plasma-reduced blood. The haemolytic process stopped immediately, without subsequent relapse. A total exchange volume of 1,420 mL was required to bring the serum bilirubin to below 300 umol/L (peak level, 546 umol/L). The infant recovered, but at 1 year of age he has athetoid cerebral palsy and is deaf, almost certainly secondary to kernicterus. Case
3
A full-term male infant presented with severe NEC at 36 hours of age. He developed haemoglobinuria during transfer to our unit. There was no record of blood product administration, but T activation was confirmed by the peanut lectin agglutination test.g As he was becoming increasingly jaundiced, an exchange transfusion was performed prior to surgery. A 400-mL exchange was carried out, using packed cells resuspended in saline-adenineglucose-mannitol (SAGM blood). During the exchange the haemolysis stopped, and the serum bilirubin fell from 410 to 318 umol/L. A laparotomy confirmed perforated NEC and two resections with primary anastomoses were carried out. An intraoperative platelet transfusion did not cause further haemolysis and the serum bilirubin continued to fall. The infant made a complete recovery. Peritoneal cultures grew clostridia and Enterococcus. JournalofPediafric Surgery, Vol27, No
7
(July), 1992: pp 808-810
HAEMOLYTIC
NECROTISING
ENTEROCOLITIS
Case 4 A 30-day-old infant boy who had been born at 30 weeks’ gestation was transferred with perforated NEC. Blood and FFP were administered prior to transfer. Upon arrival, T activation was identified, and mild haemolysis was observed on laboratory blood specimens. Further resuscitation was therefore carried out using only human albumin solution. A laparotomy showed extensive NEC, which was treated by resection and stoma formation. Intraoperative transfusion with maximally plasma-reduced (hardpacked) blood was without complication. Postoperatively he developed a severe coagulopathy, with major haemorrhage, requiring treatment with FFP and cryoprecipitate. Though the bleeding stopped, severe haemolysis ensued, the haemoglobin decreasing from 10.9 g/dL to 4.4 g/dL in a few hours. The infant died before an exchange transfusion could be effected. DISCUSSION The four cases we report reflect a learning process in the management of intravascular haemolysis complicating NEC. Infant 1 died rapidly following the onset of the haemolysis. In case 2 the haemolysis was recognised early, but surgical intervention to treat the perforation was given higher priority. Despite a successful surgical outcome, the infant progressed to develop kernicterus. In the third case previous experience indicated that exchange transfusion should precede the surgery. The exchange was associated with an immediate reduction in the haemolytic process, and this improvement persisted despite the continued presence of gangrenous, perforated bowel. The sustained remission of the haemolysis in infant 3 suggests that preoperative exchange in case 2 might have stopped the haemolysis earlier. Case 4 presented a different situation. In this infant there was proven T activation, but only mild haemolysis. The aim of management in this child was to treat the NEC without precipitating further haemolysis. Successful management of these cases has been accomplished by limiting transfusions to washed cells, human albumin solution, or low anti-T titre blood products*; maximally plasma-reduced (‘hard-packed’) blood products may be used as a last resort. In this patient the perioperative period was successfully negotiated using “hard-packed” blood, without increasing the haemolysis. The development of a severe coagulopathy introduced a dilemma, since the required infusions contained the anti-T antibody. The best alternative, low anti-T titre FFP (taken from low anti-T donors), requires special preparation, and is seldom available at short notice. The administration of FFP and cryoprecipitate stopped the bleeding, but caused lethal haemolysis. In retrospect, we suggest that the clotting agents should have been given as part of an exchange transfusion. In a recent large prospective trial of admissions to a neonatal intensive care unit, 11% of those with NEC
809
showed T activation, increasing to 28% in the subgroup that required surgical treatment. This compared with 0.1% having T activation out of all other neonatal admissions.* Prevention is better than cure, and a policy of early detection of T activation, followed by measures to avoid haemoiysis is reported to reduce the risks. Therefore, the peanut lectin agglutination test should be performed on all infants with a diagnosis of NEC,9 or when there is a strong suspicion of this diagnosis. It is cheap, effective, simple, rapid, and easily available. Although no recommendations have been made for the treatment of established haemolysis, the theoretical use of exchange transfusion has been discussed.’ Three cases have been reported in which exchange transfusion has been carried out for haemolysis complicating severe NEC. 6,8 On two occasions this was late in the course of the disease, and the infants died. In the third case the exchange was performed early, for hyperbilirubinaemia. The high level of T activation identified in this infant was reduced following exchange transfusion, and the infant survived. Including the cases in this report, exchange transfusion has now been performed early in the course of this disease in three infants, of whom two had confirmed T activation. On each occasion the haemolysis was controlled and the infant survived. The mechanism by which exchange transfusion works is not entirely certain. The transfusion may simply replace T activated erythrocytes with donor cells not expressing the antigen. This would reduce the percentage of cells showing T activation, though would not be expected to remove them completely. Also, the exchange may reduce the anti-T levels in the serum. It is unlikely that this alone is responsible, since the exchange in our second case was carried out using standard packed cells, which almost certainly contained significant quantities of anti-T. Our experience suggests that early exchange transfusion should be considered in the treatment of haemolysis complicating severe NEC, using washed cells resuspended in 4.5% human albumin, or SAGM blood. If these products are not rapidly available, we would recommend exchanging with packed cells. It may be appropriate to perform the exchange transfusion before operation. In the rare circumstance in which FFP or cryoprecipitate is essential, in the presence of activation, we suggest that these agents should be given as part of an exchange transfusion. The value of blood products from selected low anti-T donors may be paramount in this situation. Consideration should be given to keeping a limited store of low titre FFP in all centres where a substantial number of cases of severe NEC are treated.
810
SQUIRE
ET AL
REFERENCES 1. Seger R, Joller P, Kenny A, et al: Potential hazards of blood transfusion in clostridia-associated necrotising enterocolitis. Lancet 1:48-49,1979 2. Friedenreich V: The Thomsen Hemagglutination Phenomenon. Copenhagen, Denmark, Levin and Munksgaard, 1930 3. Seger R, Joller P, Bird GWG, et al: Necrotising enterocolitis and neuraminidase-producing bacteria. Helv Paediatr Acta 35:121128,198O 4. Kim YD, Prakash U, Weber GF, et al: Nature of human serum blood group T antibodies. Immunol Commun 8:397-406, 1979
5. Seger RA, Kenny A, Bird GWG, et al: Pediatric surgical patients with severe anaerobic infection: Report of 16 T-antigen positive cases and possible hazards of blood transfusion. J Pediatr Surg 16905910,198l 6. Novak RW: Bacterial-induced rbc alterations complicating necrotizing enterocolitis. Am J Dis Child 138:183-185,1984 7. Placzek MM, Gorst DW: T activation haemolysis and death after blood transfusion. Arch Dis Child 62743-744, 1987 8. Williams RA, Brown EF, Hurst D, et al: Transfusion of infants with activation of erythrocyte T antigen. J Pediatr 115:949953,1989 9. Bird GWG: Anti-T in peanuts. VOXSang 9:748-749,1964
