Delayed Hemolytic Transfusion Reaction/Hyperhemolysis Syndrome in Children With

Julie-An M. Talano, MD*ʈ; Cheryl A. Hillery, MD*§ʈ; Jerome L. Gottschall, MD‡§ʈ; Diane M. Baylerian, BS, MT§ʈ; and J. Paul Scott, MD*§ʈ

ABSTRACT. Objective. Alloimmunization in patients lower than it was at the time of original transfusion, with sickle cell disease (SCD) has a reported incidence of suggesting the of the patient’s own RBCs in 5% to 36%. One of alloimmunization is addition to hemolysis of the transfused RBCs; a negative delayed hemolytic transfusion reaction/hyperhemolysis DAT and are often present. Severe (DHTR/H) syndrome, which has a reported incidence of complications including acute chest syndrome, conges- 11%. In patients with SCD, clinical findings in DHTR/H tive heart failure, pancreatitis, and acute renal failure syndrome occur approximately 1 week after the red were associated with DHTR/H syndrome in our patients. cell (RBC) transfusion and include the onset of DHTR/H in the pediatric sickle cell population is a seri- increased hemolysis associated with pain and profound ous and potentially life-threatening complication of RBC . The (Hb) often drops below pre- transfusion. It is important to avoid additional trans- transfusion levels. In many reported adult cases, the di- fusions in these patients, if possible, because these may rect antiglobulin test (DAT) remains negative and no exacerbate the hemolysis and worsen the degree of new alloantibody is detected as the cause for these trans- anemia. DHTR/H syndrome must be included in the fusion reactions. To date, few pediatric cases have been differential of a patient who has SCD and vaso-occlusive reported with this phenomenon. The objective of this crisis who has recently had a transfusion. Pediatrics study was to describe the clinical and laboratory findings 2003;111:e661–e665. URL: http://www.pediatrics.org/cgi/ of a case series in children who had SCD and experi- content/full/111/6/e661; delayed hemolytic transfusion re- enced a DHTR/H syndrome at our institution. action/hyperhemolysis, sickle cell disease. Methods. An 11-year retrospective chart review of pa- tients with discharge diagnosis of SCD and transfusion reaction was performed. DHTR/H syndrome was defined ABBREVIATIONS. SCD, sickle cell disease; RBC, ; as the abrupt onset of signs and symptoms of accelerated DHTR/H, delayed hemolytic transfusion reaction/hyperhemoly- sis; Hb, hemoglobin; DAT, direct antiglobulin test; IVIg, intrave- hemolysis evidenced by an unexplained fall in Hb, ele- nous immunoglobulin. vated lactic dehydrogenase, elevated above baseline, and hemoglobinuria, all occurring between 4 and 10 days after an RBC transfusion. Patient character- hildren with sickle cell disease (SCD) com- istics, time from transfusion, symptoms, reported DAT, monly require red blood cell (RBC) transfu- new or alloantibody formation, laboratory sions to manage complications including ane- abnormalities, and complications were recorded. Patients C mia, acute chest syndrome, stroke, and splenic with acute transfusion reactions were excluded. sequestration. Alloimmunization in patients who Results. We encountered 7 patients who developed 9 episodes of DHTR/H syndrome occurring 6 to 10 days have SCD and have had a transfusion has a reported after RBC transfusion. Each presented with and incidence of 5% to 36% in the United States and hemoglobinuria. All but 1 patient experienced pain ini- Europe.1–3 One serious complication of alloimmuni- tially ascribed to vaso-occlusive crisis. The DAT was zation has been termed the delayed hemolytic trans- positive in only 2 of the 9 episodes. The presenting Hb fusion reaction/hyperhemolysis (DHTR/H) syn- was lower than pretransfusion levels in 8 of the 9 events. drome.3,4 In patients with SCD, clinical findings in Severe complications were observed after the onset of DHTR/H occur approximately 1 week after the RBC ؍ ؍ DHTR/H: acute chest syndrome, n 3; pancreatitis, n transfusion and include the onset of increased hemo- ,and acute renal failure ;1 ؍ congestive heart failure, n ;1 associated with pain and profound anemia. The ؍ n 1. hemoglobin (Hb) often drops below pretransfusion Conclusions. DHTR/H syndrome occurs in pediatric SCD patients, typically 1 week posttransfusion, and pre- levels. In many reported adult cases, the direct anti- sents with back, leg, or ; fever; and he- globulin test (DAT) remains negative and no new moglobinuria that may mimic pain crisis. Hb is often alloantibody is detected as the cause for the transfu- sion reactions. The DHTR/H syndrome is thought to occur after From the Departments of *Pediatrics and ‡, Medical College of alloimmunization to an RBC antigen(s) after a trans- Wisconsin, Milwaukee, Wisconsin; §The Blood Center of Southeastern Wis- consin Inc, Milwaukee, Wisconsin; and ʈThe Children’s Hospital of Wiscon- fusion. Over time, the patient’s antibody levels fall to sin, Milwaukee, Wisconsin. undetectable levels. Subsequent reexposure of the Received for publication Oct 15, 2002; accepted Feb 19, 2003. recipient to RBCs that possess the antigen triggers an Reprint requests to (J.-A.M.T.) Medical College of Wisconsin, Department of anamnestic response and subsequent hemolysis. Ac- Pediatric /Oncology, MACC Fund Research Center, 8701 Wa- tertown Plank Rd, Milwaukee, WI 53226. E-mail: [email protected]. celerated hemolysis results in profound anemia and 5 PEDIATRICS (ISSN 0031 4005). Copyright © 2003 by the American Acad- hyperbilirubinemia. The diagnosis of antibody-me- emy of Pediatrics. diated RBC hemolysis is usually confirmed by a pos- http://www.pediatrics.org/cgi/content/full/111/6/Downloaded from www.aappublications.org/newse661 by guestPEDIATRICS on October 2,Vol. 2021 111 No. 6 June 2003 e661 itive DAT and identification of a new red cell anti- DAT results, new autoantibody or alloantibody formation, other body directed against a specific red cell antigen in laboratory abnormalities, complications, and treatment. the patient. However, in the patient who has SCD and DHTR/H syndrome, the DAT is often negative Statistical Analysis and no antibody can be detected in the .4,6,7 Changes in laboratory results were compared using paired Student t test. P Ͻ .05 was considered statistically significant. Therefore, this syndrome poses a significant diagnos- Before the data collection, the study was approved by the Institu- tic challenge. tional Review Board. Cox et al6 reported a prevalence of recognized DHTR/H syndrome of 4% in their patients with RESULTS SCD. Nevertheless, the syndrome may go unrecog- Each year, our center transfuses approximately nized and may have a much higher incidence. Petz et 1000 units of RBCs to a population of 162 pediatric al8 described 8 severe cases of DHTR/H syndrome patients with SCD. Using the criteria described in and defined a sickle cell transfusion reaction syn- “Methods,” we identified 7 patients with 9 episodes drome with a characteristic constellation of findings. of DHTR/H. None of the patients was on a chronic These characteristics include sickle cell pain crisis, transfusion program. Clinical characteristics of these laboratory manifestations of hemolysis, life-threaten- episodes are depicted in Table 1. ing anemia more severe than before the transfusion, One patient had 3 separate episodes of DHTR/H and reticulocytopenia. The DAT can be negative (UPN 7.1, 7.2, 7.3). The second and third episodes of (50% of the time in Petz’s series), and identification DHTR/H in this specific patient occurred when ad- of a new red cell antibody is often absent. The afore- ditional transfusions were given approximately 6 mentioned series were adult patients; there are few and 12 months after the original DHTR/H. The orig- reports of DHTR/H in children with SCD. inal DHTR/H was managed with transfusion of a In this retrospective chart review, we report 7 pe- completely phenotypically matched unit of RBC diatric patients who had SCD and developed evi- without additional complications. The 7.2 and 7.3 dence of accelerated hemolysis 6 to 10 days after an events were managed conservatively, and the pa- RBC transfusion. Each of these patients previously tient’s Hb recovered spontaneously without the need had a transfusion. In this report, we describe the for additional transfusions. clinical and laboratory characteristics of 9 episodes of As depicted in Table 1, 6 patients had Hb SS and 1 DHTR/H syndrome in 7 children with SCD. patient had Hb SC disease. Their ages ranged from 6 to 18 years. There were 5 girls and 2 boys. Of note, all METHODS patients presented with fever and hemoglobinuria. Before 1995, all patients who had SCD and received a transfu- All but 1 episode presented with symptoms of pain sion at our center received RBCs matched only for Rh D and ABO. that was initially ascribed to vaso-occlusive crisis (in Since 1995, patients with a diagnosis of SCD have received units of RBCs that are partially phenotype matched for the Rh (C, E, c, e) the back, abdomen, and/or legs). The number of and Kell antigens in addition to routine cross-match- days after transfusion to presentation ranged from 6 ing protocols. to 10 days with a median of 6 days. As shown in We performed a retrospective chart review of patients at the Table 2, the bilirubin increased from baseline in all Children’s Hospital of Wisconsin who had SCD from 1990 to 2001 ϭ with the discharge International Classification of Diseases, Ninth patients (P .003) and the peak bilirubin ranged Revision code of Sickle Cell Disease and transfusion reaction. Pa- from 1.7 mg/dL to 10.1 mg/dL with a median of 4.2 tients who experienced an acute transfusion reaction were ex- mg/dL. The LDH increased from baseline in all pa- cluded. We defined an acute transfusion reaction as occurring tients (P ϭ .0006) with the peak LDH ranging from within 24 hours after the initiation of the transfusion. Criteria to 2667 IU/L to 17 274 IU/L with a median of 6039 meet DHTR/H included the abrupt onset of signs and symptoms of accelerated hemolysis as evidenced by an unexplained fall in IU/L. The Hb decreased from pretransfusion level in Hb, an elevated lactic dehydrogenase (LDH), elevated bilirubin 8 of 9 episodes (P ϭ .0001). The nadir Hb ranged above baseline, and hemoglobinuria. These must have occurred from 4.0 g/dL to 5.9 g/dL with a median of 4.5 g/dL. between 4 and 10 days after an RBC transfusion.7 Clinical and The net drop in Hb from posttransfusion to nadir in laboratory data were collected on these patients and included patient characteristics and clinical findings, onset of symptoms 6 episodes in which an immediate posttransfusion after RBC transfusion, type of transfusion, previous transfusion Hb was available ranged from 1.8 g/dL to 9.5 g/dL, history (including number of partial phenotype matched units), with a median of 7.7 g/dL. The count at

TABLE 1. Clinical Characteristics of DHTR/H in SCD Patients Patient Gender Age Hb type No. of Previous DAT Onset After RBC Symptoms UPN (Years) Previous Allo-Ab Transfusion RBC (Days) 1 F 9 SS 4 None ϩ 6 Pain, fever, hemoglobinuria 2 F 9 SS 41 None Ϫ 7 Pain, fever, hemoglobinuria 3 F 6 SS 4 None Ϫ 6 Pain, fever, hemoglobinuria 4 F 18 SS 23 Anti-C, S, Jkb Ϫ 10 Fever, hemoglobinuria 5 M 15 SC 11 None Ϫ 7 Pain, fever, hemoglobinuria 6 M 17 SS Ͼ6 None ϩ 10 Pain, fever, hemoglobinuria 7.1 F 9 SS Ͼ6 None Ϫ 6 Pain, fever, hemoglobinuria 7.2 F 9.5 SS Ͼ8 None Ϫ 6 Pain, fever, hemoglobinuria 7.3 F 10 SS Ͼ10 None Ϫ 6 Pain, fever, hemoglobinuria Allo-Ab indicates alloantibody.

e662 DHTR/H IN SICKLEDownloaded CELL DISEASE from www.aappublications.org/news by guest on October 2, 2021 TABLE 2. Laboratory Characteristics of DHTR/H in SCD Patients Patient Pre-Tx Hb Post-Tx Hb Nadir Hb Fall in Hb Retic Corrected New Ab Increase in Increase in Complications UPN (g/dL) (g/dL) (g/dL) (g/dL) Count Retic Count Formed LDH Bilirubin (%) (%) (IU/L) (mg/dL) 1 6.6 11.9 4.2 7.7 8.4 4.1 Warm Auto 16 302 0.9 ACS Ab 2 7.2 NA 4.5 — 9.6 2.9 None 4401 4.3 — 3 5.0 7.7 5.9 1.8 2.5 1.16 None 4954 3.1 ACS, pancreatitis 4 5.8 9.3 4.1 5.2 19.1 5.6 Fyb 1955 2.1 — 5 12.1 14.8 5.3 8.5 1 0.35 None 16 156 2.5 ACS, ARF 6 9.6 12.5 4.7 7.8 12 3.8 E 5949 1.8 — 7.1 7.7 NA 4.8 — 2.1 0.67 None 5785 9.3 CHF 7.2 7.2 NA 4.5 — 4.3 1.29 None 3041 0.9 — 7.3 9.1 13.5 4.0 9.5 0.8 0.2 E, Lea 4905 3.7 — Tx indicates transfusion; Retic, reticulocyte; Ab, antibody; ACS, acute chest syndrome; ARF, acute renal failure; CHF, congestive heart failure. the time of nadir Hb ranged from 0.8 to 19.1% with a multiple subsequent hospitalizations for vaso-occlu- median of 4.3%. The corrected reticulocyte count sive crises. This patient successfully avoided addi- accounting for the patient’s degree of anemia ranged tional RBC transfusions. Three of the 6 patients from 0.2% to 5.6% with a median of 1.16%. Five of the received additional RBC transfusions that were com- 9 episodes had severe reticulocytopenia with a cor- pletely phenotypically matched during their acute rected reticulocyte count of Ͻ2%. illness. One of the 3 patients (UPN-1) experienced As seen in Table 1, only 2 of the 9 events had a severe additional hemolysis; the other 2 patients tol- positive DAT at the presentation of the DHTR/H. erated the transfusion without any additional hemo- One patient had previous alloantibodies present, and lysis. 4 patients developed new identifiable antibodies, which included a warm autoantibody in 1 patient, DISCUSSION anti-E and anti-Lea in a second patient, anti-E in a We have identified 7 pediatric patients who had third patient, and anti-Fyb in the fourth patient. The SCD and experienced a DHTR/H event 6 to 10 days new alloantibodies appeared at the time of the event after an RBC transfusion. All of the patients pre- in 2 patients but were not detected for 1 month after sented with fever and hemoglobinuria. Vaso-occlu- the DHTR/H in a third patient. The number of pre- sive pain in the back, abdomen, or legs was present vious transfusions ranged from 4 to 43. Since 1995, all in all but 1 patient. These symptoms could be easily RBC transfusions in patients with SCD at our insti- mistaken for a simple vaso-oclusive crisis in the tution are phenotypically matched for Rh (C, E, D, c, sickle cell population. Therefore, the clinician must e) antigens and Kell to help reduce alloimmuniza- have a heightened awareness of DHTR/H in a pa- tion. In our series, only 2 of the patients had past tient who has recently had a transfusion. transfusions that all were phenotypically matched Unfortunately, there is no single test to diagnose RBCs for Rh and Kell. Both patients had no previous DHTR/H. The direct antiglobulin test is often nega- alloantibodies, and 1, who had a positive DAT at the tive, and in our series, only 2 episodes had a positive time of the DHTR/H, had developed a warm auto- DAT at presentation. Also, a new alloantibody may antibody. The remainder of the patients (4 with 6 not be identified. Only 3 patients developed detect- DHTR/H) received transfusions before 1995 and able alloantibodies, and 1 patient developed an au- did not receive solely Rh and Kell phenotypically toantibody. However, the presence of a fall in Hb, matched RBCs. This subset of patients received 6 to often below pretransfusion levels; reticulocytopenia; 43 previous transfusions. and elevated LDH and bilirubin with fever, pain, and Severe complications were observed after the on- hemoglobinuria within 10 days of a previous trans- set of DHTR/H. Three patients developed acute fusion constitute the major findings in this group of chest syndrome 1 to 2 days after their admission for patients. DHTR/H. Pancreatitis occurred in 1 patient approx- Friedman et al10 published an abstract that de- imately 1 week after the DHTR/H was recognized. scribed hyperhemolysis associated with red cell In another patient, congestive heart failure was rec- transfusion in 3 pediatric patients with SCD. All 3 ognized 1 day after the DHTR/H was diagnosed. patients had severe hemolysis that required addi- Finally, acute renal failure occurred 2 days after di- tional transfusions. However, the subsequent trans- agnosis of DHTR/H in 1 individual. fusions resulted in worsening anemia. Serial Hb elec- For stimulating and suppression of trophoreses showed clearance of Hb A cells within 1 the immune response, as well to avoid additional to 14 days from the onset of the transfusion. Sero- transfusions, corticosteroids and as logic evaluations revealed new alloantibodies in only described by Telen and Combs9 were administered 1 of the 3 patients. One patient died with severe to 6 patients. Most patients were placed on erythro- hemolysis and anemia as a contributing factor lead- poietin and corticosteroids for 1 to 2 weeks during ing to death. One can speculate that these cases were their acute illness and hospitalization for the DHTR/H. delayed hemolytic transfusion reactions. Vichinsky One patient used erythropoietin and corticosteroids et al11 reported 2 cases of DHTR/H occurring in the for approximately 2 months after DHTR/H during stroke-prevention trial in pediatric patients with

Downloaded from www.aappublications.org/newshttp://www.pediatrics.org/cgi/content/full/111/6/ by guest on October 2, 2021 e661 e663 sickle cell anemia among the 1830 transfused units. antibodies (epitope spreading) as a result of alloim- Both patients had no previous identified antibodies. munization from the transfusion. Garratty14 sug- One patient developed anti-E, and the other patient gested another possible mechanism that may worsen developed multiple antibodies (anti-Fya, -Lea, -Leb, the hemolysis by the reaction of alloantibodies with -S). An unexpected drop in Hb and a paradoxical rise transfused RBCs, which leads to the attachment of in % HbS was observed. activated complement components to autologous Recently, Aygun et al4 reported on 4 pediatric RBCs resulting in their lysis. Conversely, he pro- patients and 1 adult patient who had SCD and de- posed, in the absence of RBC alloantibodies, that veloped DHTR/H after receiving an RBC transfu- other antibody reactions with transfused foreign an- sion. Of the 4 pediatric patients, 2 had identifiable tigens (eg, HLA and plasma proteins) may cause antibodies before the DHTR/H; 3 developed new complement activation. These antibodies may be antibodies. The episodes of DHTR/H occurred in 2 present in patients who have received multiple trans- patients 5 to 8 days posttransfusion. However, in the fusions, which may lead to immune complex forma- remaining 2 patients, the DHTR/H occurred be- tion. tween 3 and 6 weeks posttransfusion. It remains In our series, inappropriately low reticulocyte unclear whether these represent isolated DHTR/H counts were seen in the majority of the DHTR/H. events or, alternatively, the concurrent pneumonia in The mechanism of the reticulocytopenia remains un- patient 3 and splenic sequestration in patient 4 con- clear. Erythropoiesis can be suppressed by the trans- tributed to their hemolysis. fusion or concurrent illness (viral infection), which Other published reports have described delayed can exacerbate the anemia. Other possible mecha- hemolytic transfusion reactions in the adult sickle nisms of reticulocytopenia include accelerated de- cell population. Diamond et al12 reported 3 patients struction of as a result of selective an- who had SCD and all experienced a DHTR/H 6 days tibody targeting of reticulocytes or decreased levels after a partial . All 3 patients of erythropoietin secondary to kidney damage. had disappearance of transfused cells documented Various strategies have been used to avoid addi- by Hb electrophoresis and differential agglutination. tional transfusions and decrease the amount of he- Two patients developed antibodies to the Kidd (Jka) molysis. Cullis et al15 reported on an adult patient antigen. One patient had no detectable antibodies. who had SCD and had a life-threatening DHTR/H Petz et al8 described 5 patients who were aged 16 that resulted in a Hb level of 3.0 g/dL. An additional to 47 years with SCD and experienced 8 episodes of transfusion was successfully given in conjunction severe DHTR/H. He found characteristic manifesta- with corticosteroids (100 mg intravenously every 6 tions including symptoms suggestive of a sickle cell hours) and high-dose intravenous immunoglobulin pain crisis, marked reticulocytopenia, and more se- (IVIg) 1 g/kg without any evidence of additional vere anemia after transfusion than was present at the hemolysis. Win et al7 reported on 2 adult patients time of diagnosis. Through Petz’s calculations of who had SCD and were treated with IVIg (0.4 g/kg) daily red cell production and senescence, he pro- for 5 days and corticosteroids (0.5 g) for 2 days. Our posed that the combination of accelerated hemolysis approach, mirrored after Telen et al,9 used cortico- and decreased erythropoiesis resulted in severe post- steroids and erythropoietin with some success. How- transfusion anemia when donor red cells are hemo- ever, the experience of using both erythropoietin and lyzed during a DHTR/H. In his series, phenotypi- corticosteroids, as well as IVIg and corticosteroids in cally matched RBCs did not prevent DHTR/H from DHTR/H, is limited and needs to be confirmed by occurring in 2 patients. additional trials. We instituted a protocol in 1995 to provide par- Severe complications were associated with the tially phenotypically matched RBCs for our sickle DHTR/H in our case series. They included acute cell population in hope of preventing alloimmuniza- chest syndrome, pancreatitis, congestive heart fail- tion and DHTR/H. All patients undergo complete ure, and acute renal failure. Aygun et al4 also noted phenotyping at presentation to our institution. Nev- severe complications, including subarachnoid hem- ertheless, 2 patients who had received only partially orrhage, acute respiratory distress syndrome, pneu- phenotypically matched RBCs for Rh and Kell still monia, and splenic sequestration. experienced DHTR/H. Aygun et al4 likewise found Our study is limited because it was retrospective that 2 patients who had received antigen-matched in nature and may have missed additional cases of packed RBCs still experienced severe DHTR/H. DHTR/H. Because the diagnosis must be made with The Hb level in DHTR/H is often lower than a high index of suspicion, we may be underrepre- pretransfusion levels. King et al13 demonstrated the senting the incidence of DHTR/H. Conversely, in the phenomenon of bystander hemolysis whereby the absence of a positive DAT, it is possible that we are patient hemolyzes both the transfused RBCs and his overestimating the frequency of DHTR/H as there or her own cells, resulting in the nadir Hb often may be some other unknown cause of accelerated lower than pretransfusion levels. He described 2 pa- hemolysis such as glucose-6-phosphate dehydroge- tients who had a decrease in Hb S after DHTR/H nase deficiency. However, all of the patients in our documenting the destruction of autologous red cells. series had normal baseline glucose-6-phosphate de- This is a consistent finding in our series in which 8 of hydrogenase levels. the 9 DHTR/Hs had lower Hbs than the starting DHTR/H in the pediatric sickle cell population is pretransfusion level. Bystander hemolysis may occur a serious and potentially life-threatening complica- by the development or augmentation of RBC auto- tion of RBC transfusion. Recognition of this compli- e664 DHTR/H IN SICKLEDownloaded CELL DISEASE from www.aappublications.org/news by guest on October 2, 2021 cation of transfusion is crucial because additional 7. Win N, Doughty H, Telfer P, Wild B, Pearson T. Hyperhemolytic transfusions in such patients may exacerbate the he- transfusion reaction in sickle cell disease. Transfusion. 2001;41:323–328 10 8. Petz L, Calhoun L, Shulman I, Johnson C, Herron R. The sickle cell molysis and resultant anemia. Optimal methods for hemolytic transfusion reaction syndrome. Transfusion. 1997;37:382–392 prevention or treatment of DHTR/H syndrome re- 9. Telen MJ, Combs M. Management of massive delayed hemolytic trans- main to be determined. fusions reactions in patients with sickle cell disease. Transfusion. 1999; 39S:97 REFERENCES 10. Friedman D, Kim H, Manno C. Hyperhemolysis associated with red cell transfusion in sickle cell disease. Transfusion. 1993;33S:14 1. Rosse W, Gallagher D, Kinney T, et al. Transfusion and alloimmuniza- 11. Vichinsky E, Luban N, Wright E, et al. Prospective RBC phenotype tion in sickle cell disease. Blood. 1990;76:1431–1437 matching in a stroke-prevention trial in sickle cell anemia: a multicenter 2. Davies S, McWilliam A, Hewitt P, Devenish A, Brozovic M. Red cell transfusion trial. Transfusion. 2001;41:1086–1092 alloimmunization in sickle cell disease. Br J Haematol. 1986;63:241–245 12. Diamond W, Brown F, Bitterman P, Klein H, Davey R, Winslow R. 3. Vichinsky E, Earles A, Johnson R, Hoag M, Williams A, Lubin B. Delayed hemolytic transfusion reaction presenting as sickle-cell crisis. Alloimmunization in sickle cell anemia and transfusion of racially un- Ann Intern Med. 1980;93:231–233 matched blood. N Engl J Med. 1990;322:1617–1621 13. King K, Shirey R, Lankiewicz M, Young-Ramsaran J, Ness P. Delayed 4. Aygun B, Padmanabham S, Paley C, Chandrasekaran V. Clinical sig- hemolytic transfusion reactions in sickle cell disease: simultaneous de- nificance of RBC alloantibodies and in sickle cell patients struction of recipients’ red cells. Transfusion. 1997;37:376–381 who received transfusions. Transfusion. 2002;42:37–43 14. Garratty G. Severe reactions associated with transfusion of patients with 5. Nathan D, Orkin S. Nathan and Oski’s Hematology of Infancy and Child- sickle cell disease. Transfusion. 1997;37:357–361 hood. 5th ed. Philadelphia, PA: WB Saunders Company; 1998:1796–1797 15. Cullis J, Win N, Dudley J, Kaye T. Post-transfusion hyperhaemolysis in 6. Cox J, Steane E, Cunningham G, Frenkle E. Risk of alloimmunization a patient with sickle cell disease: use of steroids and intravenous im- and delayed hemolytic transfusion reactions in patients with sickle cell munoglobulin to prevent further red cell destruction. Vox Sang. 1995; disease. Arch Intern Med. 1988;148:2485–2489 69:335–337

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Downloaded from www.aappublications.org/news by guest on October 2, 2021 Delayed Hemolytic Transfusion Reaction/Hyperhemolysis Syndrome in Children With Sickle Cell Disease Julie-An M. Talano, Cheryl A. Hillery, Jerome L. Gottschall, Diane M. Baylerian and J. Paul Scott Pediatrics 2003;111;e661 DOI: 10.1542/peds.111.6.e661

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