Adverse events of red blood cell transfusions in patients with sickle cell disease

  • Margo R. Rollins
    Children’s Healthcare of Atlanta, Department of Pathology and Laboratory Medicine, 1405 Clifton Rd NE, 1st Floor, Atlanta, GA 30322, USA

    Emory University School of Medicine, Department of Pediatrics, Aflac Cancer and Blood Disorders Center, 1405 Clifton Rd NE, Atlanta, GA 30322, USA
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  • Stella T. Chou
    Correspondence to: 3615 Civic Center Boulevard, Abramson Research Building Room 316D, Philadelphia, PA 19104, USA.
    The Children’s Hospital of Philadelphia, Departments of Pediatrics and Pathology and Laboratory Medicine, The School of Medicine at the University of Pennsylvania, 3615 Civic Center Boulevard, Abramson Research Building Room 316D, Philadelphia, PA 19104, USA
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      • Alloimmunization and iron overload are risks of red cell transfusion for SCD.
      • Prophylactic Rh and K matching of red cells is recommended for patients with SCD.
      • RH variation among African patients and donors contributes to Rh alloimmunization.
      • Immunosuppression can be tailored for severe hemolytic transfusion reactions.


      Blood transfusion is a common medical intervention for patients with sickle cell disease (SCD) and disease related complications. While patients with SCD are at risk for all transfusion related adverse events defined by the National Healthcare Safety Network (NHSN) Biovigilance Component Hemovigilance Module Surveillance Protocol, they are uniquely susceptible to certain adverse events. This review discusses risk factors, mitigation strategies, and management recommendations for alloimmunization, hemolytic transfusion reactions, hyperviscosity and transfusion-associated iron overload in the context of SCD.


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        • Karafin M.S.
        • et al.
        Demographic and epidemiologic characterization of transfusion recipients from four US regions: evidence from the REDS-III recipient database.
        Transfus. 2017; vol. 57: 2903-2913
      1. "Healthcare Cost and Utilization Project (HCUP) Statistical Briefs," 2006.

        • Delaney M.
        • et al.
        Transfusion reactions: prevention, diagnosis, and treatment.
        Lancet. 2016; vol. 388 (12 03): 2825-2836
      2. G.D. o H. Q. U.S Centers for Disease Control and Prevention. Atlanta and N. C. f. E. a. Z. I. D. Promotion. "The National Healthcare Safety Network (NHSN) Manual: Biovigilance Component." 〈〉. (accessed June 29, 2022).

        • Linder G.E.
        • Chou S.T.
        Red cell transfusion and alloimmunization in sickle cell disease.
        Haematol. 2021; vol. 106 (07 01): 1805-1815
        • Yazdanbakhsh K.
        • Ware R.E.
        • Noizat-Pirenne F.
        Red blood cell alloimmunization in sickle cell disease: pathophysiology, risk factors, and transfusion management.
        Blood. 2012; vol. 120: 528-537
        • Rosse W.F.
        • et al.
        Transfusion and alloimmunization in sickle cell disease. The Cooperative Study of Sickle Cell Disease.
        Blood. 1990; vol. 76 (Oct 01) (Oct 01): 1431-1437
        • Vichinsky E.P.
        • Earles A.
        • Johnson R.A.
        • Hoag M.S.
        • Williams A.
        • Lubin B.
        Alloimmunization in sickle cell anemia and transfusion of racially unmatched blood.
        N Engl J Med. 1990; vol. 322: 1617-1621
        • Chou S.T.
        • et al.
        American Society of Hematology 2020 guidelines for sickle cell disease: transfusion support.
        Blood Adv. 2020; vol. 4: 327-355
        • Osby M.
        • Shulman I.A.
        Phenotype matching of donor red blood cell units for nonalloimmunized sickle cell disease patients: a survey of 1182 North American laboratories.
        (Eng), Arch Pathol Lab Med. 2005; 129: 190-193
        • Miller S.T.
        • et al.
        Red blood cell alloimmunization in sickle cell disease: prevalence in 2010.
        Transfus. 2013; vol. 53: 704-709
        • Chou S.T.
        • Jackson T.
        • Vege S.
        • Smith-Whitley K.
        • Friedman D.F.
        • Westhoff C.M.
        High prevalence of red blood cell alloimmunization in sickle cell disease despite transfusion from Rh-matched minority donors.
        Blood. 2013; vol. 122: 1062-1071
        • Noizat-Pirenne F.
        • Tournamille C.
        Relevance of RH variants in transfusion of sickle cell patients.
        Transfus Clin Biol. 2011; vol. 18: 527-535
        • Chou S.T.
        • et al.
        genotype matching for transfusion support in sickle cell disease.
        Blood. 2018; vol. 132 (09 13): 1198-1207
      3. National Heart, National Institutes of Health,"Evidence-Based Management of Sickle Cell Disease Expert PanelReport," U.S. Department of Health and Human Services, 2014. [Online].Available: Evidence-Based Management of Sickle Cell Disease: Expert Panel, 2014(

        • Davis B.A.
        • et al.
        Guidelines on red cell transfusion in sickle cell disease. Part I: principles and laboratory aspects.
        Br J Haematol. 2017; vol. 176 (01): 179-191
        • Yawn B.P.
        • et al.
        Management of sickle cell disease: summary of the 2014 evidence-based report by expert panel members.
        JAMA. 2014; vol. 312: 1033-1048
        • Compernolle V.
        • et al.
        Red blood cell specifications for patients with hemoglobinopathies: a systematic review and guideline.
        Transfus. 2018; vol. 58 (06): 1555-1566
        • da Costa D.C.
        • Pellegrino J.
        • Guelsin G.A.
        • Ribeiro K.A.
        • Gilli S.C.
        • Castilho L.
        Molecular matching of red blood cells is superior to serological matching in sickle cell disease patients.
        Rev Bras Hematol Hemoter. 2013; vol. 35: 35-38
        • Lasalle-Williams M.
        • et al.
        Extended red blood cell antigen matching for transfusions in sickle cell disease: a review of a 14-year experience from a single center (CME).
        Transfus. 2011; vol. 51: 1732-1739
        • Pirenne F.
        • Yazdanbakhsh K.
        How I safely transfuse patients with sickle-cell disease and manage delayed hemolytic transfusion reactions.
        Blood. 2018; vol. 131 (06 21): 2773-2781
        • Win N.
        • Yeghen T.
        • Needs M.
        • Chen F.E.
        • Okpala I.
        Use of intravenous immunoglobulin and intravenous methylprednisolone in hyperhaemolysis syndrome in sickle cell disease.
        Hematol. 2004; vol. 9 (2004 Oct-Dec): 433-436
        • Noizat-Pirenne F.
        • et al.
        The use of rituximab to prevent severe delayed haemolytic transfusion reaction in immunized patients with sickle cell disease.
        Vox Sang. 2015; vol. 108: 262-267
        • Silvy M.
        • et al.
        Red blood cell immunization in sickle cell disease: evidence of a large responder group and a low rate of anti-Rh linked to partial Rh phenotype.
        Haematol. 2014; vol. 99: e115-e117
      4. AABB, C. S. Cohn, Ed. Technical Manual, 20th ed.

      5. Marion E C.R. Lomas-Francis The Blood Group Antigen Facts Book. 2nd ed..,. Elsevier Ltd, 2004
        • Vidler J.B.
        • Gardner K.
        • Amenyah K.
        • Mijovic A.
        • Thein S.L.
        Delayed haemolytic transfusion reaction in adults with sickle cell disease: a 5-year experience.
        Br J Haematol. 2015; vol. 169: 746-753
        • Nickel R.S.
        • et al.
        Impact of red blood cell alloimmunization on sickle cell disease mortality: a case series.
        Transfus. 2016; vol. 56: 107-114
        • Coleman S.
        • Westhoff C.M.
        • Friedman D.F.
        • Chou S.T.
        Alloimmunization in patients with sickle cell disease and underrecognition of accompanying delayed hemolytic transfusion reactions.
        Transfus. 2019; vol. 59 (07): 2282-2291
        • Bolton-Maggs P.H.
        • Cohen H.
        Serious hazards of transfusion (SHOT) haemovigilance and progress is improving transfusion safety.
        Br J Haematol. 2013; vol. 163: 303-314
        • Narbey D.
        • et al.
        Incidence and predictive score for delayed hemolytic transfusion reaction in adult patients with sickle cell disease.
        Am J Hematol. 2017; vol. 92: 1340-1348
        • Diamond W.J.
        • Brown F.L.
        • Bitterman P.
        • Klein H.G.
        • Davey R.J.
        • Winslow R.M.
        Delayed hemolytic transfusion reaction presenting as sickle-cell crisis.
        Ann Intern Med. 1980; vol. 93: 231-234
        • Gardner K.
        • Hoppe C.
        • Mijovic A.
        • Thein S.L.
        How we treat delayed haemolytic transfusion reactions in patients with sickle cell disease.
        Br J Haematol. 2015; vol. 170: 745-756
        • Dean C.L.
        • Maier C.L.
        • Roback J.D.
        • Stowell S.R.
        Multiple hemolytic transfusion reactions misinterpreted as severe vaso-occlusive crisis in a patient with sickle cell disease.
        Transfus. 2019; vol. 59 (02): 448-453
        • Schonewille H.
        • Haak H.L.
        • van Zijl A.M.
        RBC antibody persistence.
        Transfus. 2000; vol. 40: 1127-1131
        • Boateng L.A.
        • et al.
        One third of alloantibodies in patients with sickle cell disease transfused with African blood are missed by the standard red blood cell test panel.
        Haematol. 08 01 2021; vol. 106: 2274-2276
        • King K.E.
        • Shirey R.S.
        • Lankiewicz M.W.
        • Young-Ramsaran J.
        • Ness P.M.
        Delayed hemolytic transfusion reactions in sickle cell disease: simultaneous destruction of recipients' red cells.
        Transfus. 1997; vol. 37: 376-381
        • Chonat S.
        • et al.
        Challenges in preventing and treating hemolytic complications associated with red blood cell transfusion.
        Transfus Clin Biol. 2019; vol. 26: 130-134
        • Petz L.D.
        • Calhoun L.
        • Shulman I.A.
        • Johnson C.
        • Herron R.M.
        The sickle cell hemolytic transfusion reaction syndrome.
        Transfus. 1997; vol. 37: 382-392
        • Talano J.A.
        • Hillery C.A.
        • Gottschall J.L.
        • Baylerian D.M.
        • Scott J.P.
        Delayed hemolytic transfusion reaction/hyperhemolysis syndrome in children with sickle cell disease.
        Pediatr. 2003; vol. 111 (Pt 1): e661-e665
        • Darabi K.
        • Dzik S.
        Hyperhemolysis syndrome in anemia of chronic disease.
        Transfus. 2005; vol. 45: 1930-1933
        • Win N.
        • Sinha S.
        • Lee E.
        • Mills W.
        Treatment with intravenous immunoglobulin and steroids may correct severe anemia in hyperhemolytic transfusion reactions: case report and literature review.
        Transfus Med Rev. 2010; vol. 24: 64-67
        • Win N.
        • New H.
        • Lee E.
        • de la Fuente J.
        Hyperhemolysis syndrome in sickle cell disease: case report (recurrent episode) and literature review.
        Transfus. 2008; 48: 1231-1238
        • Garratty G.
        What do we mean by "Hyperhaemolysis" and what is the cause?.
        Transfus Med. 2012; 22: 77-79
        • Harm S.K.
        • Yazer M.H.
        • Monis G.F.
        • Triulzi D.J.
        • Aubuchon J.P.
        • Delaney M.
        A centralized recipient database enhances the serologic safety of RBC transfusions for patients with sickle cell disease.
        Am J Clin Pathol. 2014; vol. 141: 256-261
        • Chadebech P.
        • et al.
        Delayed hemolytic transfusion reaction in sickle cell disease patients: evidence of an emerging syndrome with suicidal red blood cell death.
        Transfus. 2009; vol. 49: 1785-1792
        • Dumas G.
        • et al.
        Eculizumab salvage therapy for delayed hemolysis transfusion reaction in sickle cell disease patients.
        Blood. 25 2016; vol. 127: 1062-1064
        • Gupta S.
        • Fenves A.
        • Nance S.T.
        • Sykes D.B.
        • Dzik W.S.
        Hyperhemolysis syndrome in a patient without a hemoglobinopathy, unresponsive to treatment with eculizumab.
        Transfus. 2015; vol. 55: 623-628
        • Meenan J.
        • Hall R.
        • Badle S.
        • Chatterjee B.
        • Win N.
        • Tsitsikas D.A.
        Tocilizumab in the management of posttransfusion hyperhemolysis syndrome in sickle cell disease: the experience so far.
        Transfus. 2022; vol. 62 (03): 546-550
        • Sivapalaratnam S.
        • et al.
        Treatment of post-transfusion hyperhaemolysis syndrome in Sickle Cell Disease with the anti-IL6R humanised monoclonal antibody Tocilizumab.
        Br J Haematol. 2019; vol. 186 (09): e212-e214
        • Boonyasampant M.
        • Weitz I.C.
        • Kay B.
        • Boonchalermvichian C.
        • Liebman H.A.
        • Shulman I.A.
        Life-threatening delayed hyperhemolytic transfusion reaction in a patient with sickle cell disease: effective treatment with eculizumab followed by rituximab.
        Transfus. 2015; vol. 55: 2398-2403
        • Hosoba S.
        • Jaye D.L.
        • Cohen C.
        • Roback J.D.
        • Waller E.K.
        Successful treatment of severe immune hemolytic anemia after allogeneic stem cell transplantation with bortezomib: report of a case and review of literature.
        Transfus. 2015; vol. 55: 259-264
        • Wasi P.
        • Na-Nakorn S.
        • Pootrakul P.
        • Sonakul D.
        • Piankijagum A.
        • Pacharee P.
        A syndrome of hypertension, convulsion, and cerebral haemorrhage in thalassaemic patients after multiple blood-transfusions.
        Lancet. 1978; vol. 2: 602-604
        • Serjeant G.
        Blood transfusion in sickle cell disease: a cautionary tale.
        Lancet. 2003; 361: 1659-1660
        • Royal J.E.
        • Seeler R.A.
        Hypertension, convulsions, and cerebral haemorrhage in sickle-cell anaemia patients after blood-transfusions.
        Lancet. 1978; vol. 2: 1207
        • Howard J.
        Sickle cell disease: when and how to transfuse.
        Hematol Am Soc Hematol Educ Program. 2016; 2016: 625-631
        • DeBaun M.R.
        • et al.
        American Society of Hematology 2020 guidelines for sickle cell disease: prevention, diagnosis, and treatment of cerebrovascular disease in children and adults.
        Blood Adv. 2020; vol. 4 (04 28): 1554-1588
        • Ballas S.K.
        • Kuypers F.A.
        • Gordeuk V.R.
        • Hankins J.S.
        • Thompson A.A.
        • Vichinsky E.
        Time to rethink haemoglobin threshold guidelines in sickle cell disease.
        Br J Haematol. 2021; vol. 195 (11): 518-522
        • Nader E.
        • et al.
        Blood rheology: key parameters, impact on blood flow, role in sickle cell disease and effects of exercise.
        Front Physiol. 2019; vol. 10: 1329
        • Connes P.
        • Alexy T.
        • Detterich J.
        • Romana M.
        • Hardy-Dessources M.D.
        • Ballas S.K.
        The role of blood rheology in sickle cell disease.
        Blood Rev. 2016; vol. 30: 111-118
        • Johnson C.S.
        Arterial blood pressure and hyperviscosity in sickle cell disease.
        ( Eng), Hematol Oncol Clin North Am. 2005; vol. 19 (vi, Oct): 827-837
      6. A. Taher, E. Vichinsky, K. Musallam, M.D. Cappellini, and V. Viprakasit, "Guidelines for the Management of Non-Transfusion Dependent Thalassemia (NTDT) ". [Online]. Available: 〈〉.

        • Fung E.B.
        • et al.
        Disparity in the management of iron overload between patients with sickle cell disease and thalassemia who received transfusions.
        Transfus. 2008; vol. 48: 1971-1980
        • Wood J.C.
        • et al.
        Organ iron accumulation in chronically transfused children with sickle cell anaemia: baseline results from the TWiTCH trial.
        Br J Haematol. 2016; vol. 172: 122-130
        • Kwiatkowski J.L.
        • et al.
        Transfusional iron overload in children with sickle cell anemia on chronic transfusion therapy for secondary stroke prevention.
        Am J Hematol. 2012; vol. 87: 221-223
        • Fung E.B.
        • et al.
        Increased prevalence of iron-overload associated endocrinopathy in thalassaemia versus sickle-cell disease.
        Br J Haematol. 2006; vol. 135: 574-582
        • Kaushik N.
        • Eckrich M.J.
        • Parra D.
        • Yang E.
        Chronically transfused pediatric sickle cell patients are protected from cardiac iron overload.
        Pedia Hematol Oncol. 2012; vol. 29: 254-260
        • de Montalembert M.
        • et al.
        Cardiac iron overload in chronically transfused patients with thalassemia, sickle cell anemia, or myelodysplastic syndrome.
        PLoS One. 2017; vol. 12e0172147
        • Meloni A.
        • Puliyel M.
        • Pepe A.
        • Berdoukas V.
        • Coates T.D.
        • Wood J.C.
        Cardiac iron overload in sickle-cell disease.
        Am J Hematol. 2014; vol. 89: 678-683
        • Vichinsky E.
        • et al.
        Comparison of organ dysfunction in transfused patients with SCD or beta thalassemia.
        Am J Hematol. 2005; vol. 80: 70-74
        • Piperno A.
        "Classification and diagnosis of iron overload.
        Haematol. 1998; vol. 83: 447-455
        • Hankins J.S.
        • et al.
        Patterns of liver iron accumulation in patients with sickle cell disease and thalassemia with iron overload.
        Eur J Haematol. 2010; vol. 85: 51-57
        • Risdon R.A.
        • Barry M.
        • Flynn D.M.
        Transfusional iron overload: the relationship between tissue iron concentration and hepatic fibrosis in thalassaemia.
        J Pathol. 1975; vol. 116: 83-95
        • Jensen P.D.
        • Jensen F.T.
        • Christensen T.
        • Nielsen J.L.
        • Ellegaard J.
        Relationship between hepatocellular injury and transfusional iron overload prior to and during iron chelation with desferrioxamine: a study in adult patients with acquired anemias.
        Blood. 2003; vol. 101: 91-96
        • Ghugre N.R.
        • et al.
        Patterns of hepatic iron distribution in patients with chronically transfused thalassemia and sickle cell disease.
        Am J Hematol. 2009; vol. 84: 480-483
        • Walter P.B.
        • et al.
        Oxidative stress and inflammation in iron-overloaded patients with beta-thalassaemia or sickle cell disease.
        Br J Haematol. 2006; vol. 135: 254-263
        • Porter J.B.
        Concepts and goals in the management of transfusional iron overload.
        Am J Hematol. 2007; vol. 82: 1136-1139
        • St Pierre T.G.
        • et al.
        Noninvasive measurement and imaging of liver iron concentrations using proton magnetic resonance.
        Blood. 2005; vol. 105: 855-861
        • Borgna-Pignatti C.
        • Castriota-Scanderbeg A.
        Methods for evaluating iron stores and efficacy of chelation in transfusional hemosiderosis.
        Haematol. 1991; vol. 76 (Sep-Oct 1991): 409-413
        • Adamkiewicz T.V.
        • et al.
        Serum ferritin level changes in children with sickle cell disease on chronic blood transfusion are nonlinear and are associated with iron load and liver injury.
        Blood. 2009; vol. 114: 4632-4638
        • Brown K.
        • et al.
        Hepatic iron overload in children with sickle cell anemia on chronic transfusion therapy.
        J Pedia Hematol Oncol. 2009; vol. 31: 309-312
        • Borgna-Pignatti C.
        • Marsella M.
        Iron chelation in thalassemia major.
        Clin Ther. 2015; vol. 37: 2866-2877