94
Views
0
CrossRef citations to date
0
Altmetric
Review

What is the role of complement in bystander hemolysis? Old concept, new insights

, , &
Pages 107-116 | Received 07 Jan 2024, Accepted 24 Apr 2024, Published online: 06 May 2024

References

  • Dameshek W. Autoimmunity: theoretical aspects. Ann N Y Acad Sci. 1965;124(1):6–28. doi: 10.1111/j.1749-6632.1965.tb18938.x
  • Petz LD. Bystander immune cytolysis. Transfus Med Rev. 2006;20(2):110–140. doi: 10.1016/j.tmrv.2005.11.002
  • King KE, Shirey RS, Lankiewicz MW, et al. Delayed hemolytic transfusion reactions in sickle cell disease: simultaneous destruction of recipients’ red cells. Transfusion (Paris). 1997;37(4):376–381. doi: 10.1046/j.1537-2995.1997.37497265337.x
  • Scheunemann LP, Ataga KI. Delayed hemolytic transfusion reaction in sickle cell disease. Am J Med Sci. 2010;339(3):266–269. doi: 10.1097/MAJ.0b013e3181c70e14
  • Merle NS, Boudhabhay I, Leon J, et al. Complement activation during intravascular hemolysis: implication for sickle cell disease and hemolytic transfusion reactions. Transfus Clin Biol. 2019;26(2):116–124. doi: 10.1016/j.tracli.2019.02.008
  • Walport MJ, Mackay IR, Rosen FS. Complement. N Engl J Med. 2001;344(14):1058–1066. doi: 10.1056/NEJM200104053441406
  • Gavriilaki E, Brodsky RA. Complementopathies and precision medicine. J Clin Investig. 2020;130(5):2152–2163. doi: 10.1172/JCI136094
  • Sarma JV, Ward PA. The complement system. Cell Tissue Res. 2011;343(1):227–235. doi: 10.1007/s00441-010-1034-0
  • Neth O, Jack DL, Dodds AW, et al. Mannose-binding lectin binds to a range of clinically relevant microorganisms and promotes complement deposition. Infect Immun. 2000;68(2):688–693. doi: 10.1128/IAI.68.2.688-693.2000
  • Yuan X, Gavriilaki E, Thanassi JA, et al. Small-molecule factor D inhibitors selectively block the alternative pathway of complement in Paroxysmal Nocturnal Hemoglobinuria and atypical hemolytic uremic syndrome. Haematologica. 2017;102(3):466–475. doi: 10.3324/haematol.2016.153312
  • Pangburn MK, Müller-Eberhard HJ. Initiation of the alternative complement pathway due to spontaneous hydrolysis of the thioester of C3 a. Annals Of The New York Academy Of Sciences. 1983;421(1):291–298. doi: 10.1111/j.1749-6632.1983.tb18116.x
  • Vaught AJ, Gavriilaki E, Hueppchen N, et al. Direct evidence of complement activation in HELLP syndrome: a link to atypical hemolytic uremic syndrome. Exp Hematol. 2016;44(5):390–398. doi: 10.1016/j.exphem.2016.01.005
  • Brady TM, Pruette C, Loeffler LF, et al. Typical hus: evidence of acute phase complement activation from a daycare outbreak. J Clin Exp Nephrol. 2016;1(2). doi: 10.21767/2472-5056.100011
  • Gavriilaki M, Kimiskidis VK, Gavriilaki E. Precision medicine in neurology: the inspirational paradigm of complement therapeutics. Pharmaceuticals (Basel). 2020;13(11):341. doi: 10.3390/ph13110341
  • Tampaki A, Gavriilaki E, Varelas C, et al. Complement in sickle cell disease and targeted therapy: I know one thing, that I know nothing. Blood Rev. 2021;48:100805. doi: 10.1016/j.blre.2021.100805
  • Baines AC, Brodsky RA. Complementopathies. Blood Rev. 2017;31(4):213–223. doi: 10.1016/j.blre.2017.02.003
  • Gavriilaki E, de Latour RP, Risitano AM. Advancing therapeutic complement inhibition in hematologic diseases: PNH and beyond. Blood. 2022;139(25):3571–3582. doi: 10.1182/blood.2021012860
  • Moosavi MM, Duncan A, Stowell SR, et al. Passenger lymphocyte Syndrome; a Review of the Diagnosis, treatment, and proposed detection protocol. Transfus Med Rev. 2020;34(3):178–187. doi: 10.1016/j.tmrv.2020.06.004
  • Oziel-Taieb S, Faucher-Barbey C, Chabannon C, et al. Early and fatal immune haemolysis after so-called “minor” ABO-Incompatible peripheral blood stem cell allotransplantation. Bone Marrow Transplant. 1997;19(11):1155–1156. doi: 10.1038/sj.bmt.1700794
  • Greeno EW, Perry EH, Ilstrup SJ, et al. Exchange transfusion the hard way: massive hemolysis following transplantation of bone marrow with minor ABO incompatibility. Transfusion (Paris). 1996;36(1):71–74. doi: 10.1046/j.1537-2995.1996.36196190519.x
  • Toren A, Dacosta Y, Manny N, et al. Passenger B-lymphocyte-induced severe hemolytic disease after allogeneic peripheral blood stem cell transplantation [letter]. Blood. 1996;87(2):843–844. doi: 10.1182/blood.V87.2.843.bloodjournal872843
  • Swanson JL, Sastamoinen RM, Steeper TA, et al. Gm allotyping to determine the origin of red cell antibodies in recipients of solid organ transplants. Vox Sang. 1987;52(1–2):75–78. doi: 10.1111/j.1423-0410.1987.tb02994.x
  • Gajewski JL, Petz LD, Calhoun L, et al. Hemolysis of transfused group O red blood cells in minor ABO-Incompatible unrelated-donor bone marrow transplants in patients receiving cyclosporine without posttransplant methotrexate. Blood. 1992;79(11):3076–3085. doi: 10.1182/blood.V79.11.3076.bloodjournal79113076
  • Hows J, Beddow K, Gordon-Smith E, et al. Donor-derived red blood cell antibodies and immune hemolysis after allogeneic bone marrow transplantation. Blood. 1986;67(1):177–181. doi: 10.1182/blood.V67.1.177.177
  • Klumpp TR. Immunohematologic complications of bone marrow transplantation. Bone Marrow Transplant. 1991;8(3):159–170.
  • Sokol RJ, Stamps R, Booker DJ, et al. Posttransplant immune-mediated hemolysis. Transfusion (Paris). 2002;42(2):198–204. doi: 10.1046/j.1537-2995.2002.00026.x
  • Tiplady CW, Fitzgerald JM, Jackson GH, et al. Massive haemolysis in a group a recipient of a group O peripheral blood stem cell allogeneic transplant. Transfus Med. 2001;11(6):455–458. doi: 10.1046/j.1365-3148.2001.00334.x
  • de Bruijn S, Philipse E, Couttenye MM, et al. Passenger lymphocyte syndrome (PLS): a single-center retrospective analysis of minor ABO-Incompatible liver transplants. J Clin Transl Hepatol. 2017;5(1):9–15. doi: 10.14218/JCTH.2016.00072
  • Mavrikou I, Chatzidimitriou D, Skoura L, et al. Molecular advances in sinusoidal obstruction syndrome/Veno-occlusive disease. Int J Mol Sci. 2023;24(6):6. doi: 10.3390/ijms24065620
  • Halahleh K, Arai Y, Gavriilaki E. Post-transplant complications. Blood Cell Therapy. 2023;6(1):23–29. doi: 10.31547/bct-2022-021
  • Roumenina LT, Bartolucci P, Pirenne F. The role of complement in post-transfusion hemolysis and hyperhemolysis reaction. Transfus Med Rev. 2019;33(4):225–230. doi: 10.1016/j.tmrv.2019.09.007
  • Mota M, Bley C, Aravechia MG, et al. Autoantibody formation after alloimmunization inducing bystander immune hemolysis. Immunohematology. 2009;25(1):9–12. doi: 10.21307/immunohematology-2019-223
  • Flegel WA. Pathogenesis and mechanisms of Antibody-Mediated Hemolysis. Transfusion (Paris). 2015;55 Suppl 2:S47–58. doi: 10.1111/trf.13147
  • Greene DL, Khan S. Reactive lysis–a phenomenon of delayed hemolytic transfusion reactions. Immunohematology. 1993;9(3):74–77. doi: 10.21307/immunohematology-2019-962
  • Björk I, Ylinenjärvi K, Olson ST, et al. Decreased affinity of recombinant antithrombin for heparin due to increased glycosylation. Biochem J. 1992;286(Pt 3):793–800. doi: 10.1042/bj2860793
  • Cox KO, Keast D. Erythrocyte autoantibodies induced in mice immunized with rat erythrocytes. Immunology. 1973;25(3):531–539.
  • Cox KO, Keast D. Autoimmune haemolytic anaemia induced in mice immunized with rat erythrocytes. Clin Exp Immunol. 1974;17(2):319–327.
  • Naysmith JD, Ortega-Pierres MG, Elson CJ. Rat erythrocyte-induced anti-erythrocyte autoantibody production and control in normal mice. Immunol Rev. 1981;55(1):55–87. doi: 10.1111/j.1600-065x.1981.tb00339.x
  • Cook IA. Primary rhesus immunization of male volunteers. Br J Haematol. 1971;20(4):369–375. doi: 10.1111/j.1365-2141.1971.tb07048.x
  • Beard ME, Pemberton J, Blagdon J, et al. Rh immunization following incompatible blood transfusion and a possible long-term complication of anti-D immunoglobulin therapy. J Med Genet. 1971;8(3):317–320. doi: 10.1136/jmg.8.3.317
  • Argiolu F, Diana G, Arnone M, et al. High-dose intravenous immunoglobulin in the management of autoimmune hemolytic anemia complicating thalassemia major. Acta Haematol. 1990;83(2):65–68. doi: 10.1159/000205170
  • Pirenne F. The cause and pathogenesis of hemolytic transfusion reactions in sickle-cell disease. Curr Opin Hematol. 2019;26(6):488–494. doi: 10.1097/MOH.0000000000000546
  • Win N, New H, Lee E, et al. Hyperhemolysis syndrome in sickle cell disease: case report (recurrent episode) and literature review. Transfusion (Paris). 2008;48(6):1231–1238. doi: 10.1111/j.1537-2995.2008.01693.x
  • Zupańska B, Uhrynowska M, Konopka L. Transfusion-related acute lung injury due to granulocyte-agglutinating antibody in a patient with paroxysmal nocturnal hemoglobinuria. Transfusion (Paris). 1999;39(9):944–947. doi: 10.1046/j.1537-2995.1999.39090944.x
  • Siddon AJ, Kenney BC, Hendrickson JE, et al. Delayed haemolytic and serologic transfusion reactions: pathophysiology, treatment and prevention. Curr Opin Hematol. 2018;25(6):459–467. doi: 10.1097/MOH.0000000000000462
  • Vidler JB, Gardner K, Amenyah K, et al. Delayed haemolytic transfusion reaction in adults with sickle cell disease: a 5‐year experience. Br J Haematol. 2015;169(5):746–753. doi: 10.1111/bjh.13339
  • Talano J-AM, Hillery CA, Gottschall JL, et al. Delayed hemolytic transfusion reaction/hyperhemolysis syndrome in children with sickle cell disease. Pediatrics. 2003;111(6 Pt 1):e661–5. doi: 10.1542/peds.111.6.e661
  • Habibi A, Mekontso‐Dessap A, Guillaud C, et al. Delayed hemolytic transfusion reaction in adult sickle‐cell disease: presentations, outcomes, and treatments of 99 referral center episodes. Am J Hematol. 2016;91(10):989–994. doi: 10.1002/ajh.24460
  • Narbey D, Habibi A, Chadebech P, et al. Incidence and predictive score for delayed hemolytic transfusion reaction in adult patients with sickle cell disease. Am J Hematol. 2017;92(12):1340–1348. doi: 10.1002/ajh.24908
  • Milner PF, Squires JE, Larison PJ, et al. Posttransfusion crises in sickle cell anemia: role of delayed hemolytic reactions to transfusion. South Med J. 1985;78(12):1462–1469. doi: 10.1097/00007611-198512000-00016
  • Cullis JO, Win N, Dudley JM, et al. Post-transfusion hyperhaemolysis in a patient with sickle cell disease: use of steroids and intravenous immunoglobulin to prevent further red cell destruction. Vox Sang. 1995;69(4):355–357. doi: 10.1111/j.1423-0410.1995.tb00373.x
  • Petz LD, Calhoun L, Shulman IA, et al. The sickle cell hemolytic transfusion reaction syndrome. Transfusion (Paris). 1997;37(4):382–392. doi: 10.1046/j.1537-2995.1997.37497265338.x
  • Grainger JD, Makar Y, McManus A, et al. Refractory hyperhaemolysis in a patient with Beta-Thalassaemia Major. Transfus Med. 2001;11(1):55–57. doi: 10.1046/j.1365-3148.2001.00278.x
  • Gavriilaki E, Christodoulou I, Koravou E-E, et al. Pre- and post-transfusion complement activation in transfusion-dependent β-thalassaemia. Hemasphere. 2018;2(5):e58. doi: 10.1097/HS9.0000000000000058
  • Raturi M, Dhawan V, Kusum A. A probable atypical immunologic reaction leading to bystander hemolysis after blood transfusion. Indian J Pathol Microbiol. 2021;64(3):614–617. doi: 10.4103/IJPM.IJPM_824_20
  • Strobel E. Hemolytic transfusion reactions. Transfus Med Hemother. 2008;35(5):346–353. doi: 10.1159/000154811
  • Hendrickson JE, Fasano RM. Management of hemolytic transfusion reactions. Hematology Am Soc Hematol Educ Program. 2021;2021(1):704–709. doi: 10.1182/hematology.2021000308
  • Win N, Lucas S, Hebballi S, et al. Histopathological evidence for macrophage activation driving Post‐transfusion hyperhaemolysis syndrome. Br J Haematol. 2019;186(3):499–502. doi: 10.1111/bjh.15925
  • Hinton R, Haji R, Kaczmarski R, et al. Hyperhaemolysis caused by Anti-HI Antibodies in a patient with myelodysplastic syndrome following a first ever red cell transfusion. Transfus Med. 2023;33(4):349–351. doi: 10.1111/tme.12971
  • Eberly LA, Osman D, Collins NP. Hyperhemolysis syndrome without underlying hematologic disease. Case Rep Hematol. 2015;2015:180526. doi: 10.1155/2015/180526
  • Darabi K, Dzik S. Hyperhemolysis syndrome in anemia of chronic disease. Transfusion (Paris). 2005;45(12):1930–1933. doi: 10.1111/j.1537-2995.2005.00608.x
  • Brodsky RA. Paroxysmal nocturnal hemoglobinuria. Blood. 2014;124(18):2804–2811. doi: 10.1182/blood-2014-02-522128
  • Gavriilaki E, Tragiannidis A, Papathanasiou M, et al. Aplastic anemia and Paroxysmal Nocturnal Hemoglobinuria in children and adults in two centers of Northern Greece. Front Oncol. 2022;12:947410. doi: 10.3389/fonc.2022.947410
  • Kokoris SI, Gavriilaki E, Miari A, et al. Renal involvement in paroxysmal nocturnal hemoglobinuria: an update on clinical features, pathophysiology and treatment. Hematology. 2018;23(8):558–566. doi: 10.1080/10245332.2018.1444563
  • Hill A, DeZern AE, Kinoshita T, et al. Paroxysmal nocturnal haemoglobinuria. Nat Rev Dis Primers. 2017;3(1):17028. doi: 10.1038/nrdp.2017.28
  • Sirchia G, Ferrone S, Mercuriali F. Leukocyte antigen-antibody reaction and lysis of paroxysmal nocturnal hemoglobinuria erythrocytes. Blood. 1970;36(3):334–336. doi: 10.1182/blood.V36.3.334.334
  • Nakakuma H, Hidaka M, Nagakura S, et al. Expression of cryptantigen Th on Paroxysmal Nocturnal Hemoglobinuria Erythrocytes in Association with a hemolytic exacerbation. J Clin Invest. 1995;96(1):201–206. doi: 10.1172/JCI118021
  • Nakakuma H. Mechanism of intravascular hemolysis in paroxysmal nocturnal hemoglobinuria (PNH). Am J Hematol. 1996;53(1):22–29. doi: 10.1002/(SICI)1096-8652(199609)53:1<22:AID-AJH5>3.0.CO;2-7
  • Rosse WF. Paroxysmal nocturnal hemoglobinuria: the biochemical defects and the clinical syndrome. Blood Rev. 1989;3(3):192–200. doi: 10.1016/0268-960X(89)90016-7
  • Berkowitz FE. Hemolysis and infection: categories and mechanisms of their interrelationship. Rev Infect Dis. 1991;13(6):1151–1162. doi: 10.1093/clinids/13.6.1151
  • Kasper ML, Miller WJ, Jacob HS. G6PD-Deficiency infectious haemolysis: a complement dependent innocent bystander phenomenon. Br J Haematol. 1986;63(1):85–91. doi: 10.1111/j.1365-2141.1986.tb07498.x
  • Green A, Jones H, Nero A, et al. A case of hyperhemolysis syndrome in sickle cell disease and concomitant COVID-19. Transfus Apher Sci. 2023;62(4):103712. doi: 10.1016/j.transci.2023.103712
  • Garratty G. The James Blundell award lecture 2007: do we really understand immune red cell destruction? Transfus Med. 2008;18(6):321–334. doi: 10.1111/j.1365-3148.2008.00891.x
  • Thompson RA, Rowe DS. Reactive haemolysis–a distinctive form of red cell lysis. Immunology. 1968;14(5):745–762.
  • Thompson RA, Lachmann PJ. Reactive lysis: the complement-mediated lysis of unsensitized cells. I. The characterization of the indicator factor and its identification as C7. J Exp Med. 1970;131(4):629–641. doi: 10.1084/jem.131.4.629
  • Lachmann PJ, Thompson RA. Reactive lysis: the complement-mediated lysis of unsensitized cells. II. The characterization of activated reactor as C56 and the participation of C8 and C9. J Exp Med. 1970;131(4):643–657. doi: 10.1084/jem.131.4.643
  • Götze O, Müller-Eberhard HJ. Lysis of erythrocytes by complement in the absence of antibody. J Exp Med. 1970;132(5):898–915. doi: 10.1084/jem.132.5.898
  • Goldman JN, Ruddy S, Austen KF. Reaction mechanisms of nascent C567 (reactive lysis). I. Reaction characteristics for production of EC567 and lysis by C8 and C9. J Immunol. 1972;109(2):353–359. doi: 10.4049/jimmunol.109.2.353
  • McLeod B, Baker P, Behrends C, et al. Studies of the inhibition of C56-initiated lysis (reactive lysis). IV. Antagonism of the inhibitory activity C567-INH by poly-L-Lysine. Immunology. 1975;28(2):379–390.
  • Salama A, Bhakdi S, Mueller-Eckhardt C. Evidence suggesting the occurrence of C3-independent intravascular immune hemolysis. Reactive hemolysis in vivo. Transfusion (Paris). 1987;27(1):49–53. doi: 10.1046/j.1537-2995.1987.27187121473.x
  • Salama A, Mueller-Eckhardt C. Binding of fluid phase C3b to nonsensitized bystander human red cells. A Model for in vivo effects of complement activation on blood cells. Transfusion (Paris). 1985;25(6):528–534. doi: 10.1046/j.1537-2995.1985.25686071424.x
  • Chonat S, Mener A, Verkerke H, et al. Role of complement in Alloimmunization and Hyperhemolysis. Curr Opin Hematol. 2020;27(6):406–414. doi: 10.1097/MOH.0000000000000610
  • Lutz HU, Bussolino F, Flepp R, et al. Naturally occurring anti-band-3 antibodies and complement together mediate phagocytosis of oxidatively stressed human erythrocytes. Proc Natl Acad Sci U S A. 1987;84(21):7368–7372. doi: 10.1073/pnas.84.21.7368
  • Arese P, Turrini F, Schwarzer E. Band 3/Complement-mediated recognition and removal of normally senescent and pathological human erythrocytes. Cell Physiol Biochem. 2005;16(4–6):133–146. doi: 10.1159/000089839
  • Garratty G. Autoantibodies induced by blood transfusion. Transfusion (Paris). 2004;44(1):5–9. doi: 10.1111/j.0041-1132.2004.00658.x
  • Balbuena-Merle R, Hendrickson JE. Red blood cell alloimmunization and delayed hemolytic transfusion reactions in patients with sickle cell disease. Transfus Clin Biol. 2019;26(2):112–115. doi: 10.1016/j.tracli.2019.02.003
  • Mwesigwa S, Moulds JM, Chen A, et al. Whole-exome sequencing of sickle cell disease patients with hyperhemolysis syndrome suggests a role for rare variation in disease predisposition. Transfusion (Paris). 2018;58(3):726–735. doi: 10.1111/trf.14431
  • Garred P, Honoré C, Ma YJ, et al. MBL2, FCN1, FCN2 and FCN3-the genes behind the initiation of the lectin pathway of complement. Mol Immunol. 2009;46(14):2737–2744. doi: 10.1016/j.molimm.2009.05.005
  • Yachnin S, Ruthenberg JM. The initiation and enhancement of human red cell lysis by activators of the first component of complement and by first component esterase; studies using normal red cells and red cells from patients with paroxysmal nocturnal hemoglobinuria. J Clin Invest. 1965;44(4):518–534. doi: 10.1172/JCI105165
  • Yachnin S. The hemolysis of red cells from patients with paroxysmal nocturnal hemoglobinuria by partially purified sub-components of the third complement component. J Clin Invest. 1965;44(9):1534–1546. doi: 10.1172/JCI105260
  • Bakács T, Tusnády G, Végh Z, et al. Red-Cell Bound Anti-A Is More Efficient than Anti-B in competition for fluid phase complement. Immunol Lett. 1993;35(3):213–217. doi: 10.1016/0165-2478(93)90185-5
  • Lint TF, Behrends CL, Baker PJ, et al. Activation of the complement attack mechanism in the fluid phase and its control by C567-INH: lysis of normal erythrocytes initiated by Zymosan, Endotoxin, and immune complexes. J Immunol. 1976;117(5 Pt 1):1440–1446. doi: 10.4049/jimmunol.117.5_Part_1.1440
  • Gavriilaki E, Mainou M, Christodoulou I, et al. In vitro evidence of complement activation in patients with sickle cell disease. Haematologica. 2017;102(12):e481–e482. doi: 10.3324/haematol.2017.174201
  • Varelas C, Tampaki A, Sakellari I, et al. Complement in sickle cell disease: are we ready for prime time? J Blood Med. 2021;12:177–187. doi: 10.2147/JBM.S287301
  • Roumenina LT, Rayes J, Lacroix-Desmazes S, et al. Heme: modulator of plasma systems in hemolytic diseases. Trends Mol Med. 2016;22(3):200–213. doi: 10.1016/j.molmed.2016.01.004
  • Baek JH, D’Agnillo F, Vallelian F, et al. Hemoglobin-driven pathophysiology is an in vivo consequence of the red blood cell storage lesion that can Be attenuated in Guinea pigs by haptoglobin therapy. J Clin Invest. 2012;122(4):1444–1458. doi: 10.1172/JCI59770
  • Merle NS, Grunenwald A, Figueres M-L, et al. Characterization of renal injury and inflammation in an experimental Model of intravascular hemolysis. Front Immunol. 2018;9:179. doi: 10.3389/fimmu.2018.00179
  • Merle NS, Grunenwald A, Rajaratnam H, et al. Intravascular hemolysis activates complement via cell-free heme and heme-Loaded Microvesicles. JCI Insight. 2018;3(12). doi: 10.1172/jci.insight.96910
  • Merle NS, Paule R, Leon J, et al. P-Selectin drives complement attack on endothelium during intravascular hemolysis in TLR-4/Heme-dependent manner. Proc Natl Acad Sci U S A. 2019;116(13):6280–6285. doi: 10.1073/pnas.1814797116
  • Wiatr M, Merle NS, Boudhabhay I, et al. Anti-inflammatory activity of intravenous immunoglobulin through scavenging of heme. Mol Immunol. 2019;111:205–208. doi: 10.1016/j.molimm.2019.04.020
  • Chonat S, Quarmyne M-O, Bennett CM, et al. Contribution of alternative complement pathway to delayed hemolytic transfusion reaction in sickle cell disease. Haematologica. 2018;103(10):e483–e485. doi: 10.3324/haematol.2018.194670
  • Roumenina LT, Radanova M, Atanasov BP, et al. Heme interacts with C1q and inhibits the classical complement pathway. J Biol Chem. 2011;286(18):16459–16469. doi: 10.1074/jbc.M110.206136
  • May O, Merle NS, Grunenwald A, et al. Heme drives susceptibility of glomerular endothelium to complement overactivation due to inefficient upregulation of heme oxygenase-1. Front Immunol. 2018;9:3008. doi: 10.3389/fimmu.2018.03008
  • Frimat M, Tabarin F, Dimitrov JD, et al. Complement activation by heme as a secondary hit for atypical hemolytic uremic syndrome. Blood. 2013;122(2):282–292. doi: 10.1182/blood-2013-03-489245
  • Pawluczkowycz AW, Lindorfer MA, Waitumbi JN, et al. Hematin promotes complement alternative pathway-mediated deposition of C3 activation fragments on human erythrocytes: potential implications for the Pathogenesis of Anemia in malaria. J Immunol. 2007;179(8):5543–5552. doi: 10.4049/jimmunol.179.8.5543
  • Teixeira RS, Terse-Ramos R, Ferreira TA, et al. Associations between endothelial dysfunction and clinical and laboratory parameters in children and adolescents with sickle cell anemia. PLOS ONE. 2017;12(9):e0184076. doi: 10.1371/journal.pone.0184076
  • Kucukal E, Ilich A, Key NS, et al. Red blood cell adhesion to Heme‐activated endothelial cells reflects clinical phenotype in sickle cell disease. Am J Hematol. 2018;93(8):1050–1060. doi: 10.1002/ajh.25159
  • Wang RH, Phillips G, Medof ME, et al. Activation of the alternative complement pathway by exposure of Phosphatidylethanolamine and phosphatidylserine on erythrocytes from sickle cell disease patients. J Clin Invest. 1993;92(3):1326–1335. doi: 10.1172/JCI116706
  • McLeod B, Lint TF, Baker P, et al. Studies on the inhibition of C56-initiated lysis (reactive lysis). V. The Roleof C567-INH in the Regulation of Complement-Dependent Haemolysis initiated by cobravenom factor. Immunology. 1975;28(4):741–754. doi: 10.1159/000231255
  • Lee M, Guo J-P, Schwab C, et al. Selective inhibition of the membrane attack complex of complement by low molecular weight components of the aurin tricarboxylic acid synthetic complex. Neurobiol Aging. 2012;33(10):2237–2246. doi: 10.1016/j.neurobiolaging.2011.12.005
  • Hebbel RP, Miller WJ. Phagocytosis of sickle erythrocytes: immunologic and oxidative determinants of hemolytic anemia. Blood. 1984;64(3):733–741. doi: 10.1182/blood.V64.3.733.733
  • Lin Z, Schmidt CQ, Koutsogiannaki S, et al. Complement C3dg-mediated erythrophagocytosis: implications for Paroxysmal Nocturnal Hemoglobinuria. Blood. 2015;126(7):891–894. doi: 10.1182/blood-2015-02-625871
  • Win N. Hyperhemolysis syndrome in sickle cell disease. Expert Rev Hematol. 2009;2(2):111–115. doi: 10.1586/ehm.09.2
  • Liu C, Marshall P, Schreibman I, et al. Interaction between terminal complement proteins C5b-7 and anionic phospholipids. Blood. 1999;93(7):2297–2301. doi: 10.1182/blood.V93.7.2297
  • Test ST, Woolworth VS. Defective Regulation of Complement by the sickle erythrocyte: evidence for a defect in control of membrane attack complex formation. Blood. 1994;83(3):842–852. doi: 10.1182/blood.V83.3.842.842
  • Merrill SA, Brodsky RA, Lanzkron SM, et al. A case-control analysis of hyperhemolysis syndrome in adults and laboratory correlates of complement involvement. Transfusion (Paris). 2019;59(10):3129–3139. doi: 10.1111/trf.15445
  • Chadebech P, Habibi A, Nzouakou R, et al. Delayed hemolytic transfusion reaction in sickle cell disease patients: evidence of an emerging syndrome with suicidal red blood cell death. Transfusion (Paris). 2009;49(9):1785–1792.
  • Nicholson-Weller A, March JP, Rosen CE, et al. Surface membrane expression by human blood leukocytes and Platelets of Decay-Accelerating Factor, a regulatory protein of the complement system. Blood. 1985;65(5):1237–1244. doi: 10.1182/blood.V65.5.1237.1237
  • Obaid JMAS, Abo El-Nazar SY, Ghanem AM, et al. Expression of CD55 on red blood cells of β-thalassemia patients. Hemoglobin. 2014;38(5):339–344. doi: 10.3109/03630269.2014.935787
  • Gupta S, Fenves A, Nance ST, et al. “Sunny.” hyperhemolysis syndrome in a patient without a hemoglobinopathy, unresponsive to treatment with eculizumab. Transfusion (Paris). 2015;55(3):623–628. doi: 10.1111/trf.12876
  • Weinstock C, Möhle R, Dorn C, et al. Successful use of eculizumab for treatment of an acute hemolytic reaction after ABO ‐incompatible red blood cell transfusion. Transfusion (Paris). 2015;55(3):605–610. doi: 10.1111/trf.12882
  • Dumas G, Habibi A, Onimus T, et al. Eculizumab salvage therapy for delayed hemolysis transfusion reaction in sickle cell disease patients. Blood. 2016;127(8):1062–1064. doi: 10.1182/blood-2015-09-669770
  • Vlachaki E, Gavriilaki E, Kafantari K, et al. Successful outcome of Hyperhemolysis in sickle cell disease following multiple lines of treatment: the role of complement inhibition. Hemoglobin. 2018;42(5–6):339–341. doi: 10.1080/03630269.2018.1540353
  • Mpinganzima C, Haaland A, Holm AGV, et al. Two consecutive episodes of severe delayed hemolytic transfusion reaction in a sickle cell disease patient. Case Rep Hematol. 2020;2020:2765012. doi: 10.1155/2020/2765012
  • Patel I, Odak M, Douedi S, et al. Eculizumab as a treatment for Hyper-Haemolytic and aplastic crisis in sickle cell disease. Eur J Case Rep Intern Med. 2021;8(10):002824. doi: 10.12890/2021_002824
  • Zanetti RC, Vasta LM, Romanelli K, et al. Management of hyperhemolysis in β-thalassemia with multiple immunosuppressives, including complement blockade. J Pediatr Hematol Oncol. 2021;43(8):e1145–e1147. doi: 10.1097/MPH.0000000000002059
  • Cannas G, Dubreuil L, Fichez A, et al. Delayed severe hemolytic transfusion reaction during pregnancy in a woman with β-thalassemia intermediate: successful outcome after eculizumab administration. Am J Case Rep. 2021;22:e931107. doi: 10.12659/AJCR.931107
  • Noda C, Sisler I. Long-term use of eculizumab for prolonged hemolysis following a delayed hemolytic transfusion reaction in pediatric sickle cell: a case report. J Pediatr Pharmacol Ther. 2022;27(6):569–572. doi: 10.5863/1551-6776-27.6.569
  • Shaulov A, Rund D, Filon D, et al. Successful treatment with plasma exchange in life-threatening hyperhemolytic syndrome unrelated to sickle cell disease. Transfusion (Paris). 2023;63(5):1100–1106. doi: 10.1111/trf.17302
  • Gavriilaki E, Sakellari I, Batsis I, et al. Transplant-associated thrombotic microangiopathy: incidence, prognostic factors, morbidity, and mortality in allogeneic hematopoietic cell transplantation. Clin Transplant. 2018;32(9):e13371. doi: 10.1111/ctr.13371
  • Gerber GF, Brodsky RA. Pegcetacoplan for Paroxysmal Nocturnal Hemoglobinuria. Blood. 2022;139(23):3361–3365. doi: 10.1182/blood.2021014868
  • Gavriilaki E, Papakonstantinou A, Agrios KA. Novel insights into factor D inhibition. Int J Mol Sci. 2022;23(13):13. doi: 10.3390/ijms23137216
  • Fattizzo B, Motta I. Rise of the planet of rare anemias: an update on emerging treatment strategies. Front Med. 2023;9:1097426. doi: 10.3389/fmed.2022.1097426
  • Pirenne F, Yazdanbakhsh K. How I safely transfuse patients with sickle-cell disease and manage delayed hemolytic transfusion reactions. Blood. 2018;131(25):2773–2781. doi: 10.1182/blood-2018-02-785964
  • Brodsky RA. Eculizumab and AHUS: To Stop or Not. Blood. 2021;137(18):2419–2420. doi: 10.1182/blood.2020010234
  • Brodsky RA. How I Treat Paroxysmal Nocturnal Hemoglobinuria. Blood. 2021;137(10):1304–1309. doi: 10.1182/blood.2019003812
  • Tsiftsoglou SA, Gavriilaki E, Touloumenidou T, et al. Targeted genotyping of COVID-19 patients reveals a signature of complement C3 and factor B coding SNPs associated with severe infection. Immunobiology. 2023;228(2):152351. doi: 10.1016/j.imbio.2023.152351
  • Gavriilaki E, Tsiftsoglou SA, Touloumenidou T, et al. Targeted genotyping of MIS-C patients reveals a potential alternative pathway mediated complement dysregulation during COVID-19 infection. Curr Issues Mol Biol. 2022;44(7):2811–2824. doi: 10.3390/cimb44070193
  • Asteris PG, Gavriilaki E, Touloumenidou T, et al. Genetic prediction of ICU hospitalization and mortality in COVID-19 patients using artificial neural networks. J Cell Mol Med. 2022;26(5):1445–1455. doi: 10.1111/jcmm.17098
  • Gavriilaki E, Dalampira D, Theodorakakou F, et al. Genetic and functional evidence of complement dysregulation in multiple myeloma patients with carfilzomib-induced thrombotic microangiopathy compared to controls. J Clin Med. 2022;11(12):3355. doi: 10.3390/jcm11123355
  • Varelas C, Gavriilaki E, Sakellari I, et al. Hemoglobinopathies and COVID-19: the experience of a center in Northern Greece. Hemoglobin. 2022;46(2):143–145. doi: 10.1080/03630269.2022.2090377
  • Evangelidis P, Venou T-M, Fani B, et al. On behalf of the International Hemoglobinopathy Research Network (INHERENT). Endocrinopathies in Hemoglobinopathies: what is the role of iron? Int J Mol Sci. 2023;24(22):22. doi: 10.3390/ijms242216263
  • Varelas C, Gavriilaki E. Sickle cell disease: Current understanding and future options. J Clin Med. 2023;12(18):18. doi: 10.3390/jcm12185943
  • Kountouris P, Stephanou C, Archer N, et al. The International Hemoglobinopathy Research Network (INHERENT): an International initiative to study the role of genetic modifiers in Hemoglobinopathies. Am J Hematol. 2021;96(11):E416–E420.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.