Main Article Content

Alessandro Matte
Filippo Mazzi
Enrica Federti
Oliviero Olivieri
Lucia De Franceschi


Sickle cell disease;, hemoglobinopathy, pathological hemoglobin, vaso-occlusive events


Sickle cell disease (SCD; ORPHA232; OMIM # 603903) is a chronic and invalidating disorder distributed worldwide, with high morbidity and mortality.  Given the disease complexity and the multiplicity of pathophysiological targets, development of new therapeutic options is critical, despite the positive effects of hydroxyurea (HU), for many years the only approved drug for SCD.

New therapeutic strategies might be divided into (1) pathophysiology-related novel therapies and (2) innovations in curative therapeutic options such as hematopoietic stem cell transplantation and gene therapy. The pathophysiology related novel therapies are: a) Agents which reduce sickling or prevent sickle red cell dehydration; b) Agents targeting SCD vasculopathy and sickle cell-endothelial adhesive events; c) Anti-oxidant agents.

This review highlights new therapeutic strategies in SCD and discusses future developments, research implications, and possible innovative clinical trials.



Download data is not yet available.

Abstract 5508
PDF Downloads 3052
HTML Downloads 481


1. Modell B, Darlison M. Global epidemiology of haemoglobin disorders and derived service indicators. Bulletin of the World Health Organization 2008;86:480-487.
2. Murray CJ, Vos T, Lozano R, et al. Disability-adjusted life years (DALYs) for 291 diseases and injuries in 21 regions, 1990-2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 2012;380:2197-2223.
3. Weatherall DJ, Clegg JB. Inherited haemoglobin disorders: an increasing global health problem. Bulletin of the World Health Organization 2001;79:704-712.
4. Piel FB, Patil AP, Howes RE, et al. Global epidemiology of sickle haemoglobin in neonates: a contemporary geostatistical model-based map and population estimates. Lancet 2013;381:142-151.
5. De Franceschi L, Cappellini MD, Olivieri O. Thrombosis and sickle cell disease. Semin Thromb Hemost 2011;37:226-236.
6. Eaton WA, Hofrichter J. Sickle cell hemoglobin polymerization. Advances in protein chemistry 1990;40:63-279.
7. De Franceschi L, Corrocher R. Established and experimental treatments for sickle cell disease. Haematologica 2004;89:348-356.
8. Ballas SK, Smith ED. Red blood cell changes during the evolution of the sickle cell painful crisis. Blood 1992;79:2154-2163.
9. Vinchi F, De Franceschi L, Ghigo A, et al. Hemopexin therapy improves cardiovascular function by preventing heme-induced endothelial toxicity in mouse models of hemolytic diseases. Circulation 2013;127:1317-1329.
10. Hebbel RP, Vercellotti G, Nath KA. A systems biology consideration of the vasculopathy of sickle cell anemia: the need for multi-modality chemo-prophylaxsis. Cardiovasc Hematol Disord Drug Targets 2009;9:271-292.
11. Telen MJ. Beyond hydroxyurea: new and old drugs in the pipeline for sickle cell disease. Blood 2016;127:810-819.
12. Manwani D, Frenette PS. Vaso-occlusion in sickle cell disease: pathophysiology and novel targeted therapies. Blood 2013;122:3892-3898.
13. Hebbel RP. Adhesion of sickle red cells to endothelium: myths and future directions. Transfus Clin Biol 2008;15:14-18.
14. Kalish BT, Matte A, Andolfo I, et al. Dietary omega-3 fatty acids protect against vasculopathy in a transgenic mouse model of sickle cell disease. Haematologica 2015;100:870-880.
15. Ataga KI, Kutlar A, Kanter J, et al. Crizanlizumab for the Prevention of Pain Crises in Sickle Cell Disease. N Engl J Med 2017;376:429-439.
16. Hidalgo A, Chang J, Jang JE, et al. Heterotypic interactions enabled by polarized neutrophil microdomains mediate thromboinflammatory injury. Nature medicine 2009;15:384-391.
17. Dalle Carbonare L, Matte A, Valenti MT, et al. Hypoxia-reperfusion affects osteogenic lineage and promotes sickle cell bone disease. Blood 2015;126:2320-2328.
18. Sabaa N, de Franceschi L, Bonnin P, et al. Endothelin receptor antagonism prevents hypoxia-induced mortality and morbidity in a mouse model of sickle-cell disease. J Clin Invest 2008;118:1924-1933.
19. Wieschhaus A, Khan A, Zaidi A, et al. Calpain-1 knockout reveals broad effects on erythrocyte deformability and physiology. Biochem J 2012;448:141-152.
20. Siciliano A, Turrini F, Bertoldi M, et al. Deoxygenation affects tyrosine phosphoproteome of red cell membrane from patients with sickle cell disease. Blood Cells Mol Dis 2010;44:233-242.
21. Yawn BP, Buchanan GR, Afenyi-Annan AN, et al. Management of sickle cell disease: summary of the 2014 evidence-based report by expert panel members. JAMA 2014;312:1033-1048.
22. Engert A, Balduini C, Brand A, et al. The European Hematology Association Roadmap for European Hematology Research: a consensus document. Haematologica 2016;101:115-208.
23. Platt OS. Hydroxyurea for the treatment of sickle cell anemia. N Engl J Med 2008;358:1362-1369.
24. Yarbro JW. Mechanism of action of hydroxyurea. Semin Oncol 1992;19:1-10.
25. Charache S. Mechanism of action of hydroxyurea in the management of sickle cell anemia in adults. Semin Hematol 1997;34:15-21.
26. Charache S, Terrin ML, Moore RD, et al. Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. Investigators of the Multicenter Study of Hydroxyurea in Sickle Cell Anemia [see comments]. New England Journal of Medicine 1995;332:1317-1322.
27. Saleh AW, Hillen HF, Duits AJ. Levels of endothelial, neutrophil and platelet-specific factors in sickle cell anemia patients during hydroxyurea therapy. Acta Haematol 1999;102:31-37.
28. Ware RE, de Montalembert M, Tshilolo L, et al. Sickle cell disease. Lancet 2017;390:311-323.
29. Rigano P, De Franceschi L, Sainati L, et al. Real-life experience with hydroxyurea in sickle cell disease: A multicenter study in a cohort of patients with heterogeneous descent. Blood Cells Mol Dis 2018;69:82-89.
30. Pule GD, Mowla S, Novitzky N, et al. A systematic review of known mechanisms of hydroxyurea-induced fetal hemoglobin for treatment of sickle cell disease. Expert Rev Hematol 2015;8:669-679.
31. Jison ML, Munson PJ, Barb JJ, et al. Blood mononuclear cell gene expression profiles characterize the oxidant, hemolytic, and inflammatory stress of sickle cell disease. Blood 2004;104:270-280.
32. Stettler N, McKiernan CM, Melin CQ, et al. Proportion of adults with sickle cell anemia and pain crises receiving hydroxyurea. JAMA 2015;313:1671-1672.
33. Wong TE, Brandow AM, Lim W, et al. Update on the use of hydroxyurea therapy in sickle cell disease. Blood 2014;124:3850-3857.
34. Crosby WH, Dameshek W. The significance of hemoglobinemia and associated hemosideriinuria, with particular references to various types of hemolytic anemia. J Lab Clin Med 1951;38:829.
35. Voskaridou E, Christoulas D, Bilalis A, et al. The effect of prolonged administration of hydroxyurea on morbidity and mortality in adult patients with sickle cell syndromes: results of a 17-year, single-center trial (LaSHS). Blood 2010;115:2354-2363.
36. Wang WC, Ware RE, Miller ST, et al. Hydroxycarbamide in very young children with sickle-cell anaemia: a multicentre, randomised, controlled trial (BABY HUG). Lancet 2011;377:1663-1672.
37. Brousse V, Gandhi S, de Montalembert M, et al. Combined blood transfusion and hydroxycarbamide in children with sickle cell anaemia. Br J Haematol 2013;160:259-261.
38. Bernaudin F, Verlhac S, Arnaud C, et al. Long-term treatment follow-up of children with sickle cell disease monitored with abnormal transcranial Doppler velocities. Blood 2016;127:1814-1822.
39. Ware RE, Davis BR, Schultz WH, et al. Hydroxycarbamide versus chronic transfusion for maintenance of transcranial doppler flow velocities in children with sickle cell anaemia-TCD With Transfusions Changing to Hydroxyurea (TWiTCH): a multicentre, open-label, phase 3, non-inferiority trial. Lancet 2016;387:661-670.
40. Helton KJ, Adams RJ, Kesler KL, et al. Magnetic resonance imaging/angiography and transcranial Doppler velocities in sickle cell anemia: results from the SWiTCH trial. Blood 2014;124:891-898.
41. Inoue S, Kodjebacheva G, Scherrer T, et al. Adherence to hydroxyurea medication by children with sickle cell disease (SCD) using an electronic device: a feasibility study. Int J Hematol 2016;104:200-207.
42. Han J, Bhat S, Gowhari M, et al. Impact of a Clinical Pharmacy Service on the Management of Patients in a Sickle Cell Disease Outpatient Center. Pharmacotherapy 2016;36:1166-1172.
43. Green NS, Manwani D, Qureshi M, et al. Decreased fetal hemoglobin over time among youth with sickle cell disease on hydroxyurea is associated with higher urgent hospital use. Pediatr Blood Cancer 2016;63:2146-2153.
44. Smaldone A, Findley S, Manwani D, et al. HABIT, a Randomized Feasibility Trial to Increase Hydroxyurea Adherence, Suggests Improved Health-Related Quality of Life in Youths with Sickle Cell Disease. J Pediatr 2018;197:177-185 e172.
45. Ansong D, Akoto AO, Ocloo D, et al. Sickle cell disease: management options and challenges in developing countries. Mediterr J Hematol Infect Dis 2013;5:e2013062.
46. Opoka RO, Ndugwa CM, Latham TS, et al. Novel use Of Hydroxyurea in an African Region with Malaria (NOHARM): a trial for children with sickle cell anemia. Blood 2017;130:2585-2593.
47. Tayo BO, Akingbola TS, Saraf SL, et al. Fixed Low-Dose Hydroxyurea for the Treatment of Adults with Sickle Cell Anemia in Nigeria. Am J Hematol 2018.
48. Stocker JW, De Franceschi L, McNaughton-Smith GA, et al. ICA-17043, a novel Gardos channel blocker, prevents sickled red blood cell dehydration in vitro and in vivo in SAD mice. Blood 2003;101:2412-2418.
49. De Franceschi L, Saadane N, Trudel M, et al. Treatment with oral clotrimazole blocks Ca(2+)-activated K+ transport and reverses erythrocyte dehydration in transgenic SAD mice. A model for therapy of sickle cell disease. J Clin Invest 1994;93:1670-1676.
50. Telen MJ. Developing new pharmacotherapeutic approaches to treating sickle-cell disease. ISBT Sci Ser 2017;12:239-247.
51. De Franceschi L, Franco RS, Bertoldi M, et al. Pharmacological inhibition of calpain-1 prevents red cell dehydration and reduces Gardos channel activity in a mouse model of sickle cell disease. FASEB J 2013;27:750-759.
52. De Franceschi L. Pathophisiology of sickle cell disease and new drugs for the treatment. Mediterr J Hematol Infect Dis 2009;1:e2009024.
53. McNaughton-Smith GA, Burns JF, Stocker JW, et al. Novel inhibitors of the Gardos channel for the treatment of sickle cell disease. J Med Chem 2008;51:976-982.
54. De Franceschi L, Brugnara C, Rouyer-Fessard P, et al. Formation of dense erythrocytes in SAD mice exposed to chronic hypoxia: evaluation of different therapeutic regimens and of a combination of oral clotrimazole and magnesium therapies. Blood 1999;94:4307-4313.
55. Li Q, Henry ER, Hofrichter J, et al. Kinetic assay shows that increasing red cell volume could be a treatment for sickle cell disease. Proc Natl Acad Sci U S A 2017;114:E689-E696.
56. Dufu K, Oksenberg D. GBT440 reverses sickling of sickled red blood cells under hypoxic conditions in vitro. Hematol Rep 2018;10:7419.
57. Metcalf B, Chuang C, Dufu K, et al. Discovery of GBT440, an Orally Bioavailable R-State Stabilizer of Sickle Cell Hemoglobin. ACS Med Chem Lett 2017;8:321-326.
58. Oksenberg D, Dufu K, Patel MP, et al. GBT440 increases haemoglobin oxygen affinity, reduces sickling and prolongs RBC half-life in a murine model of sickle cell disease. Br J Haematol 2016;175:141-153.
59. Dufu K OD, Zhou C, Hutchaleelaha A, Archer DR. GTx011, a potent allosteric modifier of hemoglobin oxygen affinity, prevents RBC sickling in whole blood and prolongs RNC half-life in vivo in a murine model of sickle cell disease. In: Blood, editor. American Society of Hematology; 2014. p a217.
60. Patel M CP, Dufu K, Metcalf B, Sinha U. GTx011, an anti-sickling compound, improves SS blood rheology by reduction of HbS polymerization via allosteric modulation of O2 affinity. In: Blood, editor. American Society of Hematology 2014. p a1370.
61. Telfer P, Agodoa I, Fox KM, et al. Impact of voxelotor (GBT440) on unconjugated bilirubin and jaundice in sickle cell disease. Hematol Rep 2018;10:7643.
62. Estepp JH. Voxelotor (GBT440), a first-in-class hemoglobin oxygen-affinity modulator, has promising and reassuring preclinical and clinical data. Am J Hematol 2018;93:326-329.
63. Blyden G, Bridges KR, Bronte L. Case series of patients with severe sickle cell disease treated with voxelotor (GBT440) by compassionate access. Am J Hematol 2018.
64. Kato GJ, Hebbel RP, Steinberg MH, et al. Vasculopathy in sickle cell disease: Biology, pathophysiology, genetics, translational medicine, and new research directions. Am J Hematol 2009;84:618-625.
65. Kato GJ, Piel FB, Reid CD, et al. Sickle cell disease. Nat Rev Dis Primers 2018;4:18010.
66. Solovey A, Gui L, Ramakrishnan S, et al. Sickle cell anemia as a possible state of enhanced anti-apoptotic tone: survival effect of vascular endothelial growth factor on circulating and unanchored endothelial cells. Blood 1999;93:3824-3830.
67. Schaer DJ, Buehler PW, Alayash AI, et al. Hemolysis and free hemoglobin revisited: exploring hemoglobin and hemin scavengers as a novel class of therapeutic proteins. Blood 2013;121:1276-1284.
68. Belcher JD, Chen C, Nguyen J, et al. Heme triggers TLR4 signaling leading to endothelial cell activation and vaso-occlusion in murine sickle cell disease. Blood 2014;123:377-390.
69. Reiter CD, Wang X, Tanus-Santos JE, et al. Cell-free hemoglobin limits nitric oxide bioavailability in sickle-cell disease. Nat Med 2002;8:1383-1389.
70. Belcher JD, Vineyard JV, Bruzzone CM, et al. Heme oxygenase-1 gene delivery by Sleeping Beauty inhibits vascular stasis in a murine model of sickle cell disease. J Mol Med (Berl) 2010;88:665-675.
71. Belcher JD, Beckman JD, Balla G, et al. Heme degradation and vascular injury. Antioxid Redox Signal 2010;12:233-248.
72. Muller-Eberhard U, Javid J, Liem HH, et al. Plasma concentrations of hemopexin, haptoglobin and heme in patients with various hemolytic diseases. Blood 1968;32:811-815.
73. Ballas SK, Marcolina MJ. Hyperhemolysis during the evolution of uncomplicated acute painful episodes in patients with sickle cell anemia. Transfusion 2006;46:105-110.
74. Ohga S, Higashi E, Nomura A, et al. Haptoglobin therapy for acute favism: a Japanese boy with glucose-6-phosphate dehydrogenase Guadalajara. Br J Haematol 1995;89:421-423.
75. Merle NS, Grunenwald A, Rajaratnam H, et al. Intravascular hemolysis activates complement via cell-free heme and heme-loaded microvesicles. JCI Insight 2018;3.
76. Louie JE, Anderson CJ, Fayaz MFK, et al. Case series supporting heme detoxification via therapeutic plasma exchange in acute multiorgan failure syndrome resistant to red blood cell exchange in sickle cell disease. Transfusion 2018;58:470-479.
77. Kato GJ, Gladwin MT. Evolution of novel small-molecule therapeutics targeting sickle cell vasculopathy. JAMA 2008;300:2638-2646.
78. Belcher JD, Young M, Chen C, et al. MP4CO, a pegylated hemoglobin saturated with carbon monoxide, is a modulator of HO-1, inflammation, and vaso-occlusion in transgenic sickle mice. Blood 2013;122:2757-2764.
79. de Franceschi L, Baron A, Scarpa A, et al. Inhaled nitric oxide protects transgenic SAD mice from sickle cell disease-specific lung injury induced by hypoxia/reoxygenation. Blood 2003;102:1087-1096.
80. de Franceschi L, Malpeli G, Scarpa A, et al. Protective effects of S-nitrosoalbumin on lung injury induced by hypoxia-reoxygenation in mouse model of sickle cell disease. Am J Physiol Lung Cell Mol Physiol 2006;291:L457-465.
81. De Franceschi L, Platt OS, Malpeli G, et al. Protective effects of phosphodiesterase-4 (PDE-4) inhibition in the early phase of pulmonary arterial hypertension in transgenic sickle cell mice. FASEB J 2008;22:1849-1860.
82. Gladwin MT, Kato GJ, Weiner D, et al. Nitric oxide for inhalation in the acute treatment of sickle cell pain crisis: a randomized controlled trial. JAMA 2011;305:893-902.
83. Kim-Shapiro DB, Gladwin MT. Nitric oxide pathology and therapeutics in sickle cell disease. Clin Hemorheol Microcirc 2018;68:223-237.
84. Bakshi N, Morris CR. The role of the arginine metabolome in pain: implications for sickle cell disease. Journal of pain research 2016;9:167-175.
85. Morris CR. Alterations of the arginine metabolome in sickle cell disease: a growing rationale for arginine therapy. Hematology/oncology clinics of North America 2014;28:301-321.
86. Weiner DL, Hibberd PL, Betit P, et al. Preliminary assessment of inhaled nitric oxide for acute vaso-occlusive crisis in pediatric patients with sickle cell disease. JAMA 2003;289:1136-1142.
87. Head CA, Swerdlow P, McDade WA, et al. Beneficial effects of nitric oxide breathing in adult patients with sickle cell crisis. Am J Hematol 2010;85:800-802.
88. Abid S, Kebe K, Houssaini A, et al. New Nitric Oxide Donor NCX 1443: Therapeutic Effects on Pulmonary Hypertension in the SAD Mouse Model of Sickle Cell Disease. J Cardiovasc Pharmacol 2018;71:283-292.
89. Morris CR, Kato GJ, Poljakovic M, et al. Dysregulated arginine metabolism, hemolysis-associated pulmonary hypertension, and mortality in sickle cell disease. JAMA 2005;294:81-90.
90. Tharaux PL, Hagege I, Placier S, et al. Urinary endothelin-1 as a marker of renal damage in sickle cell disease. Nephrol Dial Transplant 2005;20:2408-2413.
91. Hammerman SI, Kourembanas S, Conca TJ, et al. Endothelin-1 production during the acute chest syndrome in sickle cell disease. American journal of respiratory and critical care medicine 1997;156:280-285.
92. Koehl B, Nivoit P, El Nemer W, et al. The endothelin B receptor plays a crucial role in the adhesion of neutrophils to the endothelium in sickle cell disease. Haematologica 2017;102:1161-1172.
93. Taylor C, Kasztan M, Tao B, et al. Combined hydroxyurea and ETA receptor blockade reduces renal injury in the humanized sickle cell mouse. Acta Physiol (Oxf) 2018:e13178.
94. Smith TP, Haymond T, Smith SN, et al. Evidence for the endothelin system as an emerging therapeutic target for the treatment of chronic pain. Journal of pain research 2014;7:531-545.
95. Lutz BM, Wu S, Gu X, et al. Endothelin type A receptors mediate pain in a mouse model of sickle cell disease. Haematologica 2018;103:1124-1135.
96. Adams-Graves P, Kedar A, Koshy M, et al. RheothRx (poloxamer 188) injection for the acute painful episode of sickle cell disease: a pilot study. Blood 1997;90:2041-2046.
97. Orringer EP, Casella JF, Ataga KI, et al. Purified poloxamer 188 for treatment of acute vaso-occlusive crisis of sickle cell disease: A randomized controlled trial. JAMA 2001;286:2099-2106.
98. Koo S, Yang Y, Neu B. Poloxamer 188 reduces normal and phosphatidylserine-exposing erythrocyte adhesion to endothelial cells in dextran solutions. Colloids and surfaces B, Biointerfaces 2013;112:446-451.
99. Archer N, Galacteros F, Brugnara C. 2015 Clinical trials update in sickle cell anemia. Am J Hematol 2015;90:934-950.
100. Kaul DK, Liu XD, Zhang X, et al. Peptides based on alphaV-binding domains of erythrocyte ICAM-4 inhibit sickle red cell-endothelial interactions and vaso-occlusion in the microcirculation. Am J Physiol Cell Physiol 2006;291:C922-930.
101. Kaul DK, Liu XD, Zhang X, et al. Inhibition of sickle red cell adhesion and vasoocclusion in the microcirculation by antioxidants. Am J Physiol Heart Circ Physiol 2006;291:H167-175.
102. Pan J, Xia L, McEver RP. Comparison of promoters for the murine and human P-selectin genes suggests species-specific and conserved mechanisms for transcriptional regulation in endothelial cells. J Biol Chem 1998;273:10058-10067.
103. Matsui NM, Borsig L, Rosen SD, et al. P-selectin mediates the adhesion of sickle erythrocytes to the endothelium. Blood 2001;98:1955-1962.
104. Kutlar A, Ataga KI, McMahon L, et al. A potent oral P-selectin blocking agent improves microcirculatory blood flow and a marker of endothelial cell injury in patients with sickle cell disease. Am J Hematol 2012;87:536-539.
105. Turhan A, Weiss LA, Mohandas N, et al. Primary role for adherent leukocytes in sickle cell vascular occlusion: a new paradigm. Proc Natl Acad Sci U S A 2002;99:3047-3051.
106. Blann AD, Mohan JS, Bareford D, et al. Soluble P-selectin and vascular endothelial growth factor in steady state sickle cell disease: relationship to genotype. J Thromb Thrombolysis 2008;25:185-189.
107. Wun T, Styles L, DeCastro L, et al. Phase 1 study of the E-selectin inhibitor GMI 1070 in patients with sickle cell anemia. PLoS One 2014;9:e101301.
108. Chang J, Patton JT, Sarkar A, et al. GMI-1070, a novel pan-selectin antagonist, reverses acute vascular occlusions in sickle cell mice. Blood 2010;116:1779-1786.
109. Telen MJ, Batchvarova M, Shan S, et al. Sevuparin binds to multiple adhesive ligands and reduces sickle red blood cell-induced vaso-occlusion. Br J Haematol 2016;175:935-948.
110. Gutsaeva DR, Parkerson JB, Yerigenahally SD, et al. Inhibition of cell adhesion by anti-P-selectin aptamer: a new potential therapeutic agent for sickle cell disease. Blood 2011;117:727-735.
111. Ataga KI, Kutlar A, Kanter J. Crizanlizumab in Sickle Cell Disease. N Engl J Med 2017;376:1796.
112. Slomski A. Crizanlizumab Prevents Sickle Cell Pain Crises. JAMA 2017;317:798.
113. Telen MJ, Wun T, McCavit TL, et al. Randomized phase 2 study of GMI-1070 in SCD: reduction in time to resolution of vaso-occlusive events and decreased opioid use. Blood 2015;125:2656-2664.
114. White J, Lindgren M, Liu K, et al. Sevuparin blocks sickle blood cell adhesion and sickle-leucocyte rolling on immobilized L-selectin in a dose dependent manner. Br J Haematol 2018.
115. Field JJ, Nathan DG. Advances in sickle cell therapies in the hydroxyurea era. Mol Med 2014;20 Suppl 1:S37-42.
116. Field JJ, Ataga KI, Majerus E, Eaton CA, Mashal R, Nathan DG. A phase I single ascending dose study of NKTT120 in stable adult sickle cell patients. In: Blood, editor. American Society of Hematology; 2014. p a977.
117. Field JJ, Nathan DG, Linden J. The role of adenosine signaling in sickle cell therapeutics. Hematology/oncology clinics of North America 2014;28:287-299.
118. Field JJ, Majerus E, Gordeuk VR, et al. Randomized phase 2 trial of regadenoson for treatment of acute vaso-occlusive crises in sickle cell disease. Blood Adv 2017;1:1645-1649.
119. Massaro M, Scoditti E, Carluccio MA, et al. Basic mechanisms behind the effects of n-3 fatty acids on cardiovascular disease. Prostaglandins Leukot Essent Fatty Acids 2008;79:109-115.
120. Calder PC. Omega-3 fatty acids and inflammatory processes. Nutrients 2010;2:355-374.
121. Rangel-Huerta OD, Aguilera CM, Mesa MD, et al. Omega-3 long-chain polyunsaturated fatty acids supplementation on inflammatory biomakers: a systematic review of randomised clinical trials. Br J Nutr 2012;107 Suppl 2:S159-170.
122. Russo C, Olivieri O, Girelli D, et al. Omega-3 polyunsaturated fatty acid supplements and ambulatory blood pressure monitoring parameters in patients with mild essential hypertension. J Hypertens 1995;13:1823-1826.
123. Ren H, Obike I, Okpala I, et al. Steady-state haemoglobin level in sickle cell anaemia increases with an increase in erythrocyte membrane n-3 fatty acids. Prostaglandins Leukot Essent Fatty Acids 2005;72:415-421.
124. Ren H, Ghebremeskel K, Okpala I, et al. Abnormality of erythrocyte membrane n-3 long chain polyunsaturated fatty acids in sickle cell haemoglobin C (HbSC) disease is not as remarkable as in sickle cell anaemia (HbSS). Prostaglandins Leukot Essent Fatty Acids 2006;74:1-6.
125. Daak AA, Ghebremeskel K, Hassan Z, et al. Effect of omega-3 (n-3) fatty acid supplementation in patients with sickle cell anemia: randomized, double-blind, placebo-controlled trial. Am J Clin Nutr 2013;97:37-44.
126. Daak AA, Dampier CD, Fuh B, et al. Double-blind, randomized, multicenter phase 2 study of SC411 in children with sickle cell disease (SCOT trial). Blood Adv 2018;2:1969-1979.
127. Daak A, Rabinowicz A, Ghebremeskel K. Omega-3 fatty acids are a potential therapy for patients with sickle cell disease. Nat Rev Dis Primers 2018;4:15.
128. Tomer A, Kasey S, Connor WE, et al. Reduction of pain episodes and prothrombotic activity in sickle cell disease by dietary n-3 fatty acids. Thromb Haemost 2001;85:966-974.
129. Cabannes R, Lonsdorfer J, Castaigne JP, et al. Clinical and biological double-blind-study of ticlopidine in preventive treatment of sickle-cell disease crises. Agents and actions Supplements 1984;15:199-212.
130. Heeney MM, Hoppe CC, Abboud MR, et al. A Multinational Trial of Prasugrel for Sickle Cell Vaso-Occlusive Events. N Engl J Med 2016;374:625-635.
131. Hsu LL, Sarnaik S, Williams S, et al. A dose-ranging study of ticagrelor in children aged 3-17 years with sickle cell disease: a two-part phase 2 study. Am J Hematol 2018.
132. Reid M, Badaloo A, Forrester T, et al. In vivo rates of erythrocyte glutathione synthesis in adults with sickle cell disease. American journal of physiology Endocrinology and metabolism 2006;291:E73-79.
133. Silva DG, Belini Junior E, de Almeida EA, et al. Oxidative stress in sickle cell disease: an overview of erythrocyte redox metabolism and current antioxidant therapeutic strategies. Free Radic Biol Med 2013;65:1101-1109.
134. Joep W.R. Sins XF, Karin Fijnvandraat, Melissa Dominguez, A. W. Rijneveld, Jean-Louis Kerkhoffs, A van Meurs, M. R. De Groot, H Heijboer, Erfan Nur, Brenda M Luken, Sacha S Zeerleder, Marie-Françoise Dresse, Phu-Quoc Le, Philippe Hermans, Anna Vanderfaeillie, Eric Van Den Neste, Fleur Samantha Benghiat, Rachel Kesse-Adu, Andre Delannoy, Andre Efira, Marie-Agnes Azerad, C A de Borgie, Junmei Chen, Jose A. Lopez and Bart J. Biemond. Effects of Oral N -Acetylcysteine on Oxidative Stress in Patients with Sickle Cell Disease. In: Blood, editor. ASH. Atlanta; 2017.
135. Sins JWR, Fijnvandraat K, Rijneveld AW, et al. Effect of N-acetylcysteine on pain in daily life in patients with sickle cell disease: a randomised clinical trial. Br J Haematol 2017.
136. Joep W.R. Sins KF, Anita W. Rijneveld, Martine B. Boom, Jean-Louis Kerkhoffs, Alfred H. van Meurs, Marco R De Groot, Harriet Heijboer, Marie-Françoise Dresse, Alina Ferster, Philippe Hermans, Anna Vanderfaeillie, Eric W Van Den Neste, Fleur Samantha Benghiat, Jo Howard, Rachel Kesse-Adu, Andre Delannoy, Andre Efira, Marie-Agnes Azerad, Corianne A.J.M. de Borgie and Bart J. Biemond. N-Acetylcysteine in Patients with Sickle Cell Disease: A Randomized Controlled Trial. In: Blood, editor. ASH: Blood; 2016.
137. Niihara Y, Miller ST, Kanter J, et al. A Phase 3 Trial of l-Glutamine in Sickle Cell Disease. N Engl J Med 2018;379:226-235.
138. Niihara Y KH, Tran L, Razon R, Macan H, Stark C, Wun T, Adams-Graves P. A phase 3 study of L-Glutamine Therapy for sickle cell anemia and sickle b0-thalassemia. In: Blood, editor. American Society of Hematology: Blood; 2014. p a86.
139. Niihara Y, Zerez CR, Akiyama DS, et al. Oral L-glutamine therapy for sickle cell anemia: I. Subjective clinical improvement and favorable change in red cell NAD redox potential. Am J Hematol 1998;58:117-121.
140. Quinn CT. l-Glutamine for sickle cell anemia: more questions than answers. Blood 2018;132:689-693.
141. Lagresle-Peyrou C, Lefrere F, Magrin E, et al. Plerixafor enables safe, rapid, efficient mobilization of hematopoietic stem cells in sickle cell disease patients after exchange transfusion. Haematologica 2018;103:778-786.
142. Esrick EB, Bauer DE. Genetic therapies for sickle cell disease. Semin Hematol 2018;55:76-86.
143. Leonard A, Tisdale JF. Stem cell transplantation in sickle cell disease: therapeutic potential and challenges faced. Expert Rev Hematol 2018;11:547-565.
144. Angelucci E, Matthes-Martin S, Baronciani D, et al. Hematopoietic stem cell transplantation in thalassemia major and sickle cell disease: indications and management recommendations from an international expert panel. Haematologica 2014;99:811-820.
145. Saraf SL, Oh AL, Patel PR, et al. Haploidentical Peripheral Blood Stem Cell Transplantation Demonstrates Stable Engraftment in Adults with Sickle Cell Disease. Biol Blood Marrow Transplant 2018;24:1759-1765.
146. Ribeil JA, Hacein-Bey-Abina S, Payen E, et al. Gene Therapy in a Patient with Sickle Cell Disease. N Engl J Med 2017;376:848-855.
147. Antoniani C, Meneghini V, Lattanzi A, et al. Induction of fetal hemoglobin synthesis by CRISPR/Cas9-mediated editing of the human beta-globin locus. Blood 2018;131:1960-1973.
148. Sato M, Saitoh I, Inada E. Efficient CRISPR/Cas9-based gene correction in induced pluripotent stem cells established from fibroblasts of patients with sickle cell disease. Stem Cell Investig 2016;3:78.
149. Ye L, Wang J, Tan Y, et al. Genome editing using CRISPR-Cas9 to create the HPFH genotype in HSPCs: An approach for treating sickle cell disease and beta-thalassemia. Proc Natl Acad Sci U S A 2016;113:10661-10665.