Skip to main content
SpringerLink
Log in
Book cover

Sickle Cell Anemia pp 399–429Cite as

Future Perspectives for the Treatment of Sickle Cell Anemia

  • Chapter
  • First Online:

Abstract

After decades with few treatment options for individuals with sickle cell disease (SCD), we have entered a treatment era of promising new therapeutic agents. These novel approaches target the diverse pathophysiology associated with SCD (e.g., increased blood cell adhesion, activated coagulation system, hyperinflammation, endothelial dysfunction). Potential therapies can be classified according to the “level” of the target intervention and related to the pathophysiology of SCD (upstream versus downstream events). In this chapter, “upstream therapies” refer to those that correct the genetic defect (correction of the sickle mutation in the beta globin gene via hematopoietic stem cell transplantation or gene therapy/gene editing), alter the natural hemoglobin switch phenomenon (enhancement of fetal hemoglobin production via gene therapy/gene editing), or prevent hemoglobin polymerization (e.g., drugs that alter the hemoglobin oxygen affinity or enhance fetal hemoglobin production). “Downstream therapies” are those aimed at quelling the downstream effects of hemolysis and vaso-occlusion (e.g., anti-adhesive, anti-inflammatory, or vaso-dilatory agents). This chapter discusses new therapies both in pre-clinical and clinical stages of investigation, and emphasizes those with the highest likelihood for impact on the disease and translation into clinical use over the next decade.

This is a preview of subscription content, log in via an institution.

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

Notes

  1. 1.

    2014c. Eliquis (apixaban). Package insert, http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/202155s000lbl.pdf.

  2. 2.

    2014d. Xarelto (rivaroxaban). Package insert, http://www.xareltohcp.com/sites/default/files/pdf/xarelto_0.pdf, Accessed 1 September 2014d.

  3. 3.

    2014a. Brilinta (ticagrelor). Package insert, http://www1.astrazeneca-us.com/pi/brilinta.pdf.

  4. 4.

    2014b. Effient (prasugrel). Package insert, http://pi.lilly.com/us/effient.pdf.

References

  • Abdulmalik O, Safo MK, Chen Q et al (2005) 5-Hydroxymethyl-2-furfural modifies intracellular sickle haemoglobin and inhibits sickling of red blood cells. Br J Haematol 128(4):552–561

    Article  CAS  PubMed  Google Scholar 

  • Adams-Graves P, Kedar A, Koshy M et al (1997) RheothRx (poloxamer 188) injection for the acute painful episode of sickle cell disease: a pilot study. Blood 90(5):2041–2046

    CAS  PubMed  Google Scholar 

  • Almeida CB, Traina F, Lanaro C, Canalli AA, Saad ST, Costa FF, Conran N (2008) High expression of the cGMP-specific phosphodiesterase, PDE9A, in sickle cell disease (SCD) and the effects of its inhibition in erythroid cells and SCD neutrophils. Br J Haematol 142(5):836–844

    Article  CAS  PubMed  Google Scholar 

  • Almeida CB, Scheiermann C, Jang JE, Prophete C, Costa FF, Conran N, Frenette PS (2012) Hydroxyurea and a cGMP-amplifying agent have immediate benefits on acute vaso-occlusive events in sickle cell disease mice. Blood 120(14):2879–2888

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ataga KI, Moore CG, Hillery CA et al (2008a) Coagulation activation and inflammation in sickle cell disease-associated pulmonary hypertension. Haematologica 93(1):20–26

    Article  CAS  PubMed  Google Scholar 

  • Ataga KI, Smith WR, De Castro LM et al (2008b) Efficacy and safety of the Gardos channel blocker, senicapoc (ICA-17043), in patients with sickle cell anemia. Blood 111(8):3991–3997

    Article  CAS  PubMed  Google Scholar 

  • Aygun B, Mortier NA, Smeltzer MP et al (2013) Hydroxyurea treatment decreases glomerular hyperfiltration in children with sickle cell anemia. Am J Hematol 88(2):116–119

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bernaudin F, Socie G, Kuentz M et al (2007) Long-term results of related myeloablative stem-cell transplantation to cure sickle cell disease. Blood 110(7):2749–2756

    Article  CAS  PubMed  Google Scholar 

  • Bernini JC, Rogers ZR, Sandler ES et al (1998) Beneficial effect of intravenous dexamethasone in children with mild to moderately severe acute chest syndrome complicating sickle cell disease. Blood 92(9):3082–3089

    CAS  PubMed  Google Scholar 

  • Berthaut I, Guignedoux G, Kirsch-Noir F et al (2008) Influence of sickle cell disease and treatment with hydroxyurea on sperm parameters and fertility of human males. Haematologica 93(7):988–993

    Article  CAS  PubMed  Google Scholar 

  • Bhatia M, Jin Z, Baker C et al (2014) Reduced toxicity, myeloablative conditioning with BU, fludarabine, alemtuzumab and SCT from sibling donors in children with sickle cell disease. Bone Marrow Transplant 49(7):913–920

    Article  CAS  PubMed  Google Scholar 

  • Björk I, Lindahl U (1982) Mechanism of the anticoagulant action of heparin. Mol Cell Biochem 48(3):161–182

    Article  PubMed  Google Scholar 

  • Bolanos-Meade J, Fuchs EJ, Luznik L et al (2012) HLA-haploidentical bone marrow transplantation with posttransplant cyclophosphamide expands the donor pool for patients with sickle cell disease. Blood 120(22):4285–4291

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Brachet C, Azzi N, Demulder A et al (2004) Hydroxyurea treatment for sickle cell disease: impact on haematopoietic stem cell transplantation's outcome. Bone Marrow Transplant 33(8):799–803

    Article  CAS  PubMed  Google Scholar 

  • Brawley OW, Cornelius LJ, Edwards LR et al (2008) National Institutes of Health Consensus Development Conference statement: hydroxyurea treatment for sickle cell disease. Ann Intern Med 148(12):932–938

    Article  PubMed  Google Scholar 

  • Brugnara C, Bunn HF, Tosteson DC (1986) Regulation of erythrocyte cation and water content in sickle cell anemia. Science 232(4748):388–390

    Article  CAS  PubMed  Google Scholar 

  • Carr BI, Reilly JG, Smith SS, Winberg C, Riggs A (1984) The tumorigenicity of 5-azacytidine in the male Fischer rat. Carcinogenesis 5(12):1583–1590

    Article  CAS  PubMed  Google Scholar 

  • Carroll D (2011) Genome engineering with zinc-finger nucleases. Genetics 188(4):773–782

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cavazzana-Calvo M, Payen E, Negre O et al (2010) Transfusion independence and HMGA2 activation after gene therapy of human beta-thalassaemia. Nature 467(7313):318–322

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chang WL, Corate LM, Sinclair JM, van der Heyde HC (2008) Continuous inhaled nitric oxide therapy in a case of sickle cell disease with multiorgan involvement. J Investig Med 56(8):1023–1027

    CAS  PubMed  Google Scholar 

  • Chang J, Patton JT, Sarkar A, Ernst B, Magnani JL, Frenette PS (2010) GMI-1070, a novel pan-selectin antagonist, reverses acute vascular occlusions in sickle cell mice. Blood 116(10): 1779–1786

    Article  PubMed  PubMed Central  Google Scholar 

  • Chaplin H, Monroe MC, Malecek AC, Morgan LK, Michael J, Murphy WA (1989) Preliminary trial of minidose heparin prophylaxis for painful sickle cell crises. East Afr Med J 66(9): 574–584

    PubMed  Google Scholar 

  • Charache S, Dover G, Smith K, Talbot CC Jr, Moyer M, Boyer S (1983) Treatment of sickle cell anemia with 5-azacytidine results in increased fetal hemoglobin production and is associated with nonrandom hypomethylation of DNA around the gamma-delta-beta-globin gene complex. Proc Natl Acad Sci U S A 80(15):4842–4846

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Charache S, Terrin ML, Moore RD et al (1995) Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. Investigators of the Multicenter Study of Hydroxyurea in Sickle Cell Anemia. N Engl J Med 332(20):1317–1322

    Article  CAS  PubMed  Google Scholar 

  • Chiang EY, Frenette PS (2005) Sickle cell vaso-occlusion. Hematol Oncol Clin North Am 19(5):771–784

    Article  PubMed  Google Scholar 

  • Cokic VP, Smith RD, Beleslin-Cokic BB et al (2003) Hydroxyurea induces fetal hemoglobin by the nitric oxide-dependent activation of soluble guanylyl cyclase. J Clin Invest 111(2):231–239

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cokic VP, Andric SA, Stojilkovic SS, Noguchi CT, Schechter AN (2008) Hydroxyurea nitrosylates and activates soluble guanylyl cyclase in human erythroid cells. Blood 111(3):1117–1123

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Colella MP, De Paula EV, Conran N et al (2012) Hydroxyurea is associated with reductions in hypercoagulability markers in sickle cell anemia. J Thromb Haemost 10(9):1967–1970

    Article  CAS  PubMed  Google Scholar 

  • Creusot F, Acs G, Christman JK (1982) Inhibition of DNA methyltransferase and induction of Friend erythroleukemia cell differentiation by 5-azacytidine and 5-aza-2'-deoxycytidine. J Biol Chem 257(4):2041–2048

    CAS  PubMed  Google Scholar 

  • Daak AA, Ghebremeskel K, Hassan Z et al (2013) 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 97(1):37–44

    Article  CAS  PubMed  Google Scholar 

  • De Franceschi L, Bachir D, Galacteros F et al (1997) Oral magnesium supplements reduce erythrocyte dehydration in patients with sickle cell disease. J Clin Invest 100(7):1847–1852

    Article  PubMed  PubMed Central  Google Scholar 

  • De Franceschi L, Bachir D, Galacteros F et al (2000) Oral magnesium pidolate: effects of long-term administration in patients with sickle cell disease. Br J Haematol 108(2):284–289

    Article  PubMed  Google Scholar 

  • De Franceschi L, Cappellini MD, Olivieri O (2011) Thrombosis and sickle cell disease. Semin Thromb Hemost 37(3):226–236

    Article  PubMed  CAS  Google Scholar 

  • De Montalembert M, Bachir D, Hulin A et al (2006) Pharmacokinetics of hydroxyurea 1,000 mg coated breakable tablets and 500 mg capsules in pediatric and adult patients with sickle cell disease. Haematologica 91(12):1685–1688

    PubMed  Google Scholar 

  • DeBaun MR (2014) Hydroxyurea therapy contributes to infertility in adult men with sickle cell disease: a review. Expert Rev Hematol 7(6):767–773

    Article  CAS  PubMed  Google Scholar 

  • DeSimone J, Heller P, Hall L, Zwiers D (1982) 5-Azacytidine stimulates fetal hemoglobin synthesis in anemic baboons. Proc Natl Acad Sci U S A 79(14):4428–4431

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • DeSimone J, Heller P, Schimenti JC, Duncan CH (1983) Fetal hemoglobin production in adult baboons by 5-azacytidine or by phenylhydrazine-induced hemolysis is associated with hypomethylation of globin gene DNA. Prog Clin Biol Res 134:489–500

    CAS  PubMed  Google Scholar 

  • DeSimone J, Koshy M, Dorn L (2002) Maintenance of elevated fetal hemoglobin levels by decitabine during dose interval treatment of sickle cell anemia. Blood 99(11):3905–3908

    Article  CAS  PubMed  Google Scholar 

  • Dover GJ, Charache S, Boyer SH, Vogelsang G, Moyer M (1985) 5-Azacytidine increases HbF production and reduces anemia in sickle cell disease: dose–response analysis of subcutaneous and oral dosage regimens. Blood 66(3):527–532

    CAS  PubMed  Google Scholar 

  • Dover GJ, Humphries RK, Moore JG (1986) Hydroxyurea induction of hemoglobin F production in sickle cell disease: relationship between cytotoxicity and F cell production. Blood 67(3):735–738

    CAS  PubMed  Google Scholar 

  • Dufu K, Oksenberg D, Zhou C, Hutchaleelaha A, Archer RD (2014) GTx011, a potent allosteric modifier of hemoglobin oxygen affinity, prevents RBC sickling in whole blood and prolongs RBC half-life in vivo in a murine model of sickle cell disease. Blood 124(21):217, Abstract

    Google Scholar 

  • Eaton WA, Hofrichter J (1987) Hemoglobin S gelation and sickle cell disease. Blood 70(5):1245–1266

    CAS  PubMed  Google Scholar 

  • Estepp JH, Smeltzer MP, Wang WC, Hoehn ME, Hankins JS, Aygun B (2013) Protection from sickle cell retinopathy is associated with elevated HbF levels and hydroxycarbamide use in children. Br J Haematol 161(3):402–405

    Article  CAS  PubMed  Google Scholar 

  • Estepp JH, Smeltzer M, Kang G, Aygun B, Ware RE, Nottage KA (2014) Higher fetal hemoglobin following escalation of hydroxyurea to maximum tolerated dose provides clinical benefit to children with sickle cell anemia. Blood 124(21):85, Abstract

    Google Scholar 

  • Ferro D, Parrotto S, Basili S, Alessandri C, Violi F (2000) Simvastatin inhibits the monocyte expression of proinflammatory cytokines in patients with hypercholesterolemia. J Am Coll Cardiol 36(2):427–431

    Article  CAS  PubMed  Google Scholar 

  • Ferrone FA, Hofrichter J, Eaton WA (1985) Kinetics of sickle hemoglobin polymerization. II. A double nucleation mechanism. J Mol Biol 183(4):611–631

    Article  CAS  PubMed  Google Scholar 

  • Ferster A, Tahriri P, Vermylen C et al (2001) Five years of experience with hydroxyurea in children and young adults with sickle cell disease. Blood 97(11):3628–3632

    Article  CAS  PubMed  Google Scholar 

  • Field JJ, Lin G, Okam MM et al (2013) Sickle cell vaso-occlusion causes activation of iNKT cells that is decreased by the adenosine A2A receptor agonist regadenoson. Blood 121(17): 3329–3334

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fitzhugh CD, Wigfall DR, Ware RE (2005) Enalapril and hydroxyurea therapy for children with sickle nephropathy. Pediatr Blood Cancer 45(7):982–985

    Article  PubMed  Google Scholar 

  • Galie N, Ghofrani HA, Torbicki A et al (2005) Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med 353(20):2148–2157

    Article  CAS  PubMed  Google Scholar 

  • Garcia DA, Baglin TP, Weitz JI, Samama MM (2012) Parenteral anticoagulants: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 141(2 suppl):e24S–e43S

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ghoshal K, Datta J, Majumder S et al (2005) 5-Aza-deoxycytidine induces selective degradation of DNA methyltransferase 1 by a proteasomal pathway that requires the KEN box, bromo-adjacent homology domain, and nuclear localization signal. Mol Cell Biol 25(11):4727–4741

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gladwin MT, Kato GJ, Weiner D et al (2011) Nitric oxide for inhalation in the acute treatment of sickle cell pain crisis: a randomized controlled trial. JAMA 305(9):893–902

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gluckman E (2013) Allogeneic transplantation strategies including haploidentical transplantation in sickle cell disease. Hematology Am Soc Hematol Educ Program 2013:370–376

    Article  PubMed  Google Scholar 

  • Goldman RD, Mounstephen W, Kirby-Allen M, Friedman JN (2013) Intravenous magnesium sulfate for vaso-occlusive episodes in sickle cell disease. Pediatrics 132(6):e1634–e1641

    Article  PubMed  Google Scholar 

  • Gragert L, Eapen M, Williams E et al (2014) HLA match likelihoods for hematopoietic stem-cell grafts in the U.S. registry. N Engl J Med 371(4):339–348

    Article  CAS  PubMed  Google Scholar 

  • Green D, Scott JP (1986) Is sickle cell crisis a thrombotic event? Am J Hematol 23(4):317–321

    Article  CAS  PubMed  Google Scholar 

  • Hankins JS, Ware RE, Rogers ZR et al (2005) Long-term hydroxyurea therapy for infants with sickle cell anemia: the HUSOFT extension study. Blood 106(7):2269–2275, available from: PM:16172253

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hankins JS, Helton KJ, McCarville MB, Li CS, Wang WC, Ware RE (2008a) Preservation of spleen and brain function in children with sickle cell anemia treated with hydroxyurea. Pediatr Blood Cancer 50(2):293–297

    Article  PubMed  Google Scholar 

  • Hankins JS, Wynn LW, Brugnara C, Hillery CA, Li CS, Wang WC (2008b) Phase I study of magnesium pidolate in combination with hydroxycarbamide for children with sickle cell anaemia. Br J Haematol 140(1):80–85

    CAS  PubMed  Google Scholar 

  • Hannemann A, Cytlak UM, Rees DC, Tewari S, Gibson JS (2014) Effects of 5-hydroxymethyl-2-furfural on the volume and membrane permeability of red blood cells from patients with sickle cell disease. J Physiol 592(Pt 18):4039–4049

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hebbel RP (2014) Ischemia-reperfusion injury in sickle cell anemia: relationship to acute chest syndrome, endothelial dysfunction, arterial vasculopathy, and inflammatory pain. Hematol Oncol Clin North Am 28(2):181–198

    Article  PubMed  Google Scholar 

  • Hebbel RP, Vercellotti G, Nath KA (2009) A systems biology consideration of the vasculopathy of sickle cell anemia: the need for multi-modality chemo-prophylaxsis. Cardiovasc Hematol Disord Drug Targets 9(4):271–292

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hebbel RP, Vercellotti GM, Pace BS et al (2010) The HDAC inhibitors trichostatin A and suberoylanilide hydroxamic acid exhibit multiple modalities of benefit for the vascular pathobiology of sickle transgenic mice. Blood 115(12):2483–2490

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Heeney MM, Ware RE (2010) Hydroxyurea for children with sickle cell disease. Hematol Oncol Clin North Am 24(1):199–214

    Article  PubMed  PubMed Central  Google Scholar 

  • Hibbert JM, Hsu LL, Bhathena SJ et al (2005) Proinflammatory cytokines and the hypermetabolism of children with sickle cell disease. Exp Biol Med 230(1):68–74

    CAS  Google Scholar 

  • Hillery CA, Du MC, Wang WC, Scott JP (2000) Hydroxyurea therapy decreases the in vitro adhesion of sickle erythrocytes to thrombospondin and laminin. Br J Haematol 109(2):322–327

    Article  CAS  PubMed  Google Scholar 

  • Hirsh J, Raschke R (2004) Heparin and low-molecular-weight heparin. Chest 126(3 suppl): 188S–203S

    Article  CAS  PubMed  Google Scholar 

  • Hoban MD, Cost GJ, Mendel MC et al (2015) Correction of the sickle-cell disease mutation in human hematopoietic stem/progenitor cells. Blood 125(17):2597–2604

    Article  CAS  PubMed  Google Scholar 

  • Hoppe C, Kuypers F, Larkin S, Hagar W, Vichinsky E, Styles L (2011) A pilot study of the short-term use of simvastatin in sickle cell disease: effects on markers of vascular dysfunction. Br J Haematol 153(5):655–663

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Horwitz ME, Chao NJ, Rizzieri DA et al (2014) Umbilical cord blood expansion with nicotinamide provides long-term multilineage engraftment. J Clin Invest 124(7):3121–3128

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hsieh MM, Fitzhugh CD, Weitzel RP et al (2014) Nonmyeloablative HLA-matched sibling allogeneic hematopoietic stem cell transplantation for severe sickle cell phenotype. JAMA 312(1):48–56

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Jayabose S, Tugal O, Sandoval C et al (1996) Clinical and hematologic effects of hydroxyurea in children with sickle cell anemia. J Pediatr 129(4):559–565

    Article  CAS  PubMed  Google Scholar 

  • Johnson FL, Look AT, Gockerman J, Ruggiero MR, Dalla-Pozza L, Billings FT 3rd (1984) Bone-marrow transplantation in a patient with sickle-cell anemia. N Engl J Med 311(12):780–783

    Article  CAS  PubMed  Google Scholar 

  • Joiner CH, Platt OS, Lux SE (1986) Cation depletion by the sodium pump in red cells with pathologic cation leaks. Sickle cells and xerocytes. J Clin Invest 78(6):1487–1496

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kamani NR, Walters MC, Carter S et al (2012) Unrelated donor cord blood transplantation for children with severe sickle cell disease: results of one cohort from the phase II study from the Blood and Marrow Transplant Clinical Trials Network (BMT CTN). Biol Blood Marrow Transplant 18(8):1265–1272

    Article  PubMed  PubMed Central  Google Scholar 

  • Kato G, Lawrence MP, Mendelsohn L et al (2013) Phase 1 clinical trial of the candidate anti-sickling agent Aes-103 in adults with sickle cell anemia. Blood 122(21):1009, Abstract

    Google Scholar 

  • Kim H, Kim JS (2014) A guide to genome engineering with programmable nucleases. Nat Rev Genet 15(5):321–334

    Article  CAS  PubMed  Google Scholar 

  • Kinney TR, Helms RW, O'Branski EE et al (1999) Safety of hydroxyurea in children with sickle cell anemia: results of the HUG-KIDS study, a phase I/II trial. Pediatric Hydroxyurea Group. Blood 94(5):1550–1554

    CAS  PubMed  Google Scholar 

  • Koshy M, Dorn L, Bressler L et al (2000) 2-Deoxy 5-azacytidine and fetal hemoglobin induction in sickle cell anemia. Blood 96(7):2379–2384

    CAS  PubMed  Google Scholar 

  • Krishnamurti L, Kharbanda S, Biernacki MA et al (2008) Stable long-term donor engraftment following reduced-intensity hematopoietic cell transplantation for sickle cell disease. Biol Blood Marrow Transplant 14(11):1270–1278

    Article  PubMed  Google Scholar 

  • Lavelle D, Chin J, Vaitkus K et al (2007) Oral decitabine reactivates expression of the methylated gamma-globin gene in Papio anubis. Am J Hematol 82(11):981–985

    Article  CAS  PubMed  Google Scholar 

  • Lee SP, Ataga KI, Orringer EP, Phillips DR, Parise LV (2006) Biologically active CD40 ligand is elevated in sickle cell anemia: potential role for platelet-mediated inflammation. Arterioscler Thromb Vasc Biol 26(7):1626–1631

    Article  CAS  PubMed  Google Scholar 

  • Leikin SL, Gallagher D, Kinney TR, Sloane D, Klug P, Rida W (1989) Mortality in children and adolescents with sickle cell disease. Cooperative Study of Sickle Cell Disease. Pediatrics 84(3):500–508

    CAS  PubMed  Google Scholar 

  • Levasseur DN, Ryan TM, Pawlik KM, Townes TM (2003) Correction of a mouse model of sickle cell disease: lentiviral/antisickling beta-globin gene transduction of unmobilized, purified hematopoietic stem cells. Blood 102(13):4312–4319

    Article  CAS  PubMed  Google Scholar 

  • Ley TJ, Anagnou NP, Noguchi CT, Schechter AN, DeSimone J, Heller P, Nienhuis AW (1983a) DNA methylation and globin gene expression in patients treated with 5-azacytidine. Prog Clin Biol Res 134:457–474

    CAS  PubMed  Google Scholar 

  • Ley TJ, DeSimone J, Noguchi CT et al (1983b) 5-Azacytidine increases gamma-globin synthesis and reduces the proportion of dense cells in patients with sickle cell anemia. Blood 62(2): 370–380

    CAS  PubMed  Google Scholar 

  • Liesner R, Mackie I, Cookson J et al (1998) Prothrombotic changes in children with sickle cell disease: relationships to cerebrovascular disease and transfusion. Br J Haematol 103(4): 1037–1044

    Article  CAS  PubMed  Google Scholar 

  • Lim MY, Ataga KI, Key NS (2013) Hemostatic abnormalities in sickle cell disease. Curr Opin Hematol 20(5):472–477

    Article  CAS  PubMed  Google Scholar 

  • Little JA, Hauser KP, Martyr SE et al (2009) Hematologic, biochemical, and cardiopulmonary effects of L-arginine supplementation or phosphodiesterase 5 inhibition in patients with sickle cell disease who are on hydroxyurea therapy. Eur J Haematol 82(4):315–321

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lobo CL, Pinto JFC, Nascimento EM, Moura PG, Cardoso GP, Hankins JS (2013) The effect of hydroxycarbamide therapy on survival of children with sickle cell disease. Br J Haematol 161(6):852–860

    Article  CAS  PubMed  Google Scholar 

  • Locatelli F, Kabbara N, Ruggeri A et al (2013) Outcome of patients with hemoglobinopathies given either cord blood or bone marrow transplantation from an HLA-identical sibling. Blood 122(6):1072–1078

    Article  CAS  PubMed  Google Scholar 

  • Lv S, Liu Y, Zou Z et al (2015) The impact of statins therapy on disease activity and inflammatory factor in patients with rheumatoid arthritis: a meta-analysis. Clin Exp Rheumatol 33(1):69–76

    PubMed  Google Scholar 

  • Machado RF, Barst RJ, Yovetich NA et al (2011) Hospitalization for pain in patients with sickle cell disease treated with sildenafil for elevated TRV and low exercise capacity. Blood 118(4):855–864

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Marzilli M (2010) Pleiotropic effects of statins: evidence for benefits beyond LDL-cholesterol lowering. Am J Cardiovasc Drugs 10(Suppl 1):3–9

    Article  CAS  PubMed  Google Scholar 

  • May C, Rivella S, Callegari J et al (2000) Therapeutic haemoglobin synthesis in beta-thalassaemic mice expressing lentivirus-encoded human beta-globin. Nature 406(6791):82–86

    Article  CAS  PubMed  Google Scholar 

  • McGann PT, Howard TA, Flanagan JM, Lahti JM, Ware RE (2011) Chromosome damage and repair in children with sickle cell anaemia and long-term hydroxycarbamide exposure. Br J Haematol 154(1):134–140

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • McGann PT, Flanagan JM, Howard TA et al (2012) Genotoxicity associated with hydroxyurea exposure in infants with sickle cell anemia: results from the BABY-HUG phase III clinical trial. Pediatr Blood Cancer 59(2):254–257

    Article  PubMed  PubMed Central  Google Scholar 

  • McMahon L, Tamary H, Askin M et al (2010) A randomized phase II trial of Arginine Butyrate with standard local therapy in refractory sickle cell leg ulcers. Br J Haematol 151(5):516–524

    Article  CAS  PubMed  Google Scholar 

  • Meiler SE, Wade M, Kutlar F et al (2011) Pomalidomide augments fetal hemoglobin production without the myelosuppressive effects of hydroxyurea in transgenic sickle cell mice. Blood 118(4):1109–1112

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Miguel LI, Almeida CB, Traina F et al (2011) Inhibition of phosphodiesterase 9A reduces cytokine-stimulated in vitro adhesion of neutrophils from sickle cell anemia individuals. Inflamm Res 60(7):633–642

    Article  CAS  PubMed  Google Scholar 

  • Montero-Huerta P, Hess DR, Head CA (2006) Inhaled nitric oxide for treatment of sickle cell stroke. Anesthesiology 105(3):619–621

    Article  PubMed  Google Scholar 

  • Morris CR (2014) Alterations of the arginine metabolome in sickle cell disease: a growing rationale for arginine therapy. Hematol Oncol Clin North Am 28(2):301–321

    Article  PubMed  Google Scholar 

  • Morris CR, Kuypers FA, Larkin S, Vichinsky EP, Styles LA (2000) Patterns of arginine and nitric oxide in patients with sickle cell disease with vaso-occlusive crisis and acute chest syndrome. J Pediatr Hematol Oncol 22(6):515–520

    Article  CAS  PubMed  Google Scholar 

  • Morris CR, Morris SM Jr, Hagar W et al (2003) Arginine therapy: a new treatment for pulmonary hypertension in sickle cell disease? Am J Respir Crit Care Med 168(1):63–69

    Article  PubMed  Google Scholar 

  • Morris CR, Kato GJ, Poljakovic M et al (2005) Dysregulated arginine metabolism, hemolysis-associated pulmonary hypertension, and mortality in sickle cell disease. JAMA 294(1):81–90

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Morris CR, Kuypers FA, Lavrisha L et al (2013) A randomized, placebo-controlled trial of arginine therapy for the treatment of children with sickle cell disease hospitalized with vaso-occlusive pain episodes. Haematologica 98(9):1375–1382

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Moutouh-de Parseval LA, Verhelle D, Glezer E et al (2008) Pomalidomide and lenalidomide regulate erythropoiesis and fetal hemoglobin production in human CD34+ cells. J Clin Invest 118(1):248–258

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nahavandi M, Tavakkoli F, Wyche MQ, Perlin E, Winter WP, Castro O (2002) Nitric oxide and cyclic GMP levels in sickle cell patients receiving hydroxyurea. Br J Haematol 119(3):855–857

    Article  CAS  PubMed  Google Scholar 

  • Nathwani AC, Hanawa H, Vandergriff J, Kelly P, Vanin EF, Nienhuis AW (2000) Efficient gene transfer into human cord blood CD34+ cells and the CD34+CD38- subset using highly purified recombinant adeno-associated viral vector preparations that are free of helper virus and wild-type AAV. Gene Ther 7(3):183–195

    Article  CAS  PubMed  Google Scholar 

  • Nathwani AC, Tuddenham EG, Rangarajan S et al (2011) Adenovirus-associated virus vector-mediated gene transfer in hemophilia B. N Engl J Med 365(25):2357–2365, available from: PM:22149959

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nathwani AC, Reiss UM, Tuddenham EG et al (2014) Long-term safety and efficacy of factor IX gene therapy in hemophilia B. N Engl J Med 371(21):1994–2004

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Nebor D, Romana M, Santiago R et al (2013) Fetal hemoglobin and hydroxycarbamide moduate both plasma concentration and cellular origin of circulating microparticles in sickle cell anemia children. Haematologica 98(6):862–867

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nickel RS, Hendrickson JE, Haight AE (2014) The ethics of a proposed study of hematopoietic stem cell transplant for children with “less severe” sickle cell disease. Blood 124(6):861–866

    Article  CAS  PubMed  Google Scholar 

  • Nienhuis AW, Persons DA (2012) Development of gene therapy for thalassemia. Cold Spring Harb Perspect Med 2(11), pii: a011833

    Article  CAS  Google Scholar 

  • Nottage KA, Ware RE, Winter B et al (2014) Predictors of splenic function preservation in children with sickle cell anemia treated with hydroxyurea. Eur J Haematol 93(5):377–383

    Article  CAS  PubMed  Google Scholar 

  • Noubouossie DC, Le PQ, Rozen L et al (2013) Thrombin generation in children with sickle cell disease: relationship with age, hemolysis, transcranial Doppler velocity, and hydroxyurea treatment. Eur J Haematol 91(1):46–54

    Article  CAS  PubMed  Google Scholar 

  • Oppert M, Jorres A, Barckow D, Eckardt KU, Frei U, Kaisers U (2004) Inhaled nitric oxide for ARDS due to sickle cell disease. Swiss Med Wkly 134(11–12):165–167

    CAS  PubMed  Google Scholar 

  • Orringer EP, Blythe DS, Johnson AE, Phillips G Jr, Dover GJ, Parker JC (1991) Effects of hydroxyurea on hemoglobin F and water content in the red blood cells of dogs and of patients with sickle cell anemia. Blood 78(1):212–216

    CAS  PubMed  Google Scholar 

  • Palmer SC, Navaneethan SD, Craig JC et al (2014) HMG CoA reductase inhibitors (statins) for people with chronic kidney disease not requiring dialysis. Cochrane Database Syst Rev 5, CD007784

    PubMed  Google Scholar 

  • Panepinto JA, Walters MC, Carreras J et al (2007) Matched-related donor transplantation for sickle cell disease: report from the Center for International Blood and Transplant Research. Br J Haematol 137(5):479–485

    Article  PubMed  Google Scholar 

  • Pastuszczak M, Kotlarz A, Mostowik M, Zalewski J, Zmudka K, Undas A (2010) Prior simvastatin treatment is associated with reduced thrombin generation and platelet activation in patients with acute ST-segment elevation myocardial infarction. Thromb Res 125(5):382–386

    Article  CAS  PubMed  Google Scholar 

  • Pawliuk R, Westerman KA, Fabry ME et al (2001) Correction of sickle cell disease in transgenic mouse models by gene therapy. Science 294(5550):2368–2371

    Article  CAS  PubMed  Google Scholar 

  • Platt OS, Thorington BD, Brambilla DJ et al (1991) Pain in sickle cell disease. N Engl J Med 325(1):11–16

    Article  CAS  PubMed  Google Scholar 

  • Platt OS, Brambilla DJ, Rosse WF et al (1994) Mortality in sickle cell disease – life expectancy and risk factors for early death. N Engl J Med 330(23):1639–1644

    Article  CAS  PubMed  Google Scholar 

  • Qari MH, Aljaouni SK, Alardawi MS et al (2007) Reduction of painful vaso-occlusive crisis of sickle cell anaemia by tinzaparin in a double-blind randomized trial. Thromb Haemost 98(8):392–396

    CAS  PubMed  Google Scholar 

  • Reid ME, El Beshlawy A, Inati A et al (2014) A double-blind, placebo-controlled phase II study of the efficacy and safety of 2,2-dimethylbutyrate (HQK-1001), an oral fetal globin inducer, in sickle cell disease. Am J Hematol 89(7):709–713

    Article  CAS  PubMed  Google Scholar 

  • Rivella S, May C, Chadburn A, Riviere I, Sadelain M (2003) A novel murine model of Cooley anemia and its rescue by lentiviral-mediated human beta-globin gene transfer. Blood 101(8):2932–2939

    Article  CAS  PubMed  Google Scholar 

  • Romero Z, Urbinati F, Geiger S et al (2013) Beta-globin gene transfer to human bone marrow for sickle cell disease. J Clin Invest 123(8):3317–3330

    Article  CAS  PubMed Central  Google Scholar 

  • Rosenberg RD (1989) Biochemistry of heparin antithrombin interactions, and the physiologic role of this natural anticoagulant mechanism. Am J Med 87(3 Suppl 2):S2–S9

    Article  Google Scholar 

  • Rosenberg RD, Lam L (1979) Correlation between structure and function of heparin. Proc Natl Acad Sci U S A 76(3):1218–1222

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sander JD, Joung JK (2014) CRISPR-Cas systems for editing, regulating and targeting genomes. Nat Biotechnol 32(4):347–355

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sankaran VG, Nathan DG (2010) Reversing the hemoglobin switch. N Engl J Med 363(23):2258–2260

    Article  PubMed  Google Scholar 

  • Sankaran VG, Menne TF, Xu J et al (2008) Human fetal hemoglobin expression is regulated by the developmental stage-specific repressor BCL11A. Science 322(5909):1839–1842

    Article  CAS  PubMed  Google Scholar 

  • Saunthararajah Y, Hillery CA, Lavelle D et al (2003) Effects of 5-aza-2'-deoxycytidine on fetal hemoglobin levels, red cell adhesion, and hematopoietic differentiation in patients with sickle cell disease. Blood 102(12):3865–3870

    Article  CAS  PubMed  Google Scholar 

  • Saunthararajah Y, Molokie R, Saraf S et al (2008) Clinical effectiveness of decitabine in severe sickle cell disease. Br J Haematol 141(1):126–129

    Article  PubMed  Google Scholar 

  • Scheuplein F, Thariath A, Macdonald S, Truneh A, Mashal R, Schaub R (2013) A humanized monoclonal antibody specific for invariant Natural Killer T (iNKT) cells for in vivo depletion. PLoS One 8(9), e76692

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Serjeant GR (1995) Natural history and determinants of clinical severity of sickle cell disease. Curr Opin Hematol 2(2):103–108

    Article  CAS  PubMed  Google Scholar 

  • Shimamura K, Kawamura H, Nagura T et al (2005) Association of NKT cells and granulocytes with liver injury after reperfusion of the portal vein. Cell Immunol 234(1):31–38

    Article  CAS  PubMed  Google Scholar 

  • Singh SA, Koumbourlis AC, Aygun B (2008) Resolution of chronic hypoxemia in pediatric sickle cell patients after treatment with hydroxyurea. Pediatr Blood Cancer 50(6):1258–1260

    Article  PubMed  Google Scholar 

  • Smith-Whitley K (2014) Reproductive issues in sickle cell disease. Blood 124(24):3538–3543

    Article  CAS  PubMed  Google Scholar 

  • Sodani P, Isgro A, Gaziev J et al (2011) T cell-depleted hla-haploidentical stem cell transplantation in thalassemia young patients. Pediatr Rep 3(Suppl 2):e13

    PubMed  PubMed Central  Google Scholar 

  • Sparkenbaugh EM, Chantrathammachart P, Mickelson J et al (2014) Differential contribution of FXa and thrombin to vascular inflammation in a mouse model of sickle cell disease. Blood 123(11):1747–1756

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Stach K, Nguyen XD, Lang S et al (2012) Simvastatin and atorvastatin attenuate VCAM-1 and uPAR expression on human endothelial cells and platelet surface expression of CD40 ligand. Cardiol J 19(1):20–28

    Article  PubMed  Google Scholar 

  • Steinberg MH, Hsu H, Nagel RL et al (1995) Gender and haplotype effects upon hematological manifestations of adult sickle cell anemia. Am J Hematol 48(3):175–181

    Article  CAS  PubMed  Google Scholar 

  • Steinberg MH, Barton F, Castro O et al (2003) Effect of hydroxyurea on mortality and morbidity in adult sickle cell anemia. JAMA 289(13):1645–1651

    Article  CAS  PubMed  Google Scholar 

  • Stevens MCG, Hayes RJ, Vaidya S, Serjeant GR (1981) Fetal hemoglobin and clinical severity of homozygous sickle cell disease in early childhood. J Pediatr 98(1):37–41

    Article  CAS  PubMed  Google Scholar 

  • Strouse JJ, Takemoto CM, Keefer JR, Kato GJ, Casella JF (2008) Corticosteroids and increased risk of readmission after acute chest syndrome in children with sickle cell disease. Pediatr Blood Cancer 50(5):1006–1012

    Article  PubMed  PubMed Central  Google Scholar 

  • Styles L, Kuypers F, Kesler K (2007) Arginine therapy does not benefit children with sickle cell anemia; results of the comprehensive sickle cell center multi-center study. Convention of the National Sickle Cell Disease Program and the Sickle Cell Disease Association of America, Washington DC

    Google Scholar 

  • Taylor F, Huffman MD, Macedo AF et al (2013) Statins for the primary prevention of cardiovascular disease. Cochrane Database Syst Rev 1, CD004816

    PubMed  Google Scholar 

  • Teupser D, Bruegel M, Stein O, Stein Y, Thiery J (2001) HMG-CoA reductase inhibitors reduce adhesion of human monocytes to endothelial cells. Biochem Biophys Res Commun 289(4):838–844

    Article  CAS  PubMed  Google Scholar 

  • Tomer A, Harker LA, Kasey S, Eckman JR (2001) Thrombogenesis in sickle cell disease. J Lab Clin Med 137(6):398–407

    Article  CAS  PubMed  Google Scholar 

  • Van Beers EJ, Schaap MC, Berckmans RJ et al (2009) Circulating erythrocyte-derived microparticles are associated with coagulation activation in sickle cell disease. Haematologica 94(11):1513–1519

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Van Gorsel H, Li C, Kerbel EL, Smits M, Kader AA (1992) Compositional characterization of prune juice. J Agric Food Chem 40(5):784–789

    Article  Google Scholar 

  • van Zuuren EJ, Fedorowicz Z (2013) Low-molecular-weight heparins for managing vaso-occlusive crises in people with sickle cell disease. Cochrane Database Syst Rev 6, CD010223

    PubMed  Google Scholar 

  • Vandorpe DH, Shmukler BE, Jiang L et al (1998) cDNA cloning and functional characterization of the mouse Ca2 + −gated K+ channel, mIK1. Roles in regulatory volume decrease and erythroid differentiation. J Biol Chem 273(34):21542–21553

    Article  CAS  PubMed  Google Scholar 

  • Verstraete M (1990) Pharmacotherapeutic aspects of unfractionated and low molecular weight heparins. Drugs 40(4):498–530

    Article  CAS  PubMed  Google Scholar 

  • Wallace KL, Marshall MA, Ramos SI et al (2009) NKT cells mediate pulmonary inflammation and dysfunction in murine sickle cell disease through production of IFN-gamma and CXCR3 chemokines. Blood 114(3):667–676

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wandersee NJ, Maciaszek JL, Giger KM et al (2015) Dietary supplementation with docosahexanoic acid (DHA) increases red blood cell membrane flexibility in mice with sickle cell disease. Blood Cells Mol Dis 54(2):183–188

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang WC, Ware RE, Miller ST et al (2011) Hydroxycarbamide in very young children with sickle-cell anaemia: a multicentre, randomised, controlled trial (BABY HUG). Lancet 377(9778):1663–1672

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ware RE, Zimmerman SA, Sylvestre PB et al (2004) Prevention of secondary stroke and resolution of transfusional iron overload in children with sickle cell anemia using hydroxyurea and phlebotomy. J Pediatr 145(3):346–352

    Article  CAS  PubMed  Google Scholar 

  • Ware RE, Despotovic JM, Mortier NA et al (2011) Pharmacokinetics, pharmacodynamics, and pharmacogenetics of hydroxyurea treatment for children with sickle cell anemia. Blood 118(18):4985–4991

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ware RE, Helms RW, SWiTCH Investigators (2012) Stroke with transfusions changing to hydroxyurea (SWiTCH). Blood 119(17):3925–3932

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Weiner DL, Hibberd PL, Betit P, Cooper AB, Botelho CA, Brugnara C (2003) Preliminary assessment of inhaled nitric oxide for acute vaso-occlusive crisis in pediatric patients with sickle cell disease. JAMA 289(9):1136–1142

    Article  CAS  PubMed  Google Scholar 

  • Weitz JI (1997) Low-molecular-weight heparins. N Engl J Med 337(10):688–699

    Article  CAS  PubMed  Google Scholar 

  • Westerman MP, Green D, Gilman-Sachs A et al (1999) Antiphospholipid antibodies, proteins C and S, and coagulation changes in sickle cell disease. J Lab Clin Med 134(4):352–362

    Article  CAS  PubMed  Google Scholar 

  • Wilber A, Tschulena U, Hargrove PW et al (2010) A zinc-finger transcriptional activator designed to interact with the gamma-globin gene promoters enhances fetal hemoglobin production in primary human adult erythroblasts. Blood 115(15):3033–3041

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wun T, Soulieres D, Frelinger A et al (2013) A double-blind, randomized, multicenter phase 2 study of prasugrel versus placebo in adult patients with sickle cell disease. J Hematol Oncol 6(1):17

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wun T, Styles L, DeCastro L et al (2014) Phase 1 study of the E-selectin inhibitor GMI 1070 in patients with sickle cell anemia. PLoS One 9(7), e101301

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Xu J, Peng C, Sankaran VG et al (2011) Correction of sickle cell disease in adult mice by interference with fetal hemoglobin silencing. Science 334(6058):993–996

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yan JH, Ataga K, Kaul S et al (2005) The influence of renal function on hydroxyurea pharmacokinetics in adults with sickle cell disease. J Clin Pharmacol 45(4):434–445

    Article  CAS  PubMed  Google Scholar 

  • Yang JC, Huang F, Wu CJ, Chen YC, Lu TH, Hsieh CH (2012) Simvastatin reduces VCAM-1 expression in human umbilical vein endothelial cells exposed to lipopolysaccharide. Inflamm Res 61(5):485–491

    Article  CAS  PubMed  Google Scholar 

  • Yawn BP, Buchanan GR, Afenyi-Annan AN (2014) Management of sickle cell disease: summary of the 2014 evidence-based report by expert panel members. JAMA 312(10):1033–1048

    Article  PubMed  CAS  Google Scholar 

  • Zhou D, Liu K, Sun CW, Pawlik KM, Townes TM (2010) KLF1 regulates BCL11A expression and gamma- to beta-globin gene switching. Nat Genet 42(9):742–744

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors are indebted to Dr. Winfred Wang, MD for editing of this work, Dr. Mitchell Weiss, MD, PhD for helpful discussions during the writing of this chapter, and Terri Davis, BS, for formatting and final editing.

Author information

Authors and Affiliations

  1. Department of Hematology, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, MS # 800, Memphis, TN, 38105-3678, USA

    Kerri Nottage M.D., M.P.H., Jeremie Estepp M.D. & Jane Hankins M.D., M.S.

Authors
  1. Kerri Nottage M.D., M.P.H.
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jeremie Estepp M.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jane Hankins M.D., M.S.
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jane Hankins M.D., M.S. .

Editor information

Editors and Affiliations

  1. Centro de Hematologia e Hemoterapia, Unicamp, Campinas, São Paulo, Brazil

    Fernando Ferreira Costa

  2. Centro de Hematologia e Hemoterapia, Unicamp, Campinas, São Paulo, Brazil

    Nicola Conran

Rights and permissions

Reprints and permissions

Copyright information

© 2016 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Nottage, K., Estepp, J., Hankins, J. (2016). Future Perspectives for the Treatment of Sickle Cell Anemia. In: Costa, F., Conran, N. (eds) Sickle Cell Anemia. Springer, Cham. https://doi.org/10.1007/978-3-319-06713-1_16

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-06713-1_16

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-06712-4

  • Online ISBN: 978-3-319-06713-1

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation