sickle cell research paper examples

Articles about Sickle Cell Disease

• Featured Topics

Recent Scientific Articles

Additional selected articles.

Featured Topics on Sickle Cell Disease

Sickle Cell Data Collection Program This World Sickle Cell Day 2023, learn about CDC’s SCDC program, and find a suite of online resources that can help you or someone you know live healthy with SCD.

Stories of Sickle Cell Learn about sickle cell disease and the Stories of Sickle Cell project.

CDC Study Highlights Importance of Increasing Flu Vaccine for People with Sickle Cell Disease Flu vaccination is particularly important for people who are at higher risk of serious complications from influenza. This includes people with SCD.

What is Sickle Cell Disease? Learn about sickle cell disease and find resources for patients and caregivers.

Sickle Cell Summer Camp Learn about Sickle Cell Camp and find one near you.

Did You Know Sickle Cell Has Many Faces? Learn about the many faces of sickle cell disease and read Mimi’s story.

Sickle Cell Disease Monitoring CDC is working to raise awareness about sickle cell disease. You can help by reading and sharing our resources with friends and family.

Taking Charge of Your Health and Health Care Learn how young people with sickle cell disease can take a more active role in their health care.

Caregivers and Sickle Cell Disease Learn the effect sickle cell disease has on family members & caregivers.

* These CDC scientific articles are listed in order of date published from 2014 to present.

Use of Recommended Health Care Measures to Prevent Selected Complications of Sickle Cell Anemia in Children and Adolescents — Selected U.S. States, 2019 Schieve LA, Simmons GM, Payne AB, et al. MMWR Morb Mortal Wkly Rep 2022;71:1241–1246. DOI:  http://dx.doi.org/10.15585/mmwr.mm7139e1 .

• Vital Signs : Preventing Sickle Cell Anemia Complications in Children

Surveillance for Sickle Cell Disease — Sickle Cell Data Collection Program, Two States, 2004–2018. Snyder AB, Lakshmanan S, Hulihan MM, et al. MMWR Surveill Summ 2022;71(No. SS-9):1–18. DOI: http://dx.doi.org/10.15585/mmwr.ss7109a1 .

Prioritizing Sickle Cell Disease. Lewis L. Hsu, W. Craig Hooper, Laura A. Schieve. Pediatrics December 2022; 150 (6): e2022059491. 10.1542/peds.2022-059491

Sickle Cell Disease: A Review Kavanagh PL, Fasipe TA, Wun T. JAMA. 2022;328(1):57–68. doi:10.1001/jama.2022.10233

COVID-19 and Sickle Cell Disease-Related Deaths Reported in the United States. Payne AB, Schieve LA, Abe K, Hulihan M, Hooper WC, Hsu LL. [published online ahead of print, 2022 Jan 21]. Public Health Rep. 2022;333549211063518. doi:10.1177/00333549211063518.

• Key findings from this article

Influenza vaccination rates and hospitalizations among Medicaid enrollees with and without sickle cell disease, 2009-2015. Payne AB, Adamkiewicz TV, Grosse SD, Steffens A, Shay DK, Reed C, Schieve LA. Pediatr Blood Cancer. 2021 Sep 20:e29351. doi: 10.1002/pbc.29351. Epub ahead of print. PMID: 34542932.

Coronavirus Disease Among Persons with Sickle Cell Disease, United States, March 20–May 21, 2020 Panepinto JA, Brandow A, Mucalo L, Yusuf F, Singh A, Taylor B, Payne AB, Peacock G, Schieve LA. Emerging Infectious Diseases. 2020 Oct. doi: 10.3201/eid2610.202792.

Trends in sickle cell disease-related mortality in the United States, 1979-2017 Payne AB, Mehal JM, Chapman C, Haberling DL, Richardson LC, Bean CJ, Hooper WC. Annals of Emergency Medicine. 2020; 76 (3S):S28-S36

Using surveillance to determine the number of individuals with sickle cell disease in California and Georgia, 2005-2016 Aluc A, Zhou M, Paulukonis ST, Snyder AB, Wong D, Hulihan MM. [published online ahead of print, 2020 Aug 12]. Pediatr Hematol Oncol. 2020;1-5. doi:10.1080/08880018.2020.1779886

Impact of Medicaid expansion on access and healthcare among individuals with sickle cell disease Kayle M, Valle J, Paulukonis S, Holl JL, Tanabe P, French DD, Garg R, Liem RI, Badawy SM, Treadwell MJ. Pediatr Blood Cancer. 2020 May;67(5):e28152.

Acute Care Utilization at End of Life in Sickle Cell Disease: Highlighting the Need for a Palliative Approach Johnston EE, Adesina OO, Alvarez E, Amato H, Paulukonis S, Nichols A, Chamberlain LJ, Bhatia S. J Palliat Med. 2020 Jan;23(1):24-32.

Characterizing complication risk from multisite, intermittent transfusions for the treatment of sickle cell disease Tang A, Branscomb J, Zhou M, Snyder A, Eckman J. Pediatr Blood Cancer. 2019 Oct;66(10):e27921.

Health literacy and knowledge of chronic transfusion therapy in adolescents with sickle cell disease and caregivers Yee MEM, Meyer EK, Fasano, RM, Lane PA, Josephson CD, Brega AG. Pediatr Blood Cancer . 2019 Jul;66(7):e27733.

Understanding the Complications of Sickle Cell Disease Tanabe P, Spratling R, Smith D, Grissom P, Hulihan M.  American Journal of Nursing 2019 June; 119 (6) 26-35. doi: 10.1097/01.NAJ.0000559779.40570.2c

Improving an Administrative Case Definition for Longitudinal Surveillance of Sickle Cell Disease Snyder AB, Zhou M, Theodore R, Quarmyne MO, Eckman J, Lane PA. Public Health Rep. 2019 May/Jun;134(3):274-281. doi: 10.1177/0033354919839072.

Transfusion service knowledge and immunohaematological practices related to sickle cell disease and thalassemia Fasano RM, Branscomb J, Lane PA, Josephson CD, Snyder AB, Eckman JR. Transfus Med. 2019 Feb 10.

Facilitators and Barriers to Minority Blood Donations: A Systematic Review Spratling R, Lawrence RH. Nurs Res. 2019 Mar 1. [Epub ahead of print].

A Strategic Planning Tool for Increasing African American Blood Donation Singleton A, Spratling R. Health Promot Pract. 2018 May 1:1524839918775733. doi: 10.1177/1524839918775733.

Hemoglobin A clearance in children with sickle cell anemia on chronic transfusion therapy Yee MEM, Josephson CD, Winkler AM, Webb J, Luban NLC, Leong T, Stowell SR, Roback JD, Fasano RM. Transfusion. 2018 Apr 17. doi: 10.1111/trf.14610.

CDC Grand Rounds: Improving the Lives of Persons with Sickle Cell Disease Hulihan M, Hassell KL, Raphael JL, Smith-Whitley K, Thorpe P. MMWR Morb Mortal Wkly Rep. 2017 Nov 24;66(46):1269-1271. doi: 10.15585/mmwr.mm6646a2.

Red blood cell minor antigen mismatches during chronic transfusion therapy for sickle cell anemia Yee MEM, Josephson CD, Winkler AM, Webb J, Luban NLC, Leong T, Stowell SR, Fasano RM. Transfusion. 2017 Nov;57(11):2738-2746. doi: 10.1111/trf.14282.

The accuracy of hospital ICD-9-CM codes for determining Sickle Cell Disease genotype Snyder AB, Lane PA, Zhou M, Paulukonis ST, Hulihan MM. J Rare Dis Res Treat. 2017;2(4):39-45.

Emergency Department Utilization by Californians with Sickle Cell Disease, 2005-2014 Paulukonis ST, Feuchtbaum L, Coates TD, Neumayr LD, Treadwell MJ, Vichinsky EP, Hulihan MM. Pediatric Blood & Cancer. 2016 Dec 21. Published online ahead of print.

• Key findings from this article.

Community engagement to inform the development of a sickle cell counselor training and certification program in Ghana Anie KA, Treadwell MJ, Grant AM, Dennis-Antwi JA, Asafo MK, Lamptey ME, Ojodu J, Yusuf C, Otaigbe A, Ohene-Frempong K. J Community Genet. 2016 Jul;7(3):195-202. doi: 10.1007/s12687-016-0267-3.

Emergency Department Visits and Inpatient Admissions Associated with Priapism among Males with Sickle Cell Disease in the United States, 2006-2010 Dupervil B, Grosse S, Burnett A, Parker C. PLoS One. 2016 Apr 14;11(4):e0153257. doi: 10.1371/journal.pone.0153257.

Defining Sickle Cell Disease Mortality Using a Population-Based Surveillance System, 2004 through 2008 Paulukonis ST, Eckman JR, Snyder AB, Hagar W, Feuchtbaum LB, Zhou M, Grant AM, Hulihan MM. Public Health Rep. 2016 Mar-Apr;131(2):367-75.

Observed and expected frequencies of structural hemoglobin variants in newborn screening surveys in Africa and the Middle East: deviations from Hardy-Weinberg equilibrium Piel FB, Adamkiewicz TV, Amendah D, Williams TN, Gupta S, Grosse SD. Genet Med. 2016 Mar;18(3):265-74. doi: 10.1038/gim.2015.143.

Contribution of Sickle Cell Disease to the Pediatric Stroke Burden Among Hospital Discharges of African-Americans-United States, 1997-2012 Baker C, Grant AM, George MG, Grosse SD, Adamkiewicz TV. Pediatr Blood Cancer. 2015 Dec;62(12):2076-81. doi: 10.1002/pbc.25655.

Mortality of New York children with sickle cell disease identified through newborn screening Wang Y, Liu G, Caggana M, Kennedy J, Zimmerman R, Oyeku SO, Werner EM, Grant AM, Green NS, Grosse SD. Genet Med. 2015 Jun;17(6):452-9. doi: 10.1038/gim.2014.123.

Health policy for sickle cell disease in Africa: experience from Tanzania on interventions to reduce under-five mortality Makani J, Soka D, Rwezaula S, Krag M, Mghamba J, Ramaiya K, Cox SE, Grosse SD. Trop Med Int Health. 2015 Feb;20(2):184-7. doi: 10.1111/tmi.12428.

State-based surveillance for selected hemoglobinopathies Hulihan MM, Feuchtbaum L, Jordan L, Kirby RS, Snyder A, Young W, Greene Y, Telfair J, Wang Y, Cramer W, Werner EM, Kenney K, Creary M, Grant AM. Genet Med. 2015 Feb;17(2):125-30. doi: 10.1038/gim.2014.81.

Attitudes toward Management of Sickle Cell Disease and Its Complications: A National Survey of Academic Family Physicians Mainous AG 3rd, Tanner RJ, Harle CA, Baker R, Shokar NK, Hulihan MM. Anemia. 2015;2015:853835. doi: 10.1155/2015/853835.

Population based surveillance in sickle cell disease: methods, findings and implications from the California registry and surveillance system in hemoglobinopathies project (RuSH). Pediatr Blood Cancer Paulukonis ST, Harris WT, Coates TD, Neumayr L, Treadwell M, Vichinsky E, Feuchtbaum LB. 2014 Dec;61(12):2271-6. doi: 10.1002/pbc.25208.

Incidence of sickle cell trait–United States, 2010 Ojodu J, Hulihan MM, Pope SN, Grant AM; Centers for Disease Control and Prevention (CDC). MMWR Morb Mortal Wkly Rep. 2014 Dec 12;63(49):1155-8.

Obstetrician-gynecologists’ knowledge of sickle cell disease screening and management Azonobi IC, Anderson BL, Byams VR, Grant AM, Schulkin J. BMC Pregnancy Childbirth. 2014 Oct 14;14:356. doi: 10.1186/1471-2393-14-356.

Discordance between self-report and genetic confirmation of sickle cell disease status in African-American adults Bean CJ, Hooper WC, Ellingsen D, DeBaun MR, Sonderman J, Blot WJ. Public Health Genomics. 2014;17(3):169-72. doi: 10.1159/000360260.

Invasive pneumococcal disease among children with and without sickle cell disease in the United States, 1998 to 2009 Payne AB, Link-Gelles R, Azonobi I, Hooper WC, Beall BW, Jorgensen JH, Juni B, Moore M; Active Bacterial Core Surveillance Team. Pediatr Infect Dis J. 2013 Dec;32(12):1308-12. doi: 10.1097/INF.0b013e3182a11808.

Acute chest syndrome is associated with single nucleotide polymorphism-defined beta globin cluster haplotype in children with sickle cell anaemia Bean CJ, Boulet SL, Yang G, Payne AB, Ghaji N, Pyle ME, Hooper WC, Bhatnagar P, Keefer J, Barron-Casella EA, Casella JF, Debaun MR. Br J Haematol. 2013 Oct;163(2):268-76. doi: 10.1111/bjh.12507.

Hydroxyurea is associated with lower costs of care of young children with sickle cell anemia Wang WC, Oyeku SO, Luo Z, Boulet SL, Miller ST, Casella JF, Fish B, Thompson BW, Grosse SD; BABY HUG Investigators. Pediatrics. 2013 Oct;132(4):677-83. doi: 10.1542/peds.2013-0333.

Sickle cell disease incidence among newborns in New York State by maternal race/ethnicity and nativity Wang Y, Kennedy J, Caggana M, Zimmerman R, Thomas S, Berninger J, Harris K, Green NS, Oyeku S, Hulihan M, Grant AM, Grosse SD. Genet Med. 2013 Mar;15(3):222-8. doi: 10.1038/gim.2012.128.

Sickle cell disease in pregnancy: maternal complications in a Medicaid-enrolled population Boulet SL, Okoroh EM, Azonobi I, Grant A, Craig Hooper W. Matern Child Health J. 2013 Feb;17(2):200-7. doi: 10.1007/s10995-012-1216-3.

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• Open access
• Published: 03 March 2022

Advances in the diagnosis and treatment of sickle cell disease

• A. M. Brandow 1 &
• R. I. Liem   ORCID: orcid.org/0000-0003-2057-3749 2  

Journal of Hematology & Oncology volume  15 , Article number:  20 ( 2022 ) Cite this article

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Sickle cell disease (SCD), which affects approximately 100,000 individuals in the USA and more than 3 million worldwide, is caused by mutations in the βb globin gene that result in sickle hemoglobin production. Sickle hemoglobin polymerization leads to red blood cell sickling, chronic hemolysis and vaso-occlusion. Acute and chronic pain as well as end-organ damage occur throughout the lifespan of individuals living with SCD resulting in significant disease morbidity and a median life expectancy of 43 years in the USA. In this review, we discuss advances in the diagnosis and management of four major complications: acute and chronic pain, cardiopulmonary disease, central nervous system disease and kidney disease. We also discuss advances in disease-modifying and curative therapeutic options for SCD. The recent availability of l -glutamine, crizanlizumab and voxelotor provides an alternative or supplement to hydroxyurea, which remains the mainstay for disease-modifying therapy. Five-year event-free and overall survival rates remain high for individuals with SCD undergoing allogeneic hematopoietic stem cell transplant using matched sibling donors. However, newer approaches to graft-versus-host (GVHD) prophylaxis and the incorporation of post-transplant cyclophosphamide have improved engraftment rates, reduced GVHD and have allowed for alternative donors for individuals without an HLA-matched sibling. Despite progress in the field, additional longitudinal studies, clinical trials as well as dissemination and implementation studies are needed to optimize outcomes in SCD.

Introduction

Sickle cell disease (SCD), a group of inherited hemoglobinopathies characterized by mutations that affect the β-globin chain of hemoglobin, affects approximately 100,000 people in the USA and more than 3 million people worldwide [ 1 , 2 ]. SCD is characterized by chronic hemolytic anemia, severe acute and chronic pain as well as end-organ damage that occurs across the lifespan. SCD is associated with premature mortality with a median age of death of 43 years (IQR 31.5–55 years) [ 3 ]. Treatment requires early diagnosis, prevention of complications and management of end-organ damage. In this review, we discuss recent advances in the diagnosis and management of four major complications in SCD: acute and chronic pain, cardiopulmonary disease, central nervous system disease and kidney disease. Updates in disease-modifying and curative therapies for SCD are also discussed.

Molecular basis and pathophysiology

Hemoglobin S (HbS) results from the replacement of glutamic acid by valine in the sixth position of the β-globin chain of hemoglobin (Fig.  1 ). Severe forms of SCD include hemoglobin SS due to homozygous inheritance of HbS and S/β 0 thalassemia due to co-inheritance of HbS with the β 0 thalassemia mutation. Other forms include co-inheritance of HbS with other β-globin gene mutations such as hemoglobin C, hemoglobin D-Los Angeles/Punjab or β + thalassemia. Hb S has reduced solubility and increased polymerization, which cause red blood cell sickling, hemolysis and vaso-occlusion (Table 1 ) that subsequently lead to pain episodes and end-organ damage such as cardiopulmonary, cerebrovascular and kidney disease (Table 2 ).

Genetic and molecular basis of sickle cell disease. SCD is caused by mutations in the β globin gene, located on the β globin locus found on the short arm of chromosome 11. The homozygous inheritance of Hb S or co-inheritance of Hb S with the β 0 thalassemia mutation results in the most common forms of severe SCD. Co-inheritance of Hb S with other variants such as Hb C, Hb D-Los Angeles/Punjab, Hb O-Arab or β + thalassemia also leads to clinically significant sickling syndromes (LCR, locus control region; HS, hypersensitivity site)

Acute and chronic pain

Severe intermittent acute pain is the most common SCD complication and accounts for over 70% of acute care visits for individuals with SCD [ 4 ]. Chronic daily pain increases with older age, occurring in 30–40% of adolescents and adults with SCD [ 5 , 6 ]. Acute pain is largely related to vaso-occlusion of sickled red blood cells with ischemia–reperfusion injury and tissue infarction and presents in one isolated anatomic location (e.g., arm, leg, back) or multiple locations. Chronic pain can be caused by sensitization of the central and/or peripheral nervous system and is often diffuse with neuropathic pain features [ 7 , 8 ]. A consensus definition for chronic pain includes “Reports of ongoing pain on most days over the past 6 months either in a single location or multiple locations” [ 9 ]. Disease complications such as avascular necrosis (hip, shoulder) and leg ulcers also cause chronic pain [ 9 ].

Diagnosis of acute and chronic pain

The gold standard for pain assessment and diagnosis is patient self-report. There are no reliable diagnostic tests to confirm the presence of acute or chronic pain in individuals with SCD except when there are identifiable causes like avascular necrosis on imaging or leg ulcers on exam. The effects of pain on individuals’ function are assessed using patient-reported outcome measures (PROs) that determine to what extent pain interferes with individuals’ daily function. Tools shown to be valid, reliable and responsive can be used in clinical practice to track patients’ pain-related function over time to determine additional treatment needs and to compare to population norms [ 10 ]. There are currently no plasma pain biomarkers that improve assessment and management of SCD acute or chronic pain.

Depression and anxiety as co-morbid conditions in SCD can contribute to increased pain, more pain-related distress/interference and poor coping [ 11 ]. The prevalence of depression and anxiety range from 26–33% and 6.5–36%, respectively, in adults with SCD [ 11 , 12 , 13 ]. Adults with SCD have an 11% higher prevalence of depression compared to Black American adults without SCD [ 14 ]. Depression and anxiety can be assessed using self-reported validated screening tools (e.g., Depression: Patient Health Questionnaire (PHQ-9) [ 15 ] for adults, Center for Epidemiologic Studies Depression Scale for Children (CES-DC) [ 16 ], PROMIS assessments for adults and children; Anxiety: Generalized Anxiety Disorder 7-item (GAD-7) scale for adults, State-Trait Anxiety Inventory for Children (STAIC) [ 17 ], PROMIS assessments for adults and children). Individuals who screen positive using these tools should be referred for evaluation by a psychologist/psychiatrist.

Management of acute and chronic pain

The goal of acute pain management is to provide sufficient analgesia to return patients to their usual function, which may mean complete resolution of pain for some or return to baseline chronic pain for others. The goal of chronic pain management is to optimize individuals’ function, which may not mean being pain free. When there is an identifiable cause of chronic pain, treatment of the underlying issue (e.g., joint replacement for avascular necrosis, leg ulcer treatment) is important. Opioids, oral for outpatient management and intravenous for inpatient management, are first line therapy for acute SCD pain. In the acute care setting, analgesics should be initiated within 30–60 min of triage [ 18 ]. Ketamine, a non-opioid analgesic, can be prescribed at sub-anesthetic (analgesic) intravenous doses (0.1–0.3 mg/kg per h, maximum 1 mg/kg per h) as adjuvant treatment for acute SCD pain refractory to opioids [ 18 , 19 ]. In an uncontrolled observational study of 85 patients with SCD receiving ketamine infusions for acute pain, ketamine was associated with a decrease in mean opioid consumption by oral morphine equivalents (3.1 vs. 2.2 mg/kg/day, p  < 0.001) and reductions in mean pain scores (0–10 scale) from baseline until discontinuation of the infusion (7.81 vs. 5.44, p  < 0.001) [ 20 ]. Nonsteroidal anti-inflammatory drugs (NSAIDs) are routinely used as adjuvant therapy for acute pain treatment [ 18 ]. In a RCT ( n  = 20) of hospitalized patients with acute pain, ketorolac was associated with lower total dose of meperidine required (1866.7 ± 12.4 vs. 2804.5 ± 795.1 mg, p  < 0.05) and shorter hospitalization (median 3.3 vs. 7.2 days, p  = 0.027) [ 21 ]. In a case series of children treated for 70 acute pain events in the ED, 53% of events resolved with ketorolac and hydration alone with reduction in 100 mm visual analog scale (VAS) pain score from 60 to 13 ( p  < 0.001) [ 22 ]. Patients at risk for NSAID toxicity (e.g., renal impairment, on anticoagulation) should be identified.

Despite paucity of data, chronic opioid therapy (COT) can be considered after assessing benefits versus harms [ 23 ] and the functional status of patients with SCD who have chronic pain. Harms of COT seen in patient populations other than SCD are dose dependent and include myocardial infarction, bone fracture, increased risk of motor vehicle collisions, sexual dysfunction and mortality [ 23 ]. There are few published studies investigating non-opioid analgesics for chronic SCD pain [ 24 , 25 , 26 ]. In a randomized trial of 39 participants, those who received Vitamin D experienced a range of 6–10 pain days over 24 weeks while those who received placebo experienced 10–16 pain days, which was not significantly different [ 26 ]. In a phase 1, uncontrolled trial of 18 participants taking trifluoperazine, an antipsychotic drug, 8 participants showed a 50% reduction in the VAS (10 cm horizontal line) pain score from baseline on at least 3 assessments over 24 h without severe sedation or supplemental opioid analgesics, 7 participants showed pain reduction on 1 assessment, and the remaining 3 participants showed no reduction [ 24 ]. Although published data are not available for serotonin and norepinephrine reuptake inhibitors (SNRIs), gabapentinoids and tricyclic antidepressants (TCAs) in individuals with SCD, evidence supports their use in fibromyalgia, a chronic pain condition similar to SCD chronic pain in mechanism. A Cochrane Review that included 10 RCTs ( n  = 6038) showed that the SNRIs milnacipran and duloxetine, compared to placebo, were associated with a reduction in pain [ 27 ]. A systematic review and meta-analysis of 9 studies ( n  = 520) showed the TCA amitriptyline improved pain intensity and function [ 28 ]. Finally, a meta-analysis of 5 RCTs ( n  = 1874) of the gabapentinoid pregabalin showed a reduction in pain intensity [ 29 ]. Collectively, the indirect evidence from fibromyalgia supports the conditional recommendation in current SCD practice guidelines to consider these 3 drug classes for chronic SCD pain treatment [ 18 ]. Standard formulary dosing recommendations should be followed and reported adverse effects considered.

Non-pharmacologic therapies (e.g., integrative, psychological-based therapies) are important components of SCD pain treatment. In a case–control study of 101 children with SCD and chronic pain referred for cognitive behavioral therapy (CBT) (57 CBT, 44 no CBT) [ 30 ], CBT was associated with more rapid decrease in pain hospitalizations (estimate − 0.63, p  < 0.05) and faster reduction in hospital days over time (estimate − 5.50, p  < 0.05). Among 18 children who received CBT and completed PROs pre- and 12 months posttreatment, improvements were seen in mean pain intensity (5.47 vs. 3.76, p  = 0.009; 0–10 numeric rating pain scale), functional disability (26.24 vs. 15.18, p  < 0.001; 0–60 score range) and pain coping (8.00 vs. 9.65, p  = 0.03; 3–15 score range) post treatment [ 30 ]. In 2 uncontrolled clinical trials, acupuncture was associated with a significant reduction in pain scores by 2.1 points (0–10 numeric pain scale) in 24 participants immediately after treatment [ 31 ] or a significant mean difference in pre-post pain scores of 0.9333 (0–10 numeric pain scale) ( p  < 0.000) after 33 acupuncture sessions [ 32 ].

Cardiopulmonary disease

Cardiopulmonary disease is associated with increased morbidity and mortality in individuals with SCD. Pulmonary hypertension (PH), most commonly pulmonary arterial hypertension (PAH), is present based on right-heart catheterization in up to 10% of adults with SCD [ 33 ]. Chronic intravascular hemolysis represents the biggest risk factor for development of PAH in SCD and leads to pulmonary arteriole vasoconstriction and smooth muscle proliferation. Based on pulmonary function testing (PFT), obstructive lung disease may be observed in 16% of children and 8% of adults with SCD, while restrictive lung disease may be seen in up to 28% of adults and only 7% of children with SCD [ 34 , 35 ]. Sleep-disordered breathing, which can manifest as obstructive sleep apnea or nocturnal hypoxemia, occurs in up to 42% of children and 46% of adults with SCD [ 36 , 37 ]. Cardiopulmonary disease, including PH or restrictive lung disease, presents with dyspnea with or without exertion, chest pain, hypoxemia or exercise intolerance that is unexplained or increased from baseline. Obstructive lung disease can also present with wheezing.

Diagnosis of cardiopulmonary disease

The confirmation of PH in patients with SCD requires right-heart catheterization. Recently, the mean pulmonary artery pressure threshold used to define PH in the general population was lowered from ≥ 25 to ≥ 20 mm Hg [ 38 ]. Elevated peak tricuspid regurgitant jet velocity (TRJV) ≥ 2.5 m/s on Doppler echocardiogram (ECHO) is associated with early mortality in adults with SCD and may suggest elevated pulmonary artery pressures, especially when other signs of PH (e.g., right-heart strain, septal flattening) or left ventricular diastolic dysfunction, which may contribute to PH, are present [ 39 ]. However, the positive predictive value (PPV) of peak TRJV alone for identifying PH in adults with SCD is only 25% [ 40 ]. Increasing the peak TRJV threshold to at least 2.9 m/s has been shown to increase the PPV to 64%. For a peak TRJV of 2.5–2.8 m/s, an increased N-terminal pro-brain natriuretic peptide (NT-proBNP) ≥ 164.5 pg/mL or a reduced 6-min walk distance (6MWD) < 333 m can also improve the PPV to 62% with a false negative rate of 7% [ 33 , 40 , 41 ].

PFT, which includes spirometry and measurement of lung volumes and diffusion capacity, is standard for diagnosing obstructive and restrictive lung disease in patients with SCD. Emerging modalities include impulse oscillometry, a non-invasive method using forced sound waves to detect changes in lower airway mechanics in individuals unable to perform spirometry [ 42 ], and airway provocation studies using cold air or methacholine to reveal latent airway hyperreactivity [ 43 ]. Formal in-lab, sleep study/polysomnography remains the gold standard to evaluate for sleep-disordered breathing, which may include nocturnal hypoxemia, apnea/hypopnea events and other causes of sleep disruption. Nocturnal hypoxemia may increase red blood cell sickling, cellular adhesion and endothelial dysfunction. In 47 children with SCD, mean overnight oxygen saturation was higher in those with grade 0 compared to grade 2 or 3 cerebral arteriopathy (97 ± 1.6 vs. 93.9 ± 3.7 vs. 93.5 ± 3.0%, p  < 0.01) on magnetic resonance angiography and lower overnight oxygen saturation was independently associated with mild, moderate or severe cerebral arteriopathy after adjusting for reticulocytosis (OR 0.50, 95% CI 0.26–0.96, p  < 0.05) [ 44 ].

Management of cardiopulmonary disease

Patients with SCD who have symptoms suggestive of cardiopulmonary disease, such as worsening dyspnea, hypoxemia or reduced exercise tolerance, should be evaluated with a diagnostic ECHO and PFT. The presence of snoring, witnessed apnea, respiratory pauses or hypoxemia during sleep, daytime somnolence or nocturnal enuresis in older children and adults is sufficient for a diagnostic sleep study.

Without treatment, the mortality rate in SCD patients with PH is high compared to those without (5-year, all-cause mortality rate of 32 vs. 16%, p  < 0.001) [ 33 ]. PAH-targeted therapies should be considered for SCD patients with PAH confirmed by right-heart catheterization. However, the only RCT ( n  = 6) in individuals with SCD and PAH confirmed by right-heart catheterization (bosentan versus placebo) was stopped early for poor accrual with no efficacy endpoints analyzed [ 45 ]. In SCD patients with elevated peak TRJV, a randomized controlled trial ( n  = 74) of sildenafil, a phosphodiesterase-5 inhibitor, was discontinued early due to increased pain events in the sildenafil versus placebo arm (35 vs. 14%, p  = 0.029) with no treatment benefit [ 46 ]. Despite absence of clinical trial data, patients with SCD and confirmed PH should be considered for hydroxyurea or monthly red blood cell transfusions given their disease-modifying benefits. In a retrospective analysis of 13 adults with SCD and PAH, 77% of patients starting at a New York Heart Association (NYHA) functional capacity class III or IV achieved class I/II after a median of 4 exchange transfusions with improvement in median pulmonary vascular resistance (3.7 vs. 2.8 Wood units, p  = 0.01) [ 47 ].

Approximately 28% of children with SCD have asthma, which is associated with increased pain episodes that may result from impaired oxygenation leading to sickling and vaso-occlusion as well as with acute chest syndrome and higher mortality [ 48 , 49 , 50 ]. First line therapies include standard beta-adrenergic bronchodilators and supplemental oxygen as needed. When corticosteroids are indicated, courses should be tapered over several days given the risk of rebound SCD pain from abrupt discontinuation. Inhaled corticosteroids such as fluticasone proprionate or beclomethasone diproprionate are reserved for patients with recurrent asthma exacerbations, but their anti-inflammatory effects and impact on preventing pain episodes in patients with SCD who do not have asthma is under investigation [ 51 ]. Finally, management of sleep-disordered breathing is tailored to findings on formal sleep study in consultation with a sleep/pulmonary specialist.

Central nervous system (CNS) complications

CNS complications, such as overt and silent cerebral infarcts, cause significant morbidity in individuals with SCD. Eleven percent of patients with HbSS disease by age 20 years and 24% by age 45 years will have had an overt stroke [ 52 ]. Silent cerebral infarcts occur in 39% by 18 years and in > 50% by 30 years [ 53 , 54 ]. Patients with either type of stroke are at increased risk of recurrent stroke [ 55 ]. Overt stroke involves large-arteries, including middle cerebral arteries and intracranial internal carotid arteries, while silent cerebral infarcts involve penetrating arteries. The pathophysiology of overt stroke includes vasculopathy, increased sickled red blood cell adherence, and hemolysis-induced endothelial activation and altered vasomotor tone [ 56 ]. Overt strokes present as weakness or paresis, dysarthria or aphasia, seizures, sensory deficits, headache or altered level of consciousness, while silent cerebral infarcts are associated with cognitive deficits, including lower IQ and impaired academic performance.

Diagnosis of CNS complications in SCD

Overt stroke is diagnosed by evidence of acute infarct on brain MRI diffusion-weighted imaging and focal deficit on neurologic exam. A silent cerebral infarct is defined by a brain “MRI signal abnormality at least 3 mm in one dimension and visible in 2 planes on fluid-attenuated inversion recovery (FLAIR) T2-weighted images” and no deficit on neurologic exam [ 57 ]. Since silent cerebral infarcts cannot be detected clinically, a screening baseline brain MRI is recommended in school-aged children with SCD [ 58 ]. Recent SCD clinical practice guidelines also suggest a screening brain MRI in adults with SCD to facilitate rehabilitation services, patient and family understanding of cognitive deficits and further needs assessment [ 58 ]. An MRA should be added to screening/diagnostic MRIs to evaluate for cerebral vasculopathy (e.g., moyamoya), which may increase risk for recurrent stroke or hemorrhage [ 59 ].

Annual screening for increased stroke risk by transcranial doppler (TCD) ultrasound is recommended by the American Society of Hematology for children 2–16 years old with HbSS or HbS/β° thalassemia [ 58 ]. Increased stroke risk on non-imaging TCD is indicated by abnormally elevated cerebral blood flow velocity, defined as ≥ 200 cm/s (time-averaged mean of the maximum velocity) on 2 occasions or a single velocity of > 220 cm/s in the distal internal carotid or proximal middle cerebral artery [ 60 ]. Many centers rely on imaging TCD, which results in velocities 10–15% lower than values obtained by non-imaging protocols and therefore, require adjustments to cut-offs for abnormal velocities. Data supporting stroke risk assessment using TCD are lacking for adults with SCD and standard recommendations do not exist.

Neurocognitive deficits occur in over 30% of children and adults with severe SCD [ 61 , 62 ]. These occur as a result of overt and/or silent cerebral infarcts but in some patients, the etiology is unknown. The Bright Futures Guidelines for Health Supervision of Infants, Children and Adolescents or the Cognitive Assessment Toolkit for adults are commonly used tools to screen for developmental delays or neurocognitive impairment [ 58 ]. Abnormal results should prompt referral for formal neuropsychological evaluation, which directs the need for brain imaging to evaluate for silent cerebral infarcts and facilitate educational/vocational accommodations.

Management of CNS complications

Monthly chronic red blood cell transfusions to suppress HbS < 30% are standard of care for primary stroke prevention in children with an abnormal TCD. In an RCT of 130 children, chronic transfusions, compared to no transfusions, were associated with a difference in stroke risk of 92% (1 vs. 10 strokes, p  < 0.001) [ 60 ]. However, children with abnormal TCD and no MRI/MRA evidence of cerebral vasculopathy can safely transition to hydroxyurea after 1 year of transfusions [ 63 ]. Lifelong transfusions to maintain HbS < 30% remain standard of care for secondary stroke prevention in individuals with overt stroke [ 64 ]. Chronic monthly red blood cell transfusions should also be considered for children with silent cerebral infarct [ 58 ]. In a randomized controlled trial ( n  = 196), monthly transfusions, compared to observation without hydroxyurea, reduced risk of overt stroke, new silent cerebral infarct or enlarging silent cerebral infarct in children with HbSS or HbS/β 0 thalassemia and an existing silent cerebral infarct (2 vs. 4.8 events, incidence rate ratio of 0.41, 95% CI 0.12–0.99, p  = 0.04) [ 57 ].

Acute stroke treatment requires transfusion therapy to increase cerebral oxygen delivery. Red blood cell exchange transfusion, defined as replacement of patients’ red blood cells with donor red blood cells, to rapidly reduce HbS to < 30% is the recommended treatment as simple transfusion alone is shown to have a fivefold greater relative risk (57 vs. 21% with recurrent stroke, RR = 5.0; 95% CI 1.3–18.6) of subsequent stroke compared to exchange transfusion [ 65 ]. However, a simple transfusion is often given urgently while preparing for exchange transfusion [ 58 ]. Tissue plasminogen activator (tPA) is not recommended for children with SCD who have an acute stroke since the pathophysiology of SCD stroke is less likely to be thromboembolic in origin and there is risk for harm. Since the benefits and risks of tPA in adults with SCD and overt stroke are not clear, its use depends on co-morbidities, risk factors and stroke protocols but should not delay or replace prompt transfusion therapy.

Data guiding treatment of SCD cerebral vasculopathy (e.g., moyamoya) are limited, and only nonrandomized, low-quality evidence exists for neurosurgical interventions (e.g., encephaloduroarteriosynangiosis) [ 66 ]. Consultation with a neurosurgeon to discuss surgical options in patients with moyamoya and history of stroke or transient ischemic attack should be considered [ 58 ].

Kidney disease

Glomerulopathy, characterized by hyperfiltration leading to albuminuria, is an early asymptomatic manifestation of SCD nephropathy and worsens with age. Hyperfiltration, defined by an absolute increase in glomerular filtration rate, may be seen in 43% of children with SCD [ 67 ]. Albuminuria, defined by the presence of urine albumin ≥ 30 mg/g over 24 h, has been observed in 32% of adults with SCD [ 68 ]. Glomerulopathy results from intravascular hemolysis and endothelial dysfunction in the renal cortex. Medullary hypoperfusion and ischemia also contribute to kidney disease in SCD, causing hematuria, urine concentrating defects and distal tubular dysfunction [ 69 ]. Approximately 20–40% of adults with SCD develop chronic kidney disease (CKD) and are at risk of developing end-stage renal disease (ESRD), with rapid declines in estimated glomerular filtration rate (eGFR) > 3 mL/min/1.73 m 2 associated with increased mortality (HR 2.4, 95% CI 1.31–4.42, p  = 0.005) [ 68 ].

Diagnosis of kidney disease in SCD

The diagnosis of sickle cell nephropathy is made by detecting abnormalities such as albuminuria, hematuria or CKD rather than by distinct diagnostic criteria in SCD, which have not been developed. Traditional markers of kidney function such as serum creatinine and eGFR should be interpreted with caution in individuals with SCD because renal hyperfiltration affects their accuracy by increasing both. Practical considerations preclude directly measuring GFR by urine or plasma clearance techniques, which achieves the most accurate results. The accuracy of eGFR, however, may be improved by equations that incorporate serum cystatin C [ 70 ].

Since microalbuminuria/proteinuria precedes CKD in SCD, annual screening for urine microalbumin/protein is recommended beginning at age 10 years [ 71 ]. When evaluating urine for microalbumin concentration, samples from first morning rather than random voids are preferable to exclude orthostatic proteinuria. Recent studies suggest HMOX1 and APOL1 gene variants may be associated with CKD in individuals with SCD [ 72 ]. Potential novel predictors of acute kidney injury in individuals with SCD include urine biomarkers kidney injury molecule 1 (KIM-1) [ 73 ], monocyte chemotactic protein 1 (MCP-1) [ 74 ] and neutrophil gelatinase-associated lipocalin (NGAL) [ 75 ]. Their contribution to chronic kidney disease and interaction with other causes of kidney injury in SCD (e.g., inflammation, hemolysis) are not clear.

Management of kidney disease

Managing kidney complications in SCD should focus on mitigating risk factors for acute and chronic kidney injury such as medication toxicity, reduced kidney perfusion from hypotension and dehydration, and general disease progression, as well as early screening and treatment of microalbuminuria/proteinuria. Acute kidney injury, either an increase in serum creatinine ≥ 0.3 mg/dL or a 50% increase in serum creatinine from baseline, is associated with ketorolac use in children with SCD hospitalized for pain [ 76 ]. Increasing intravenous fluids to maintain urine output > 0.5 to 1 mL/kg/h and limiting NSAIDs and antibiotics associated with nephrotoxicity in this setting are important. Despite absence of controlled clinical trials, hydroxyurea may be associated with improvements in glomerular hyperfiltration and urine concentrating ability in children with SCD [ 77 , 78 ]. Hydroxyurea is also associated with a lower prevalence (34.7 vs. 55.4%, p  = 0.01) and likelihood of albuminuria (OR 0.28, 95% CI 0.11–0.75, p  = 0.01) in adults with SCD after adjusting for age, angiotensin-converting enzyme inhibitor (ACE-I)/angiotensin receptor blockade (ARB) use and major disease risk factors [ 79 ].

ACE-I or ARB therapy reduces microalbuminuria in patients with SCD. In a phase 2 trial of 36 children and adults, a ≥ 25% reduction in urine albumin-to-creatinine ratio was observed in 83% ( p  < 0.0001) and 58% ( p  < 0.0001) of patients with macroalbuminuria (> 300 mg/g creatinine) and microalbuminuria (30–300 mg/g creatinine), respectively, after 6 months of treatment with losartan at a dose of 0.7 mg/kg/day (max of 50 mg) in children and 50 mg daily in adults [ 80 ]. However, ACE-I or ARB therapy has not been shown to improve kidney function or prevent CKD. Hemodialysis is associated with a 1-year mortality rate of 26.3% after starting hemodialysis and an increase risk of death in SCD patients with ESRD compared to non-SCD patients with ESRD (44.6 vs. 34.5% deaths, mortality hazard ratio of 2.8, 95% CI 2.31–3.38) [ 81 ]. Renal transplant should be considered for individuals with SCD and ESRD because of recent improvements in renal graft survival and post-transplant mortality [ 82 ].

Disease-modifying therapies in SCD

Since publication of its landmark trial in 1995, hydroxyurea continues to represent a mainstay of disease-modifying therapy for SCD. Hydroxyurea induces fetal hemoglobin production through stress erythropoiesis, reduces inflammation, increases nitric oxide and decreases cell adhesion. The FDA approved hydroxyurea in 1998 for adults with SCD. Subsequently, hydroxyurea was FDA approved for children in 2017 to reduce the frequency pain events and need for blood transfusions in children ≥ 2 years of age [ 63 ]. The landscape of disease-modifying therapies, however, has improved with the recent FDA approval of 3 other treatments— l -glutamine and crizanlizumab for reducing acute complications (e.g., pain), and voxelotor for improving anemia (Table 3 ) [ 83 , 84 , 85 ]. Other therapies in current development focus on inducing fetal hemoglobin, reducing anti-sickling or cellular adhesion, or activating pyruvate kinase-R.

l -glutamine

Glutamine is required for the synthesis of glutathione, nicotinamide adenine dinucleotide and arginine. The essential amino acid protects red blood cells against oxidative damage, which forms the basis for its proposed utility in SCD. The exact mechanism of benefit in SCD, however, remains unclear. In a phase 3 RCT of 230 participants (hemoglobin SS or S/β 0 thalassemia), l -glutamine compared to placebo was associated with fewer pain events (median 3 vs. 4, p  = 0.005) and hospitalizations for pain (median 2 vs. 3, p  = 0.005) over the 48-week treatment period [ 84 ]. The percentage of patients who had at least 1 episode of acute chest syndrome, defined as presence of chest wall pain with fever and a new pulmonary infiltrate, was lower in the l -glutamine group (8.6 vs. 23.1%, p  = 0.003). There were no significant between-group differences in hemoglobin, hematocrit or reticulocyte count. Common side effects of l -glutamine include GI upset (constipation, nausea, vomiting and abdominal pain) and headaches.

Crizanlizumab

P-selectin expression, triggered by inflammation, promotes adhesion of neutrophils, activated platelets and sickle red blood cells to the endothelial surface and to each other, which promotes vaso-occlusion in SCD. Crizanlizumab, given as a monthly intravenous infusion, is a humanized monoclonal antibody that binds P-selectin and blocks the adhesion molecule’s interaction with its ligand, P-selectin glycoprotein ligand 1. FDA approval for crizanlizumab was based on a phase 2 RCT ( n  = 198, all genotypes), in which the median rate of pain events (primary endpoint) was lower (1.63 vs. 2.68, p  = 0.01) and time to first pain event (secondary endpoint) was longer (4.07 vs. 1.38 months, p  = 0.001) for patients on high-dose crizanlizumab (5 mg/kg/dose) compared to placebo treated for 52 weeks (14 doses total) [ 83 ]. In this trial, patients with SCD on chronic transfusion therapy were excluded, but those on stable hydroxyurea dosing were not. Adverse events were uncommon but included headache, back pain, nausea, arthralgia and pain in the extremity.

Polymerization of Hb S in the deoxygenated state represents the initial step in red blood cell sickling, which leads to reduced red blood cell deformability and increased hemolysis. Voxelotor is a first-in-class allosteric modifier of Hb S that increases oxygen affinity. The primary endpoint for the phase 3 RCT of voxelotor ( n  = 274, all genotypes) that led to FDA approval was an increase in hemoglobin of at least 1 g/dL after 24 weeks of treatment [ 85 ]. More participants receiving 1500 mg daily of oral voxelotor versus placebo had a hemoglobin response of at least 1 g/dL (51%, 95% CI 41–61 vs. 7%, 95% CI 1–12, p < 0.001). Approximately 2/3 of the participants in these trials were on hydroxyurea, with treatment benefits observed regardless of hydroxyurea status. Despite improvements associated with voxelotor in biomarkers of hemolysis (reticulocyte count, indirect bilirubin and lactate dehydrogenase), annualized incidence rate of vaso-occlusive crisis was not significantly different among treatment groups. Adverse events included headaches, GI symptoms, arthralgia, fatigue and rash.

Curative therapies in SCD

For individuals with SCD undergoing hematopoietic stem cell transplantation (HSCT) using HLA-matched sibling donors and either myeloablative or reduced-intensity conditioning regimens, the five-year event-free and overall survival is high at 91% and 93%, respectively [ 86 ]. Limited availability of HLA-matched sibling donors in this population requires alternative donors or the promise of autologous strategies such as gene-based therapies (i.e. gene addition, transfer or editing) (Table 4 ). Matched unrelated donors have not been used routinely due to increased risk of graft-versus-host disease (GVHD) as high as 19% (95% CI 12–28) in the first 100 days for acute GVHD and 29% (95% CI 21–38) over 3 years for chronic GVHD [ 87 ]. Haplo-identical HSCT, using biological parents or siblings as donors, that incorporate post-transplant cyclophosphamide demonstrates acceptable engraftment rates, transplant-related morbidity and overall mortality [ 88 ]. Regardless of allogeneic HSCT type, older age is associated with lower event-free (102/418 vs. 72/491 events, HR 1.74, 95% CI 1.24–2.45) and overall survival (54/418 vs. 22/491 events, HR 3.15, 95% CI 1.86–5.34) in patients ≥ 13 years old compared to < 12 years old undergoing HSCT [ 87 ].

Advancing research in SCD

Despite progress to date, additional high-quality, longitudinal data are needed to better understand the natural history of the disease and to inform optimal screening for SCD-related complications. In the era of multiple FDA-approved therapies with disease-modifying potential, clinical trials to evaluate additional indications and test them in combination with or compared to each other are needed. Dissemination and implementation studies are also needed to identify barriers and facilitators related to treatment in everyday life, which can be incorporated into decision aids and treatment algorithms for patients and their providers [ 89 ]. Lastly, continued efforts should acknowledge social determinants of health and other factors that affect access and disease-related outcomes such as the role of third-party payers, provider and patient education, health literacy and patient trust. Establishing evidence-derived quality of care metrics can also drive public policy changes required to ensure care optimization for this population.

Conclusions

SCD is associated with complications that include acute and chronic pain as well as end-organ damage such as cardiopulmonary, cerebrovascular and kidney disease that result in increased morbidity and mortality. Several well-designed clinical trials have resulted in key advances in management of SCD in the past decade. Data from these trials have led to FDA approval of 3 new drugs, l -glutamine, crizanlizumab and voxelotor, which prevent acute pain and improve chronic anemia. Moderate to high-quality data support recommendations for managing SCD cerebrovascular disease and early kidney disease. However, further research is needed to determine the best treatment for chronic pain and cardiopulmonary disease in SCD. Comparative effectiveness research, dissemination and implementation studies and a continued focus on social determinants of health are also essential.

Availability of data and materials

Not applicable.

Abbreviations

Six-minute walk distance

Angiotensin-converting enzyme inhibitor

Angiotensin receptor blockade

Cognitive behavioral therapy

Chronic kidney disease

Chronic opioid therapy

Echocardiogram

End stage renal disease

Fluid-attenuated inversion recovery

Glomerular filtration rate

Graft-versus-host disease

Hemoglobin S

Hematopoietic stem cell transplant

Nonsteroidal anti-inflammatory drugs

N-terminal pro-brain natriuretic peptide

New York Heart Association

Pulmonary arterial hypertension

Pulmonary function test

Pulmonary hypertension

Positive predictive value

Patient-reported outcomes

Randomized controlled trial

• Sickle cell disease

Serotonin and norepinephrine reuptake inhibitors

Tricyclic antidepressants

Transcranial Doppler

Tissue plasminogen activator

Tricuspid regurgitant jet velocity

Visual Analog Scale

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Brandow, A.M., Liem, R.I. Advances in the diagnosis and treatment of sickle cell disease. J Hematol Oncol 15 , 20 (2022). https://doi.org/10.1186/s13045-022-01237-z

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Sickle cell anemia.

Ankit Mangla ; Moavia Ehsan ; Nikki Agarwal ; Smita Maruvada .

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• Continuing Education Activity

Sickle cell anemia is an inherited disorder of the globin chains that causes hemolysis and chronic organ damage. Sickle cell anemia is the most common form of sickle cell disease (SCD), with a lifelong affliction of hemolytic anemia requiring blood transfusions, pain crises, and organ damage. Since the first description of the irregular sickle-shaped red blood cells (RBC) more than 100 years ago, our understanding of the disease has evolved tremendously. Recent advances in the field, more so within the last three decades, have alleviated symptoms for countless patients, especially in high-income countries. This activity reviews the pathophysiology, presentation, complications, diagnosis, and treatment of sickle cell anemia and also highlights the role of the interprofessional team in the management of these patients.

• Describe the pathophysiology of sickle cell anemia.
• Summarize the epidemiology of sickle-cell anemia.
• List the management options for sickle cell anemia.
• Outline the importance of cooperation among healthcare professionals to educate the patients on getting vaccinated, remaining hydrated, and timely follow-up to prevent the development of complications in those with sickle cell disease.
• Introduction

Sickle cell disease (SCD) refers to a group of hemoglobinopathies that include mutations in the gene encoding the beta subunit of hemoglobin. The first description of SCA 'like' disorder was provided by Dr. Africanus Horton in his book The Disease of Tropical Climates and their treatment (1872). However, it was not until 1910 when Dr. James B Herrick and Dr. Ernest Irons reported noticing 'sickle-shaped' red cells in a dental student (Walter Clement Noel from Grenada). [1] In 1949, independent reports from Dr. James V Neel and Col. E. A. Beet described the patterns of inheritance in patients with SCD. In the same year, Dr. Linus Pauling described the molecular nature of sickle hemoglobin (HbS) in his paper 'Sickle Cell Anemia Hemoglobin.' Ingram Vernon, in 1956, used a fingerprinting technique to describe the replacement of negatively charged glutamine with neutral valine and validated the findings of Linus Pauling. [2]   

Within the umbrella of SCD, many subgroups exist, namely sickle cell anemia (SCA), hemoglobin SC disease (HbSC), and hemoglobin sickle-beta-thalassemia (beta-thalassemia positive or beta-thalassemia negative). Several other minor variants within the group of SCDs also, albeit not as common as the varieties mentioned above. Lastly, it is essential to mention the sickle cell trait (HbAS), which carries a heterozygous mutation and seldom presents clinical signs or symptoms. Sickle cell anemia is the most common form of SCD, with a lifelong affliction of hemolytic anemia requiring blood transfusions, pain crises, and organ damage. [3]  

Since the first description of the irregular sickle-shaped red blood cells (RBC) more than 100 years ago, our understanding of the disease has evolved tremendously. Recent advances in the field, more so within the last three decades, have alleviated symptoms for countless patients, especially in high-income countries. In 1984, Platt et al. first reported the use of hydroxyurea in increasing the levels of HbF. [4]  Since then, the treatment of sickle cell has taken to new heights by introducing several new agents (voxelotor, crinzalizumab, L-glutamine) and, most recently, gene therapy.

Hemoglobin (Hb) is a significant protein within the red blood cell (RBC). It comprises four globin chains, two derived from alpha-globin (locus on chromosome 16) and two from beta-globin (locus on chromosome 11). There are many subtypes of Hb. The most common ones that are found in adults without hemoglobinopathies are listed here:

• HbA1- comprises two chains of the alpha-globin and two chains of the beta-globin (a2b2) - This constitutes 95% of the adult hemoglobin.
• HbA2- comprises two chains of the alpha-globin and two chains of the delta-globin (a2d2) - This constitutes less than 4% of the adult hemoglobin.
• HbF- comprises two chains of the alpha-globin and two chains of the gamma-globin (a2g2) - This Hb is more prevalent in the fetus (due to the high oxygen binding affinity that helps extract oxygen from maternal circulation).

The sickle cell mutation occurs when negatively charged glutamine is replaced by a neutral valine at the sixth position of the beta-globin chain. The mutation is transmitted via Mendelian genetics and is inherited in an autosomal codominant fashion. [5]  A homozygous mutation leads to the severest form of SCD, i.e., SCA- also called HBSS disease. The coinheritance of beta-naught thalassemia and sickle cell mutation leads to HBS-Beta-0 disease, which phenotypically behaves like HBSS disease.

A heterozygous inheritance leads to HbAS. Patients with HbAS are not considered within the spectrum of SCD as most of them never present with typical symptoms of SCA. They might only be detected during childbirth, blood donation, or screening procedures. 

Several other compound heterozygotes exist where a single copy of the mutated beta-globin gene is coinherited with a single copy of another mutated gene. The second most common variant of SCD is the HbSC disease, where the sickle cell gene is coinherited with a single copy of the mutated hemoglobin C gene. HbC is formed when lysine replaces glutamine at the sixth position on the beta-globin chain. HbSC disease accounts for 30% of patients in the United States. 

• Epidemiology

The epidemiological data on SCD is scarce. It is well known that SCD and HbAS are more prevalent in sub-Saharan Africa, where the carrier of HbAS is afforded natural protection against severe Plasmodium falciparum malaria. It is estimated that ~230,000 children were born with SCA, and more than 3.5 million neonates were born with HbAS in sub-Saharan Africa in 2010. an estimated 75% of SCD-related births take place in sub-Saharan Africa. West Africa is home to the largest population of individuals with HbSC disease. [3]

The United States (US) Center for Disease Control (CDC) estimates that approximately 100,000 Americans have SCD. The CDC also estimates that 1 in 13 babies born to African-American parents have sickle cell trait, and 1 in 365 African-Americans have SCD. The estimated ratio of Hispanic Americans with SCD is 1 in 16,300. Children and adolescents make up to 40% of all SCD patients in the US. The incidence varies by state and geographical concentration of ethnicities. Besides, migration within the country and immigration from foreign countries alter the prevalence of SCD and HbAS. This is true for several countries where patients with SCD and SCA are living. Genetic studies in Brazil have also tied the origin of such patients to the slave trade originating from West Africa (Mina Coast and Angola). [6]  With the improvement in technology and ease of international migration, the incidence of SCA is predicted to rise. It is estimated that the annual number of newborns with SCA will exceed 400,000 by 2050.

There is also a stark difference in mortality and morbidity in high-income and low-income countries. Adopting vaccination guidelines for children with SCD and intensive screening procedures has sharply reduced the mortality of kids with SCD between 0 to 4 years (68% drop noted from 1999 to 2002 compared to 1983 to 1986). On the other hand, in sub-Saharan Africa, 50 to 90% of children born with SCD will die before their fifth birthday. Improving the care afforded in high-income countries and targeted training of healthcare providers have improved life expectancy. However, it still lags by decades compared to matched non-SCD cohorts (54 versus 76 years - projected life expectancy, and 33 years versus 67 years- quality-adjusted life expectancy). [7]

HbSC disease accounts for 30% of all patients with SCD in the US. As with HbAS, patients with the Hb C trait (heterozygous mutation) also remain asymptomatic for most of their lives. Although considered a milder variant of SCD, HbSC disease may present with severe morbidities. [8]

• Pathophysiology

Sickle cell anemia is characterized by two major components: Hemolysis and vaso-occlusive crises (VOC). The defect in the beta-globin gene makes the sickle hemoglobin (HbS) molecule susceptible to converting into rigid, elongated polymers in a deoxygenated state. The sickling process is cyclical initially, where sickle erythrocytes oscillate between the normal biconcave shape and the abnormal crescent shape (acquired under low oxygen pressure). However, there comes a time when the change becomes irreversible, and the sickle erythrocytes develop a permanent sickle shape increasing the risk for hemolysis and VOC. All variants of SCD share the same pathophysiology leading to polymerization of the HbS component. [3]  

Multiple factors inherent to sickle erythrocytes, like low affinity of HbS to oxygen, physiologically high 2,3-diphosphoglycerate, and increased sphingokinase-1 activity, lead to deoxygenation, which promotes polymerization of HbS. In addition to this, high concentration of HbS, abnormal activity of Gados channel leading to dehydration, and repeated damage to red blood cell (RBC) membrane also increase the risk of polymerization of HbS.

Oxidative stress contributes to hemolysis by auto-oxidation of HbS, leading to erythrocyte cell membrane damage. The increased expression of xanthine dehydrogenase, xanthine oxidase, and decreased expression of NADPH oxidase increase the oxidative stress within sickle RBC. A hemolyzed cell releases free hemoglobin (scavenges nitrous oxide) and arginase 1 (competes for L-arginine) that prevent the action and formation of nitrous oxide and contribute to oxidative stress and vascular remodeling (arginase-1 converts arginine to ornithine). [3]   

Besides the polymerization of the HbS and intravascular hemolysis, several other factors also contribute to vaso-occlusion. For example, the sickle RBC (expresses several adhesion molecules on the surface), free heme and Hb, reactive oxygen species, and endothelium interact with each other and with neutrophils and platelets to promote vaso-occlusion and thrombosis.  

• Histopathology

In patients with SCA, peripheral blood smear shows elongated RBC with tapering ends that look like a sickle (also called drepanocytes). Additional findings are present in a few patients. 

• Howell-Jolly bodies- Remnants of DNA are seen in the RBC and commonly seen in patients in whom the spleen has been removed. Therefore, patients with SCA have auto-splenectomy.
• Target cells (Leptocytes)- Most commonly seen in patients with Thalassemia. They are seen frequently in sickle-thalassemia syndromes and are sometimes noted in patients with SCA.
• Polychromatic cells - these are reticulocytes that signify marrow response to hemolysis. 
• Nucleated red blood cells can sometimes be visible on the peripheral smear. 

None of these findings are confirmatory. Confirmation is obtained only through hemoglobin electrophoresis, high-performance liquid chromatography, or isoelectric focusing. DNA-based techniques are not used routinely. Instead, they are used in patients with uncertain diagnoses. Pre-natal fetal testing involves using fetal DNA obtained through amniocentesis. Techniques to capture the fetal DNA in maternal blood remain investigational.

• History and Physical

Most patients with HbSS phenotype do not present with classical 'sickle cell crises' soon after birth. HbF is still present in the blood, helping maintain adequate tissue oxygenation, and it takes around 6-9 months to wean off completely. Not all SCA have the same phenotype, and multiple phenotypes exist that can either co-exist or present as a spectrum of the disease. [3]  

• Vaso-occlusive subphenotype - Distinguished by higher hematocrit (Hct) compared to other SCA. A higher Hct leads to higher viscosity that promotes frequent vaso-occlusive crises and acute chest syndrome. 
• Higher risk of gallstones, pulmonary hypertension, ischemic stroke, priapism, and nephropathy
• Severe anemia increases cardiac workload and blood flow through organs, making them susceptible to damage
• Higher free heme and Hb in blood vessels cause oxidative damage
• High Hb F subtype- A 10 to 15% level of HbF alleviates the symptoms of SCA. However, the distribution of HbF is not consistent throughout the body.
• Pain-sensitive subphenotype- Altered neurophysiology amongst various individuals make them susceptible to pain. Some individuals are more susceptible to pain compared to others with SCA.

The patients with SCA present wither with acute or chronic complications associated with the disease. The most common acute complication of SCA is Vaso-occlusive crisis (VOC). The treatment section below discusses the management of acute and chronic issues. 

Important points to be noted in the history of patients with SCA

• All patients with SCA will experience VOC during their lives. The earliest presentation is dactylitis in kids as young as six months of age.
• Any body organ can develop VOC (head, eyes, etc.), although extremities and the chest are most commonly involved. If a VOC pain sounds atypical, obtain a history to rule out other causes.
• When was the last pain crisis, and how many times in the previous year have they been admitted to the hospital with pain crises?
• If they take analgesics daily, it is prudent to know the type and quantity of the analgesic (opioid or non-opioid), the last use of analgesics, and whether they take the analgesics before coming to the ER/office
• History of taking disease-modifying drugs (hydroxyurea, voxelotor, crinzalizumab, etc.) 
• A history of substance abuse, psychiatric disorders, and use of psychotropic medications must be obtained. 
• History of receiving blood transfusions and exchange transfusions- helps assess the risk of iron overload, presence of alloantibodies (multiple transfusions in the past can lead to the development of alloantibodies, which will help assess the risk of transfusion reactions), and previous transfusion reactions. 
• History of any other diseases that may or may not be associated with SCA - previous history of stroke, thrombosis, priapism, etc.
• It is also advised to get in touch with the primary hematologist taking care of the patient- it is valuable to have their input in understanding the patient's normal physiology. 
• History of previous surgeries.
• History of life-threatening crises in the past- if present, should alert the clinician to ensure that a similar event is not occurring again. For example, fat embolism may occur more frequently in patients with SCA. 

The physical exam should focus on the general system exam to determine the need for oxygen requirements, pain management, and blood/exchange transfusion. However, a focused exam is also necessary to rule out any organ-specific problem. For example, a rapidly enlarging liver or spleen should alert the physician about sequestration crises. 

Patients with SCA are usually diagnosed in childhood. Intensive newborn screening programs in developed countries can identify patients in the neonatal stage. In the US, universal screening for SCA was implemented in all states by 2007. High-performance liquid chromatography and isoelectric focusing are the methods used in the US. In Europe, most countries deploy targeted screening in high-risk areas (where SCA is more common) and not a universal screen. In sub-Saharan Africa, no country has adopted a screening program. In India, the solubility test is used as the first step- if positive, then high-performance liquid chromatography is used to confirm at the reference center. [3]

Acute Complications in Patients with SCA

Acute Chest Syndrome (ACS):  ACS is the most common complication of SCA. It is also the most common cause of death and the second most common cause of hospital admission. A patient can either present with ACS or may develop it during hospitalization for any other reason. Hence, it is prudent to monitor all patients with SCA admitted to the hospital for ACS. It is important to recognize ACS early and act upon it to prevent respiratory failure.

• The risk factors for ACS include a previous history of ACS, asthma, or recent events like recent surgical procedures, pulmonary embolism, fluid overload, infection, etc.
• The clinical features include sudden onset of cough and shortness of breath. Fever may or may not be a part of the spectrum of presentation. If present, then it usually points towards infection.
• Laboratory evaluation includes a complete blood count with differential chemistries, including liver and kidney evaluation, blood cultures, and sputum cultures.
• Chest X-ray shows a new pulmonary infiltrate- this is a quintessential feature of defining ACS. CT and perfusion mismatch scans are only used if there is a strong clinical suspicion of pulmonary embolism or fat embolism. Therefore, they are not usually helpful in acute settings.

Sequestration Crises: This can either be hepatic or splenic sequestration.

• Patients experience rapid spleen enlargement associated with pain in the left upper quadrant. In children with SCA, it is common in children between 1 to 4 years of age, as the spleen is still intact.
• Patients with non-SCA variants (HbSC, HbS-beta+ thalassemia) are not prone to 'auto-splenectomy' commonly seen in patients with SCA. Hence they can develop splenic sequestration later in life. Such patients may have baseline splenomegaly, causing hypersplenism. Parents and patients must receive counseling regarding the signs and symptoms of an enlarging spleen.
• Younger patients present with acute anemia and hypovolemic shock due to smaller circulating volumes, whereas adults may present with a more insidious onset.
• Pain occurs due to stretching of the splenic capsule and new infarcts.
• Blood count shows a drop in Hb by more than 2gm/dL, increased reticulocyte count, and nucleated red blood cells. 
• Hepatic sequestration: Hepatic sequestration can occur across all phenotypes of SCA. Like the spleen, patients may have a baseline enlargement of the liver. Hepatic sequestration is also defined as rapid enlargement of the liver with stretching of the capsule. The hemoglobin shows a drop of more than 2gm/dL. Liver enzymes may not get elevated.

Acute Stroke:  Stroke is the most devastating complication of SCA. Since the advent of transcranial doppler (TCD) and the institution of primary prevention programs, the incidence of stroke has gone down in patients with SCA. In the absence of primary prevention, ~10% of children suffer from overt stroke, and approximately 20 to 35% have silent cerebral infarcts. TCD is not useful for adults. 

• Severe headache, altered mental status, slurred speech, seizures, and paralysis- are signs of stroke. 
• Urgent neurological consultation and CT scan followed by MRI/MRA must be done. 

Aplastic crises:  It is usually precipitated by parvovirus B-19 and is defined as a rapid drop in Hb at least 3 to 6 gm/dL below the baseline. Patients present with severe fatigue, anemia, shortness of breath, and even syncope. Blood counts show severely low hemoglobin with near-absent reticulocytes. Bone marrow biopsy shows arrest in the pro-normoblast stage in patients with acute parvovirus infections. [9]

Acute intrahepatic cholestasis (AIC):  Presents with sudden onset right upper quadrant pain. Physical exam shows worsening jaundice, enlarging and tender liver, and clay-colored stools. Labs show very high bilirubin levels, elevated alkaline phosphatase, and coagulopathy. The hemolysis parameters may be normal. AIC is a medical emergency.

Infections in patients with SCA can be a harbinger of infection with Streptococcus pneumoniae infection or osteomyelitis.

• The use of prophylactic antibiotics and pneumococcal vaccinations has reduced their incidence. However, loss of splenic function in SCA patients puts them at risk of invasive bacterial species.
• Osteomyelitis can be unifocal or multifocal- Staphylococcus aureus , Salmonella , and other enteric organisms can cause osteomyelitis in SCA patients. 

Priapism  is defined as a sustained, unwanted painful erection lasting more than 4 hours. It is a common condition among patients with SCA, affecting 35% of all men/boys. 

Acute Ocular Complications

• The complication presents similarly in patients with SCA and sickle cell trait.
• The low oxygen pressure and acidotic nature of the aqueous humor promote sickling of the RBC, leading to blockage of the trabecular network leading to an acute rise in intraocular pressure (IOP). 
• High IOP is poorly handled in patients with SCA - which can lead to CRAO and secondary hemorrhages. 
• Central Retinal Artery Occlusion (CRAO)- Results from thrombus formation in the retinal artery leading to infarction of the retina, macular ischemia, or macular infarction. CRAO can occur spontaneously or secondary to increased IOP (from hyphema), Moyamoya syndrome, or ACS in patients with SCA. 
• Patients present with proptosis, local pain, and edema of the lid or orbit.
• The exam shows reduced extraocular motility and decreased visual acuity.
• CT scan helps in distinguishing this from orbital cellulitis/ infection. 
• Orbital Compression Syndrome (OCS) - also called orbital apex syndrome, is characterized by ophthalmoplegia and vision loss secondary to events occurring at the orbital apex. Cranial nerves II, III, IV, VI, and the first division of CN V can be involved. MRI of the orbits is the best modality for diagnosis. 

Chronic Complications in Patients with SCA

Iron Overload:  Iron (Fe) overload is a common problem in SCA patients due to repeated transfusions and chronic hemolysis. Each unit of packed RBC contains 200 to 250 mg of iron. Excessive iron mainly affects the heart, lungs, and endocrine glands. [10]  Hepatic cirrhosis from excessive iron is a major cause of death in patients with SCA. Clinical trials in patients with thalassemia have shown that systemic iron load correlates directly with survival and cardiac incidents. [11]

Avascular Necrosis (AVN) of Joints:  AVN of the femoral head is a common cause of chronic pain and disability in SCA patients. Although the hip joint is the most common joint to be involved, other joints can also be affected. AVN occurs at the distal portion of the bone, where collateral circulation is poor. The capillaries get occluded by sickle RBCs leading to hypoxia and bone death. Risk factors for AVN of the femoral head include age, frequency of painful episodes, hemoglobin level, and alpha-gene deletion. In patients with HbSS, the overall prevalence is 50 percent by age 33. HbSS-alpha thalassemia and HbSS-Beta-0 thalassemia are at higher risk of developing AVN early in life. 

Leg Ulcers : More common in SCA compared to other SCD genotypes. Approximately 2.5% of patients with SCA above ten years of age have leg ulcers. Leg ulcers are more common in men and older people and less common in people with high total hemoglobin, alpha-gene deletion, and high levels of HbF. Trauma, infections, and severe anemia also increase the risk of leg ulcers. The ulcers occur more commonly on the medial and lateral surfaces of the ankles. They vary in size and depth, and chronic ulcers may lead to osteomyelitis, especially if they are deep enough to expose the bone.

Pulmonary Artery Hypertension (PAH) : Affects 6 to 11% of patients with SCA. PAH in SCA is classified under World Health Organization (WHO) group V. However; chronic hemolysis leads to pulmonary vascular changes classified under WHO group 1 in up to 10% of all SCA patients. PAH in SCA can also occur due to left heart dysfunction (Group II), chronic lung disease from SCA (Group III), chronic thromboembolism (Group IV), or extrathoracic causes (Group V). 

The patient may complain of dyspnea on exertion, swelling in the legs, or present with symptoms of underlying disease (like a history of thrombosis, heart failure, etc.). An echocardiogram helps in estimating the tricuspid regurgitant jet velocity (TRV). Elevated TRV is associated with increased mortality in adults. However, TRV can be transiently elevated during acute chest syndrome. Serum NT-pro-BNP is directly correlated with mortality as well. The final diagnosis is made with a right heart catheterization.  

Renal complications: Chronic kidney disease (CKD) occurs in approximately 30% of adult patients with SCA. The acidotic, osmotic, and hypoxic environment of the kidney increases the risk of polymerization of HbS, leading to the sickling of RBC. SCA patients secrete excessive creatinine in their proximal tubules. Hence, it becomes challenging to identify early signs of kidney disease, as creatinine takes a longer time to rise. Microalbuminuria (30-300mg albumin in 24-hour urine collection) is often the first manifestation of CKD. Spot urine-creatinine ratio is not validated in SCA patients due to hypersecretion of creatinine.

• Hypoesthenuria- Inability to concentrate urine due to loss of deep juxtamedullary nephrons. It is the most common complication in SCA patients. It leads to frequent urination and increases the risk of dehydration. It also increases the risk of enuresis in children.
• Renal papillary necrosis occurs due to obstruction of the vessels supplying the vasa recta resulting in medullary infarction. It presents with hematuria. It is more common in patients with HbSC disease.
• Asymptomatic Proteinuria: It is present in 15 to 50% of patients. It develops early in life due to hyperfiltration and loss of selectivity for albumin.

Ophthalmologic Complications: Chronic eye complications are more common in patients with HbSC and HbSS disease. They are found in up to 50% of patients.

• Proliferative Sickle Retinopathy occurs due to vaso-occlusion of vitreal arterioles leading to ischemia which leads to neovascularization. Neovascular tissue is predisposed to hemorrhage and vitreal traction forces resulting in vitreal hemorrhage (the most severe complication of proliferative sickle retinopathy). 
• Treatment / Management

Patients with SCA present with acute and chronic complications. 

Management of Acute Complications

Pain management is a critical part of SCA. It is challenging for clinicians to accurately assess patients' needs, especially if they meet them for the first time. Patients with SCA often suffer from the stigma of requiring high doses of opioids for pain control, which leads to them being labeled as 'opioid abusers,' 'manipulators,' or even' drug seekers.'  [12]

• Analgesic administration starts simultaneous with evaluating the cause, ideally within 30 minutes of triage and 60 minutes of registration.
• Develop individualized pain management plans - this should be made available to the emergency room and should be implemented each time the patient presents with VOC and pain.
• NSAIDs are used in patients with mild to moderate pain who report prior episodes of relief with NSAIDs
• Any patient presenting with severe pain- preferably used parenteral opioids. An intravenous route is preferred; however, if access is difficult, use the subcutaneous route.
• The dose of parenteral opioids is calculated based on the total dose of short-acting oral opioids taken at home.
• Pain should be reassessed every 15 to 30 minutes, and readminister opioids if needed. The escalation of opioids is done in 25% increments.
• Patient-controlled analgesia (PCA) is preferred. If an "on-demand" setting is used in PCA, then continue long-acting analgesia.
• When pain control is achieved, "wean off" parenteral opioids before converting to oral medications.
• Calculate the inpatient analgesic requirement at discharge and adjust home doses of short and long-acting opioids accordingly.
• Meperidine is not used in managing VOC-related pain unless this is the only medication that controls the pain.
• Antihistamines only help in controlling opioid-related itching. When required, use oral formulations only—readminister every 4 to 6 hours as needed.
• Incentive spirometry
• Intravenous hydration
• Supplemental oxygen is needed only if saturation drops below 95% on the room air.

Management of Chronic Pain

Chronic pain management in SCA patients focuses on the safe and adequate use of pain medications, particularly opioids. A comprehensive assessment of the patient's ailment, the kind and doses of pain medicine required to control pain, and the functional outcomes of using these medications are made at each encounter. The process involves collaboration with multiple specialties, like psychiatry, social work, etc., to administer the right pain medicine in the proper doses. 

The strategy adopted in the clinic to prescribe pain medicine involves:

• One person must be assigned to prescribe long-term opioids. They should document all encounters extensively involving the physical exam, lab work, etc. 
• Assess each patient for non-SCA-related pain and treat/refer to the appropriate specialty for managing this pain.
• Limit prescribing pain medicines without meeting the patient- every patient must be physically assessed every 2 to 3 months or sooner.
• Develop an individualized pain management plan for each patient, reassess this plan annually, and modify it accordingly.
• Encourage patients to explore alternative methods of controlling pain, like direct massage, self-hypnosis, and music therapy.

Acute Chest Syndrome (ACS):  It is an emergency regardless of the sickle cell disease phenotype. It can lead to respiratory failure and death if not managed as an emergency.

• All patients must be hospitalized-
• Upon admission, start treatment with antibiotics, including coverage for atypical bacteria.
• Supplemental oxygen is provided to those with oxygen saturation of less than 95% at room air.
• "Early" administration of simple blood transfusion is recommended for hypoxic patients. However, exchange transfusion is recommended at the earliest opportunity.
• Close monitoring for worsening respiratory status, increasing oxygen requirement, worsening anemia, and bronchospasm (use of beta-adrenergic dilators is encouraged in asthmatics) must be done. Intensive care units must be on standby to receive such patients who experience worsening respiratory status.
• Closely monitor predictors of severity- increasing respiratory rate, worsening hypoxia, decreasing hemoglobin or platelet count, multilobar involvement on chest X-ray, and developing neurological complications.
• Incentive spirometry and hydration (intravenous or oral) must always be encouraged. 
• ACS is a strong indicator for initiating disease-modifying therapy (hydroxyurea, etc.) or starting the patient on a chronic blood transfusion program.

Sequestration Crises

• Intravenous fluids for hydration, pain control, and simple/exchange blood transfusion are central to managing sequestration crises.
• Never correct anemia completely- when the crises resolve, and the organs shrink, the sequestered blood re-enters the circulation, leading to increased hematocrit and viscosity, increasing the risk of thrombotic and ischemic events.
• Splenectomy is recommended for patients with life-threatening episode splenic sequestration crises or with recurrent splenic sequestration. It is also offered to those who have baseline hypersplenism.
• Instruct patients and parents in monitoring the size of the liver and spleen regularly.

Acute Stroke:  Urgent neurology and transfusion medicine consultation are needed to provide optimal care and prevent long-term damage.

• Simple or exchange blood transfusion emergently.
• Start a program of chronic exchanges or blood transfusion. 
• Where blood transfusion cannot be used (iron overload, excessive alloantibodies) or is unavailable, start on long-term disease-modifying therapy. SWiTCH trial demonstrated that chronic transfusions are a better way to manage patients with stroke.

Aplastic Crises:  Parvovirus infections cause a transient drop in hemoglobin. Humoral immunity develops within 7 to 10 days that stays for life. The patient is extremely susceptible to developing ACS or stroke during the acute period. Initiate exchange/simple transfusion to bring Hb to a safe level, not necessarily to normal/baseline level.

Infections presenting with fever:  Oral empiric antibiotics are given promptly while evaluating the reason for the fever. For ill-appearing patients, admit them and administer intravenous antibiotics.

Priapism: Early recognition is the key to management. Delayed management can lead to impotence. Urologists need to be involved early on in the care of such patients. 

• Conservative measures include using analgesics, hydration, and sedation - which usually leads to detumescence and retains potency. Most experts would call for upfront urologic management rather than losing time trying conservative measures. [13]
• Urologists can perform penile aspiration or irrigation of corpora cavernosa with alpha-adrenergic drugs.
• Blood transfusion/ exchange transfusion is not useful - few authors have reported neurological complications with the use of blood transfusion (ASPEN syndrome). Hence it is best to avoid blood transfusion.

Acute ocular Complications:  All ocular complications must be managed in consultation with ophthalmologists and hematologists to prevent vision loss. 

• Hyphema- Anterior chamber paracentesis or surgical intervention to manage the thrombus must be done promptly.
• Reducing intraocular pressure helps prevent CRAO and other compression issues. 
• Infections are managed with prompt administration of antibiotics. 
• Corticosteroids are used to relieve excessive pressure in patients with OCS.

Chronic Complications

Avascular Necrosis:  About 40 to 80% of cases of hip joint AVN are bilateral; therefore, both joints should be investigated simultaneously. Pain management and physical therapy are to be initiated as early as possible. Advanced cases may require hip arthroplasty.

Leg Ulcer: Conservative measures involve wound care, wet-to-dry dressings, and pain control. Hydroxyurea is avoided in patients with open leg ulcers, as it may prevent healing. Frequent evaluation for the stage of healing or lack of infection, osteomyelitis must be done. Local and systemic antibiotics are used for infected ulcers.

Pulmonary Hypertension:  Patients with higher TRV are referred to pulmonologists for management. Small studies have shown increased mortality with sildenafil.

Renal Complications: Refer SCA patients with micro- or microalbuminuria to nephrologists for detailed workup and consideration of angiotensin-converting enzyme inhibitor (ACE-inhibitor). Follow patients closely who have modest elevation in creatinine (>0.7 mg/dL in children, >1.0 mg/dL in adults), and refer to a nephrologist at the earliest sign of worsening creatinine.

Ophthalmologic Complications: Refer SCA patients regularly for ophthalmologic evaluation, especially if they complain of slow vision changes. Direct and indirect ophthalmoscopy, slit-lamp biomicroscopy, and fluorescein angiography are used to evaluate SCA patients. Laser photocoagulation therapy is used to manage proliferative sickle retinopathy. A vitrectomy or retinal repair may be needed in the rare event of vitreal hemorrhage or retinal detachment. 

Iron Overload

Unlike hemochromatosis, phlebotomy is not an option in patients with SCA. Preventing iron overload with good transfusion practices is the best way to deal with iron overload. Patients with SCA need not follow the rule of having hemoglobin close to 7gm/dL. Packed RBC transfusion should be restricted to the management of symptoms. Choosing exchange transfusion over simple transfusion also helps to reduce/prevent iron overload.

Indications to start iron chelation therapy

• A liver iron concentration (LIC) greater than 3 mg iron (Fe)/gm dry weight
• Cardiac T2* < 20 milliseconds
• Serum ferritin greater than 1000 on two different occasions 15 days apart
• Age greater than two years
• Expected survival beyond one year
• Number of transfusion of Packed RBC in 1 year- > 10 in pediatric patients OR > 20 in adults. 

Goals of therapy

• Serum ferritin < 1000 mcg/L,
• LIC <7mg Fe/gm dry weight
• Cardiac T2* > 20 milliseconds

When do patients need modification of treatment?

• Treatment needs to be intensified if LIC > 15 mg Fe/gm dry weight and deescalated when LIC < 3 mg Fe/gm dry weight.
• Treatment needs to be intensified if serum ferritin > 2500 IU/L and deescalated when serum ferritin < 300 IU/L
• Treatment needs to be intensified when cardiac MRI shows T2* < 15 milliseconds or when cardiac symptoms occur (like heart failure, arrhythmias)

Iron Chelators

• Disperse tab formulation: Initial dose: 10mg/kg/day. Maximum dose: 20mg/kg/day
• Tablet or granule formulation: Initial dose: 7mg/kg/day. Maximum dose: 14mg/kg/day
• It does not interfere with the pharmacodynamics of hydroxyurea; hence it can be used simultaneously.
• Adverse effects- gastrointestinal intolerance, dose-dependent rise in serum creatinine, liver dysfunction.
• Daily subcutaneous infusions via portable infusion pump given over 8 to 24 hours; 1 to 2 gm/day 
• It can be given as a daily IV infusion also. 40 to 50 mg/kg/day (max dose 60 mg/kg/day) over 8 to 12 hours (max rate 15 mg/kg/hour) 
• IM route is acceptable for children but not preferred for adults. 0.5 to 1mg/day
• Adverse effects- Injection site reactions, cardiovascular shock (if administered too fast), blood dyscrasias, growth retardation.  
• Adverse effects - agranulocytosis, hepatotoxicity, gastrointestinal symptoms, and arthralgia.

Blood transfusion:  Blood transfusions form an integral part of the management of SCA. The goal of transfusion is to increase the oxygen-carrying capacity of blood and reduce the HbS component. A blood transfusion (simple or exchange) is given to keep the HbS level below 30% (STOP 1 and 2 trials). [14]  In patients receiving regular exchange transfusions (history of stroke, intolerance, or contraindication to hydroxyurea), a more practical target for HbS is 25% to prevent a rise of HbS beyond 30%.

What types of blood transfusion are used in SCA?

• Simple transfusion: Transfusion of matched packed red blood cells (PRBC)
• Exchange transfusion: Transfusion of PRBC while removing blood from the patient at the same time.

Who should receive blood transfusions?

• Hb < 7gm/dL or drop of >2 gm/dL from baseline- consider simple or exchange transfusion. 
• Twin pregnancy- consider prophylactic exchange transfusion
• Hb less than 9 gm/dL- Simple transfusion
• Hb more than 9gm/dL- Partial exchange transfusion

What kind of transfusion practice should be followed?

• Severe ACS - oxygen saturation less than 90% even when started on supplemental oxygen. 
• Multiorgan Failure
• Acute ischemic stroke
• Splenic sequestration - never corrects the anemia completely.
• Acute anemia

Complications from Chronic Transfusions

• Alloimmunization- increases the risk of transfusion reactions, especially delayed hemolytic transfusion reactions. 
• Iron overload
• Transmission of blood-borne diseases like hepatitis B, C, and HIV; extremely low risk due to intensive screening of donors and blood products.
• Differential Diagnosis

In general, globin gene mutations affecting hemoglobin are common and affect 7% of the entire world population. [15]  Over 1000 variations of hemoglobin exist. However, only a handful of variations are significant clinically. 

Common Variants of SCA or HbSS Disease

• Hemoglobin S-beta-0 thalassemia (Clinically behaves exactly like HbSS disease)
• Hemoglobin SC (a milder variant of SCD) - can have a phenotypic presentation of sickle cell anemia
• Hemoglobin S-beta+ thalassemia (a milder variant of SCD)

Several other hemoglobin variants are present that can mimic SCA if they are inherited along with HbS.

• Hemoglobin Jamaica-Plain (beta-68 [E12] Leu -> Phe)
• Hemoglobin Quebec-Chori (beta-87 [F3] Thr > Ile)
• Hemoglobin D-Punjab (beta-globin, codon 121, glutamine to glutamic acid)
• Hemoglobin O-Arab
• Hemoglobin E

Other conditions that can present with hemolysis, where SCA can be ruled out with history, examination, hemoglobin electrophoresis, and study of the peripheral smear

• Antibody-mediated autoimmune hemolytic anemia (both warm and cold antibodies)
• Other hemoglobinopathies- alpha or beta-thalassemia
• Paroxysmal nocturnal hemoglobinuria
• RBC-membrane defects (hereditary spherocytosis, hereditary elliptocytosis)
• Enzyme defects (pyruvate kinase deficiency, glucose-6-phosphate deficiency)
• Drug-induced hemolysis
• Transfusion-related hemolysis (acute or delayed hemolytic reaction)
• Microangiopathic hemolytic anemia (atypical or typical hemolytic uremic syndrome, thrombotic thrombocytopenic purpura)
• Infectious causes (malaria, babesiosis, Rickettsia , Clostridia , Bartonella )
• Vasculitis-induced hemolysis
• Medical Oncology

The goal of disease-modifying therapy in sickle cell anemia is to reduce the frequency of vaso-occlusive crises (VOC) and pain crises and prevent organ damage. These medications usually do not have a role "during" acute crises. Hydroxycarbamide, or hydroxyurea, was the first drug approved by the FDA for use in patients with SCA. However, the USFDA approved hydroxyurea for pediatric patients two years and above only in 2017 (based on the ESCORT HU trial).   

Disease-Modifying Drugs/Therapy

The goal of disease-modifying therapy in patients with SCA is to alter the kinetics of sickle erythrocytes. Hydroxyurea does this by increasing the concentration of fetal hemoglobin (HbF).

Hydroxyurea:  This is a ribonucleotide reductase inhibitor that increases the concentration of HbF in patients with SCD. It not only increases the intracellular concentration of HbF but also increases the number of erythrocytes containing HbF. In addition to this, hydroxyurea also reduces the number of circulating reticulocytes and leukocytes, raises the volume of an RBC (high MCV is noted in patients receiving hydroxyurea), reduces the deformability of RBC, improves the flow of blood through capillaries, and alters the expression of adhesion molecules hence preventing vaso-occlusive crises. The initial trials with hydroxyurea (Phase-III Multicenter Study of Hydroxyurea in Sickle Cell Anemia (MSH)) demonstrated a clear benefit over placebo in reducing the incidence of pain crises and the cost of care. Long term, the MSH study also showed a mortality benefit. In the pediatric age group, two seminal trials (HUG-KIDS-Phase I/II and BABY HUG-phase III) demonstrated good tolerability and led to the drug's approval. [16] [17]  

• Having three or more sickle cell-associated moderate to severe pain crises within a 12-month period; treat with hydroxyurea
• Those with sickle cell-associated pain that interferes with daily activities of living and quality of life
• History of severe and/or recurrent ACS
• Severe symptomatic chronic anemia that interferes with daily activities or quality of life
• Infants 9 months of age and older, children, and adolescents with SCA, offer hydroxyurea regardless of clinical severity to reduce SCA-related complications (e.g., pain, dactylitis, ACS, anemia)
• For those with chronic kidney disease taking erythropoietin and hydroxyurea can be added to improve anemia
• DO NOT give hydroxyurea to pregnant women and lactating mothers who choose to breastfeed their babies
• Dosing for adults: Start with 15 mg/kg/day. Round up to the closest 500 mg. For patients with CKD- start at 5 to 10 mg/kg/day. 
• Dosing for infants and children: start at 20 mg/kg/day
• Target absolute neutrophil count (ANC) of above 2000/microL and platelet count above 80,000/microL. In younger patients, an ANC of 1250/microL is allowed if baseline counts are low.
• Monitor blood counts every four weeks when increasing the dose of hydroxyurea.
• Clinical response takes 3 to 6 months to come. Hence a minimal trial of 6 months of daily continued use of hydroxyurea is done before considering alternative therapies. 
• Daily adherence is a must. It must be emphasized to the patient.
• If a positive response is seen, then hydroxyurea must be continued indefinitely. 
• Myelotoxicity is the most common and most substantiated adverse effect of hydroxyurea. The rest of the adverse effects reported in the literature, especially carcinogenesis and leukemia, have never been demonstrated in large studies. 
• Avoid the use of hydroxyurea in patients with leg ulcers.

Voxelotor:  Voxelotor acts by inhibiting the polymerization of HbS and increasing the affinity for oxygen. It is dosed at 1500 mg by mouth daily and is approved for SCA treatment in patients 12 years of age and older. Voxelotor can be given with or without hydroxyurea. USFDA approved it in 2019 based on the results of the phase 3 HOPE trial (Hemoglobin Oxygen Affinity Modulation to Inhibit HbS Polymerization) evaluating voxelotor (1500 mg versus 900 mg versus placebo in 1:1:1 design). [18] [19]  

The most common adverse reactions are headache, diarrhea, abdominal pain, nausea, fatigue, rash, and pyrexia. Voxelotor interferes with high-performance liquid chromatography (HPLC). Hence the hemoglobin quantification is not accurate when the patient is on voxelotor. HPLC should be done when the patient is off therapy. Also, the use of voxelotor may increase the Hb, but there is no evidence to suggest discontinuation of exchange transfusion in patients receiving this for stroke prophylaxis.

Crizanlizumab:  A humanized immunoglobulin G2-Kappa monoclonal antibody inhibits P-selectin, thereby blocking its interaction with P-selecting glycoprotein-1. This leads to reduced interaction between activated endothelium, platelets, leukocytes, and sickled RBCs, leading to reduced VOC. [20]  The phase II SUSTAIN trial demonstrated a clinical benefit of Crizanlizumab by demonstrating a reduction in pain crises, VOC, emergency room visits, and increased median time to first crises. Although the hospitalization rate was numerically lower in the intervention group, the difference was not statistically significant compared to the placebo group. [21]

It is approved for the treatment of SCA in patients 16 years of age and older. It is dosed as a 5mg/kg intravenous infusion administered over 30 minutes at weeks 0, 2, and then every four weeks. The most common adverse reactions are nausea, arthralgia, back pain, and pyrexia. Infusion-related reactions can occur. Crizanlizumab can interfere with platelet counts; send the blood immediately before administration or send blood in citrated tubes. 

L-Glutamine:  Glutamine is the most abundant amino acid in the body. It is not an essential amino acid under normal circumstances, but in patients with SCA, a high hemolysis rate increases the demand for glutamine. L-glutamine is available in a medical formulation. The exact mechanism of action of L-glutamine remains anecdotal. It is believed to work by scavenging for reactive oxygen species and acting as a substrate for the regeneration of nitrous oxide, NAD, and NADH. [22]  The USFDA approved L-glutamine in 2017 after positive results from the phase III trial. The authors demonstrated a statistically lower number of pain crises, fewer hospitalizations, fewer cumulative days in the hospital, prolonged time to first and second pain crises, and a reduced number of ACS. [23]  Adverse events include constipation, nausea, headache, abdominal pain, cough, extremity pain, back pain, and chest pain. There is an additional concern that L-glutamine may increase mortality and the rate of multiorgan failure. However, these are yet exploratory. 

Hematopoietic Stem Cell Transplant

Allogeneic hematopoietic stem cell transplant (HSCT) is a potentially curative option in SCA patients where cure rates approach approximately 90%. Improving the quality of life and reducing the cost of managing long-term complications trumps the cost of performing allogeneic HSC. Pre-school age is considered the best time to perform HSCT, with increased mortality recorded in older patients. A myeloablative or a non-myeloablative regimen can be used; however, myeloablative regimens are not recommended for adults. Matched sibling donor is preferred for performing allogeneic HSCT. Due to the lack of matched sibling donors, other approaches like a matched unrelated donor, umbilical cord blood transplant, and haploidentical transplant are also being explored. [24] [25]

Potential barriers to performing allogeneic HSCT

• Alloimmunization due to repetitive transfusions (exchange of blood)
• Organ dysfunction due to SCA (possibly a reason why younger patients do better)
• Lack of matched sibling donors/ insurance.

Indications for performing allogeneic HSCT

• Stroke (most common and strongest indication to perform allogeneic HSCT.
• Abnormal transcranial doppler
• Acute chest syndrome
• Recurrent VOC not controlled with medical therapy or chronic transfusions

The complications with allogeneic HSCT:

• Transplant-related mortality approaches 7 to 10%, comparable with SCD-related mortality
• Graft rejection OR graft failure - less with myeloablative regimens (7 to 11%) compared to non-myeloablative regimens (11 to 50%)
• Graft-versus-host disease and related morbidity
• Transplant-related complications like lung injury, endocrine, and metabolic adverse events

The recent approvals of newer agents and the emergence of gene-editing techniques have expanded the options for SCA patients. Also, extending the benefit of HSCT to low-income countries remains a significant challenge. 

Future Perspectives

Gene editing is a new therapy focus whereby researchers attempt to increase the HbF level in patients with SCA. This technique is being developed alongside HSCT. Many approaches to gene editing are in clinical trials right now. [26] [27]

• Viral gene addition using lentivirus: The technique aims to add a modified beta or gamma-globin gene to reduce the HbS component and increase the HbA (beta-globin gene) or the HbF (gamma-globin gene).
• CRISPR (Clustered regularly interspaced short palindromic repeats): Targets the expression of BCL11A, which normally downregulates gamma-globin expression. By introducing insertions and deletions in the BCL11A erythroid lineage-specific enhancer on chromosome 2, BCL11A is downregulated, resulting in increased expression of the gamma-globin gene, which subsequently increases HbF.

Cost Factor

The annual cost of the voxelotor is approximately $125,000. Each vial of crizanlizumab costs approximately $2400, with a yearly cost of $84,852 and $113,136 per year for most patients. The monthly cost of the L-glutamine formulation is $3000 for adults and up to $1000 for the pediatric age group. A myeloablative regimen for HSCT can lead to a cost of approximately $280,000 at 100 days of care/admission. [28]  In addition, the advanced level of expertise and dedicated infrastructure required to deliver such care also comes at a considerably high cost. Considering such high costs for the newer therapies, bringing them to lower-income regions like sub-Saharan Africa is a challenge, where approximately 6 million suffer from sickle cell anemia. 

Most of the survival data in patients with SCA does not factor in the advent of new medications. The Cooperative Study of Sickle Cell Disease (CSSCD) (between 1978-88) reported the median age of death for women and men as 42 and 48 years, respectively. This study also showed that acute chest syndrome, renal failure, seizures, high leukocyte count, and low levels of HbF were associated with an increased risk of early death in patients with SCA. [29]  More recent studies have shown that elevated tricuspid regurgitant jet velocity on echocardiography, prolonged QTc interval, pulmonary hypertension, high N-terminal pro-brain natriuretic peptide, history of asthma and/or wheezing, history of end-stage renal disease requiring dialysis, and the severity of hemolysis are independent risk factors towards early death in patients with SCA. [30]

More recent data combining nine studies from Europe and North America (evaluating 3257 patients) listed the following as predictors of mortality:

• Age (per 10-year increase in age)
• Tricuspid regurgitant jet velocity 2.5 m/s or more
• Reticulocyte count
• Log(N-terminal-pro-brain natriuretic peptide)
• Fetal hemoglobin [30]

With the approval of newer drugs in 2019 (voxelotor and crizanlizumab), increased use of hematopoietic stem cell transplant, and exploring newer techniques like gene therapy, survival is bound to increase along with the quality of life. 

• Complications

SCA can lead to acute complications and chronic complications

Acute complications: Most acute complications are associated with occlusion of the small to medium-sized vessels (sometimes large-sized vessels) due to polymerization of HbS and hemolysis. 

• Sequestration crises: splenic or hepatic sequestration
• Fat embolism
• Bone infarction/necrosis
• Coagulopathy: increases the risk of both arterial and venous clots- stroke, myocardial infarction, venous thrombosis
• Ophthalmic: vitreous hemorrhage, retinal detachment, retinal artery/vein occlusion
• Aplastic crises: in association with parvovirus infection
• Papillary necrosis
• Delayed growth and development and growth retardation
• Cardiac: cardiomegaly, cardiomyopathy, left ventricular hypertrophy, arrhythmia, congestive heart failure
• Pulmonary: pulmonary edema, sickle cell lung disease, pulmonary hypertension
• Hepatobiliary: Hepatomegaly, intrahepatic cholestasis, cholelithiasis, viral hepatitis
• Splenic complications: splenomegaly, hyposplenia, asplenia
• Renal: acute and chronic renal failure, pyelonephritis, renal medullary carcinoma
• Musculoskeletal: degenerative changes, osteomyelitis, septic arthritis, osteonecrosis, osteopenia/osteoporosis
• Neurologic: aneurysm, mental retardation
• Ophthalmic: proliferative sickle retinopathy, vitreous hemorrhage, retinal detachment, nonproliferative retinal changes
• Endocrine: primary hypogonadism, hypopituitarism, hypothalamic insufficiency
• Iron overload due to repeated transfusions and chronic hemolysis
• Deterrence and Patient Education

SCA is a debilitating disease that affects a patient physically and has significant emotional and psychiatric consequences. The stigma of being diagnosed with SCA has been well documented. Many SCA patients are inaccurately labeled as drug seekers and opioid abusers due to the need for an inordinately high amount of opioids for pain control. In addition, frequent interactions with different providers (in the emergency rooms, hospital admissions, etc.) can lead to inconsistent care. In such a scenario, the patients need to be an advocate for themselves. The following points can act as a guide for patient education.

• Show consistency in outpatient clinics and show up for your appointments. Regularity in visits to your providers helps to build trust within the system.
• Discuss pain requirements for pain medications with your provider with an open mindset- They may appear restrictive in prescribing pain medications, especially opioids. Still, they are trying to help you by protecting you against overdosing. 
• Try and use the same emergency room, or at least the ER within the same hospital system. It is useful and helps in developing familiarity with the people who work in that ER. It also allows easy access to your individualized plan of care, which your provider develops for such situations. 
• Adherence to disease-modifying therapy will help reduce the events of pain crises and prevent long-term organ damage. 
• Always be receptive to alternative ways of getting control over pain - including music therapy, self-hypnosis, and deep muscle relaxation. 
• Patients can adopt protective measures- stay warm and avoid exposure to extreme temperatures, adequate hydration, and breathing exercises at home. 
• Enhancing Healthcare Team Outcomes

SCA is a systemic disorder that affects the entire body. The disease not only manifests with physical symptoms (pain crises, organ damage, etc.) but also has numerous psycho-social implications. Most patients with SCA belong to the African-American community and a minority to Hispanic and other communities, which makes them prone to certain prejudices. Besides, the high demand for opioids to manage chronic pain makes the situation even more challenging. [31]  All providers must keep aside their inherent prejudice when caring for a patient with SCA, working collaboratively as an interprofessional team. Almost all specialties need to be involved in managing patients with SCA. However, the hematology team dedicated to taking care of SCA patients must be the primary physicians for these patients.

Specialties like ophthalmology, orthopedics, psychiatry, gastroenterology, and cardiovascular medicine interact closely with SCA patients. However, this does not diminish the importance of other specialties. Pharmacy and nursing also play a vital role. With the advent of newer drugs and infusions and SCA affecting liver and kidney function, pharmacists and nursing experts are required to ensure safe dosage and medication delivery to the patient. 

The data presented here is derived mostly from large and small randomized clinical trials. [Level 1 and 2] Few aspects of care presented here are from cohort and case-control studies. [Level 3]

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Sickle cell disease is an autosomal recessive blood disorder that can lead to anaemia. It is caused by a mutation in the haemoglobin gene, which leads to deformation of red blood cells. Deformed red blood cells can obstruct small vessels and they are prone to destruction.

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Review article, recent advances in the treatment of sickle cell disease.

• 1 Sickle Cell Branch, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD, United States
• 2 Division of Hematology and Oncology, Children’s National Medical Center, Washington, DC, United States

Sickle cell anemia (SCA) was first described in the Western literature more than 100 years ago. Elucidation of its molecular basis prompted numerous biochemical and genetic studies that have contributed to a better understanding of its pathophysiology. Unfortunately, the translation of such knowledge into developing treatments has been disproportionately slow and elusive. In the last 10 years, discovery of BCL11A , a major γ-globin gene repressor, has led to a better understanding of the switch from fetal to adult hemoglobin and a resurgence of efforts on exploring pharmacological and genetic/genomic approaches for reactivating fetal hemoglobin as possible therapeutic options. Alongside therapeutic reactivation of fetal hemoglobin, further understanding of stem cell transplantation and mixed chimerism as well as gene editing, and genomics have yielded very encouraging outcomes. Other advances have contributed to the FDA approval of three new medications in 2017 and 2019 for management of sickle cell disease, with several other drugs currently under development. In this review, we will focus on the most important advances in the last decade.

Introduction

Sickle cell disease (SCD) is an inherited blood disorder that first appeared in the Western literature in 1910 when Dr. James Herrick described a case of severe malaise and anemia in a 20-year-old dental student from Grenada ( Herrick, 1910 ). On examining his blood smear, he noticed many bizarrely shaped red blood cells, leading him to surmise that “…the cause of the disease may be some unrecognized change in the red corpuscle itself” ( Herrick, 2014 ). More than 100 years later we recognize that the change in the red corpuscle is caused by a single base substitution in β-globin, and that the disease is not just present in the United States (US), but prevalent in regions where malaria was historically endemic, including sub-Saharan Africa, India, the Middle East, and the Mediterranean ( Williams and Thein, 2018 ). Presence of SCD in the non-malarial regions is related to the recent migration patterns.

Currently, an estimated 300,000 affected babies are born each year, more than 80% of whom are in Africa. Due to recent population migrations, increasing numbers of individuals affected by SCD are encountered in countries that are not historically endemic for malaria, such as the US. It is estimated that 100,000 Americans are affected with SCD, the majority of whom are of African descent ( Hassell, 2010 , 2016 ). The numbers affected with SCD are predicted to increase exponentially; Piel et al. (2013) estimated that between 2010 and 2050, the overall number of births affected by SCD will be 14,242,000; human migration and further globalization will continue to expand SCD throughout the world in the coming decades. While 75% or more of newborns with SCD in sub-Saharan Africa do not make their fifth birthday ( McGann, 2014 ), in medium- to well-resourced countries almost all of affected babies can now expect to live to adulthood but overall survival still lags behind that of a non-SCD person by 20–30 years ( Telfer et al., 2007 ; Quinn et al., 2010 ; Elmariah et al., 2014 ; Gardner et al., 2016 ; Serjeant et al., 2018 ). Despite these global prevalence figures, and the fact that SCD is by far the largest public health concern among the hemoglobinopathies, it was not until 2006 when the World Health Organization (WHO) recognized SCD as a global public health problem 1 .

In 1949, Linus Pauling showed that an abnormal protein (hemoglobin S, HbS) was the cause of sickle cell anemia (SCA), making SCD the first molecular disease and motivating an enormous amount of scientific and medical research. Because of its genetic simplicity, SCA has been used to illustrate many of the advances in molecular genetics such as detection of a DNA mutation by restriction fragment enzyme analysis, and was used as proof of principle for the polymerase chain reaction (PCR) that we now take for granted ( Wilson et al., 1982 ; Saiki et al., 1985 ).

In the last 50 years, tremendous progress has been made in understanding the pathophysiology and pathobiological complexities of SCD, but developing treatments has been disproportionately slow and elusive; a history of Perils and Progress, so succinctly summarized by Wailoo (2017) . We are confident that in the next 30 years, the therapeutic landscape for SCD will change due to a combination of recent advancements in genetics and genomics, an increase in the number of competing clinical trials, and also an increased awareness from the funding bodies, in particular the NIH, USA.

Here, after a brief review of the pathophysiology, we will focus on the advances in treatment of SCD that have occurred in the last 10 years and that have reached phase 2/3 of clinical trials ( Figure 1 ).

Figure 1. Timeline review of historic events since the diagnosis of sickle cell disease with an emphasis over the last decade. SCD, sickle cell disease; HSCT, hematopoietic stem cell transplant; HU, hydroxyurea.

Pathophysiology of Sickle Cell Disease

Sickle cell disease is caused by an abnormal HbS (α 2 β S 2 ) in which glutamic acid at position 6 of the β-globin chain of hemoglobin is changed to valine. Goldstein et al. (1963) showed that this amino acid substitution arose from a single base change (A>T) at codon 6 ( rs334 ). The genetic causes of SCD include homozygosity for the rs334 mutation (HbSS, commonly referred as SCA) and compound heterozygosity between rs334 and mutations that lead to either other structural variants of β-globin (such as HbC, causing HbSC) or reduced levels of β-globin production as in β-thalassemia (causing HbS/β-thalassemia). In patients of African ancestry, HbSS is the most common cause of SCD (65–70%), followed by HbSC (about 30%), with HbS/β-thalassemia being responsible for most of the rest ( Steinberg et al., 2001 ). SCA in which the intracellular concentration of HbS is almost 100%, is by far the most severe and well described ( Brittenham et al., 1985 ). The majority of the therapeutic developments and interventions have focused on this genotype, which is also the focus of this review, although they also impact the other SCD genotypes.

The fundamental event that underlies the complex pathophysiology and multi-systemic consequences of SCD is the polymerization of HbS that occurs under low oxygen tension ( Figure 2 ). Polymerization of the de-oxygenated HbS alters the structure and function of the red blood cells (RBCs). These damaged (typically sickled shaped) RBCs are not only less flexible compared to normal RBCs, but also highly adhesive. Repeated cycles of sickling and unsickling shortens the lifespan of the damaged sickle RBCs to about 1/6th that of normal RBCs ( Bunn, 1997 ; Hebbel, 2011 ). The outcome is the occlusion of blood vessels in almost every organ of the body and chronic hemolytic anemia, the two hallmarks of the disease, that result in recurrent episodic acute clinical events, of which acute pain is the most common, and accumulative organ damage. Acute sickle pain is so severe that it is often referred to as “vaso-occlusive sickle crisis” or VOC.

Figure 2. Schematic pathophysiology review of sickle cell disease and its main different targets for intervention. Hb S, hemoglobin S.

These events trigger a cascade of pro-inflammatory activity setting off multiple pathophysiological factors that also involve neutrophils, platelets, and vascular endothelium ( Sundd et al., 2019 ). The continual release of cell-free hemoglobin from hemolysis depletes hemopexin and haptoglobin, a consequence of which is the reduced bioavailability of nitric oxide (NO), and vascular endothelial dysfunction that underlies the chronic organ damage in SCD pathology.

The sickle red blood cells do not just interact with the vascular endothelium but trigger activation of neutrophils, monocytes and platelets. During steady-state, patients with SCD have above normal values of neutrophils, monocytes and platelets which further increase during acute events ( Villagra et al., 2007 ). Neutrophilia has been consistently correlated with SCD severity ( Ohene-Frempong et al., 1998 ; Miller et al., 2000 ); neutrophils play a central role in vaso-occlusion through their interactions with both erythrocytes and endothelium upregulating expression of cytoadhesion molecules such as P- and E-selectins, current therapeutic targets ( Zhang et al., 2016 ).

Platelets, when activated, form aggregates with erythrocytes, monocytes, and neutrophils both in patients and in murine models ( Wun et al., 1997 ; Zhang et al., 2016 ). As with neutrophils, it appears that platelet aggregation is dependent on P-selectin. As part of this constant inflammatory state, the coagulation cascade is also hyperactivated in SCD. The repeated interaction between RBCs and endothelium promote expression of pro-adhesive and procoagulant proteins evidenced by increased levels of plasma coagulation factors, tissue factor (TF) and interactions between monocyte-endothelium, platelet-neutrophil and platelet-RBC. Patients with SCD have increased rates of venous and arterial thrombotic events ( Brunson et al., 2017 ).

Unraveling these pathophysiological targets has provided insights on clinical trials on anti-platelet and anti-adhesion agents, as well as anti-coagulation factors for the prevention of acute VOC pain in SCD ( Telen, 2016 ; Nasimuzzaman and Malik, 2019 ; Telen et al., 2019 ). A case in point is the development of an anti-P-selection molecule (Crizanlizumab) for treatment of sickle VOC, recently approved by the FDA in November 2019 and marketed as Adakveo ® .

New therapeutic approaches that use drugs to ameliorate the downstream sequelae of HbS polymerization have not proved to be as effective as hydroxyurea (HU) which has an “anti-sickling” effect via induction of fetal hemoglobin (HbF, α2γ2) ( Ware and Aygun, 2009 ). Other effects of HU include improvement of RBC hydration, reduction of neutrophil count, reduction of leucocyte adhesion, and reduction of pro-inflammatory markers, all of which add to the clinical efficacy of HU. In addition, HU also acts as NO donor, promoting vasodilation ( Cokic et al., 2003 ). Increasing HbF is highly effective because it dilutes the intracellular HbS concentration, thereby increasing the delay time to HbS polymerization ( Eaton and Bunn, 2017 ); in addition to which, the γ-chains also have an inhibitory effect on the polymerization process. Hydroxyurea, however, is only partially successful because the increase in fetal hemoglobin is uneven and not present in all cells. Nonetheless, the well-established clinical efficacy of HbF increase, substantiated by numerous clinical and epidemiological studies, has motivated both pharmacological and genetic approaches to induce HbF ( Nevitt et al., 2017 ).

A more detailed understanding of the switch from fetal to adult hemoglobin, and identification of transcriptional regulators such as BCL11A, aided by the developments in genetic and genomic platforms, provide hope that genomic-based approaches for therapeutic reactivation of HbF may soon be possible ( Vinjamur et al., 2018 ). In the meanwhile, a gene addition approach that infects the patient’s stem cells with a virus expressing an anti-sickling β-globin variant, T87Q, shows great promise ( Negre et al., 2016 ; Ribeil et al., 2017 ). The most successful “curative” approach so far, is transplantation with stem cells from an immunologically matched sibling but this is severely limited by the lack of availability of matched donors ( Walters et al., 1996a ; Gluckman et al., 2017 ).

Parallel to the new medications being developed blood transfusions with normal red blood cells, remain an effective and increasing therapeutic option for managing and preventing SCD complications, but this strategy has limitations (not uniformly accessible, accompanied by risks of alloimmunization, hemolytic transfusion reactions and transfusional iron overload). Blood transfusion improves the oxygen-carrying capacity and improves microvascular perfusion by decreasing the HbS percentage. A major complication of blood transfusion is hemolytic transfusion reactions that occur primarily in RBC alloimmunized patients and SCD patients, in particular, are at high risk because of the mismatch in donor pool (predominantly Northern European descent) while SCD patients are predominantly of African descent ( Vichinsky et al., 1990 ; Thein et al., 2020 ). Limiting blood from ethnic-matched donors has reduced but did not eliminate alloimmunization ( Chou et al., 2013 ), and a major cause is the mismatch between serologic Rh phenotype and RHD or RHCE genotype due to variant RH alleles in a large proportion of the individuals ( Chou et al., 2013 ). RH genotyping in addition to serologic typing may be required to identify the most compatible RBCs and recent studies have shown that a prospective rather than reactive (after appearance of allo-antibodies) genotyping approach may be feasible ( Chou et al., 2018 , 2020 ; Hendrickson and Tormey, 2018 ). Until prospective genotyping of RBC antigens become a practical feasibility, as a prevention, many blood transfusion centers have adopted extended red cell phenotyping, including ABO, Rh, Kell, Kidd, Duffy, and S and s antigens, and some centers have also adopted molecular genotyping for red blood cell phenotype prediction using microarray chips (e.g., the PreciseType HEA BeadChip assay). It should be noted that, while blood transfusion remains an important therapeutic option in SCD, evidence for its role in management of acute or chronic complications is lacking except for prevention of primary and secondary strokes ( Howard, 2016 ). Supportive evidence for the role of preoperative transfusion in patients with HbSS or HbS/β 0 -thalassemia was demonstrated in the Transfusion Alternatives Preoperatively in Sickle Cell disease (TAPS) study ( Howard et al., 2013 ).

Insight on the pathophysiology of SCD ( Figure 2 ) has allowed different targets for interventions in patients with SCD summarized under four categories of its pathobiology – (1). Modifying the genotype, (2). Targeting HbS polymerization, (3). Targeting vasocclusion, and (4). Targeting inflammation.

Understanding of the kinetics of HbS polymerization suggest that there are many ways to inhibit HbS polymerization ( Eaton and Bunn, 2017 ) other than induction of HbF ( Table 1 ). One approach is to increase oxygen affinity of the hemoglobin molecule, an example is Oxbryta TM (Voxelotor/GBT440) ( Vichinsky et al., 2019 ) that was recently approved by the FDA in November 2019, making this the second anti-sickling agent.

Table 1. Current advances on therapy for sickle cell disease.

One of the biggest challenges in managing SCD is the clinical complexity and extreme variable clinical course that cannot be explained by the specific disease genotype. Patients with identical sickle genotype still display extreme clinical course; both acquired and inherited factors contribute to this clinical complexity of SCD ( Gardner and Thein, 2016 ). Although laboratory prognostic factors (HbF, hemoglobin, reticulocyte count, leukocytosis) and clinical phenotypes (such as stroke/TIA, acute chest syndrome/pulmonary hypertension, avascular necrosis, kidney injury, or skin ulcers) have been described and analyzed, classifying disease severity remains complex and should be assessed individually. Prediction of disease severity and clinical course of SCD has been the topic of many reviews and, to date there is no clear algorithm using genetic and/or imaging, and/or laboratory markers that can reliably predict mortality risk in SCD ( Quinn, 2016 ).

Current Advances in Therapy

(1) modifying the patient’s genotype.

Modifying the patient’s genotype via hemopoietic stem cell transplantation (HSCT) was first reported to be performed over 30 years ago in an 8-year-old child who had SCD (HbSS) with frequent VOCs; she subsequently developed acute myeloid leukemia. The patient received HSCT for the acute myeloid leukemia from an HLA-matched sister who was a carrier for HbS (HbAS). She was cured of her leukemia and at the same time, her sickle cell complications also resolved ( Johnson et al., 1984 ; Johnson, 1985 ). Until then, HSCT had not been considered as a therapeutic option for SCD. This successful HSCT demonstrated that reversal of SCD could be achieved without complete reversal of the hematological phenotype to HbAA, and paved the way for bone marrow transplant (BMT) as a curative option for children with severe SCD ( Walters et al., 1996b ).

The conclusion was that, as long as stable mixed hemopoietic chimerism after BMT can be achieved, patients can be cured of their SCD without complete replacement of their bone marrow ( Walters et al., 2001 ).

Allogeneic Bone Marrow Transplant

Hematopoietic stem cell transplant (HSCT) has now become an important therapeutic option for patients with SCD. Currently there are about 35 clinical trials at ClinicalTrials.gov studying allogeneic BMT in patients with SCD. As described by Walters et al. (2010) , HSCT can establish donor-derived erythropoiesis, but even more importantly, can stabilize or even restore function in affected organs of patients with SCD when performed in time.

Between 1986 and 2013, 1,000 patients received HLA-identical matched sibling donor (MSD) HSCTs ( Gluckman et al., 2017 ). The outcomes for both children and adults were excellent, demonstrating 93% overall survival. Eighty seven percent of the patients received myeloablative chemotherapy (MAC) and the rest (13%) received reduced intensity chemotherapy (RIC). It is important to note that patients 16 years or older had worse overall survival (95% vs. 81% p = 0.001) and a higher probability of graft versus host disease (GVHD)-free survival (77% vs. 86% p = 0.001). These results should encourage physicians to provide early referrals to SCD patients for transplant evaluation so that the donor search can be started in a timely matter ( Gluckman et al., 2017 ).

Although myeloablative conditioning has achieved high rates of overall and event free survival, the conditioning is too toxic for adult patients with pre-existing organ dysfunction. Reversal of the sickle hematology without complete replacement of the patient’s bone marrow led to the development of less intense conditioning regimens expanding allogeneic transplantation in adult patients, who otherwise would not be able to tolerate the intense myeloablative conditioning. Donors could be HbAA or HbAS, and in order to reverse the sickle hematological genotype, the myeloid donor chimerism has to be >20% ( Fitzhugh et al., 2017 ).

In an international, multicenter study, 59 patients had MSD HSCT, of which 50 survived and were cured of SCD. Of the nine patients that had a negative outcome, five had graft rejection and four intracranial hemorrhage. Thirteen patients developed mixed chimerism. Of those patients that developed mixed chimerism, there was no GVHD or disease recurrence/graft rejection. Patients with stable mixed chimerism did not have worse outcomes related to complications of SCD. Hsieh et al. (2009) developed a protocol for non-myeloablative HSCT with low dose total body radiation, alemtuzumab, and sirolimus. In the initial 10 patients with SCD, nine had long-term, stable, mixed donor chimerism and reversal of their sickle cell phenotype ( Hsieh et al., 2009 ). An updated report showed that 87% of the 30 patients had long-term stable donor engraftment without acute or chronic graft-versus-host disease (Clinical trials [NCT00061568]) ( Walters et al., 2001 ; Hsieh et al., 2014 ). More recent data reported at least 95% cure rate in 234 children and young adults (<30 years) with SCA after MSD with no increased mortality compared to SCA itself and better quality of life. The data also showed that myeloablative HSCT can be a safe option for patients <15 years old if a MSD is available unless there is a clear and strong recommendation not to undergo transplant ( Bernaudin et al., 2020 ).

However, in the US, less than 15% of patients with SCD have HLA- matched siblings as donors, but a promising alternative donor source is haplo-identical family members. Studies are now underway in several centers to find a balance of conditioning regime that provides adequate immunosuppression without rejection and minimal GVHD ( Joseph et al., 2018 ). Matched unrelated donors (MUD) have shown promising results in patients with thalassemia major and are currently being evaluated in patients with SCD ( Fitzhugh et al., 2014 ). One of the main limitations, unfortunately, is the low probability of finding suitable donors for African and African American populations as per the National Marrow Donor Program and so, not sufficient MUD transplants have been completed in patients with SCD. HLA-haploidentical HSCT following RIC has been reported to show promising results with prolonged and stable engraftment, but for both unrelated umbilical cord blood (UCB) and haploidentical HSCT, rejection remains a major obstacle in the context of RIC ( Bolanos-Meade et al., 2012 ; Angelucci et al., 2014 ; Fitzhugh et al., 2014 ; Saraf et al., 2018 ; Bolanos-Meade et al., 2019 ).

Although encouraging options with promising results in clinical trials, acute and chronic GVHD remain major complications which can be life threatening and have severe effects on quality of life. Multiple factors affect the development of GVHD in patients undergoing transplant, including the source of the stem cells, the intensity of immunosuppression in the conditioning regime (dose of anti-thymoglobulin) and the mismatch status of the donor to the recipient ( Shenoy, 2013 ; Inamoto et al., 2016 ; Bernaudin et al., 2020 ).

Acute GVHD remains a concern in patients receiving mismatched donor transplants but UCB continues to show reduced rates of chronic GVHD ( Kamani et al., 2012 ). Reduced-intensity conditioning regimens have also been studied in related and unrelated HSCT, and while a suitable option for patients with a matched sibling, patients with unrelated donor should be made aware of the not-so-favorable short and long-term outcomes ( Guilcher et al., 2018 ).

As new transplant modalities emerge with less transplant related mortality, better immunomodulators to prevent GVHD are being developed and graft rejection has become less frequent and accepted indications for HSCT have become less restrictive ( Table 2 ). Nonetheless, clinicians continue to have reservation toward transplant and tend to delay the referral to a HSCT specialist because of concerns for GVHD, mortality/morbidity related to transplant itself and the risk of graft rejection, which has not been eliminated completely ( Leonard and Tisdale, 2018 ). An ongoing clinical trial will compare 2-year overall survival and outcomes related to SCD in patients that undergo transplant compared with current standard of care (ClinicalTrail.gov Identifier: NCT02766465).

Table 2. Indications for HSCT balanced with donor availability: Risk/benefit ratio considerations.

In allogeneic transplant, the source of hematopoietic stem cells (HSCs) is from a donor (matched sibling, haplo-identical family members, UCB or MUD). Allogeneic BMT using HSCs from the latter 3 donor sources are still risky; and donor availability presents a huge limitation. These limitations can be overcome by autologous transplant, in which the patient receives his own cells after being modified by gene therapy.

Autologous Hematopoietic Stem Cell Transplant Modification: Gene Editing or Gene Therapy

Genetically engineered autologous cells eliminate the need to find a HSCT donor, and thus available to all patients. Since these are the patient’s own stem cells, there is no need for immunosuppression, thus eliminating the risks of GVHD and immune-mediated graft rejection ( Esrick and Bauer, 2018 ; Orkin and Bauer, 2019 ).

Sickle cell disease patients represent a special and complicated population for this therapy for two major reasons. First, patients that undergo autologous stem cell transplant require collection of hematopoietic stem cells (CD34+) and the traditional method of collection is a bone marrow harvest done by a specialist but in patients with SCD this process yields CD34+ cells with suboptimal quantity and quality requiring multiple harvests, each harvesting procedure increasing the risk of triggering acute pain crisis. Second, the current gold standard procedure for cell mobilization is with granulocyte-colony stimulating factor (G-CSF) but this is contraindicated in patients with SCD due to risk of causing complications such as pain crisis, acute chest syndrome, and even death, from the increased white cell counts.

Recently, great advances have been made in using an alternative approach for harvesting CD34+ cells using Plerixafor. Plerixafor acts by reversibly blocking the binding between chemokine CXC-receptor 4 (CXCR4) and the stromal cell derived factor-1α triggering the mobilization of progenitor cells into the peripheral blood. It allows peripheral mobilization of stem cells by releasing CD34+ cells from the bone marrow niches, without the massive increase in white blood cells. Its development has been crucial in optimization of CD34+ collection in patients with SCD. Results have shown appropriate mobilization of CD34+ cells 6 h after a single dose of Plerixafor and are of higher quality and purity, decreasing the need for multiple bone marrow harvests and the associated stress/pain. Associated with hyper-transfusion therapy, it has become the preferred way of marrow stimulation to yield appropriate hematopoietic stem/progenitor cells in patients with SCD ( Boulad et al., 2018 ; Esrick et al., 2018 ; Hsieh and Tisdale, 2018 ; Lagresle-Peyrou et al., 2018 ).

The genetic defect in the sickle HSPCs can be corrected via several approaches.

(A) Gene addition using lentiviral vector-based strategies

(a) Anti- or non-sickling strategies: Several gene therapies based on gene addition using viral vectors to carry therapeutic genes in HSCs are being actively developed with curative purposes. Gene addition strategies that have reached clinical trials include a promising one where the patient’s stem cells are infected with a lentivirus expressing an anti-sickling β-globin variant, T87Q. The unique feature of this vector is that the amino acid substitution (β A–T 87 Q ) allows for high performance liquid chromatography (HPLC) monitoring of the transgene globin levels in the patient’s cells ( Cavazzana-Calvo et al., 2010 ). The first SCD patient who received this Bluebird vector (protocol HGB-205) was reported in 2017; engraftment was stable with no sickle cell crises reported at 15 months of follow up ( Ribeil et al., 2017 ), with further undergoing studies ( ClinicalTrials.gov Identifier: NCT02140554, NCT03282656). Other approaches to anti-sickling gene therapy in erythroid-specific lentiviral vectors include utilizing a β-globin gene with three specific point mutations that confer anti-sickling properties ( ClinicalTrials.gov Identifier: NCT02247843) or the introduction of a γ-globin coding sequence in a β-globin gene to increase HbF levels and decrease HbS ( ClinicalTrials.gov Identifier: NCT02186418) ( Cavazzana et al., 2017 ). Thus far, the most promising of these LV vectors is the one utilizing anti-sickling β-globin variant, T87Q.

(b) Hb F induction: The well-established efficacy of increasing HbF has motivated both pharmacological and genetic approaches to HbF induction.

A gene addition approach that is already in clinical trials ( ClinicalTrials.gov Identifier: NCT03282656) utilizes a lentiviral mediated erythroid specific short hairpin RNA (shRNA) for BCL11A. This shRNA is modified to target the specific gene and downregulate its expression ( Brendel et al., 2016 ). As of December 2018, three adults have been enrolled, utilizing plerixafor mobilized HSC, all three patients showed prompt neutrophil engraftment, and at 2 months follow up, the average HbF was 30% (ASH abstract #1023 – 2018 ASH conference). Other lentiviral therapies using zinc-finger nucleases (ZFN) directed against the γ-globin promoter have been proposed. This would force an interacting loop between the LCR and γ-globin which would reactivate γ-globin production, increasing HbF and decreasing HbS production at the same time. These lentiviral-based approaches still need preclinical in vivo studies to address safety and specificity before they can be considered in human patients ( Breda et al., 2016 ; Orkin and Bauer, 2019 ).

Viral vectors, such as lentivirus, are a great tool for gene therapy but these results underscore the need to develop gene transfer protocols that ensure efficient and consistent delivery of the therapeutic globin gene cargo to HSC. Their major limitations include:

(1) Their immunogenicity which can create an inflammatory response in the donor which can lead to degeneration of the transducted tissue, (2) they can produce non-specific toxins, (3) due to the semi-random integration to the genome, there is a theoretical risk of insertional mutagenesis, (4) they have limitations of transgenic capacity size. An additional challenge in SCD is the ability to maintain a persistent myeloid donor chimerism of >20% to prevent return of SCD symptoms ( Fitzhugh et al., 2017 ). Due to these limitations, long-term monitoring of patients to evaluate both safety and efficacy is necessary. Until now, over the last decade of clinical trials, no genotoxicity secondary to LV vectors has been reported but the main challenge has been to keep the myeloid donor chimerism above the 20% threshold ( Nayerossadat et al., 2012 ).

(B) Gene editing

Gene-editing corrects a specific defective DNA in its native location. SCD with its simple single base change presents a very attractive prototype. Over the last couple of decades, there has been a spectacular growth of such strategies, setting the scene for developing therapies that could precisely genetically correct a single base mutation in patient with SCD. These strategies include ZFNs, transcription activator-like effector nucleases (TALENs) and the clustered regularly interspaced short palindromic repeat (CRISPR)-associated nuclease Cas9 approach which is the most advanced of the three. The CRISPR-Cas9 technology typically make a double-stranded break (DSB) in a particular genomic sequence directed to that site by a guide RNA. The most common method of DSB repair is non-homologous end joining, often resulting in gene disruption or knockout. This strategy is currently being tested in a clinical trial ( ClinicalTrials.gov Identifier: NCT03745287) in which the patient’s own BCL11A gene (a major inhibitor of γ-globin gene expression) is disrupted to induce HbF expression. BCL11A also has roles in lymphoid and neurological development but gene-editing for SCD exploits the erythroid-specific enhancers in intron 2 of the gene ( Bauer et al., 2013 ; Brendel et al., 2016 ). CRISPR-Cas9 technology is also being explored to mimic the rare, genetic variants that promote expression of the γ-globin genes as in hereditary persistence of fetal hemoglobin ( Traxler et al., 2016 ; Wienert et al., 2018 ). Disrupting the putative binding sites for γ-globin repressors like BCL11A to induce HbF production will be an attractive therapeutic strategy for both β-thalassemic and SCD patients ( Masuda et al., 2016 ; Liu et al., 2018 ; Martyn et al., 2018 ). The ultimate challenge, however, is to genetically correct the mutation, a single nucleotide change in the codon of the globin gene from GAG to GTG, by providing a homology template with the correct sequence at the sixth codon. Although this has been completed in preclinical studies, current techniques do not allow for specific transversion mutations like those required to cure SCD in humans ( Dever et al., 2016 ; Orkin and Bauer, 2019 ). The enormous selective advantage of red blood cells with normal hemoglobin or anti-sickling hemoglobin predicts that genetic modification of a proportion of HSCs (estimated 10–20%) may suffice as a one-off treatment ( Fitzhugh et al., 2017 ). Before gene therapy can become a reality, however, many hurdles need to be overcome; genetically manipulated HSCs need to be able to retain long-term repopulating potential; pre-transplant conditioning is toxic and needs to be modified to reduce the morbidity. A clinical trial exploring antibody-mediated non-chemotherapy conditioning is being evaluated in patients with severe combined immunodeficiency, in an attempt to reduce the exposure to chemotherapy and its toxicities is currently recruiting patients ( ClincialTrials.gov Identifier: NCT02963064). Further understanding of this technology could represent a new option for patients with SCD.

Although different gene strategies have reached clinical trials showing promising results they remain in early phases of development and allogeneic HSCT remain the only curative treatment modality for SCD. For the majority of patients without a MSD, haploidentical HSCT with recent promising data of improved overall survival presents an alternative for curative therapy. Multiple gene therapy strategies utilizing patient’s own stem cells, are also being pursued, but this has the disadvantage of myeloablative conditioning ( Leonard et al., 2020 ).

In addition to great advances in HSCT and gene therapy, new pharmacological anti-sickling approaches have developed.

(2) Targeting Hemoglobin S Polymerization

Approaches targeting HbS polymerization presents a very attractive strategy as this “puts out the fire” rather than dealing with the sequelae of the sickling event ( Eaton and Bunn, 2017 ). HbF has long been known to have a major beneficial effect in SCD – increased intracellular HbF not only dilutes the intracellular HbS concentration but inhibits sickling as the mixed hybrid tetramers do not partake in HbS polymerization. Hydroxyurea (HU) works via induction of fetal hemoglobin (HbF, α2γ2) synthesis, but hydroxyurea is only partially successful as the increase in HbF is uneven and not equally present in all the red blood cells ( Ware, 2015 ). Nonetheless, use of HU therapy in SCD has expanded substantially in recent years. Follow on studies include demontration of its efficacy and safety in the pediatric population (BABY HUG) ( Wang et al., 2011 ), the Transcranial doppler with Transfusion Changing to Hydroxyurea Study (TWiTCH) that showed HU was comparable to blood transfusions for primary stroke prevention ( Ware et al., 2016 ) although the Stroke with Transfusion Changing to Hydroxyurea study (SWiTCH) concluded that HU is not comparable to blood transfusion in secondary stroke prevention ( Ware et al., 2011 ).

More recently, two clinical studies have shown that HU is relatively safe in Sub Saharan Africa, a setting with high infectious disease and SCD burden. Hydroxyurea has been shown to not only decrease complications from SCD such as VOC, acute chest syndrome, frequency of transfusions, death and infections – including malaria but also to be a feasible approach in these under-resourced countries ( Opoka et al., 2017 ; Tshilolo et al., 2019 ).

Despite having a significant impact in patients with SCD, there are still multiple unanswered questions regarding HU. Its mechanism of action has not been fully understood and its impact on HbF will decrease over time. Older patients become more sensitive to the dosage and they require frequent blood tests and readjustment of their dose. Regardless of the advances, there is no clear evidence of the long-term effect of hydroxyurea in preventing end organ damage ( Nevitt et al., 2017 ; Luzzatto and Makani, 2019 ). There is also conflicting evidence of the effects of HU on male fertility ( DeBaun, 2014 ). Chronic complications of SCD such as recurrent episodes of priapism, asymptomatic testicular infarctions and primary hypogonadism have been described as potential etiologies of low fertility in male SCD patients. Studies in transgenic SCD mice showed that SCD itself was associated with inhibition of spermatogenesis and primary hypogonadism but when compared to HU (25 mg/kg/day), testicular volume was lower in those mice with SCD exposed to HU, inferring lower spermatogenesis. Berthaut et al. (2008) measured the semen quality of 4 patients with SCA at baseline and 4 years after starting hydroxyurea. In three of four patients the spermatozoan concentration continued to drop while patients were taking the medication and did not return to baseline after discontinuing HU ( Berthaut et al., 2008 ). Although the evidence is limited, full disclosure regarding implications on male fertility should be given to patients and families in order to make an informed decision before starting HU ( Jones et al., 2009 ).

Other than HU, other pharmacological options to increase HbF are still experimental undergoing clinical trials. Molecular studies on γ-globin identified regulatory elements in the gene expression and subsequent HbF production. Such molecules; histone deacetylase (HDAC), DNA methyltransferase 1 (DNMT1), BCL11A and SOX6 modifying HbF expression have been explored as possible therapeutic options.

One of the proposed mechanisms for HU effect on HbF is stimulation of cyclic guanosine monophosphate (cGMP). Phosphodiesterase 9 (PDE9) is a specific enzyme in charge of degrading cGMP and is highly present in neutrophils and RBCs of patients with SCD. A novel, potent and selective PDE9 inhibitor (IMR-687) has been shown to increase levels of cGMP and HbF without signs of myelosuppression in cell lines of patients with SCD. An open-label extension to a previous phase 2a study is ongoing in adults with SCD ( ClinicalTrials.gov Identifier: NCT04053803) ( McArthur et al., 2019 ).

Panobinostat is a pan HDAC inhibitor currently being studied in adult patients with SCD as a phase 1 study ( ClinicalTrials.gov Identifier: NCT01245179). In vitro analysis of human erythroid progenitor cells that underwent shRNA knockdown of HDAC1 or HDAC2 genes resulted in increased levels of γ-globin but without altering cellular proliferation of the cell cycle phase.

Associated with HU, HDAC gene inhibition produced a more pronounced increase of γ-globin and HbF ( Esrick et al., 2015 ).

DNA Methyltransferase 1 is involved in the shutting down of γ-globin gene after birth and its subsequent production. DNA methylransferase inhibitor 5-azacytidine was one of the chemotherapeutic agents used to reactivate HbF but it was quickly abandoned due to its toxicity and carcinogenicity. Decitabine, an analog of 5-azacytidine, is also a potent DNMT1 inhibitor with a more favorable safety profile but decitabine is rapidly deaminated and inactivated by cytosine deaminase, if taken orally. To overcome this limitation, a clinical study combines decitabine and tetrahydrouridine (THU), a cytosine deaminase inhibitor, as a therapeutic strategy for inducing HbF ( ClinicalTrials.gov Identifier: NCT01685515). In a phase 1 study, Molokie et al. (2017) showed that the inhibition of DNMT1 led to appropriate blood levels of decitabine that were safe and induced a large increase in fetal hemoglobin in healthy red blood cells. These agents did not induce cytoreduction, but increased platelets count that can potentially trigger vaso-occlusion in SCD patients ( Molokie et al., 2017 ).

Voxelotor (Oxbryta/GBT440) binds specifically to the N-terminus of the alpha subunit of HbS to stabilize the oxygenated hemoglobin state ( Strader et al., 2019 ), thus reducing the predisposition to sickling. Voxelotor (Oxbryta/GBT440) was approved by the FDA in November 2019 for the treatment of SCD in adults and pediatric patients 12 years of age and older. The HOPE study showed an increase in hemoglobin levels and reduced markers of hemolysis in 274 patients with HbS that were randomly assigned to receive the study drug versus placebo. These findings have not correlated with reduced episodes of pain crisis and/or end organ damage. Agents that shift Hb oxygen affinity present some concerns of potential negative effects as the bound oxygen cannot be off loaded in tissues with high oxygen requirements, particularly concerning in a disease characterized by decreased oxygen delivery ( Hebbel and Hedlund, 2018 ; Thompson, 2019 ). These concerns are being addressed in a current phase 3, double-blind, randomized, placebo-controlled, multicenter study of Voxelotor ( ClinicalTrials.gov Identifier: NCT03036813) ( Vichinsky et al., 2019 ).

Dehydration of the RBC appears to be closely controlled by the efflux of potassium through 2 specific pathways; one is the potassium chloride cotransport and the other, calcium-activated potassium efflux (Gardos channel). Senicapoc blocks the Gardos channels, thus preventing dehydration of the red cells. Preclinical and phase 1/2 showed that inhibition of potassium flow through the Gardos channel increased Hb levels and decreased hemolysis ( ClinicalTrials.gov Identifier: NCT00040677). A phase 3 study was terminated for lack of efficacy ( ClinicalTrials.gov Identifier: NCT00294541) ( Ataga et al., 2008 ; Ataga and Stocker, 2009 ).

N -Methyl D -aspartate receptors (NMDARs) are non-selective calcium channels present in erythroid precursors and circulating RBCs and have been shown to be abnormally increased in RBCs of patients with SCD ( Hanggi et al., 2014 ). These channels are closely related with RBC hydration that affects the intracellular HbS concentration and thereby HbS polymerization and sickling of RBCs. Memantine is a NMDAR inhibitor which has shown to improve hydration of RBCs of patients with SCD in vitro and to reduce sickling in the setting of deoxygenation. It is being explored in an ongoing phase 2 clinical trial ( ClinicalTrials.gov Identifier: NCT03247218).

Sanguinate which is a bovine PEGylated hemoglobin product attempts to block polymerization by targeting carbon monoxide (CO) delivery. By binding to HbS polymers, CO enhances their melting and minimize their persistence in peripheral blood. However, this equilibrium is based on high concentrations of CO. A phase 1/2 single-blind, randomized, placebo-controlled study of this agent in the management of pain crisis has been carried out but no results have yet been posted ( ClinicalTrials.gov Identifier: NCT02411708).

(3) Targeting Vasocclusion

Increased expression and activation of normally inactive erythroid adhesion molecules promote cytoadherence of sickle RBCs to the endothelium accompanied by platelets and leukocytes. Activated leukocytes and platelets further increase the risk to develop VOC ( Nasimuzzaman and Malik, 2019 ; Sundd et al., 2019 ; Telen et al., 2019 ).

Previous in vitro studies had demonstrated that glutamine depletion contributed to red blood cell membrane damage and adhesion. Uptake of L -glutamine uptake is markedly increased in patients with SCD, primarily to increase the total intracellular NAD level ( Morris et al., 2008 ). In a phase 3 study, L -glutamine demonstrated a 25% reduction in the median number of pain crisis, 30% less hospitalizations and reduced acute chest episodes in children and adults with SCD with or without HU over a 48-week period. There were 36% drop-out rate in the glutamine arm and 24% in the placebo control arm from unknown reasons. L -Glutamine appears to significantly increase NADH and NAD redox potential and decrease endothelial adhesion, but its mechanism remains still unknown and there are concerns regarding its use in patients with renal impairment, a common sickle-related complication ( Quinn, 2018 ). In July 2017, the pharmacological grade of L -glutamine (Endari) was approved by the FDA for use in patients with SCD, 5 years or older ( Niihara et al., 2018 ). Of note, L -glutamine has not been approved by the European Medicines Agency for treating SCD.

In the future it could be a useful combination therapy with HU ( Minniti, 2018 ) but uptake among patients is still low, one of the reasons is the unpleasant taste. There are potentially less expensive pharmaceutical formulations of L -glutamine available off the counter, but purity of the effective agents in these compounds have not been validated.

As the endothelium emerge as a key factor in the constant activation of adhesion molecules in sickle RBCs, these adhesion molecules present a very attractive therapeutic target. Selectins, which are present in endothelial cells and are the initial step toward a firm adhesion between RBCs and the endothelium, have been further studied and targeted as possible therapeutic approaches.

Crizanlizumab is a monoclonal antibody to P-selectin and its mechanism of action is to block the adhesion of activated erythrocytes, neutrophils and platelets. In a phase 2, multicenter, randomized, placebo controlled double blind study, crizanlizumab with or without hydroxyurea (SUSTAIN study) ( ClinicalTrails.gov Identifier: NCT01895361) showed that patients on the treatment arm had significantly lower rate of sickle-related pain crises compared to placebo with a lower incidence of adverse events - 10% of patients suffered from moderate side effects while one patient suffered from an intracranial bleed during treatment with this drug that could also interfere with platelet function via its effects on selectins ( Ataga et al., 2017 ). Post hoc analyses showed that more patients were VOC event-free in the crizanlizumab arm than in the placebo arm, and that crizanlizumab also significantly increased time-to-first VOC compared to the placebo ( Kutlar et al., 2019 ). A phase 3 interventional, multicenter, randomized, double-blind clinical trial is ongoing to assess safety and efficacy of crinalizumab with or without hydroxyurea in patients with SCD and history of VOC ( ClinicalTrials.gov Identifier: NCT03814716). In November 2019, the US Food and Drug Administration approved crizanlizumab-tmca (ADAKVEO, Novartis) to reduce the frequency of VOC in adults and pediatric patients aged 16 years and older with SCD.

Rivipansel is a pan-selectin inhibitor with its strongest activity against E-selectin. In a multicenter, randomized, double−blind, placebo−controlled phase 2 study ( ClinicalTrails.gov Identifier: NCT01119833), Rivipansel showed clinical and meaningful reductions in multiple measures of VOC compared with those receiving standard of care treatment ( Telen et al., 2015 ). A phase 3 study (Identifier: NCT02187003) to evaluate the efficacy and safety of rivipansel in the treatment of VOC in hospitalized patients with SCD was terminated (posted on ClinicalTrials.gov February 20, 2020) based on failure of the primary study (NCT02433158) to meet the study efficacy endpoints of time to readiness-for-discharge.

In a phase 1, dose-escalation study propranolol showed it significantly reduced epinephrine-stimulated sickle RBCs adhesion. A phase 2 study (NCT01077921) showed decrease in adhesion molecules such as E-selectin and P-selectin but results were not statistically significant and no clinical endpoints were discussed ( De Castro et al., 2012 ).

Due to their P-selectin mediated adhesion inhibition properties, heparinoids have been additionally investigated with interesting results. Sevuparin, a heparin derivate polysaccharide that has shown to bind to P− and L−selectins, thrombospondin, fibronectin and von Willebrand factor, all of which are thought to contribute to vasocclusion in SCD. It has been reported to inhibit sickle RBC adhesion to the endothelial cells and to reduce tumor necrosis factor-induced vasocclusion. It is currently being tested in a phase 2 clinical trial, placebo controlled, to study its efficacy and safety in patients with SCD during VOC ( ClinicalTrials.gov Identifier: NCT02515838) ( Telen et al., 2016 ). Other heparinoids such as Dalteparin showed incomplete evidence to support or refute its effectiveness in the management of patients with SCD. There are ongoing trials ( ClinicalTrials.gov Identifier: NCT02098993) to assess the feasibility of unfractionated heparin in patients with SCD admitted with pain crisis. Well-designed studies are still needed to clarify its role in the management of patients with SCD and to assess the safety of this approach ( van Zuuren and Fedorowicz, 2015 ).

Poloxamer 188 is a non-ionic block copolymer surfactant thought to seal stable defects in the microvasculature leading to an improvement in blood flow and decreasing blood viscosity. Although its mechanism is not well understood, a randomized, double-blind, placebo-controlled trial showed that it decreased the duration of sickle crisis by 8 h compared to placebo (133 h vs. 141 h, p = 0.04) and more patients receiving the medication reported crisis resolution (52% vs. 37%, p = 0.02) ( Orringer et al., 2001 ). In an early phase 2 study, one patient receiving the medication developed renal dysfunction due to presence of low molecular weight substances and a purified version was designed ( Adams-Graves et al., 1997 ). Vepoloxamer, a purified form of Poloxamer 188 with multi mechanistic properties, was believed to improve RBC adhesion, membrane fragility and organ damage. Unfortunately, a phase 3 study failed to reduce the mean duration of VOC in patients with SCD compared to placebo ( Adams-Graves et al., 1997 ).

(4) Targeting Inflammation

Continual background inflammation contributes to organ damage in patients with SCD. Persistent activation of platelets, neutrophils, monocytes, endothelium, and coagulation factors are key participants in this vicious cycle. Different therapeutic approaches have been proposed to assess the impact in patients with SCD ( Nasimuzzaman and Malik, 2019 ; Sundd et al., 2019 ; Telen et al., 2019 ).

Intravenous immunoglobulin (IVIG) and statins have been studied for their anti-inflammatory effects on neutrophils and monocyte adhesion. Patients on statin demonstrated a decrease in C-reactive protein, soluble ICAM1, soluble E-selectin and vascular endothelial growth. Simvastatin was found to reduce adhesion of white blood cells and in combination with hydroxyurea, was found to decrease the number of pain crisis and markers of inflammation ( Hoppe et al., 2017 ). Currently, there is an active clinical trial to assess the effect of simvastatin on central nervous system vasculature in patients with SCD ( ClinicalTrials.gov Identifier: NCT03599609).

N -Acetylcysteine (NAC) commonly used in respiratory conditions has also been tested for patients with SCD. In a phase 2 study, NAC proved to inhibit dense cell formation and restored glutathione levels toward normal. The decrease in irreversible sickling of RBCs was not statistically significant but a downward trend was observed ( Pace et al., 2003 ; Nur et al., 2012 ). Further studies have shown decreased red cell membrane expression of phosphatidylserine which seems to reflect overall reduced oxidative stress. To better assess its clinical effect in patients with SCD, a pilot study, currently enrolling with invitation is studying its effect in redox and RBC function during VOC ( ClinicalTrials.gov Identifier: NCT01800526).

Aberrant activation of the coagulation cascade, abnormal excess of TF on the endothelial wall and high plasma levels of different coagulation factors drive increased thrombin and fibrin production leading to further inflammation and risk of VOC ( Sundd et al., 2019 ). In a SCD mouse model, factor Xa, TF, and thrombin differentially contributed to vascular inflammation ( Sparkenbaugh and Pawlinski, 2013 ). Factor Xa inhibition demonstrated a decrease in vascular inflammation as assessed by the lower interleukin 6 levels. Although thrombin had no effect on interleukin 6, it was a significant factor for neutrophil infiltration and further inflammation ( Sparkenbaugh et al., 2014 ). A retrospective analysis of rivaroxaban, a factor Xa inhibitor, demonstrated non-inferiority with regard to thrombosis compared to warfarin with the advantage of less outpatient visits and monitoring ( Bhat and Han, 2017 ). Currently, a two-treatment phase clinical trial with rivaroxaban on the pathology of SCD has been completed but results are pending ( ClinicalTrials.gov Identifier: NCT02072668). Patients with SCD have increased platelet levels at baseline that are further increased during acute VOC. Platelet activation triggers further leukocyte activation and promote RBC adhesion to an exposed endothelium ( Conran and Belcher, 2018 ) setting off a vicious cycle of adhesion events. Antiplatelet therapy with Clopidogrel in patients with SCD, unfortunately, were disappointing. New, third generation P2Y12 inhibitors such as ticagrelor and prasugrel have also been studied in patients with SCD. Prasugrel showed appropriate levels of anti-platelet aggregation compared to healthy patients in ex vivo studies, and was well tolerated by patients, but on a 24-month follow up, patients on the treatment arm failed to show reduction in the frequency of VOC ( Heeney et al., 2016 ; Conran and Rees, 2017 ). Ticagrelor, in a phase 2b study, was well tolerated, but failed to show effect in the frequency of VOC ( Kanter et al., 2019 ) ( ClinicalTrials.gov identifier: NCT02482298). Previous studies have also showed that aspirin as an anticoagulant therapy did not provide benefit over placebo, although it is used as an analgesic in many parts of Africa ( Sins et al., 2017 ).

In patients with SCD, continual lysis of RBCs activates the inflammasome triggering the release of multiple cytokines, including IL-1β ( Awojoodu et al., 2014 ). Canakinumab is a humanized monoclonal antibody that targets interleukin 1-β (IL-1β), and thus potentially could be useful in mitigating some of the inflammation in SCD. Canakinumab was shown to be well tolerated and not associated with major side effects in pediatric and young adult patients ( Rees, 2019 ). A clinical trial to assess its efficacy, safety and tolerability is ongoing in the pediatric population ( ClinicalTrials.gov Identifier: NCT02961218).

In the last 30 years, there has been a revolution in the medical sciences, and SCD because of its genetic simplicity, has been at the forefront of the numerous scientific discoveries. Tremendous progress has been made in understanding its pathophysiology and pathobiological complexities, but developing treatments, has been disproportionately slow and elusive. However, after a century of neglect, going back to basics offers hope for translating these insights into better therapeutic options – pharmacological and genetic – and for finding curative genetic options for SCD ( Figure 3 ). Although frequent in the US, SCD is far more prevalent in Africa where patients have less access to resources, medical treatment and facilities and the consequences of the disease are devastating. As we move forward, we have to continue focus our therapeutic approaches so that they can be accessed by those that suffer the most.

Figure 3. The different therapeutic approaches for sickle cell disease and their mechanisms and current status in clinical trials. Orange: targeting hemoglobin S polymerization; gray: targeting vasocclusion; light blue: targeting inflammation and green: modification of the genotype. shRNA, short hairpin RNA; Hb S, hemoglobin S; Hb F, hemoglobin F; PDE9, phosphodiesterase 9. *FDA approved July 2017; **FDA approved November 2019; ***Terminated in February 20, 2020 due to failure to meet primary endpoints.

Author Contributions

GSC and ST wrote and revised the manuscript.

This work was supported by the Intramural Research Program of the National Heart, Lungs, and Blood Institute, NIH (ST).

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

• ^ https://apps.who.int/iris/handle/10665/20890

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Keywords : sickle cell disease, anti-sickling agents, gene editing, gene therapy, hemoglobinopathies

Citation: Salinas Cisneros G and Thein SL (2020) Recent Advances in the Treatment of Sickle Cell Disease. Front. Physiol. 11:435. doi: 10.3389/fphys.2020.00435

Received: 30 December 2019; Accepted: 08 April 2020; Published: 20 May 2020.

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Copyright © 2020 Salinas Cisneros and Thein. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Swee L. Thein, [email protected]

This article is part of the Research Topic

Red Blood Cells at the Mount of Truth: Highlights of the 22 nd Meeting of the European Red Cell Research Society