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SCD DamageSCD ChallengesSCD ChallengesSymptoms & ComplicationsSCD in NumbersLiving With SCDResourcesContact Us
There is no wait and see in SCD The pathophysiology of sickle cell disease (SCD) drives complications and may lead to premature mortality1,2 A 2019 cohort simulation used data from the Centers for Disease Control and Prevention (CDC), the National Newborn Screening Information System, and published literature. The target population was individuals with SCD and the time horizon was lifetime. Data from a combination of published data and publicly available, de-identified vital statistics were used to build a simulation model. Due to the simulated nature of the cohorts, details on demographics and clinical characteristics were not included. The study estimated mortality rates and life expectancy for both the SCD population and a comparable non-SCD group with similar age, sex, and race/ethnicity. To account for the racial/ethnic makeup of the SCD population, mortality rates from the national data were proportionally combined to create a representative non-SCD cohort.3

Limitations of this simulation included that life expectancy was based on a cohort model; although it was balanced for age, sex, and race/ethnicity, this model may have underreported patients. In addition, no genotype information and clinical characteristics were included.3

A study reviewing SCD-related mortality data in 25,665 African American patients between 1979 and 2017 found that the top causes of death were (in no particular order)2:

  • Acute infections
  • Stroke
  • Acute and chronic cardiovascular
complications
  • Acute and chronic pulmonary
complications
  • Liver disorder complications
  • Renal disorder complications
  • SCD-related acute complications such as infection and stroke were more likely causes of death in younger age groups
  • SCD-related chronic renal and cardiac diseases were more common causes of death in older patients
A 2020 study of multiple cause-of-death mortality data provided by the National Center for Health Statistics, CDC, included all deaths between 1979 and 2017. The study included all ages (<5 to 60+); percentages of male/female breakdown were not available. Genotypes were based on ICD-9 codes. In addition, the study included Hb-S disease, Hb-S/Hb-C disease, Hb-S/Hb-D disease, Hb-S/Hb-E disease, sickle cell/Hb-C disease, sickle cell/Hb-D disease, and sickle cell/Hb-E disease. The analysis focused on African Americans, and may not represent all ethnicities. Deaths were classified as "SCD related" if an SCD ICD code appeared on the death record. Identification of SCD subtypes using ICD codes was not feasible.2

Limitations of the study included the use of information from death certificates to identify people with SCD and the cause of death. The cause of death was not always accurately reported on death certificates. Trends reported may not reflect current trends in SCD-related illness.2For more statistics and prevalence data, explore SCD in numbersSCD-related complications may be preceded by
cycles of red blood cell sicklingSCD is an autosomal recessive disorder in which the affected individual inherits 2 copies of abnormal hemoglobin beta (HBB) gene alleles. A single-point mutation in the HBB gene leads to the formation of sickle β-chains (HbS).5 The homozygous inheritance of HbS represents the most predominant form of SCD, homozygous SCD, or HbSS disease.5,6 HbS polymerizes when it is in its deoxygenated state.5 Polymerization leads to the distortion of red blood cells (RBCs), resulting in the characteristic sickled shape.5 Sickled RBCs may go back to a normal shape when oxygen binds to hemoglobin. Over time, these transitions become irreversible, causing cell membrane damage and permanently sickled RBCs.7

Sickled RBCs undergo hemolysis, leading to hemolytic anemia, endothelial dysfunction, and inflammation, resulting in vaso-occlusions. The continuous cycle of HbS polymerization and hemolysis may lead to other downstream consequences, including end-organ damage.5, 8-11The complex SCD cascade may lead to end-organ damage5,7,8,10,12-18 While SCD pathologies may occur among patients with SCD, the extent to which they associate with organ damage is unknown. More research is needed to better understand how SCD pathologies contribute to organ damage. The degree to which SCD pathophysiology may be associated with end-organ damage is not known, as multiple factors—including age, sex, genotype or genogroup, treatment status, and other patient-specific variables—may also affect its etiology.1,5,10,19

Hemolysis

Anemia

Endothelial Dysfunction

RBC sickling may trigger hemolysis12,13 Sickled RBC lifespan may vary based on genetic type.HbS polymerization results in fragile, sickled RBCs that can hemolyze. Hemolysis may lead to hemolytic anemia, endothelial dysfunction, vaso-occlusion, and more.10,12,20 The process of hemolysis may lead to a reduction in nitric oxide levels, causing endothelial dysfunction. Oxidative stress and inflammation due to the release of free hemoglobin, arginase, and ferric heme from RBCs further contributes to vascular damage in the patient.10,12,20
Anemia may impact several end-organ systems14,21

Chronic hemolytic anemia deprives organ tissues of oxygen, potentially leading to end-organ damage.22

In response to severe anemia, the heart increases stroke volume, resulting in raised systolic pressure—a risk factor for cardiovascular remodeling and renal damage—while cerebral blood flow may also increase to maintain oxygen supply. A high resting blood flow and reduced vascular reserve, along with other factors, may cause renal damage, and increases the risk of stroke and silent cerebral infarction (SCI).23,24

Chronic anemia is also accompanied by chronic hypoxia (one of the important causes of pulmonary hypertension). In addition, left ventricular diastolic dysfunction may lead to pulmonary hypertension and is common in SCD as a result of ventricular dilation and hypertrophy of the myocardium.12
Endothelial dysfunction may lead to chronic organ damage16

Endothelial dysfunction may be characterized by a depletion of nitric oxide (NO), a contributing mediator of vasodilation.16 Depletion of NO may lead to vasoconstriction and endothelial injury. Endothelial injury may increase leukocyte adhesion, resulting in subsequent ischemia, and potentially contribute to the development of vaso-occlusions and SCD complications.28 Endothelial dysfunction may be associated with pathologies that impact the heart, cerebral vasculature, and kidneys.28 In patients with SCD, endothelial dysfunction can be linked to end-organ damage across multiple systems.16,29,30

Inflammation

The activation of pro-inflammatory cells and cytokines can contribute to organ damage17

Sickled cells undergoing hemolysis and occlusion in blood vessels contribute to the production of an inflammatory state in SCD. Activation of the inflammatory pathway leads to secretion of molecules that cause further inflammation.17

These inflammatory processes (eg, elevated activity of circulating neutrophils, CD40L, TGF-β, IL-6, IL-18, IFN-γ, CXCL8, and CXCR3) may not only play a role in vaso-occlusive episodes, but in addition to other parts of the SCD cascade, may cause complications throughout the body such as acute chest syndrome, pulmonary hypertension, leg ulcers, nephropathy, and stroke.17

Vaso-occlusion

Vaso-occlusion may be associated with end-organ damage13,18,31

Acute vaso-occlusive pain is thought to be caused by vascular obstruction and tissue ischemia, which occur when sickled RBCs and other cells become trapped in the microvasculature.13,18,31

Ischemia-reperfusion injury occurs when the initial ischemic insult due to VOCs is followed by reperfusion of the tissue, which is paradoxically accompanied by a pro-inflammatory response, resulting in microvascular dysfunction.13,18,31

In SCD, chronic organ damage often goes underreported32Retrospective study of autopsies across the United States (N=306) Organ damage in patients with SCD was explored in a retrospective study of autopsies from 306 patients at multiple sites across the United States between 1976 and 1996. All available clinical data, autopsy gross and microscopic findings, photographs, and/or histological slides were studied by a single pathologist to determine the most precise cause of death in a consistent manner.32Limitations of the study included bias toward clinically remarkable or severe cases and the possibility that many cases may not have been examined because autopsies were contingent upon consent of next of kin or judgment of the medical examiners.32The types of SCD complications may not relate to the frequency of VOC-related hospitalization33In a cohort of adult patients at a single clinic in the Netherlands, progression of organ damage was monitored prospectively over a 7-year period. At baseline in 2006, 104 patients were enrolled; all patients were included in this follow-up study and were screened systematically for sickle cell–related manifestations biannually.33SCD-related end-organ damage and frequency of VOC-related hospital admissions monitored in adult patients over 7 years33
Scroll left to view table
  0 VOCs/Year (n=24) 0-1 VOCs/Year (n=45) >1 VOCs/Year (n=17)
Cholelithiasis 42% 60% 47%
Retinopathy 61% 60% 33%
Pulmonary hypertension* 33% 47% 60%
Microalbuminuria 17% 36% 35%
Osteonecrosis 4% 24% 24%
Renal failure 25% 21% 29%
Leg ulcer 13% 11% 18%
Stroke 0% 11% 12%
Priapism 0% 9% 25%
Iron overload 0% 12% 31%
Acute chest syndrome 8% 50% 53%

*Defined as tricuspid regurgitation velocity (TRV) ≥2.5 m/s.

Limitations of this study included33:
  • Data were from a study conducted outside the United States, where the management of SCD may differ
  • Limited sample size
  • The inclusion of elevated TRV, previously thought to be a reliable marker for pulmonary hypertension, as a form of organ damage
  • No significant association between the prevalence of SCD complications (with the exceptions of iron overload and acute chest syndrome) and the frequency of hospital admissions for VOCs was observed among patients monitored for organ damage and VOCs for 7 years
  • Generalizability of study conclusions were limited by the single study site in the Netherlands during the study period (2006-2013)
References:Buchanan G, Vichinsky E, Krishnamurti L, Shenoy S. Severe sickle cell disease—pathophysiology and therapy. Biol Blood Marrow Transplant. 2010;16(1 suppl):S64-S67. Payne AB, Mehal JM, Chapman C, et al. Trends in sickle cell disease-related mortality in the United States, 1979 to 2017. Ann Emerg Med. 2020;76(3S):S28-S36.Lubeck D, Agodoa I, Bhakta N, et al. Estimated life expectancy and income of patients with sickle cell disease compared with those without sickle cell disease. JAMA Netw Open. 2019;2(11):e1915374.National Heart, Lung, and Blood Institute. Evidence-Based Management of Sickle Cell Disease. Expert Panel Report, 2014. Updated September 2014. Accessed May 4, 2024. https://www.nhlbi.nih.gov/sites/default/files/media/docs/sickle-cell-disease-report%20020816_0.pdfKato GJ, Piel FB, Reid CD, et al. Sickle cell disease. Nat Rev Dis Primers. 2018;4:18010.Kanter J, Kruse‐Jarres R. Management of sickle cell disease from childhood through adulthood. Blood Rev. 2013;27(6):279‐287.Gabriel A, Przybylski J. Sickle-cell anemia: a look at global haplotype distribution. Nat Educ. 2010;3(3):2. Accessed May 4, 2024. https://www.nature.com/scitable/topicpage/sickle-cell-anemia-a-look-at-global-8756219/Telen MJ, Malik P, Vercellotti GM. Therapeutic strategies for sickle cell disease: towards a multi‐agent approach. Nat Rev Drug Discov. 2019;18(2):139-158.Kato GJ, McGowan V, Machado RF, et al. Lactate dehydrogenase as a biomarker of hemolysis-associated nitric oxide resistance, priapism, leg ulceration, pulmonary hypertension, and death in patients with sickle cell disease. Blood. 2006;107(6):2279-2285.Kato GJ, Steinberg MH, Gladwin MT. Intravascular hemolysis and the pathophysiology of sickle cell disease. J Clin Invest. 2017;127(3):750-760.Saunthararajah Y. Targeting sickle cell disease root-cause pathophysiology with small molecules. Haematologica. 2019;104(9):1720-1730.Gordeuk VR, Castro OL, Machado RF. Pathophysiology and treatment of pulmonary hypertension in sickle cell disease. Blood. 2016;127(7):820‐828.Rees DC, Williams TN, Gladwin MT. Sickle-cell disease. Lancet. 2010;376(9757):2018-2031.Guasch A, Navarrete J, Nass K, Zayas CF. Glomerular involvement in adults with sickle cell hemoglobinopathies: prevalence and clinical correlates of progressive renal failure. J Am Soc Nephrol. 2006;17(8):2228-2235.Versari D, Daghini E, Virdis A, Ghiadoni L, Taddei S. Endothelial dysfunction as a target for prevention of cardiovascular disease. Diabetes Care. 2009;32(suppl 2):S314-S321.Palomarez A, Jha M, Medina Romero X, Horton RE. Cardiovascular consequences of sickle cell disease. Biophys Rev (Melville). 2022;3(3):031302.Conran N, Belcher JD. Inflammation in sickle cell disease. Clin Hemorheol Microcirc. 2018;68(2-3):263-299. Sundd P, Gladwin MT, Novelli EM. Pathophysiology of sickle cell disease. Annu Rev Pathol. 2019;14:263‐292. Damanhouri GA, Jarullah J, Marouf S, Hindawi SI, Mushtaq G, Kamal MA. Clinical biomarkers in sickle cell disease. Saudi J Biol Sci. 2015;22(1):24-31. Rother RP, Bell L, Hillmen P, Gladwin MT. The clinical sequelae of intravascular hemolysis and extracellular plasma hemoglobin: a novel mechanism of human disease. JAMA. 2005;293(13):1653-1662.Ershler WB, De Castro LM, Pakbaz Z, et al. Hemoglobin and end-organ damage in individuals with sickle cell disease. Curr Ther Res Clin Exp. 2023;98:100696.Baldwin C, Pandey J, Olarewaju O. Hemolytic anemia. In: StatPearls. Treasure Island, FL: StatPearls Publishing; 2023. National Library of Medicine website. Updated July 24, 2023. Accessed May 4, 2024. https://www.ncbi.nlm.nih.gov/books/NBK558904/?report=printableGladwin MT. Cardiovascular complications and risk of death in sickle-cell disease. Lancet. 2016;387(10037):2565-2574. Bush AM, Borzage MT, Choi S, et al. Determinants of resting cerebral blood flow in sickle cell disease. Am J Hematol. 2016;91(9):912-917.DeBaun MR, Sarnaik SA, Rodeghier MJ, et al. Associated risk factors for silent cerebral infarcts in sickle cell anemia: low baseline hemoglobin, sex, and relative high systolic blood pressure. Blood. 2012;119(16):3684-3690.Olaniran KO, Eneanya ND, Nigwekar SU, et al. Sickle cell nephropathy in the pediatric population. Blood Purif. 2019;47(1-3):205-213.Nath KA, Hebbel RP. Sickle cell disease: renal manifestations and mechanisms. Nat Rev Nephrol. 2015;11(3):161-171.Gupta P, Kumar R. Nitric oxide: a potential etiological agent for vaso-occlusive crises in sickle cell disease. Nitric Oxide. 2024;144:40-46.Palomo M, Diaz-Ricart M, Carreras E. Is sickle cell disease-related neurotoxicity a systemic endotheliopathy? Hematol Oncol Stem Cell Ther. 2020;13(2):111-115.Stotesbury H, Kawadler JM, Hales PW, Saunders DE, Clark CA, Kirkham FJ. Vascular instability and neurological morbidity in sickle cell disease: an integrative framework. Front Neurol. 2019;10:871.Ansari J, Gavins FNE. Ischemia-reperfusion injury in sickle cell disease: from basics to therapeutics. Am J Pathol. 2019;189(4):706-718.Manci EA, Culberson DE, Yang YM, et al. Causes of death in sickle cell disease: an autopsy study. Br J Haematol. 2003;123(2):359-365.van Tuijn CFJ, Schimmel M, van Beers EJ, Nur E, Biemond BJ. Prospective evaluation of chronic organ damage in adult sickle cell patients: a seven-year follow-up study. Am J Hematol. 2017;92(10):E584-E590. See the impact that a mutation in HBB and polymerization of HbS have on RBC function Watch videoLoading SCD leads to chronic complications4 Symptoms & complicationsLoading SIGN UP FOR SCD INSIGHTS

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