Pathophysiology

HbS polymerization results in sickled and fragile red blood cells (RBCs) that lead to hemolysis^1,2

Deoxygenation of RBCs causes HbS polymerization, which results in a sickle-like shape¹

As RBCs deoxygenate and reoxygenate, they sickle and unsickle, leading to irreversible sickling^2-4

Sickling cycles and other stress contribute to metabolic imbalance in RBCs, which increases 2,3-DPG (increasing sickling) and reducing ATP^2,5-7

Due to metabolic imbalances, sickled RBCs are fragile and lack sufficient energy (ATP) to withstand stress, resulting in early hemolysis

Sickled RBCs live only 10-20 days (vs 120 days for healthy RBCs)^2,5,8,9

2,3-DPG=2,3-diphosphoglycerate; ATP=adenosine triphosphate; HbS=sickle hemoglobin; RBC=red blood cell.

Hemolysis leads to anemia and contributes to vaso-occlusion⁹

HEALTHY BLOOD VESSEL

SCD BLOOD VESSEL

HEALTHY BLOOD VESSEL

Hemolysis leads to anemia and contributes to vaso-occlusion, resulting in end-organ damage and early mortality.^8,9

SCD=sickle cell disease.

Vaso-occlusion can block blood flow, leading to sudden severe pain called vaso-occlusive crisis^13,15

Vaso-occlusion most often occurs in the bones, back, chest, and extremities^1,15

Vaso-occlusion triggers can include cold temperature, dehydration, infection, and stress¹⁶

Vaso-occlusion can lead to sudden and severe pain (vaso-occlusive crisis), which is the most common complication associated with vaso-occlusion^13,15

Vaso-occlusion leads to hypoxia, which can cause tissue injury and tissue death, and lead to organ damage (eg, acute chest syndrome in the lungs)^17,18

Because of the severe pain associated with VOCs, they tend to be the most visible manifestation of the disease; however, there is also other damage occurring, contributing to a high total disease burden.^13,19

Organ damage can occur regardless of vaso-occlusive crisis frequency¹⁹

Prevalence of SCD-related organ damage and complications¹⁹

Complication

SCD patients with 0–1 VOC per year (n=45)

Cholelithiasis

60%

Retinopathy

60%

Acute chest syndrome

50%

Pulmonary hypertension*

47%

Microalbuminuria

36%

Osteonecrosis

24%

Renal failure

21%

Leg ulcer

11%

Stroke

11%

Priapism

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Study design

This study enrolled 104 adult patients from a clinic in the Netherlands, with all genotypes of SCD in 2006. All were included in this 7-year follow-up study. Patients were systematically screened for SCD-related complications twice yearly. Microalbuminuria was defined as a ratio between urinary microalbumin (mg/L) to urinary creatinine (mmol/L) of more than 3.5. Decreased renal function was defined as a creatinine clearance of less than 100 mL/minutes.¹⁹

*Tricuspid regurgitant jet velocity ≥2.5 meters per second on echocardiography is a surrogate marker for pulmonary hypertension in adults with SCD.²⁰

VOC=vaso-occlusive crisis.

Organ damage is the leading cause of mortality in SCD²¹

Causes of mortality in adults with SCD²²

Bar chart of causes of mortality in adults with sickle cell disease

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Study design

In this study, a physician recorded circumstances of death among 141 adult SCD patients from 1976 to 2001. Of these 141 patients, 114 (80.9%) had SS phenotype and 66 (46.8%) were female. These findings were determined by autopsy report and/or clinical assessment. In a subset of 31 patients, autopsy records were reviewed for reports of iron deposition in liver and heart and of organ pathology. The mean ± SD age at death was 36 ± 11 years.²²

SD=standard deviation; SS phenotype=sickle cell disease.

Hemolysis is quiet. The damage and
complications of SCD are not

Explore sickle cell disease

See the link between hemolysis markers and organ damage

Explore data

References:

1. Kavanagh PL, Fasipe TA, Wun T. Sickle cell disease: a review. JAMA. 2022;328(1):57-68. doi:10.1001/jama.2022.10233 2. Gibson JS, Rees DC. Emerging drug targets for sickle cell disease: shedding light on new knowledge and advances at the molecular level. Expert Opin Ther Targets. 2023;27(2):133-149. doi:10.1080/14728222.2023.2179484 3. Ballas SK, Kuypers FA, Gordeuk VR, Hankins JS, Thompson AA, Vichinsky E. Time to rethink haemoglobin threshold guidelines in sickle cell disease. Br J Haematol. 2021;195(4):518-522. doi:10.1111/bjh.17578 4. Kato GJ, Piel FB, Reid CD, et al. Sickle cell disease. Nat Rev Dis Primers. 2018;4:18010. doi:10.1038/nrdp.2018.10 5. McMahon TJ, Darrow CC, Hoehn BA, Zhu H. Generation and export of red blood cell ATP in health and disease. Front Physiol. 2021;12:754638. doi:10.3389/fphys.2021.754638 6. Xu JZ, Vercellotti GM. Pyruvate kinase activators: targeting red cell metabolism in sickle cell disease. Hematology Am Soc Hematol Educ Program. 2023;2023(1):107-113. doi:10.1182/hematology.2023000467 7. Rab MAE, Bos J, van Oirschot BA, et al. Decreased activity and stability of pyruvate kinase in sickle cell disease: a novel target for mitapivat therapy. Blood. 2021;137(21):2997-3001. doi:10.1182/blood.2020008635 8. Xu JZ, Thein SL. Revisiting anemia in sickle cell disease and finding the balance with therapeutic approaches. Blood. 2022;139(20):3030-3039. doi:10.1182/blood.2021013873 9. Xue J, Li XA. Therapeutics for sickle cell disease intravascular hemolysis. Front Physiol. 2024;15:1474569. doi:10.3389/fphys.2024.1474569 10. Wang Q, Zennadi R. The role of RBC oxidative stress in sickle cell disease: from the molecular basis to pathologic implications. Antioxidants (Basel). 2021;10(10):1608. doi:10.3390/antiox10101608 11. Anemia. Mayo Clinic. Accessed June 25, 2026. https://www.mayoclinic.org/diseases-conditions/anemia/symptoms-causes/syc-20351360 12. Dimitrov JD, Roumenina LT, Perrella G, Rayes J. Basic mechanisms of hemolysis-associated thrombo-inflammation and immune dysregulation. Arterioscler Thromb Vasc Biol. 2023;43(8):1349-1361. doi:10.1161/ATVBAHA.123.318780 13. Zadeh FJ, Fateh A, Saffari H, et al. The vaso-occlusive pain crisis in sickle cell patients: a focus on pathogenesis. Curr Res Transl Med. 2025;73(3):103512. doi:10.1016/j.retram.2025.103512 14. Jang T, Poplawska M, Cimpeanu E, Mo G, Dutta D, Lim SH. Vaso-occlusive crisis in sickle cell disease: a vicious cycle of secondary events. J Transl Med. 2021;19(1):397. doi:10.1186/s12967-021-03074-z 15. Evidence-based management of sickle cell disease: expert panel report, 2014. National Institutes of Health. National Heart, Lung, and Blood Institute. Accessed July 7, 2026. http://www.nhlbi.nih.gov/health-pro/guidelines/sickle-cell-disease-guidelines 16. Mak V, Davies SC. The pulmonary physician in critical care. Illustrative case 6: acute chest syndrome of sickle cell anaemia. Thorax. 2003;58(8):726-728. doi:10.1136/thorax.58.8.726 17. Ballas SK, Gupta K, Adams-Graves P. Sickle cell pain: a critical reappraisal. Blood. 2012;120(18):3647-3656. doi:10.1182/blood-2012-04-383430 18. Friend A, Settelmeyer TP, Girzadas D. Acute Chest Syndrome. In: StatPearls. Treasure Island (FL): StatPearls Publishing; November 25, 2023. 19. 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. doi:10.1002/ajh.24855 20. Liem RI, Young LT, Thompson AA. Tricuspid regurgitant jet velocity is associated with hemolysis in children and young adults with sickle cell disease evaluated for pulmonary hypertension. Haematologica. 2007;92(11):1549-1552. doi:10.3324/haematol.11576s 21. 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. doi:10.1016/j.curtheres.2023.100696 22. Darbari DS, Kple-Faget P, Kwagyan J, Rana S, Gordeuk VR, Castro O. Circumstances of death in adult sickle cell disease patients. Am J Hematol. 2006;81(11):858-863. doi:10.1002/ajh.20685

Pathophysiology

HbS polymerization results in sickled and fragile red blood cells (RBCs) that lead to hemolysis1,2

Hemolysis leads to anemia and contributes to vaso-occlusion9

Vaso-occlusion can block blood flow, leading to sudden severe pain called vaso-occlusive crisis13,15

Organ damage can occur regardless of vaso-occlusive crisis frequency19

Prevalence of SCD-related organ damage and complications19

Study design

Organ damage is the leading cause of mortality in SCD21

Causes of mortality in adults with SCD22

Study design

Hemolysis is quiet. The damage and complications of SCD are not

See the link between hemolysis markers and organ damage

HbS polymerization results in sickled and fragile red blood cells (RBCs) that lead to hemolysis^1,2

Hemolysis leads to anemia and contributes to vaso-occlusion⁹

Vaso-occlusion can block blood flow, leading to sudden severe pain called vaso-occlusive crisis^13,15

Organ damage can occur regardless of vaso-occlusive crisis frequency¹⁹

Prevalence of SCD-related organ damage and complications¹⁹

Organ damage is the leading cause of mortality in SCD²¹

Causes of mortality in adults with SCD²²

Hemolysis is quiet. The damage and
complications of SCD are not