Sickle Cell Disease (SCD)

Sickle cell disease (SCD) is a group of inherited disorders affecting red blood cell (RBC) morphology and oxygen transport function. Due to the abnormal sickle shape of RBCs, SCD causes serious problems such as occlusion of blood flow, organ damage, and pain crises.¹ Many comorbidities of SCD are complications associated with the disease itself, which may be acute or chronic in nature.

Acute Comorbidities

Vaso-Occlusive Crises

The most common reason that individuals with SCD use healthcare emergency or inpatient services is pain caused by acute vaso-occlusive crises. Vaso-occlusive crises result from sickled RBCs getting stuck in and obstructing the small blood vessels or capillaries. This in turn decreases blood flow to the target tissue or organ in any body region, causing ischemic injury and pain.^2,3 

These vaso-occlusive episodes commonly involve the abdominal organs (particularly the liver, spleen, and kidneys), bones, soft tissue, and joints, resulting in acute abdomen, avascular necrosis, bone marrow infarction, especially in the long bones, dactylitis (edematous and painful hands/feet in children), or acute joint necrosis. 

These pain episodes have a sudden onset and last several hours to days, ending as abruptly as they started. Pain accompanying SCD can also become a chronic feature due to long-term tissue or organ damage following recurrent vaso-occlusive crises.^2,3 

The most probable trigger for vaso-occlusive crisis is hypoxemia secondary to acute chest syndrome or respiratory problems. Dehydration, acidosis, hemoconcentration, and body temperature changes from fever or environmental exposures are other triggers.³

Stroke

One potential complication related to vaso-occlusive events in SCD is cerebral infarction when the small blood vessels within the brain are occluded by the abnormal sickle cells, causing ischemia and death to brain cells. This causes overt stroke symptoms such as death or significant sensory or motor deficits, or cumulative symptoms of “silent” stroke, such as cognitive impairment, which is apparent only due to magnetic resonance imaging (MRI).⁴ 

Stroke, as the main neurological comorbidity found in SCD, is more frequently observed in children than in adults.² Due to this fact, children with SCD typically undergo transcranial Doppler or magnetic resonance angiography to diagnose vasculopathy and to predict stroke probability.⁴ 

Acute Chest Syndrome

Acute chest syndrome (ACS) is the main comorbidity of SCD leading to death among children and adults with SCD and the second most common reason for hospitalization among individuals with SCD.^2,5 ACS is defined as a new radiodensity on chest radiograph in the presence of fever and/or respiratory symptoms. Severity of the syndrome in patients with SCD is classified as either mild, moderate, or severe.⁶

The mortality rate due to ACS is higher in adults with SCD secondary to increasing incidence of bone marrow and fat emboli, which are estimated to contribute to 77% of adult ACS episodes.⁶ Other risk factors for ACS include infection, bronchial hyper-responsiveness, hypoxia, and opioid use.⁵ Primary clinical goals are early recognition and prompt treatment of ACS to minimize irreversible lung tissue damage and prevent acute respiratory failure and death.⁵ 

Acute Renal Failure

Patients with SCD experience significant changes in renal structure and function secondary to the predisposition of RBCs to sickle within the renal medulla due to the medulla’s hypoxic, acidotic, and hyperosmolar environment. Acute kidney injury accounts for between 4% and 10% of hospitalized individuals with SCD.⁷ 

Acute renal injury frequently co-occurs more in patients experiencing ACS (13.6%) than pain crises (2.3%). However, renal failure does coincide in approximately 75% of painful crisis episodes that involve multiorgan failure. Risk factors that trigger acute kidney injury include hypovolemia, infections, nonsteroidal pain medications, and rhabdomyolysis.⁷

Priapism

Priapism is a painful, sustained erection unrelated to sexual stimulus or arousal. Male patients with SCD may experience priapism secondary to lack of penile blood drainage, which is blocked by sickled RBCs. If this condition is left untreated, it may result in erectile dysfunction, infertility, scarring, or permanent tissue damage to the penis.⁸

Splenic Sequestration

In SCD, sickled RBCs can occlude the blood vessels exiting the spleen, resulting in blood accumulation within the spleen; this causes splenomegaly and decreased blood counts. This potentially life-threatening comorbidity of SCD is known as splenic sequestration, or a spleen crisis.⁹

Hepatobiliary Complications 

Hepatobiliary complications include cholelithiasis, cholecystitis, splenic sequestration, and sickle hepatopathy.²

Acute Ocular Conditions

Ocular comorbidities of SCD are related to vascular occlusion due to sickled RBCs in the conjunctiva, iris, retina, and choroid. Treatment is aimed at prevention of vision loss secondary to retinal detachment, vitreous hemorrhage, and epiretinal membranes.¹⁰ Ophthalmic conditions related to SCD increase with age, becoming more chronic in nature and requiring more frequent monitoring.² 

Chronic Comorbidities

Anemia

One comorbidity of SCD is anemia, which is a specific symptom that especially characterizes the HbSS and HbS beta zero thalassemia genotypes.¹¹ Anemia in SCD is directly caused by the premature hemolysis of sickled RBCs. Normal RBCs survive up to 120 days in the body, whereas sickled RBCs last only 10 to 20 days. This results in decreased amounts of functional RBCs required to sufficiently transport oxygen throughout the body.¹² 

Avascular Osteonecrosis

Avascular necrosis (AVN), a type of osteonecrosis, is caused by the permanent loss of blood supply to the bone tissue, which dies due to lack of oxygen. Blood flow to one or more bones, especially bones of the shoulder or hip joints, can be blocked by inflexible, sickled RBCs. AVN is diagnosed via imaging such as x-rays, MRI, bone scans, or computerized tomography. Early AVN is best identified on MRI, whereas advanced AVN is easily seen on x-ray.¹³

Leg Ulcers

Leg ulcers are a chronic comorbidity in SCD that usually begin in late adolescence or young adulthood and, regardless of competent medical attention, may last for years.² Leg ulcers are caused by chronic hemolysis. Leg ulcer incidence is linked to total and fetal hemoglobin rates. Characteristics of vascular abnormalities associated with leg ulcers include pulmonary hypertension, endothelial dysfunction causing nitric oxide deficiency, vascular intimal hyperplasia, and proliferation of smooth muscle cells within the vasculature.¹⁴

Pulmonary Hypertension

Recurrent episodes of ACS may contribute to the development of pulmonary hypertension secondary to increased pulmonary vascular resistance and diastolic heart dysfunction.² Pulmonary hypertension is a comorbidity in about 10% of adults with SCD, especially those of the homozygous genotype. Identified etiologies of pulmonary hypertension in 50% of these adults are related to nitric oxide deficiency, vasculopathy caused by intravascular hemolysis, chronic pulmonary embolisms, and/or hypoxic reactions to anemia, low oxygen saturation, and dysfunction of the small blood vessels.¹⁵ 

Diastolic Heart Dysfunctions

Cardiopulmonary complications are the leading cause of death in individuals with SCD, primarily due to diastolic heart failure and/or pulmonary hypertension. Diastolic heart failure in SCD is characterized by biventricular cardiac hypertrophy and left ventricular diastolic dysfunction. Usually when heart failure coincides with pulmonary hypertension, it is postcapillary in origin.¹⁶

Gout

Gout is a painful inflammatory disorder with characteristic crystallization and deposition of uric acid in the joints as well as hyperuricemia. In SCD, hyperuricemia occurs due to increased production of uric acid as a byproduct of inefficient erythropoiesis and decreased clearance secondary to damage to the kidneys.¹⁷

End-Stage Renal Disease

Progressive damage to renal tissues and recurrent acute kidney injuries may result in end-stage renal disease in adults with SCD, requiring dialysis.² Chronic kidney disease advances secondary to complex interactions between the vascular, tubular, glomerular, and interstitial compartments found within the kidney.⁷

Infections 

Individuals with SCD are more prone to infections due to damage to the spleen, which plays a major immune system role in protecting against infection by filtering out bacteria from the blood and by producing antibodies to fight infection.^{18, 19} Splenic dysfunction becomes apparent with the presence of Howell-Jolly bodies in the blood. The most common infections to which individuals with SCD are susceptible include sepsis, meningitis, upper and lower respiratory tract infections, osteomyelitis, skin, muscle, and soft tissue infections, septic arthritis, gastrointestinal infections, urinary tract infections, malaria, tuberculosis, HIV, Dengue fever, and parasites.¹⁹

References

1. What is sickle cell disease? Centers for Disease Control and Prevention. Reviewed December 14, 2020. Accessed November 23, 2021.
2. Ogu UO, Billett HH. Comorbidities in sickle cell disease: adult providers needed! Indian J Med Res. 2018;147(6):527-529. doi:10.4103/ijmr.IJMR_1019_18
3. Maakaron JE. Sickle cell disease clinical presentation. Medscape. Updated November 2, 2021. Accessed November 23, 2021. 
4. Hirtz D, Kirkham FJ. Sickle cell disease and stroke. Pediatr Neurol. 2019;95:34-41. doi:10.1016/j.pediatrneurol.2019.02.018
5. Farooq S, Abu Omar M, Salzman GA. Acute chest syndrome in sickle cell disease. Hosp Pract. 2018;46(3):144-151. doi:10.1080/21548331.2018.1464363
6. Field JJ, DeBaun MR. Acute chest syndrome in adults with sickle cell disease. UpToDate. Updated June 8, 2020. Accessed November 23, 2021.
7. Nath KA, Hebbel RP. Sickle cell disease: renal manifestations and mechanisms. Nat Rev Nephrol. 2015;11(3):161-171. doi:10.1038/nrneph.2015.8
8. Priapism and sickle cell disease. St. Jude Children’s Research Hospital. Accessed November 23, 2021.
9. Sickle cell disease and spleen crisis (splenic sequestration). Nationwide Children’s. Accessed November 23, 2021.
10. Ventocilla M. Ophthalmologic manifestations of sickle cell disease (SCD): overview. Medscape. Updated July 22, 2021. Accessed November 23, 2021.
11. Maakaron JE. What are the major sickle genotypes? Medscape. Updated May 12, 2021. Accessed November 23, 2021.
12. Sickle cell anemia. Mayo Clinic. Accessed November 23, 2021.
13. Avascular necrosis and sickle cell disease. St. Jude Children’s Research Hospital. Accessed November 23, 2021.
14. Monfort JB, Senet P. Leg ulcers in sickle-cell disease: treatment update. Adv Wound Care (New Rochelle). 2020;9(6):348-356. doi:10.1089/wound.2018.0918
15. Gordeuk VR, Castro OL, Machado RF. Pathophysiology and treatment of pulmonary hypertension in sickle cell disease. Blood. 2016;127(7):820-828. doi:10.1182/blood-2015-08-618561
16. Wood KC, Gladwin MT, Straub AC. Sickle cell disease: at the crossroads of pulmonary hypertension and diastolic heart failure. Heart. 2020;106(8):562-568. doi:10.1136/heartjnl-2019-314810
17. Gupta S, Yui JC, Xu D, et al. Gout and sickle cell disease: not all pain is sickle cell pain. Br J Haematol. 2015;171(5):872-875. doi:10.1111/bjh.13433
18. Infection and sickle cell disease. St. Jude Children’s Research Hospital. Accessed November 22, 2021.
19. Ochocinski D, Dalal M, Black LV, et al. Life-threatening infectious complications in sickle cell disease: a concise narrative review. Front Pediatr. 2020;8:38. doi:10.3389/fped.2020.00038

Reviewed by Debjyoti Talukdar, MD, on 11/24/2021.

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Maria Arini Lopez, PT, DPT, CSCS, CMTPT, CIMT

Maria Arini Lopez, PT, DPT, CSCS, CMTPT, CIMT is a freelance medical writer and Doctor of Physical Therapy from Maryland. She has expertise in the therapeutic areas of orthopedics, neurology, chronic pain, gastrointestinal dysfunctions, and rare diseases especially Ehlers Danlos Syndrome.