The spleen is at particular risk for complications from SCD due to its role as a filter of the blood.^6,7

Splenic sequestration crises are thought to occur when an area of sickled cells within the red pulp of the spleen obstructs a larger draining vein. This mechanical obstruction quickly propagates as more red blood cells (RBCs) sickle in response to sluggish flow and low-oxygen tension. Splenic sequestration can compromise the immune system and lead to increased susceptibility to infection.^6,7

Loss of splenic function can begin before 12 months of age.⁸

The severity of splenic sequestration can vary depending on SCD genotype.^6,7
 

Sickle cell retinopathy (SCR) can be proliferative and nonproliferative. Nonproliferative SCR is characterized by sudden occlusion and rupture of a medium-sized arteriole by sickled RBCs.⁹

The severity of SCR may differ based on the SCD genotype.⁹

Proliferative SCR is the most serious vision complication of SCD and the main cause of vision loss in these patients. In response to hypoxia, sickled red blood cells promote release of inflammatory mediators, which lead to vascular occlusion. Repeated vascular occlusions lead to the production of vascular endothelial growth factor and fibroblast growth factor, which give rise to angiogenesis and proliferative retinopathy.⁹

The American Academy of Ophthalmology and the National Heart, Lung, and Blood Institute recommend that patients with SCD be referred to an ophthalmologist starting from age 10 and get screened for retinopathy every 1 to 2 years.¹⁰
 

Both types of stroke—ischemic and hemorrhagic, and SCI can be a complication in pediatric patients with SCD, which may also affect adults.^11-13

SCIs do not have outward physical signs, such as arm or leg weakness, but are visible on a brain MRI. Silent strokes may cause problems in thinking, learning, and decision-making and are a risk factor for future strokes. The pathophysiology of SCD-related cerebrovascular dysfunction can occur by way of leading to intimal hyperplasia and the proliferation in the arteries, which thickens the vessel walls, narrowing their diameter and limiting blood flow. Endothelial dysfunction also commonly occurs, reducing nitric oxide and promoting vascular inflammation and thrombosis. These abnormal interactions among sickle cells, endothelial cells, platelets, and coagulation factors result in abnormal clotting.^11-13

Before 1990, a large cohort study in the United States demonstrated that 11% of pediatric patients with phenotype homozygous hemoglobin S (HbSS) or hemoglobin sickle C (HbSC) living in low- and middle-income settings will have a stroke by the time they are 18 years of age.¹⁴

Risk and severity of stroke may vary depending on SCD genotype.¹²

The pathophysiology of ACS is based on vaso-occlusion within the pulmonary microvasculature. Regardless of the inciting event, the process starts with the deoxygenation of hemoglobin, leading to polymerization and sickling of erythrocytes. Sickled erythrocytes further contribute to vaso-occlusion, causing ischemia and injury to endothelial cells. Inflammation and vaso-occlusive crises can also lead to the release of bone marrow or fat emboli to the pulmonary circulation, which is one of the primary causes of ACS.¹⁵
 

Without appropriate blood supply, the bone tissue begins to die, causing progressive weakness and changes to the normal shape of the bone.¹⁶

AVN is associated with a higher number of sickle cell pain crises that require hospitalization, organ damage, and mortality. AVN typically is asymptomatic until late-stage disease.¹⁶
 

Major cardiovascular complications of SCD include elevated pulmonary artery systolic pressure, pulmonary hypertension (PH), left ventricular diastolic heart disease, dysrhythmia, sudden death, and renal dysfunction. As patients with SCD get older, cardiac dysfunction may have significant effects on morbidity and premature mortality.¹⁷

Chronic anemia in SCD can result in cardiac chamber dilation and a compensatory increase in left ventricular mass.¹⁷

Often accompanied by¹⁷:

• Left ventricular diastolic dysfunction, a strong independent predictor of mortality in patients with SCD

• PH and diastolic dysfunction are linked with marked abnormalities in exercise capacity

Precapillary PH refers to PH where there is elevated pressure in the pulmonary arteries. PH may present in 2 forms—precapillary and postcapillary. This condition can arise from several potential causes. One possibility is a lack of sufficient nitric oxide. This deficiency, along with damage to blood vessels due to intravascular hemolysis, can contribute to the problem. Additionally, chronic pulmonary thromboembolism, where blood clots repeatedly lodge in the lungs and cause poor oxygen saturation, can also play a role.¹⁸

The remaining patients with SCD who have pulmonary hypertension develop a different form, postcapillary pulmonary hypertension, which stems from dysfunction in the left ventricle of the heart. Importantly, even though the blood pressure in the pulmonary artery is only moderately elevated in patients with SCD who have pulmonary hypertension, they may face an increased risk of death compared to those without this complication.¹⁸
 

As sickled RBCs become fragile, less deformable, and prone to lysis, they release pro-inflammatory hemoglobin and extracellular vesicles that can induce platelet activation.¹⁹

The overall SCD cascade can impact blood flow, causing venous stasis and increasing prothrombotic complications.¹⁹
 

It is believed that acute sickle hepatic crisis is due to sickling of erythrocytes leading to sinusoidal obstruction.²⁰

Additionally, hemolysis causes an increase in unconjugated bilirubin and growth of bilirubinate crystals, leading to gallstones.²⁰

Gallstone disease is common in patients with SCD due to excessive breakdown of heme, causing increased unconjugated bilirubin and precipitating pigment gallstones. Fifty percent of these gallstones are made of calcium bilirubin.²⁰

Sickle cell hepatopathy may manifest in acute and chronic presentations. Up to 40% of patients who experience sickle cell crises also have involvement of the liver.²¹
 

Sickle cell nephropathy (SCN) is considered one of the most severe complications of SCD. Renal consequences of SCD can involve different portions of the nephron.^22,23

SCN results from a cascade of events triggered by RBC vascular occlusion, infarction, and reperfusion injury occurring within the renal medullary, cortex, and collecting systems.^22,23

Renal consequences of SCD can occur throughout the lifetime of a patient with SCD. Early infancy is characterized by hyperfiltration, hypertrophy, and impaired urinary concentrating ability. As a patient with SCD ages, the risk of chronic kidney disease, progressive reduction of glomerular filtration rate, and end-stage renal disease increases, whereas hematuria and acute kidney injury (AKI) can occur at any age.^23,24