Sickle cell syndromes

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What is sickle cell disease?

Sickle cell disease is an autosomal recessive inherited blood disorder caused by mutation in the ß-globin gene resulting in production of an abnormal hemoglobin (Hb), hemoglobin S (HbS), which polymerizes under deoxygenated conditions leading to formation of distorted “sickle-shaped” erythrocytes from which the disease derived its name. It is prevalent in individuals of African, Middle Eastern, Southern European, and Indian ethnicity. Globally, an estimated 300,000 babies are born with the disease annually, with 80% in Africa. In the United States, about 100,000 people are affected, primarily in the African American population and to a lesser degree in the Hispanic population of immigrants from the Caribbean.

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What are the different disorders covered by the term sickle cell disease?

The term sickle cell disease includes homozygous HbS (HbSS) and the compound heterozygous combination of HbS with another structural variant of ß globin, such as Hb C, D, E, O (HbSC, HbSD, HbSE, HbSO), or reduced production of ß globin as in ß ⁰ and ß ⁺ thalassemia (HbSß ⁰ thalassemia and HbSß ⁺ thalassemia). Although the clinical manifestations of these sickling syndromes are similar, there is wide heterogeneity and severity is variable. Typical findings in the common variants of sickle cell disease are shown in the following table.

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What is the underlying pathophysiology of sickle cell disease?

The pathophysiology of vaso-occlusion and sickle cell-related injury is complex and not simply obstruction by poorly deformable sickle erythrocytes within blood vessels under hypoxic conditions. Damaged sickle erythrocytes interact with the vascular endothelium causing upregulation of adhesion molecules such as E- and P-selectins, intercellular adhesion molecule 1 (ICAM-1), and vascular cell adhesion molecule 1 (VCAM-1). This leads to recruitment of neutrophils, platelets, and coagulation proteins contributing to worsening vascular stasis and vaso-occlusion. Chronic red cell hemolysis leads to release of free Hb and free heme into the circulation contributing further to endothelial dysfunction by creating reactive oxygen species and by depleting nitric oxide, an effective natural vasodilator. Ischemia-reperfusion injury and the presence of circulating free heme leads to a state of chronic “sterile inflammation.”

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List some of the clinical manifestations of the disease.

Sickle cell disease can affect every organ of the body and presents with acute and chronic clinical manifestations:

• Acute:

• Acute vaso-occlusive pain

• Acute chest syndrome

• Acute splenic sequestration

• Aplastic crisis

• Stroke

• Priapism

• Chronic:

• Chronic anemia and resultant complications (cardiomegaly, hypoxemia, stunted growth, and delayed sexual maturation)

• Chronic hemolysis and consequent complications (gallstone formation, pulmonary hypertension)

• Functional asplenia and increased risk for bacterial infections (sepsis, osteomyelitis)

• Avascular necrosis (femoral and humeral heads)

• Nephropathy (glomerular hyperfiltration, microalbuminuria)

• Retinopathy

• Leg ulcers

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