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Pathophysiology

Pathophysiology

The abnormal hemoglobins produced in individuals with SCD form rigid polymers in response to deoxygenation. These polymers give red blood cells their characteristic sickled shape.3 Although it was originally postulated that the manifestations of SCD were due to the peculiar shape of the RBCs, this theory has been rejected as our understanding of the pathophysiology of SCD progressed.4 Today, we know that the blood in individuals with SCD behaves abnormally at all times, whether or not sickled cells are present. Several systems are abnormally activated at baseline and during a sickle cell crisis including
platelet activation,5,6 endothelial activation,7-9 leukocyte activation,8,10 acute phase reactants,11 and cell adhesion molecule activation.7,12-15 The result of these processes is an increase in both blood viscosity and cell adhesion that causes intermittent vaso-occlusion which manifests most frequently as an acute painful episode or VOC.

Phenotypic Variation In Sickle Cell Disease
The severity of SCD presentations varies tremendously. Some patients exhibit incredibly mild courses
and survive into the eighth decade of life, while others have a relentless and progressive course and do not live past early childhood. The clinical manifestations of SCD affect every organ system. The hallmark of SCD is the VOC. Other manifestations include acute chest syndrome, stroke, splenic and hepatic sequestration, progressive renal injury and failure, avascular necrosis, osteomyelitis, sepsis, pulmonary hypertension, skin ulcers, priapism, retinopathy, and several others.

The factors that determine why some patients have severe presentations while others do not are poorly understood; however, certain markers of SCD severity are well-accepted. The persistence of elevated
fetal hemoglobin (HbF) levels (an alternative hemoglobin that can function in place of the defective HbS) is associated with decreased morbidity. Elevated baseline leukocyte counts, elevated inflammatory markers, and the presence of a comorbid diagnosis of asthma16-18 are associated with increased SCD morbidity.

Based on these manifestations, patients with SCD generally fall into 2 phenotypic groups: hemolytic and vaso-occlusive.19 Vaso-occlusion is the process that results in the manifestations of SCD that are best known to the emergency clinician (VOC pain crises, acute chest syndrome, stroke); however, hemolysis also makes an important contribution. The vaso-occlusive phenotype, marked by relatively higher hemoglobin levels, typically manifests with frequent painful crises and higher risk for the development of acute chest syndrome or stroke. In contrast, the hemolytic phenotype is associated with lower baseline levels of hemoglobin and elevated markers of hemolysis. These patients tend not to have painful crises or acute chest syndrome. Instead, they present with leg ulcers and pulmonary hypertension.19

Patients with SCD exhibit a range of laboratory findings. All patients will have some degree of anemia, with baseline hemoglobin levels ranging from as low as 4 mg/dL to as high as 14 mg/dL along with a compensatory reticulocytosis. Markers of hemolysis, including increased serum lactate dehydrogenase (LDH), indirect hyperbilirubinemia, and low haptoglobin will be present to varying degrees. Many patients with SCD are placed on chronic transfusion regimens to mitigate or prevent severe complications, resulting in iron overload. Laboratory findings include markedly elevated ferritin levels and low total iron binding capacity. Clinical findings of iron overload include liver, pancreas, and heart failure.

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Last Modified: 07/23/2017
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