Sickle Cell Disease

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Diagnosis and reasoning

This young man has presented with acute quadriparesis, an ominous presentation which mandates urgent evaluation. Examination reveals the absence of pain and light touch below the level of C5, but preservation of vibration and proprioception throughout. These findings suggest a pathology affecting the antero-lateral portion of the spinal cord, very likely in the cervical spinal region. The abrupt presentation favors a vascular etiology; in particular, note that the anterior portion of the spinal cord (except the posterior funiculus and horns), are supplied by the single anterior spinal artery; this well corresponds to the affected tracts. The presence of neck pain is a further point in favor of a stroke involving the anterior spinal artery; it should be appreciated that both infarction and hemorrhage of the artery can give rise to pain. Last but not least, note the history of sickle cell disease which has been poorly managed; these patients are well known to have an increased risk of infarction, although involvement of the anterior spinal artery is somewhat rare. Magnetic Resonance Imaging (MRI) of the spine is a good first imaging study; the unremarkable findings favor an infarction (as a hemorrhage would have shown up in T2 weighted images as a hyperintense signal). Nor does the MRI show any other findings which might alter the working diagnosis, such a tumor or other compressive lesion; thus, anterior spinal artery infarction does indeed appear to be the diagnosis. As mentioned earlier, sickle cell disease can give rise to spinal infarction, but this is somewhat rare. Therefore, before assuming the infarction to be due to his pre-existing condition, it makes sense to exclude other, more common causes of spinal infarction - particularly hypercoagulable states, connective tissue diseases and vasculitides, and cardiac sources of emboli. However, his ESR and CRP are within normal limits, while ANA is negative; nor are there any other clinical manifestations which would suggest a vasculitis or connective tissue disease. In addition, the hypercoagulable screen is also normal, while his ECG and Echocardiogram both show no abnormalities. Thus, sickle cell disease does appear to be the underlying etiology. This patient should be started on antiplatelet therapy, as there is evidence that these agents may exert a beneficial effect in this setting. Unfortunately, there is minimal (controlled) data on the use of thrombolytics in acute spinal cord infarction; in particular, systemic thrombolytic therapy is generally not advised, due to the risk of serious bleeding complications. Another key element of his management is to reduce the sickle hemoglobin (HbS) level by means of exchange transfusion; this will reverse or ameliorate central nervous system vessel sickling. IV Antibiotics are not indicated in his current management.


Sickle cell disease (SCD) is a chronic hematological disorder; this encompasses sickle cell anemia, as well as hemoglobin SC disease, HbS/β-Thalassaemia, and other rarer genetic variants. The condition results from an autosomal recessive mutation of the beta chain of the hemoglobin molecule; the 6th amino acid is replaced by valine in place of glutamic acid, and the 17th nucleotide is replaced by adenine in place of thymine. These changes produce a hydrophobic HbS tetramer which ultimately disrupts red cell architecture and flexibility, making erythrocytes more liable to dehydration, and physical and oxidative damage. Note also that the rigid erythrocytes (also termed sickle cells, due to their characteristic shape) find it difficult to pass through the microcirculation, resulting in sludging; they also demonstrate increased binding ability to the vascular endothelium and one another, forming clumps easily. It has also been found that sickle cells release more free oxygen radicals than normal erythrocytes, thus promoting inflammation within the vascular endothelium. Last but not least, it should be appreciated that the HbS molecule shows a reduced oxygen carrying capacity, as compared to normal hemoglobin. The condition is most prevalent in Africa and in the countries surrounding the Mediterranean sea; the male to female ratio is approximately 1:1. An interesting epidemiological observation is the fact that the areas of highest prevalence of SCD are also the regions in whch malaria is most common. This is attributed to a survival advantage, as the red cells of these individuals lyse easily, destroying the malaria parasites. Individuals who are heterozygous for the sickle cell gene are generally asymptomatic; in homozygotes, the condition often presents for the first time during early childhood, as fetal hemoglobin levels start to decline. Vaso-occlusive crises are the commonest cause for acute presentation; the obstruction causes tissue ischemia, infarction, and pain of sudden onset, which can last from hours to days. Fortunately, episodes tend to be self-limiting. Acute chest syndrome is another common manifestation, and is believed to be due to a combination of microvascular obstruction and infection; affected patients present with fever and chest pain, while hypoxemia and leukocytosis are often present. Chronic hemolytic anemia is also common; most patients tend to tolerate this well, although they may become symptomatic upon exertion. Other important manifestations of SCD include bone infarctions (i.e. hand-foot syndrome, and epiphyseal ischemic necrosis); cerebral infarctions (which can be both hemorrhagic or ischemic); cholelithiasis (due to the hemolysis); a variety of hepatic and splenic complications; priapism (in males); leg ulcer formation; and ophthalmological complications. In particular, note that hyposplenism or asplenism is common in these patients, and greatly increases their susceptibility to infections from encapsulated organisms. Note also that parvovirus B19 infection may potentially precipitate an aplastic crisis in these patients; fortunately though, most such episodes are self-limiting. A complete blood count and peripheral blood film are two key initial tests in patients in whom SCD is suspected. Hemoglobin levels are typically reduced, and can be as low as 5 g/dL in certain individuals, possibly due to tolerance of chronic anemia; in addition, the reticulocyte count is often elevated, while leukocyte and platelet counts may show a modest elevation. Peripheral blood smears typically show sickled red cells and target cells; if the patient is hyposplenic or asplenic, Howell-Jolly bodies may be present as well. The definitive diagnosis of SCD requires hemoglobin studies; hemoglobin electrophoresis is able to identify homozygous and heterozygous SCD, as well as the other common genotypes. Hemoglobin quantification via high performance liquid chromatography (HPLC) is of value mainly as a baseline test; in homozygous SCD, HbS may be as high as 90%, with an HbA2 level <4%; this is as opposed to heterozygous SCD, where the carrier will typically have an HbS level of between 35% to 40%, and an HbA of over 50%.
Other laboratory tests helpful in diagnosing SCD include the sickle solubility test, and sickling test; these are generally used in urgent situations (such as pre-operatively). While identifying sickling disorders during the prenatal period has been challenging until recently, advances in DNA diagnostics now allow this to be performed in the first trimester itself, allowing the parents to make an informed decision regarding continuation of pregnancy. The management of SCD is aimed at maintaining HbS levels at a minimum, and identifying and treating the complications of the disease effectively. Hydroxyurea is the only drug known to modify the disease course; it helps reduce the incidence of painful crises, and the overall mortality of adult patients, and is also effective in the treatment of acute chest syndrome and priapism. The drug is believed to act by promoting erythroid regeneration, thus increasing HbF levels; and also by reducing leukocyte levels, thus diminishing the degree of inflammation. Otherwise, the management is mainly supportive, and involves good hydration, analgesics, antibiotics, blood transfusion and iron chelation. Note that mild episodes of pain can be treated on an outpatient basis with nonsteroidal anti-inflammatory drugs (NSAIDs) or acetaminophen; however, in a painful crisis, opioids should be considered. The use of blood transfusions should be balanced against the potential adverse effects (i.e. iron overload, transfusion reactions and transmission of infectious agents); the use of leucodepleted erythrocytes with extended phenotype matching helps reduce the aforementioned complications. Note also that blood transfusion is generally not indicated in patients with chronic disease who have only mild or moderate anemia. It is also important to bear in mind that top-up transfusions increase blood viscosity, potentially reducing further blood flow. Thus, exchange transfusion is the therapy of choice if complications such as acute stroke, acute chest syndrome with severe hypoxia, acute multi-organ failure, or acute severe priapism are present, as well as whenever the hemoglobin level or the hematocrit are high. In addition, in patients undergoing surgery, exchange therapy should be performed pre-operatively to reduce HbS to 30% or less. As infections by encapsulated organisms are a major cause of morbidity and mortality, prophylaxis with penicillin and immunisation is advisable; this has been shown to substantially affect the prognosis of these patients. Note that hematopoietic cell transplantation is the only curative treatment, but is currently limited to HLA compatible siblings only. SCD is a lifelong condition; early detection and treatment significantly improves the ultimate prognosis. Overall, mortality is highest during early childhood, with acute chest syndrome being the most common cause of death.

Take home messages

  1. Sickle cell disease is an inherited disorder which most often presents for the first time during early childhood.
  2. Key complications of the disease include vaso-occlusive crises, acute chest syndrome, and chronic anemia.
  3. Asplenia or hyposplenism is common, due to recurrent splenic infarctions; thus, most patients are highly susceptible to infection from encapsulated organisms.
  4. Hydroxyurea is the only agent known to modify the course of the disease; stem cell transplantation is curative, but limited to a very small subset of patients.

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