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Sickle cell anemia: causes, symptoms, diagnosis, treatment
Last reviewed: 07.07.2025
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Sickle cell anemia (hemoglobinopathies) is a chronic hemolytic anemia that occurs predominantly in blacks of America and Africa, caused by homozygous inheritance of HbS. Sickle-shaped red blood cells block capillaries, causing organ ischemia. Periodically, crises develop, accompanied by pain. Infectious complications, bone marrow aplasia, pulmonary complications (acute respiratory syndrome) can be characterized by acute development and a fatal outcome. Normocytic hemolytic anemia is the most typical. Diagnosis requires hemoglobin electrophoresis and demonstration of the sickle shape of red blood cells in an unstained drop of blood. Crisis therapy consists of prescribing analgesics and supportive therapy. Sometimes transfusion therapy is required. Vaccination against bacterial infections, prophylactic administration of antibiotics and intensive treatment of infectious complications prolongs the survival of patients. Hydroxyurea reduces the incidence of crises.
In homozygotes (about 0.3% of people of the Negroid race), the disease occurs in the form of severe hemolytic anemia; in the heterozygous form (from 8 to 13% of people of the Negroid race), anemia does not manifest itself.
Pathogenesis
In hemoglobin S, glutamic acid in the 6th position of the beta chain is replaced by valine. The solubility of deoxygenated hemoglobin S is significantly lower than that of deoxygenated hemoglobin A, which leads to the formation of a semi-solid gel and sickle-shaped deformation of erythrocytes under conditions of low pO 2. Deformed, inelastic erythrocytes adhere to the vascular endothelium and clog small arterioles and capillaries, which leads to ischemia. Venous aggregates of erythrocytes predispose to the development of thrombosis. Since sickle-shaped erythrocytes have increased fragility, mechanical trauma to vessels leads to hemolysis. Chronic compensatory hyperplasia of the bone marrow causes bone deformation.
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Symptoms sickle cell anemia
Acute exacerbations (crises) occur periodically, often without an apparent cause. In some cases, elevated body temperature, viral infection, local trauma contribute to the exacerbation of the disease. The most common type of exacerbation of the disease is a pain crisis caused by ischemia and infarction of the bones, but it can also occur in the spleen, lungs, and kidneys. Aplastic crisis occurs in cases of slow bone marrow erythropoiesis during an acute infection (especially viral), when acute erythroblastopenia may occur.
Most symptoms occur in homozygotes and result from anemia and vascular occlusion, leading to tissue ischemia and infarction. Anemia is usually severe but varies greatly among patients. Mild jaundice and pallor are typical.
Patients may be poorly developed and often have a relatively short trunk with long limbs and a "tower-shaped" skull. Hepatosplenomegaly is typical in children, but because of frequent infarctions and subsequent fibrotic changes (autosplenectomy), the spleen in adults is usually very small. Cardiomegaly and systolic ejection murmurs are common, as are cholelithiasis and chronic leg ulcers.
Pain crises cause severe pain in the tubular bones (e.g., tibia), arms, hands, feet (hand-foot syndrome), and joints. Typically, hemarthrosis and necrosis of the femoral head occur. Severe abdominal pain may develop with or without nausea and, if caused by sickle cells, is usually accompanied by back or joint pain. In children, anemia may worsen as a result of acute destruction of sickle cells in the spleen.
Acute "thoracic" syndrome caused by microvascular occlusion is the main cause of death and occurs in 10% of patients. The syndrome occurs at any age, but is most typical for children. It is characterized by sudden fever, chest pain and the appearance of pulmonary infiltrates. Infiltrates appear in the lower lobes, in 1/3 of cases on both sides, and may be accompanied by pleural effusion. Subsequently, bacterial pneumonia and rapidly developing hypoxemia may develop. Repeated episodes predispose to the development of chronic pulmonary hypertension.
Priapism is a serious complication that can cause erectile dysfunction and is more common in young men. It can lead to ischemic strokes and damage to the CNS vessels.
In the heterozygous form (HbAS), hemolysis, pain crises, or thrombotic complications do not develop, except for possible hypoxic conditions (for example, when climbing mountains). Rhabdomyolysis and sudden death may develop during periods of intense physical exertion. Impaired ability to concentrate urine (hyposthenuria) is a typical complication. Unilateral hematuria (of unknown origin and usually from the left kidney) may occur in half of patients. Papillary necrosis of the kidneys is sometimes diagnosed, but it is more typical for homozygotes.
Complications and consequences
Late complications include growth and developmental delays. There is also increased susceptibility to infection, especially pneumococcal and Salmonella infections (including Salmonella osteomyelitis). These infections are particularly common in early childhood and can be fatal. Other complications include avascular necrosis of the femoral head, impaired renal concentrating function, renal failure, and pulmonary fibrosis.
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Diagnostics sickle cell anemia
Patients with a family history but no evidence of disease are screened with a rapid tube test, which depends on the different solubility of HbS.
Patients with symptoms or signs of the disease or its complications (eg, growth retardation, acute unexplained bone pain, aseptic necrosis of the femoral head) and blacks with normocytic anemia (especially if hemolysis is present) require laboratory tests for hemolytic anemia, hemoglobin electrophoresis, and examination of red blood cells for sickling. The red blood cell count is usually about 2-3 million/μl with a proportional decrease in hemoglobin, normocytes are usually detected (while microcytes suggest the presence of a-thalassemia). Nucleated red blood cells are often detected in the blood, reticulocytosis > 10%. The white blood cell count is elevated, often with a left shift during a crisis or bacterial infection. The platelet count is usually elevated. Serum bilirubin is also often higher than normal (eg, 34-68 μmol/l), and the urine contains urobilinogen. Dried stained smears may contain only a small number of sickled red cells (crescent-shaped with elongated or pointed ends). The pathognomonic criterion for all S-hemoglobinopathies is sickling in an unstained blood drop, which is protected from drying or treated with a preservative reagent (e.g., sodium metabisulfite). Sickle formation may also be caused by a decrease in O 2 tension. Such conditions ensure that the blood drop is sealed under a cover glass with oil gel.
Bone marrow examination, when necessary for differential diagnosis with other anemias, demonstrates hyperplasia with a predominance of normoblasts in crises or severe infection; aplasia may be determined. ESR, when measured to exclude other diseases (for example, juvenile rheumatoid arthritis causing pain in the hands and feet), is low. An incidental finding on bone radiography may be the detection of widened diplopic spaces in the bones of the skull with a “sunbeam” structure. In tubular bones, cortical thinning, uneven density, and new bone formations within the medullary canal are often detected.
The homozygous state is differentiated from other sickle hemoglobinopathies by the detection of only HbS with variable amounts of HbF on electrophoresis. The heterozygous form is determined by the detection of more HbA than HbS on electrophoresis. HbS must be differentiated from other hemoglobins with a similar electrophoresis pattern by identifying pathognomonic erythrocyte morphology. The diagnosis is important for subsequent genetic studies. The sensitivity of prenatal diagnosis can be significantly improved by PCR technology.
In patients with sickle cell disease during an exacerbation with pain, fever, and signs of infection, aplastic crisis should be considered, and hemoglobin and reticulocyte counts should be performed. In patients with chest pain and difficulty breathing, acute thoracic syndrome and pulmonary embolism should be considered; chest radiography and arterial oxygenation should be performed. Hypoxemia or infiltrates on chest radiography suggest acute "thoracic" syndrome or pneumonia. Hypoxemia without pulmonary infiltrates should prompt consideration of pulmonary embolism. In patients with fever, infection, or acute thoracic syndrome, cultures and other appropriate diagnostic tests should be performed. Unexplained hematuria, even in patients not suspected of having sickle cell disease, should be considered for sickle cell disease.
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Treatment sickle cell anemia
There are no effective drugs for the treatment of sickle cell anemia, and splenectomy is also ineffective. Symptomatic therapy is used in complications. During crises, analgesics are prescribed, possibly opioids. Continuous intravenous morphine is an effective and safe method; at the same time, meperidine should be avoided. Although dehydration contributes to the development of the disease and can cause a crisis, the effectiveness of hyperhydration is also unclear. However, maintaining normal intravascular volume is the mainstay of therapy. During crises, pain and fever can last up to 5 days.
Indications for hospitalization are suspicion of a serious (including systemic) infection, aplastic crisis, acute "thoracic" syndrome, persistent pain, or the need for blood transfusions. Patients with suspected severe bacterial infection or acute "thoracic" syndrome require immediate administration of broad-spectrum antibiotics.
In sickle cell anemia, transfusion therapy is indicated, but in most cases its effectiveness is low. However, long-term transfusion therapy is used to prevent recurrent cerebral thrombosis, especially in children under 18 years of age. Transfusions are also indicated when hemoglobin is less than 50 g/L. Special indications include the need to restore blood volume (eg, acute splenic sequestration), aplastic crises, cardiopulmonary syndrome (eg, cardiac output failure, hypoxia with PO2 < 65 mmHg), before surgery, priapism, life-threatening conditions that can be improved by increasing tissue oxygenation (eg, sepsis, severe infections, acute thoracic syndrome, stroke, acute organ ischemia). Transfusion therapy is ineffective in uncomplicated pain crises, but it can interrupt the cycle if the onset of a pain crisis is imminent. Transfusions may be indicated during pregnancy.
Partial replacement transfusions are usually preferred over conventional transfusions when long-term, multiple transfusions are required. Partial replacement transfusions minimize iron accumulation or increase in blood viscosity. They are performed in adults as follows: exfoliate 500 mL by phlebotomy, infuse 300 mL of normal saline, exfoliate another 500 mL by phlebotomy, and then infuse 4 to 5 units of packed red cells. The hematocrit should be maintained less than 46% and the HbS less than 60%.
Long-term treatment requires vaccination against pneumococcal, Haemophilus influenzae, and meningococcal infections, early diagnosis and treatment of serious bacterial infections, and prophylactic antibiotics, including long-term prophylaxis with oral penicillin from 4 months to 6 years of age, which reduces mortality, especially in childhood.
Folic acid 1 mg/day orally is often prescribed. Hydroxyurea increases fetal hemoglobin levels and thereby reduces sickling, reduces the incidence of pain crises (by 50%), and reduces the incidence of acute "thoracic" syndrome and the need for transfusions. The dose of hydroxyurea varies and is adjusted to increase HbF levels. Hydroxyurea may be more effective in combination with erythropoietin (e.g., 40,000-60,000 U per week).
Stem cell transplantation can cure a small number of patients, but the mortality rate of this treatment method is 5-10%, so this method has not found wide application. Gene therapy may have good prospects.