Sickle-cell anemia: causes, symptoms, diagnosis, treatment

Sickle-cell anemia (hemoglobinopathy) is a chronic hemolytic anemia, found predominantly in blacks in America and Africa, due to homozygous inheritance of HbS. Crescent erythrocytes block capillaries, causing ischemia of the organs. Periodically, crises develop, accompanied by pain. Infectious complications, bone marrow aplasia, pulmonary complications (acute respiratory syndrome) can be characterized by acute development and death. The most typical is normocytic hemolytic anemia. For the diagnosis is required to carry out hemoglobin electrophoresis and demonstration of sickle-shaped erythrocyte form in an unpainted drop of blood. Therapy of crises consists in the appointment of analgesics and maintenance therapy. Sometimes transfusion therapy is required. Vaccination against bacterial infections, the prophylactic use of antibiotics and intensive treatment of infectious complications prolong the survival of patients. Hydroxyurea reduces the incidence of crises.

In homozygotes (about 0.3% of persons of the Negroid race), the disease occurs as severe hemolytic anemia, with heterozygous form (8% to 13% of blacks), anemia does not appear.

[1], [2], [3], [4]

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 much less than that of deoxygenated hemoglobin A, which leads to the formation of a semi-solid gel and crescent deformation of erythrocytes in 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 thromboses. Since crescent erythrocytes have increased brittleness, mechanical trauma of the vessels leads to hemolysis. Chronic compensatory bone marrow hyperplasia causes deformity of the bones.

[5], [6], [7], [8], [9], [10], [11], [12], [13],

Symptoms of the sickle-cell anemia

Acute exacerbations (crises) occur periodically, often for no apparent reason. In some cases, elevated body temperature, viral infection, local trauma contribute to exacerbation of the disease. The most frequent type of exacerbation of the disease is a painful crisis, caused by ischemia and a heart attack of bones, but it can also occur in the spleen, lungs, kidneys. Aplastic crisis occurs in cases of slowing of bone marrow erythropoiesis in the period of acute infection (especially viral infection), when acute erythroblastopenia can manifest itself.

Most of the symptoms appear in homozygotes and are the result of anemia and vessel occlusion, leading to tissue ischemia and a heart attack. Anemia is usually severe, but varies greatly among patients. Typical manifestations are mild jaundice and pallor.

Patients may be poorly developed and often have a relatively short body with long limbs and a skull of a "tower" shape. Hepatosplenomegaly is typical for children, but because of frequent heart attacks and subsequent fibrotic changes (autosplenectomy), the spleen in adults is usually very small. Often marked cardiomegaly and systolic ejection noise, as well as cholelithiasis and chronic ulcers of the shins.

Painful crises cause severe pain in the tubular bones (for example, tibia), hands, hands and feet ("brush-stop" syndrome), joints. Typically, the appearance of hemarthrosis and necrosis of the femoral head. Severe abdominal pain can develop with or without nausea, and if they are caused by sickle-shaped erythrocytes, usually accompanied by pain in the back or in the joints. In children, anemia can worsen as a result of acute destruction of sickle-shaped erythrocytes in the spleen.

Acute "thoracic" syndrome due to microvascular occlusion is the leading cause of death and occurs in 10% of patients. The syndrome occurs at any age, but is most typical for children. Characterized by sudden fever, chest pain and the appearance of pulmonary infiltrates. Infiltrates appear in the lower lobes, in 1/3 of the cases from both sides, and may be accompanied by pleural effusion. Subsequently, bacterial pneumonia can develop, rapidly developing hypoxemia. 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 is possible to develop ischemic strokes and CNS vascular lesions.

When heterozygous form (HbAS) does not develop hemolysis, pain crises or thrombotic complications, except possible hypoxic conditions (for example, when climbing the mountains). Rhabdomyolysis and sudden death can develop during a period of pronounced physical exertion. Disturbance of the ability to concentrate urine (hypostenuria) is a typical complication. Unilateral hematuria (of unknown nature and usually of the left kidney) can occur in half of the patients. Sometimes papillary necrosis of the kidneys is diagnosed, but it is more characteristic of homozygotes.

Complications and consequences

Later complications are manifested in the retardation of growth and development. There is also an increased sensitivity to infection, especially pneumococcal and Salmonella (including osteomyelitis caused by Salmonella). These infections are especially typical of early childhood and can be fatal. Other complications may include avascular necrosis of the femoral head, a violation of the concentrating function of the kidneys, renal failure and pulmonary fibrosis.

[14], [15], [16], [17], [18], [19], [20], [21],

Diagnostics of the sickle-cell anemia

Patients with a family history, but without signs of disease, are screened by a rapid test tube, which depends on the different solubility of HbS.

Patients with symptoms or signs of the disease or its complications (eg, stunted growth, acute unexplained bone pain, aseptic necrosis of the femoral head), and blacks with normocytic anemia (especially in the presence of hemolysis) need laboratory tests for hemolytic anemia, hemoglobin electrophoresis and study erythrocytes for the presence of sickle-shapedness. The number of erythrocytes in the blood is usually about 2-3 million in μl with a proportional decrease in hemoglobin, usually normocytes are determined (while microcytics suggest the presence of a-thalassemia). Blood often contains nucleated red blood cells, reticulocytosis> 10%. The level of leukocytes is elevated, often with a shift to the left during a crisis or bacterial infection. The number of platelets is usually increased. Serum bilirubin is also often higher than normal (eg, 34-68 μmol / L), urine contains urobilinogen. Dry dried stains can contain only a small amount of crescent erythrocytes (crescent-shaped forms with spaced or pointed ends). The pathognomonic criterion for all S-hemoglobinopathies is crescent in an unpainted drop of blood, which is protected from drying or treated with a preserving reagent (eg sodium metabisulfite). Sickling can also be caused by a decrease in the O ₂ voltage . Such conditions ensure the sealing of a drop of blood under the cover glass with an oil gel.

The study of bone marrow, if necessary differential diagnosis with other anemia, demonstrates hyperplasia with prevalence of normoblasts in case of crises or severe infection, aplasia can be determined. ESR in the case of its measurement in order to exclude other diseases (for example, juvenile rheumatoid arthritis, causing pain in the hands and feet) is low. An accidental finding in the radiography of bones may be the identification of an expansion of diplopic spaces in the bones of the skull with a structure in the form of "sunrays." In tubular bones, thinning of the cortical layer, uneven density and new bone formations within the medullary canal are often detected.

The homozygous condition differentiates from other sickle-shaped hemoglobinopathies by detecting only HbS with a variable amount of HbF during electrophoresis. The heterozygous form is determined by the detection of more HbA than HbS during electrophoresis. HbS must be differentiated from other hemoglobins that have a similar pattern of electrophoresis, by revealing the pathognomonic morphology of red blood cells. Diagnosis is important for subsequent genetic studies. The sensitivity of prenatal diagnosis can be greatly improved by PCR technology.

In patients with sickle-cell anemia in the period of exacerbation, accompanied by pain, fever, symptoms of infection, the possibility of the aplastic crisis is considered, hemoglobin studies and reticulocytes are performed. In patients with chest pain and difficulty breathing, the possibility of an acute thoracic syndrome and pulmonary embolism is considered; it is necessary to perform lung X-ray and evaluate arterial oxygenation. Hypoxemia or the presence of infiltrates in the radiography of the lungs suggests the emergence of an acute "thoracic" syndrome or pneumonia. With hypoxemia without the presence of infiltrates in the lungs, one should think about pulmonary embolism. In patients with fever, infection, or acute thoracic syndrome, crops and other appropriate diagnostic tests are performed. With unexplained hematuria, even if the patient is not suspected of having sickle-cell anemia, the possibility of having this disease should be considered.

[22], [23], [24], [25], [26], [27], [28]

Treatment of the sickle-cell anemia

Effective drugs for the treatment of sickle-cell anemia are not present, splenectomy is also ineffective. In case of complications, symptomatic therapy is performed. During the crisis, analgesics are prescribed, possibly opioids. Continuous intravenous administration of morphine is an effective and safe method; at the same time, the appointment of 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. Nevertheless, the maintenance of a normal intravascular volume is the basis for the therapy of the disease. During the crisis, pain and fever can last up to 5 days.

Indication for hospitalization is a suspicion of having a serious (including systemic) infection, aplastic crisis, acute "thoracic" syndrome, persistent pain, or the need for blood transfusions. Patients with suspected serious bacterial infection or acute "thoracic" syndrome require immediate prescription of broad-spectrum antibiotics.

With sickle cell anemia, transfusion therapy is indicated, but in most cases its effectiveness is low. Nevertheless, long-term transfusion therapy is used to prevent recurrence of cerebral thrombosis, especially in children under 18 years of age. Transfusions are also shown with hemoglobin less than 50 g / l. Special indications are the need to restore blood volume (for example, with acute sequestration in the spleen), aplastic crises, cardiopulmonary syndrome (eg, cardiac output, hypoxia with PO ₂ <65 mm Hg), before surgery, priapism, life-threatening Conditions that can be improved by increasing tissue oxygenation (for example, sepsis, severe infections, acute thoracic syndrome, stroke, acute organ ischemia). Transfusion therapy is ineffective in uncomplicated painful crises, but it can interrupt the cycle at a near start of a painful crisis. Transfusions can be shown during pregnancy.

Transfusions with partial substitution are usually more preferable than conventional transfusions if there is a need for prolonged multiple transfusions. Partial replacement transfusions minimize the accumulation of iron or increase the viscosity of the blood. They are performed in adults as follows: 500 ml are exfused by phlebotomy, infused with 300 ml of physiological saline, the next 500 ml is exfoliated by phlebotomy and then 4 to 5 doses of erythrocyte mass are infused. Hematocrit should be maintained at less than 46% and HbS less than 60%.

With long-term treatment, vaccination against pneumococcal, Haemophilus influenzae, and meningococcal infections, early diagnosis and treatment of serious bacterial infections is necessary ; preventive administration of antibiotics, including long-term prophylaxis with penicillin drugs from the age of 4 months to 6 years, which reduces mortality, especially in childhood.

Often prescribe folic acid 1 mg / day inside. Hydroxyurea increases the level of fetal hemoglobin and thereby reduces sicklebeariness, reduces the frequency of painful crises (by 50%) and reduces the incidence of acute "thoracic" syndrome and the need for transfusions. The dose of hydroxyurea varies and is selected to increase the level of HbF. Hydroxyurea may be more effective in combination with erythropoietin (eg, 40,000-60,000 units per week).

With the help of stem cell transplantation, a small number of patients can be cured, but with this method of treatment the lethality is 5-10%, this method therefore has not found wide application. Gene therapy can have good prospects.

Forecast

The average life expectancy of homozygous patients stably exceeds 50 years. The most frequent causes of death are acute "thoracic" syndrome, intercurrent infections, pulmonary embolism, heart attacks of vital organs and renal failure.

[29], [30], [31]