Hemoglobinopathies are a group of severe hereditary blood diseases caused by a violation of the structure of hemoglobin or a decrease in the synthesis of one or more globin chains. The clinical picture is extremely diverse. Common symptoms are hemolytic anemia, enlargement of the spleen, bone damage. Diagnosis is carried out using peripheral blood smear microscopy, hemoglobin electrophoresis, genetic studies. Transfusion of blood components, hydroxyurea preparations, infusion therapy are used for treatment. Splenectomy and allografting of stem cells are performed in severe patients.
ICD 10
D58.2 D56 D57
Meaning
Hemoglobinopathies are a number of congenital hemolytic anemias characterized by a change in the amino acid sequence of hemoglobin or suppression of the formation of globin chains. These pathologies often end fatally already in early childhood. About 50 types of hemoglobinopathies are known. Sickle cell anemia (SCA) and thalassemia are considered the most frequent and life-threatening. Hemoglobinopathies are common in Central Africa, South Asia and are observed mainly in persons of the Negroid race. Thalassemia is also found in Mediterranean countries. About 350,000 children with hemoglobin defects are born every year.
Causes
Hemoglobinopathies are autosomal recessive genetic diseases. Qualitative hemoglobinopathies develop due to mutations of genes responsible for the synthesis of certain amino acids in the beta chain of globin. As a result, one amino acid is replaced by another (glutamic acid for valine, lysine, etc.). This leads to the formation of abnormal hemoglobin, much less soluble than normal hemoglobin A, which gives red blood cells a different shape (target-shaped, sickle-shaped), which disrupts their functions and reduces life expectancy.
Quantitative hemoglobinopathies are caused by mutation of genes that encode the whole globin chain (more often alpha and beta). At the same time, the balance between globin chains shifts – with insufficient synthesis of alpha chains, an excess of beta chains occurs, and vice versa. The size of red blood cells decreases, their hemoglobin content decreases, and the membrane becomes more susceptible to various damage.
There are factors that provoke severe attacks (crises). These include dehydration, hypothermia, infections accompanied by high fever. In women, exacerbations often develop during pregnancy. But the main pathological stimulus of high–quality hemoglobinopathies is a decrease in the concentration of oxygen in the blood (hypoxia). This can happen, for example, when climbing to a high altitude (climbing a mountain, flying on an airplane), where the partial pressure of oxygen in the air is reduced, or with severe diseases of the respiratory system (pneumonia).
Pathogenesis
Hemoglobinopathies have similar pathogenetic mechanisms. The altered structure of hemoglobin predisposes to intensive hemolysis. Long-term anemia contributes to compensatory bone marrow hyperplasia. There is a deformation of the bones of the skull, a curvature of the spine. Extramedullary foci of hematopoiesis develop, leading to an increase in the size of the liver and spleen (hepatosplenomegaly). Due to splenomegaly, hypersplenism occurs – increased destruction of red blood cells by the sinusoids of the spleen.
Due to the regular hemolysis of red blood cells, the liver secretes a large amount of bilirubin into the bile, which creates conditions for the formation of gallstones. Patients with hemoglobinopathies often experience iron overload, both due to constant blood transfusions and due to increased absorption of iron by the gastrointestinal tract. A large amount of iron in the tissues enhances the processes of lipid peroxidation, which damages various organs.
With high-quality hemoglobinopathies, under the influence of a reduced oxygen content in the blood, molecules of insoluble abnormal hemoglobin stretch the membrane of red blood cells, which leads to a change in their shape. Deformed red blood cells tolerate oxygen worse, and are also able to stick to the vascular endothelium, thereby clogging small vessels, causing thrombosis, occlusion and heart attacks.
Classification
Hemoglobinopathies are divided into qualitative, caused by a violation of the structure (sequence of amino acids) of hemoglobin, and quantitative, characterized by a decrease in the formation of globin chains. Qualitative hemoglobinopathies are represented by the following forms:
- Sickle cell anemia (Hemoglobinopathy S). The most frequent type. It is divided into a homozygous form (SKA proper) with vivid clinical symptoms and a heterozygous carrier (sickle cell anomaly) with an asymptomatic or mild course.
- Hemoglobinopathy C. The clinic is similar to SKA, but less pronounced. It differs in a greater degree of splenomegaly than in SKA.
- Hemoglobinopathy CS (African rheumatism). Downstream resembles SKA. Paroxysmal osteoarticular pains prevail.
- Hemoglobinopathies E and D. They occur with a slight hemolytic anemia.
- Hereditary methemoglobinemia. In this variety, under the influence of various factors, an oxidized form of hemoglobin is formed – methemoglobin, which binds more strongly to oxygen and does not give it to tissues.
- Anemia caused by the carriage of unstable hemoglobins. This is a benign pathology in which minor hemolytic anemia occurs after taking sulfonamide preparations.
Quantitative abnormalities of hemoglobin include:
- Beta-thalassemia. The most common option. It is divided into small thalassemia (heterozygous carrier with asymptomatic course or mild hemolytic anemia) and large thalassemia (Cooley anemia) with a detailed severe clinical picture.
- Alpha-thalassemia. The course may be different depending on the number of mutant genes. Basically similar to heterozygous beta-thalassemia.
- Fetal dropsy syndrome with hemoglobin Bart (Hb Bart’s). The most severe type of alpha-thalassemia. The child dies in utero.
- Hemoglobinopathy H. Favorable low-symptomatic form of alpha-thalassemia.
- Beta-delta thalassemia. Practically indistinguishable from beta-thalassemia.
- Hemoglobinopathy Lepore. This form develops due to the fusion of beta chains of globin and is similar to beta thalassemia.
Symptoms
The clinical picture of hemoglobinopathies is diverse. Heterozygous patients have either asymptomatic or mild course. Homozygous forms begin to manifest themselves from early childhood (6 months – 1 year). General symptoms include signs of hemolytic anemia (pallor, jaundice of the skin and mucous membranes, enlargement of the spleen), pathology of skeletal development – a towering skull (quadrangular), a flattened bridge of the nose, a curved spine.
Due to the increased secretion of bilirubin into the bile, symptoms of cholelithiasis may be bothered already in childhood – severity or aching pains in the right hypochondrium, attacks of biliary colic, fecal discoloration. Long-term non-healing ulcers often occur on the skin of the shins. For diseases with a defect in the structure of hemoglobin, a crisis course is characteristic. The most severe attacks, often ending fatally, occur with sickle cell anemia.
Vaso – occlusive crisis
The most typical. There is a blockage of small vessels of various organs. Children experience pain in long tubular bones, their hands and feet swell, which makes it difficult to move the wrist and ankle joints (hand-foot syndrome). Microthrombosis of intestinal vessels causes abdominal pain. Young men often develop priapism, which subsequently leads to erectile dysfunction. The crisis is accompanied by fever, tachycardia, sweating.
Hemolytic crisis
With a hemolytic crisis, a massive destruction of red cells occurs with a sharp decrease in the content of hemoglobin, red blood cells in the blood. The existing jaundice, pallor of the skin, mucous membranes increases, fever, lumbar and abdominal pain occur, symptoms of a decrease in blood pressure (dizziness, fainting) are added. Urine acquires a dark color due to a large amount of hemoglobin.
Sequestration crisis
During the sequestration crisis, the hemoglobin level also drops rapidly. But this is not due to hemolysis, but due to venous thrombosis and the accumulation of a large amount of blood in the enlarged sinusoids of the liver and spleen, which leads to depletion of the general blood flow. In addition to the symptoms of severe anemia due to severe hepatosplenomegaly, severe and bursting pains appear in the left and right hypochondrium.
Aplastic crisis
A fairly rare form of crisis. It develops when infected with parvovirus B19, which is able to inhibit bone marrow hematopoiesis. This is accompanied by a rapid (but reversible) decrease in the concentration of not only red blood cells, but also all other peripheral blood cells (leukocytes, platelets). Therefore, the signs of anemia are joined by hemorrhagic syndrome (nosebleeds, gums), various infections (mainly ARVI).
Complications
Common complications of hemoglobinopathies are considered to be GI, pathological fractures of long tubular bones. Heterozygous forms are rarely accompanied by adverse events, as they have a mild course. With quantitative hemoglobinopathies, due to the deposition of excess iron in the internal organs, heart failure, cirrhosis of the liver, type 2 diabetes mellitus develops.
Qualitative hemoglobin pathologies are characterized by a wide range of adverse effects. The most dangerous are pulmonary embolism, myocardial infarction, ONMC, which lead to death in about 10% of patients. Blockage of microvessels feeding bones leads to aseptic necrosis of the femoral head (ANGBC). As a result of constant spleen infarctions, functional aspleznism occurs, which is why bacterial infections (bronchitis, pneumonia) often develop with a severe course, often with a fatal outcome.
Diagnostics
Hematologists and geneticists are involved in the curation of patients with hemoglobinopathies. During the general examination, attention is drawn to the color of the skin (pallor, jaundice), constitutional disorders (delayed neuropsychic, physical development of the child, anomalies of the skeleton structure). Additional examination includes:
- Blood test. For blood analysis of patients with qualitative hemoglobinopathies, normocytic anemia of moderate severity is typical, for patients with quantitative hemoglobinopathies, severe microcytic anemia is typical. Altered deformed erythrocytes (sickle-shaped, spherical) are found in the blood smear. The concentrations of free iron, ferritin and indirect bilirubin were increased in the biochemical analysis of blood.
- Hemoglobin electrophoresis. The main method of diagnosing hemoglobin pathologies, widely used in clinical hematology, which determines the ratio of hemoglobin fractions is electrophoresis on a film with cellulose acetate or citric acid agar. A high content of abnormal hemoglobins (HbS, HbF, HBA2) is detected.
- Genetic research. DNA testing by PCR is performed only as part of prenatal diagnostics for the purpose of genetic counseling of families with an increased risk of developing hemoglobin pathologies. DNA samples are obtained by amniocentesis at 8-10 and 14-16 weeks of pregnancy. Determine the presence of mutations of various genes.
- Instrumental research. On the radiography of the bones of the extremities, signs of bone marrow proliferation are noted – thinning of the cortical layer, areas of osteoporosis, expansion of the bone marrow canal. An skull X-ray reveals needle periostosis (“hairy skull phenomenon”). Abdominal ultrasound reveals hepatosplenomegaly, gallstones.
Hemoglobinopathies differentiate with other congenital hemolytic anemias (membranopathies, fermentopathies, Minkowski-Shoffar microspherocytic anemia). Permanent thrombosis needs to be differentiated from various thrombophilia. Iron overload should be distinguished from hereditary hemochromatosis. Anemia, ossalgia require the exclusion of malignant myeloproliferative diseases.
Treatment
People suffering from hemoglobinopathies require complex multicomponent therapy, therefore all patients with homozygous forms are subject to mandatory hospitalization in a hematology hospital. Treatment is not indicated for patients with heterozygous forms. The basic principles of the management of qualitative and quantitative hemoglobin pathologies differ somewhat from each other.
Conservative therapy
The selection of conservative therapy is made taking into account the type of hemoglobinopathy, the course of the disease, the presence of certain complications. Both clinical symptoms and laboratory data (mainly red blood indicators) are evaluated. The following treatment directions are distinguished:
- Relief of crises. In vaso-occlusive crises, painkillers (nonsteroidal anti-inflammatory drugs) are used, and in severe pain syndrome, narcotic analgesics are used. Oxygen inhalation, oral or intravenous rehydration are also prescribed to suppress the precipitation of deformed erythrocytes.
- Prevention of crises. Hydroxyurea is prescribed for permanent admission to patients with high-quality hemoglobinopathies. This drug stimulates the formation of fetal hemoglobin, suppressing the expression of the gene responsible for the synthesis of abnormal insoluble hemoglobins, which reduces the tendency of red blood cells to deformation, reduces the frequency of crises.
- Treatment of complications. Infectious complications before receiving the results of bacteriological studies are treated with antibacterial drugs active against Pneumococcus, Hemophilus bacillus, Meningococcus. Antibiotics from the penicillin group (amoxicillin) are used. With the development of thrombosis, anticoagulants (low molecular weight, unfractionated heparins) are used.
- Blood transfusion. Since anemia in patients with quantitative hemoglobin pathologies is always severe, the basis of treatment is regular hemotransfusion. For people suffering from high-quality hemoglobinopathies, blood transfusions are carried out only with sequestration, hemolytic, and aplastic crises.
- Fighting iron overload and folate deficiency. Chelating agents (deferoxamine) are used to remove excess iron from the body. This drug is usually prescribed together with ascorbic acid, as it potentiates the chelating effect of deferoxamine. Due to constant hemolysis, folate consumption is increased in patients, so they are shown long-term intake of large doses of folic acid.
Surgical treatment
For a number of patients with pronounced signs of hemolysis, splenectomy is an effective treatment – surgical removal of the spleen. Another surgical type of treatment that allows to achieve complete remission is allotransplantation of hematopoietic stem cells. However, this method is rarely used, only in very severe cases, since it is associated with a high frequency of deaths. With cholelithiasis, a cholecystectomy is performed.
Experimental treatment
Currently, clinical studies are underway to find a cure for hemoglobinopathies. There are successful results of gene therapy of SKA. The essence of the treatment is the introduction of a gene encoding the synthesis of a normal beta-globin chain into the patient’s stem cells with the help of a neutralized lentivirus. The drug is called LentiGlobin BB305. Its use led to an improvement in blood parameters, which made it possible to abandon the constant standard therapy. This drug is also being tested for beta-thalassemia.
Prognosis and prevention
Hemoglobinopathies are serious diseases with dangerous life-threatening complications. Patients with homozygous alpha-thalassemia die before birth in the womb. Patients with beta-thalassemia die before puberty from heart failure. People with high-quality hemoglobinopathies, with proper treatment, can live longer than 50 years. The main cause of death is bacterial infections, thrombotic complications. In heterozygous forms of the disease, in most cases, life expectancy does not differ from the general population.
Primary prevention is carried out among families with a high risk of developing hemoglobinopathies. It consists in prenatal diagnosis with termination of pregnancy according to medical indications. Patients suffering from qualitative abnormalities of hemoglobin should definitely receive a vaccine against hemophilic bacillus, pneumococcus, meningococcus. Children from 4 months to 6 years of age are shown long-term use of penicillin antibiotics for the prevention of infections. The same applies to patients who have undergone splenectomy.