What is Thalassemia?
Thalassemia is a heterogeneous group of hemoglobinopathies, which are based on a decrease in the synthesis of polypeptide chains that are part of the structure of normal hemoglobin A. Thalassemia is target-cell anemia with an impaired ratio of HLA and HbF in biochemical parameters; in this case, partial insufficiency of a certain chain or its complete absence with the predominance of another chain is possible. So, in violation of the synthesis of the ß-chain, a-chains will prevail and vice versa. Beta-thalassemia is caused by a decrease in the production of hemoglobin ß-chains. Intact a-chains accumulate excessively in erythropoiesis cells, which leads to membrane damage and destruction of both erythroid cells in the bone marrow and erythrocytes in the peripheral blood; inefficient erythropoiesis and hemolysis with red blood cell hypochromia develop, because the hemoglobin content in red blood cells is insufficient. American pediatricians Cooley and Lee were the first to describe ß-thalassemia in 1925. The severe homozygous form of ß-thalassemia was called Cooley’s disease, or large thalassemia. In addition, intermediate, small and minimal thalassemia are distinguished by the severity of anemia and other clinical symptoms. In addition to the Mediterranean countries, thalassemia is found in France, Yugoslavia, Switzerland, England, Poland, as well as among residents of Transcaucasia and Central Asia, where in some regions the frequency of carriage reaches 10-27%.
Causes of Thalassemia
With thalassemia, the synthesis of one of the four chains of the globin is disrupted. Inheritance of pathology from one (heterozygosity) or both parents (homozygosity), type of broken chain determine the severity of clinical manifestations. The reasons for the increased death of red blood cells are associated with a disturbed cell structure due to an incorrect ratio of globin chains to hemoglobin. In addition to shortening the life of red blood cells in this disease, the death of erythrocyte precursor cells in the bone marrow occurs.
Pathogenesis during Thalassemia
The pathogenesis of ß-thalassemia is associated with a mutation at the ß-globin locus on the 11th chromosome pair, which disrupts the synthesis of the ß-globin chain. Hypochromic anemia develops due to inadequate hemoglobin synthesis. Precipitates of excess a-chains are removed from red blood cells and red blood cells by cells of the reticulohistiocytic system; while the cells are damaged and destroyed faster. This is the mechanism of ineffective erythropoiesis and hemolysis of red blood cells and reticulocytes; the death of the latter occurs in the spleen. With ß-thalassemia, HbF also accumulates, which has a high affinity for oxygen; however, the return to its tissues is difficult, which leads to their hypoxia. Ineffective erythropoiesis contributes to the expansion of the hematopoietic bridgehead, which affects the structure of the skeleton; however, the destruction of red blood cells in the bone marrow leads to increased absorption of iron and pathological overload of the body with iron. Hematological signs of ß-thalassemia are sometimes detected in anemic patients among Russians.
Symptoms of Thalassemia
The clinic of large thalassemia is already evident in childhood. In sick children, a kind of tower skull, a Mongoloid face with an enlarged upper jaw. An early sign of Cooley’s disease is splenitis and hepatomegaly, developing due to extramedullary hematopoiesis and hemosiderosis. Over time, they develop cirrhosis of the liver, diabetes as a result of pancreatic fibrosis, and myocardial hemosiderosis leads to congestive heart failure.
Homozygous beta-thalassemia (large thalassemia, Cooley anemia) is characterized by a sharp decrease in the formation of HbA1, a significant increase in the content of HbF, low, normal or high content of HbA2. The content of HbF can vary from 30 to 90%, sometimes below 10%. The course of the disease is characterized by severe hemolytic anemia, which manifests itself towards the end of the first year of a child’s life, hepato- and splenomegaly, Mongoloid face and a tower skull, lagging of a child in physical development, often yellowness and pale skin. Some patients develop ulcers in the lower leg. X-ray detect a symptom of a “hedgehog” or “brush”, which is positive with an increase in the content of HbF, negative with an increase in the percentage of HbA2. In children from the age of 6 months. up to 1 year in the small bones of the feet and hands reveals a thinning of the cortical layer with swelling of the bone and the formation of a coarse mesh structure of the bone marrow. Starting from the 1st year of a child’s life, a violation of bone development is noted, rapidly progressing until puberty. Long-term hemolysis (reticulocytosis, an increase in the free fraction of serum bilirubin, urobilinuria, hypersidemia), frequent transfusions of red blood cells lead to the development of hemosiderosis of the liver and spleen. Often there is the formation of bilirubin stones in the bile ducts. The hemoglobin level reaches 30-50 g / l, the color index is 0> 5 and below. Target erythrocytes are found in blood smears, characterized by a low hemoglobin content and shortened life expectancy, anisopoikilocytosis, erythro and normoblasts. There is an increase in the osmotic resistance of red blood cells, leukopenia (during the hemolytic crisis). In the bone marrow – irritation of an erythro-normoblastic germ. Sometimes aplastic crisis or hypersplenism occurs. In severe homozygous thalassemia, patients die in the first year of life, with a relatively more relaxed form of the disease, they can survive to adulthood.
Heterozygous beta-thalassemia proceeds in the form of both asymptomatic and manifest forms with a slightly enlarged spleen, specific bone changes, often pronounced hypochromic anemia, often anisocytosis, poikilocytosis and erythrocyte targeting (approximately 8% increase in osmotic resistance to 2% hemoglobin), in some patients – HbF (up to 5%). With heterozygous deltabeta-thalassemia (F), a high HbF content is observed at a normal level of HbA2. Clinical signs and hematological changes are similar to those found in heterozygous beta-thalassemia. Homozygous forms of deltabet-thalassemia (F) are manifested by almost the same clinical and hematological disorders as homozygous beta-thalassemia. In patients with this form of the disease, only HbF is detected. Among patients with thalassemia, it is possible to distinguish individuals with hetero- and homozygous forms of A2F-thalassemia, which, according to the signs characterizing their course, essentially differ little from beta-thalassemia. In the group of patients with beta-thalassemia, cases of large thalassemia with severe clinical manifestations are less common than intermediate and small forms. When examining the relatives of patients, a minimal form of beta-thalassemia is more often found. The following forms of a-thalassemia are distinguished: fetal dropsy with Bart’s hemoglobin (v4). hemoglobinopathy H (beta4), a-thalassemia-1 and a-thalassemia-2. Dropsy of the fetus is a homozygous state (according to the a-th-l genes), incompatible with life. Pregnancy in such cases is involuntarily interrupted, and dropsy of the brain and hepatomegaly are revealed in the fetus. An electrophoretic study of hemoglobin revealed Hb Bart’s (80-90%, combined with traces of HbH. Hemoglobinopathy H – one of the variants of a-thalassemia – is manifested by hemolytic anemia, enlarged spleen, severe bone changes. The picture of peripheral blood is characterized by a decrease in hemoglobin, aniso- and poikilocytosis, hypochromia and multiple inclusions in red blood cells (hemoglobin H precipitated). Heterozygous forms of a-thalassemia are detected in relatives of patients with hemoglobinopathy N. a-T lassemia-1 (a small form of the disease) occurs when the a-th-l gene is combined with the normal a-chain synthesis gene.It is characterized by slight anemia, moderate aniso- and poikilocytosis, intra-erythrocyte inclusions, increased osmotic resistance of red blood cells. In adult patients with a-thalassemia -1 hemoglobin fractions are within normal limits, Hb Bart’s is detected in newborns (5-10%). А-Thalassemia-2 (the minimal form of the disease) develops when the a-th-2 gene is combined with the normal a-chain synthesis gene. Clinical manifestations are absent.
Diagnosis of Thalassemia
A blood test determines hypochromic hyperregenerative anemia of varying severity. In a blood smear, hypochromic red blood cells of small sizes, target-like, of various shapes are found; many normocytes. In the biochemical analysis of blood, hyperbilirubinemia due to the free fraction, hypersidemia, a decrease in OSHSS, an increase in LDH activity are detected. In red blood cells, the level of fetal hemoglobin is increased. Alpha-thalassemia is prevalent mainly in Southeast Asia, China, Africa and the Mediterranean. The synthesis of a-chains is encoded by 4 genes; therefore, the degree of violation of their synthesis is less than with ß-thalassemia; pronounced imbalance develops only when all 4 genes are affected. At the same time, aggregates from ß-chains, the amount of which is found in excess during a-thalassemia, are more soluble than aggregates from a-chains, therefore hemolysis with a-thalassemia is less pronounced than with ß-thalassemia, and erythropoiesis is more effective. Therefore, clinical and laboratory data with a-thalassemia are less pronounced than with ß-thalassemia; their main difference in the biochemical composition of erythrocyte hemoglobin: with a-thalassemia, the content of hemoglobin a-chains is reduced.
If both parents suffer from thalassemia, it is advisable to examine the fetus during pregnancy for thalassemia with a view to the possible timely termination of pregnancy. Detection of so-called “Homozygous” (more severe) forms of thalassemia in the fetus – an indication for abortion. 2 main methods are used – fetoscopy and amniocentesis. Both of them are associated with obtaining fetal cells by puncture through the anterior abdominal wall (the first of which is done under the supervision of an ultrasound scan), followed by a medical and genetic study of the obtained cells. The geneticist will determine the preferred research method depending on the duration of pregnancy, ultrasound data and the individual characteristics of the pregnant woman. Both methods have their own risk, first of all, premature birth. There is also, albeit very small, the risk of infection and even fetal death (according to the literature, about 3%). To resolve the issue of family planning, people with relatives with thalassemia patients should definitely contact a geneticist and he will appoint you, if necessary, the necessary antenatal examination.
Red blood cell transfusion
In severe forms of thalassemia, the need for transfusions of red blood cells arises from the first months of life and persists, although to varying degrees, for life – the so-called transfusion dependence develops. This means that hemoglobin in the blood of patients constantly continues to decline and there are no other real ways to increase it, except for such transfusions. It is desirable that the hemoglobin content in the patient’s blood does not drop to low numbers, it is better to re-transfuse with its satisfactory levels of 95-100 g / l. The fact is that with a marked decrease in hemoglobin, many pathological processes inherent in thalassemia are activated: for example, the mentioned excessive pathological bone formation, an increase in the size of the liver and spleen; the function of all organs worsens, and resistance to infections decreases due to increased oxygen starvation. With large b-thalassemia, in addition to replacing the lack of red blood cells in the circulating bloodstream, transfusions of red blood cells can suppress the patient’s own excess, but ineffective blood formation in the patient’s bone marrow, and iron absorption in the intestine also decreases. Thus, in observing a patient with thalassemia, it is important to prevent the development of episodes of a pronounced drop in hemoglobin level – this, firstly, can directly threaten life, and secondly, contributes to the progression of pathological manifestations of thalassemia. At the same time, transfusion of red blood cells has its significant disadvantages. As you know, when transfusing blood products, the compatibility of the donor and the recipient in the blood group, Rh factor must be taken into account. But since genetically identical people do not exist in nature, during repeated transfusions, the patient’s body sooner or later begins to produce antibody proteins that react with other, more complex parts of the membranes of transfused blood cells (erythrocytes). Therefore, after some time (usually 3-4 years), the patient’s body becomes biologically “compatible” not with any donor that is suitable for blood type and Rh factor, but only with certain donors that have a specific set of protein antigens on red blood cells. Therefore, transfusion of red blood cells in thalassemia is preferably carried out according to an individual selection carried out by a special isoserological laboratory of blood transfusion stations. In addition, erythrocyte media for patients with thalassemia must be specially purified from other biological components contained in the blood (leukocytes, numerous plasma proteins), since they are the cause of the so-called “Pyrogenic” reactions, manifested by chills and fever, often to high numbers. Whole blood is not currently being transfused; transfusions of untreated red blood cell mass by additional methods are also not desirable. Thawed, washed or filtered red blood cells, which are much less likely to cause reactions, are now used as highly purified red blood cells. But be that as it may, in the presence of a transfusion dependence, transfusions are inevitable, therefore, you can only take measures to reduce their side effects and prevent reactions and complications. In milder forms of thalassemia, when patients either have mild anemia (at the level of 90-110 g / l), or hemoglobin is normal, and most importantly, that it stays stable in the patient over time and does not continue to decrease steadily, blood transfusions not carried out.
An important part of treatment is the removal of excess iron from the body with the help of drugs from the “chelates” group (the so-called “chelate therapy”), carried out by the “Desferal” preparation. Currently, subcutaneous injections have been treated for many hours, the most convenient use of special devices is the so-called. Pumps that attach to clothing. From a syringe fixed in the pump, desferal is gradually subcutaneously administered to the patient over several hours. Ideally, patients with severe thalassemia should receive desferal throughout their lives for 5 days a week, but in real life this is still difficult to achieve. In countries with a high prevalence of thalassemia, especially highly developed ones (for example, Italy), there are special state programs for the care of patients with thalassemia, which include, among other treatments, providing the necessary desferal and pumps for its administration. From the countries of the former USSR, a similar program exists in Azerbaijan. Store desferal in a dark place at + 8-15 ° C, dilute immediately before the start of administration. With caution, desferal is prescribed in children under 2 years of age due to the relatively greater risk of side effects of treatment. In such children, desferal treatment is started if about 15-20 blood transfusions have already been performed, i.e. the need for transfusions is already quite large. To improve the quality of life of patients, night infusion of Desferal is preferred. Subcutaneous injection sites should be systematically changed to avoid local damage to the skin and underlying soft tissues. Like any treatment, desferal therapy has its possible side effects. Allergic reactions to the drug are more common, a febrile reaction is also possible. If any new complaints appear during the treatment with Desferal, you should consult a doctor, he will decide on the continuation of treatment and how to treat side effects of Desferal.
Spleen removal (splenectomy)
In some patients, the very large sizes of the spleen themselves begin to negatively affect the state of hemoglobin and other indicators of the blood system. In such cases, surgical removal is performed. This operation does not cure thalassemia itself, although it can mitigate its manifestations (which, however, may not happen). Splenectomy is performed only with very large sizes of the spleen, and also when there are clear signs of its pathological effect on other blood parameters (the so-called “hypersplenism”). The operation is not advisable before reaching the age of 5 years, the age of 8-10 years is considered optimal. The first year, usually a good effect is observed, but then a relapse of thalassemia is possible, and liver enlargement may increase. In addition, the infectious risk increases, especially regarding the accession of the so-called “Pneumococcal” infection in the form of sepsis, pneumonia. In this regard, vaccination against pneumococcus is mandatory, preferably carried out in the preoperative period. In general, the decision to remove the spleen should always be taken with great care.
Bone marrow transplantation
Currently, thalassemia treatment with bone marrow transplantation is becoming more common. This is the only radical treatment for thalassemia. When thalassemia is detected, it is desirable that patients and their families be “typed by the HLA system” (that is, they undergo a rather complicated biological compatibility test) in order to search for a possible bone marrow donor. However, it is usually difficult to find a suitable donor; the procedure for finding a compatible unrelated donor remains expensive and time consuming. The bone marrow transplant itself is very expensive. Close relatives, even if they are compatible with HLA antigens, themselves often have thalassemia. Therefore, relatively few patients with thalassemia are still real candidates for bone marrow transplant treatment. It should be noted that the results of bone marrow transplantation are largely dependent on the quality of the previous treatment to the patient. Better bone marrow transplant results in children. Although the development and implementation of new methods of treatment of thalassemia, including bone marrow transplantation, continues, for the vast majority of patients, the “traditional” methods of treatment mentioned above are still possible. Genetic engineering treatments for thalassemia are also being developed. Patients with thalassemia should follow a diet (table No. 5). Useful drinks containing tannin: tea, cocoa, as well as nuts, soybeans – these products reduce the absorption of iron. Due to the tendency to caries, fluoride toothpastes and timely oral sanitation are recommended. To improve liver function, the doctor prescribes medications – the so-called “Hepatoprotectors.” These include lipoic acid, Vit E, preparations of the type of the well-known “essentials”. Ascorbic acid (vitamin C) in a dose of 50 mg / day up to 10 years and 100 mg / day in children over 10 years improves the excretion of iron from the body. Also used is treatment with B vitamins, folic acid. An increase in the dose of vitamins is carried out under stress, pregnancy. Courses of choleretic herbs are prescribed – mint, oats, corn stigmas, barberries, as well as tubas.
Features of the treatment of other forms of thalassemia
“Intermediate” thalassemia. Due to the milder course, the disease does not require constant transfusions – usually no more than 1 time in 2-3 weeks – 2-3 months. When intercurrent diseases are attached, during operations, red blood cell transfusions are carried out at a hemoglobin level below 70 g / l. As a rule, treatment with desferal is prescribed, but it is preferable after a special study of iron metabolism by the level of its content in the blood and the response to a single injection of desferal (the so-called “desferal test”). With a large size of the spleen with signs of excessively increased function, the question of its surgical removal of the “Small” thalassemia is considered. Red blood cell transfusion does not require. In case of anemia, folic acid is prescribed, it is also possible to resolve the issue of treatment with desferal according to the level of serum iron or desferal test. In severe forms of thalassemia, especially with the presence of transfusion dependence, the patient becomes disabled.
Thalassemia prevention is based on identifying individuals at risk through media screening programs or family history studies and providing adequate information about the risk and how to reduce that risk. Beta-thalassemia has a unique property: healthy carriers can be determined by a simple, inexpensive and accurate blood test. In this way, carrier pairs can be identified and informed about genetic risk before they start a family. Screening is an inexpensive and affordable way to identify carriers that can be offered in a wide range of situations in various conditions: in high school, before marriage or in antenatal clinics. Couples of carriers identified in this way are informed of genetic risk and possible mitigation options, which usually include prenatal diagnosis. Most couples at risk for thalassemia seek prenatal diagnosis of hemoglobinopathy. The standard diagnostic method is to take a sample of chorionic villi and a DNA test with a gestational age of 10-12 weeks. Screening and counseling programs can lead to a significant reduction in disease-prone infants. These programs can be analyzed through conversations with parents with sick children, although they had access to screening and counseling. In most cases, the birth of affected children is the result of the inability of health systems to adequately inform parents of potential risks and preventive measures, rather than the fact that they reject fetal testing. The choice of an appropriate strategy for introducing thalassemia prophylaxis depends on the specific conditions. In some societies, you can start by providing prenatal diagnostics for couples who already know that there is a risk, either through screening or because they have a sick child. This approach significantly reduces the number of newborns with the disease. On the other hand, in societies where prenatal diagnosis is not yet provided, screening can be offered for people of reproductive age. This strategy leads to a smaller reduction in the number of children with the disease, but usually stimulates the demand for antenatal services. Currently, in many countries there are examples of the effective use of thalassemia prevention methods based on various carrier screening programs. For example, in Greece, Cyprus, the Islamic Republic of Iran and Italy, screening for thalassemia prior to marriage is standard; most at-risk couples are determined timely enough to offer early diagnosis on their first pregnancy. Most of these couples use this service and have healthy children. In the United Kingdom of Great Britain and Northern Ireland and other countries of northwestern Europe, where prenatal diagnosis is widespread, screening is offered during pregnancy. Screening programs need support in the form of public education and regulatory structures so that individuals can make informed decisions and that people are protected from discrimination based on their test results. Some national programs aimed at promoting screening of carriers have, in turn, stimulated social change, including the adoption of termination of pregnancy in many countries when it is proven that the fetus is suffering from a serious genetic disorder. This has led to the development of appropriate technologies and services in Bahrain, the Islamic Republic of Iran and Saudi Arabia. The adoption and implementation of prevention programs is expanding in many parts of Asia, such as India, Indonesia, China, Malaysia, the Maldives, Singapore and Thailand. Genetic counseling plays an important role in protecting the autonomy of an individual or couple and in exercising their right to the maximum information about the disease and available opportunities. The effectiveness of thalassemia control services depends on their employees taking cultural practices into account and taking action appropriate to the social context. Counseling also needs to take into account the cultural, religious and ethical views of the individual or couple. The success of genetic counseling is largely determined by its educational, voluntary and non-prescriptive nature.