There are congenital (constitutional) and acquired forms of hypoplastic anemia. Congenital hypoplastic anemias are relatively rare. Depending on the nature of the oppression of hematopoiesis, forms are distinguished with the defeat of all three germs (true hypoplastic anemia) or only erythropoiesis (partial hypoplastic anemia). Hypoplastic anemia with a hemolytic component is sometimes isolated, but some authors believe that it represents the hypoplastic stage of paroxysmal nocturnal hemoglobinuria.
In 1888, P. Ehrlich described a disease in a young woman, in which hemorrhage, fever, severe anemia and leukopenia developed acutely (platelets were not counted at that time); the autopsy showed no signs of hematopoiesis in the bone marrow, which P. Ehrlich explained by the primary inhibition of its function. The term “aplastic anemia” was first proposed by Chauffard (AM Chauffard, 1904). Later, aplastic anemia of the Ehrlich type was isolated, in which, along with steadily progressing pancytopenia, often complicated by sepsis, pronounced hemorrhages and necrotic phenomena, histological signs of hematopoiesis were not detected in the bone marrow; the disease was observed in persons aged 18 to 20 years. A similar disease called “hemorrhagic aleukia” was described by Frank (E. Frank, 1915). With the introduction of puncture examination of the bone marrow by MI Arinkin in 1927, it became possible to distinguish true hypoplastic anemia from pancytopenia due to leukemic or metastatic lesions of the bone marrow. In the domestic literature, the first descriptions of hypoplastic anemia under the name “clinical-hematological syndrome” belong to G. P. Khosroev (1913). Hypoplastic anemia as a separate nosological form is devoted to the works of XX Vlados (1937), E. A. Kost (1952), I. A. Kassirsky and G. A. Alekseev (1962), F. E. Fainstein (1965), G. S. Mukhamedzyanova (1970) and others.
Hypoplasia of hematopoiesis can be caused by the influence of various external factors, which are usually divided into two groups: 1) factors with an obligate myelotoxic effect proportional to the dose – ionizing radiation, benzene and its derivatives (benzene anemia develops), anticancer drugs (chlorethylamines; phosphoramides; antimetabolites – folic acid antagonists, analogues of purines, pyrimidines and others; antimitotic agents – colchicine, vinca alkaloids; antibiotics – bruneomycin, rubomycin, adriamycin, carminomycin), inorganic arsenic compounds, estrogens and others; 2) factors with an optional myelotoxic effect, found only in isolated cases – antibacterial, anticonvulsant, antithyroid, antihistamines, tranquilizers (aplastic post-drug anemia develops), insecticides and others; There is no direct relationship between the development of hypoplastic anemia and the dose and duration of the drug in these cases.
The second group should include relatively rare cases of the development of hypoplastic anemia in tuberculosis, pregnancy.
Of the factors with an optional myelotoxic effect, the most dangerous antibiotic is levomycetin (chloramphenicol). According to Wallerstein et al. (R. O. Wallerstein, 1969), people taking chloramphenicol have a 13 times higher chance of developing hypoplastic anemia than the general population. Less commonly, hypoplastic anemia is described in connection with the intake of organic arsenic compounds (mafarsen and others), antimalarial drugs, hydantoin derivatives, phenylbutazone, and gold salts.
Hypoplastic anemia caused by exposure to various external factors is called myelotoxic anemia. In about 50% of cases of hypoplastic anemia, it is not possible to identify the cause of the disease – the so-called idiopathic form.
The etiology of constitutional hypoplastic anemia (Fanconi syndrome, or anemia, partial hypoplastic anemia of Josephs – Diamond – Blackfan and familial hypoplastic anemia of Estren – Dameshek) is most likely associated with the inheritance of the gene from one of the parents in a recessive manner. In a cytogenetic study, Bloom (GE Bloom) with employees (1966) found in patients a variety of chromosomal aberrations in hematopoietic cells. Cases of illness in children born from intermarriages are described. Some authors note the similarity of Fanconi syndrome with embryopathy) caused by thalidomide.
The development of hypoplastic anemia can be associated either with damage to the stem cell, the parent for granulo-, erythro- and thrombopoiesis, or with a defect in its microenvironment that prevents the normal functioning of this cell. The detection of chromosomal aberrations in congenital hypoplastic anemia, the therapeutic efficacy of bone marrow transplantation from identical twins, as well as a small number of stem cells detected during bone marrow cultivation of patients confirm the first assumption. The rarity of hypoplastic anemia under the influence of these optional factors indicates the role of an individual, possibly hereditary, predisposition. The participation of autoimmune mechanisms is assumed only in partial hypoplastic anemia, in which Krantz (S. V. Krantz, 1973) and L. I. Idelson et al. (1976) found antibodies to the nuclei of erythrocytes. About 50% of cases of partial hypoplastic anemia develop in patients suffering from benign thymoma; the reasons for this are not yet clear. With hypoplastic anemia, there is no deficiency of hematopoietic factors. On the contrary, their content in the blood is even increased due to incomplete use of the erythropoietic tissue reduced in volume.
Hemorrhagic manifestations in hypoplastic anemia are caused by impaired hemostasis as a result of deep thrombocytopenia and damage to the vascular wall. The increased permeability of the vascular wall is secondary and is associated with hypoxia, a lack of serotonin. Histochemical and immunomorphological studies reveal deep structural disorders in the vascular wall.
An autopsy reveals signs of anemia and dystrophy of internal organs, abundant fat deposition in the subcutaneous tissue, epicardium, omentum, multiple hemorrhages in the skin, mucous membranes, serous integuments, and internal organs. Sometimes massive hemorrhages in the brain or heart muscle are noted, which are the direct cause of death. Bone marrow of flat bones is pale pink or yellowish in color, sometimes with dark red areas of hemorrhages. When the bone is compressed, a bloody fluid rich in fat flows from the cut surface. Among the fatty bone marrow, areas of preserved hematopoietic tissue may be observed. The sizes of a spleen and limf, nodes are often reduced.
|Micropreparation of the liver (hypoplastic anemia): the arrow indicates the deposition of hemosiderin.|
|. Micropreparation of the kidney (hypoplastic anemia): arrows indicate the deposition of hemosiderin in the epithelium of the tubules.|
Microscopic examination of the bone marrow reveals varying degrees of its devastation. In the case of aplasia, only small accumulations of lymphocytes, plasma cells and undifferentiated elements, single granulocytes and normoblasts are found in the fatty bone marrow. With hypoplasia, areas of hematopoietic tissue are somewhat more often found. The uneven distribution of hematopoietic foci is characteristic not only in different parts of the skeleton, but also within the same bone. The structure of the bone tissue is often preserved. Both early and late phases of the disease are characterized by the deposition of hemosiderin in the spleen, liver (Figure 1) and bone marrow, less often in the kidneys (Figure 2), lymph nodes.
Frequent complications of hypoplastic anemia include fibrinous-hemorrhagic pneumonia and necrotic changes in the mucous membranes and serous integuments, skin, and internal organs.
Course and symptoms.
The disease can be acute, subacute or chronic. In acute cases, the process begins with rapid hemorrhagic diathesis, severe general intoxication, and infectious complications. More often there is a gradual increase in symptoms. There are adynamia, weakness, dizziness, fatigue, shortness of breath during physical exertion, sometimes pain in the bones and heart area. There is a waxy pallor of the skin without jaundice, anemia of visible mucous membranes. Subcutaneous adipose tissue is preserved. With the development of deep thrombocytopenia, hemorrhages occur on the skin, mucous membranes and fundus, nasal, gingival, uterine, intestinal, renal and other bleeding. With the progression of the process, neurological symptoms may occur due to hemorrhages in the brain. With partial hypoplastic anemia, bleeding is absent. The size of the lymph nodes, spleen and liver do not change.
Blood picture . Anemia is normochromic, normocytic, less often macrocytic. Polychromatophilia is absent, the number of reticulocytes is normal or reduced. Leukopenia can reach 1000 cells in 1 microliter. and less; it is due mainly to granulocytopenia and is accompanied by relative lymphocytosis. The absolute number of lymphocytes with severe leukopenia is also reduced. Thrombocytopenia is noted with prolonged bleeding time and decreased retraction of the blood clot. Plasma coagulation factors do not change. The content of serum iron is increased, the total iron-binding capacity of serum is often increased.
Partial hypoplastic anemia is characterized by chronic normocytic anemia, often without leukocytopenia and thrombocytopenia, with deep reticulocytopenia.
The bone marrow punctate is usually poor, nuclear elements are represented mainly by lymphocytes, a few granulocytes and normoblasts. Megakaryocytes are often absent. Sometimes, despite obvious pancytopenia, the punctate is quite rich; this is due to the needle entering the focus of the preserved hematopoiesis. In addition to a purely quantitative deficiency of erythroblastic elements, with hypoplastic anemia, signs of their qualitative pathology (dyserythropoiesis), megaloblastoidness, atypical mitoses, and multinucleation are noted. With partial hypoplastic anemia, bone marrow punctate is rich in nuclear elements, leukothrombocytopoiesis is not disturbed, but the number of red cells is often sharply reduced or they are completely absent.
|. Micropreparation of the bone marrow of the ilium (hypoplastic anemia): a sharp predominance of fatty bone marrow over hematopoietic. The bone marrow cavities are filled mainly with adipose tissue, myeloid tissue is represented by small black islands; × 280.|
Trepanobiopsy of the ilium reveals a sharp predominance of fatty bone marrow over hematopoietic (Figure 3), sometimes the latter is absent.
A study with radioactive iron 59 Fe gives the most accurate overall assessment of erythropoiesis: the clearance of the isotope from plasma is slow, it accumulates mainly in the liver, and the incorporation of the label into erythrocytes is sharply slowed down.
Complications. The main complications and the direct cause of death of patients are bleeding and infectious and inflammatory processes. Hemorrhages are detected when the platelet count drops below a critical level.
(20,000-30,000 in 1 microliter.), can be provoked even by minor injuries (subcutaneous injections, and so on). Infections (pneumonia and others) develop with a sufficiently long and pronounced (less than 500 in 1 microliter.) decrease in the number of neutrophils.
Any fever in patients with hypoplastic anemia, as a rule, is associated with the presence of an infectious focus; many cases of acute leukemia have been described. Leukemias against the background of hypoplasia of radiation or benzene origin belong to the group of myeloblastic or myelomonoblastic and are apparently a late result of the leukemogenic action of the factor that caused anemia. Significantly less often, there is an attachment to hypoplastic anemia of paroxysmal nocturnal hemoglobinuria, although some authors interpret hypoplastic anemia in these cases as a hypoplastic stage of this form of hemolytic anemia.
The diagnosis is based on the presence of pancytopenia and punctate or trepanate of the bone marrow poor in nuclear cells in the absence of enlargement of the lymph nodes, spleen and liver. Hypoplastic anemia should be differentiated mainly from pancytopenia of other origin. The detection of young white or red cells in the blood, even a slight enlargement of the spleen, should always cast doubt on the diagnosis of hypoplastic anemia. In these cases, we can assume the presence of aleukemic forms of leukemia, cancerous metastases in the bone marrow, multiple myeloma. The diagnosis is usually made on the basis of a study of bone marrow punctate; multiple myeloma, in addition, characteristic changes in serum and (or) urine proteins are inherent. Pancytopenia in myelofibrosis is accompanied, in contrast to hypoplastic anemia, by enlargement and myeloid metaplasia of the spleen. Addison-Birmer anemia is distinguished from hypoplastic anemia by the presence of glossitis, neurological disorders, achlorhydria, severe bone marrow megaloblastosis, and a good therapeutic effect from vitamin B12 . The diagnosis of paroxysmal nocturnal hemoglobinuria, even in its early, hypoplastic stage, is confirmed by positive results of sucrose and acid tests. In the subacute variant of lymphogranulomatosis, pancytopenia is accompanied by fever, there is no sharp lymphocytosis, sometimes it is possible to detect Berezovsky-Sternberg cells in the bone marrow trepanate. Pancytopenia due to hypersplenism is usually accompanied by an enlarged spleen.
Methods of radical cure of hypoplastic anemia do not exist, however, therapeutic measures help to lengthen the life expectancy of patients. If an etiological factor is identified, it is necessary to stop its further exposure. To combat anemia, transfusions of blood or red blood cells are indicated; this measure should not pursue the goal of complete normalization of red blood parameters – it is enough to maintain them at a level compatible with cardiovascular compensation. The number of transfusions should be minimal to reduce the risk of transfusion siderosis (when transfusing 450 milliliters of blood, 200-250 milligrams of iron is introduced into the body), hepatitis and other complications. In order to avoid isosensitization by antigens of leukocytes and platelets, it is advisable to transfuse washed erythrocytes. With multiple blood transfusions, the development of isosensitization by erythrocyte antigens is often; in these cases, blood for transfusion is selected using an indirect Coombs test.
In the case of a combination of anemia with hemorrhagic diathesis, platelet concentrates obtained using a blood cell separator from one donor or by centrifuging a large number of blood doses taken from different donors have a more pronounced hemostatic effect. The hemostatic effect of thromboconcentrates is manifested if the number of platelets in a patient can be increased to at least 15,000-20,000 in 1 microliter. blood. With repeated transfusions of platelet concentrates, especially those obtained from the blood of different donors, isosensitization to platelet antigens inevitably develops and a decrease in the therapeutic efficacy of transfusions is noted. Therefore, it is desirable to use a limited number of individuals as donors, better than relatives who are as compatible as possible in terms of antigens of the HL-A system.
Among drugs, only anabolic steroids have the ability to stimulate erythropoiesis. A necessary condition for achieving a therapeutic effect is the duration of the use of hormones in a sufficiently high dose. The first manifestation of the therapeutic efficacy of drugs may be an improvement in peripheral blood parameters. If signs of side effects appear (fluid retention, liver damage), hormones are canceled. For the treatment of hypoplastic anemia, corticosteroids are also used (prednisolone 0.5-1.0 mg per 1 kilogram of body weight or equivalent doses of other steroids), mainly for the purpose of hemostatic action (decrease in vascular permeability); for this, other so-called vasoconstrictive agents are used – ascorbic acid, rutin, calcium preparations. In order to reduce hemosiderosis of organs and tissues, drugs such as desferal can be prescribed.
There are also two theoretical possibilities for correcting anemia – replacing the missing amount of stem cells with donor ones and removing the inhibition of proliferation of residual stem cells. In the first case, allogeneic bone marrow transplantation is performed, in the second, immunosuppressive therapy.
Numerous attempts to transplant donor bone marrow to patients, undertaken without proper immunological selection (only for the main erythrocyte antigens), were unsuccessful, that is, they ended in graft rejection due to biological incompatibility. Cases of genuine transplantation are few. Thomas (E. D. Thomas) with employees (1974) performed a successful transplantation of syngeneic bone marrow obtained from identical twins of patients in four patients with hypoplastic anemia, which led to complete recovery; the operation was performed without special preparation due to the antigenic identity of recipients and donors. However, this possibility is casuistic. Allogeneic transplants (from H1-A matched donors) require complex preparation of recipients to prevent graft rejection (general irradiation or administration of cyclophosphamide for immunosuppression), as well as postoperative use of cytostatics to suppress graft-versus-host disease (see Full Body of Knowledge Immunological incompatibility). Of the 24 hypoplastic anemia patients described by Thomas et al., 12 survived more than 3 months; engraftment in them was proved by analysis of the sex chromatin. In patients who have previously received numerous blood transfusions, the chances of graft engraftment due to the formation of isoantibodies are reduced. The complexity of the bone marrow transplant technique makes it accessible only to individual specialized institutions. BMT should be performed as early as possible in all children and young patients who have a genoidentically identical donor.
Antithymocyte globulin therapy as a first-line treatment has become the “gold standard” for the treatment of anemia in young patients not eligible for bone marrow transplantation, as well as in all patients over the age of 40 years. The effectiveness of therapy ranges from 30-70%. The effectiveness of therapy ranges from 30-70%. The onset of a hematological response after antithymocyte globuling therapy is recorded on average at 8-12 weeks of therapy. The second drug effective in the treatment of anemia is cyclosporine A. It causes selective suppression of cell-mediated immune responses. Combined immunosuppressive therapy is considered the therapy of choice for children with severe and super-severe forms of aplastic anemia who do not have an HLA-compatible related donor.
The question of the effectiveness of splenectomy has not been finally resolved. With severe hemorrhages, surgery is contraindicated due to high mortality. Probably, splenectomy is more appropriate in patients with increased sequestration of platelets and erythrocytes in the spleen, proven by the radioisotope method, and with the preservation of foci of normal hematopoiesis in the bone marrow.
An acute onset of the disease is considered a prognostically unfavorable sign. Forms with an acute course are usually resistant to therapy and end in death after a few weeks. More often, the course of the disease is protracted, many months and even many years. Perhaps a long-term absence of a wedge, manifestations of the disease, however, patients have signs of defective bone marrow hematopoiesis.
Persons professionally associated with exposure to myelotoxic factors (sources of ionizing radiation, benzene production) should be under constant medical supervision. Carrying out cytostatic treatment for tumors and other diseases requires regular monitoring of blood composition and timely termination if there is a threat of hematopoietic hypoplasia. The use of potentially dangerous drugs, primarily chloramphenicol, should be limited to direct indications and be under the control of blood composition. Prevention of hemorrhages with already developed hypoplastic anemia includes hormonal suppression of the menstrual cycle in women with massive menorrhagia, replacement (if possible) of injectable medications with oral ones, sparing of mucous membranes (exclusion of coarse food, replacement of hard toothbrushes with cotton swabs). To prevent infectious complications in deep granulocytopenia, suppression of intestinal autoflora with nonabsorbable antibiotics is recommended, patients should be kept in aseptic or similar conditions, and personal hygiene should be observed.
Fanconi anemia (synonyms: Fanconi syndrome, congenital pancytopenia). Described in 1927 under the name “familial childhood pernicious anemia.” Since then, about 200 observations have been published. Anemia, as a rule, comes to light in the first years of life, occasionally later. Boys get sick 2 times more often than girls. A combination of pancytopenia and bone marrow hypoplasia with other congenital defects is characteristic – brown pigmentation of the skin due to the deposition of melanin, atrophy of the kidneys and spleen, absence or underdevelopment of 1 metacarpal or radius bones, mental, physical and sexual developmental delay, microcephaly, microophthalmia. When cultivating lymphocytes and fibroblasts of the skin of patients, numerous chromosomal aberrations are revealed. Relatives of patients often have leukemia.
Treatment – systematic blood transfusions (erythrocyte mass) are prescribed. The prognosis is unfavorable.
Familial hypoplastic Estren-Dameshek anemia was first described in 1947. It is characterized by the same changes in hematopoiesis that are observed in Fanconi anemia, but there are no abnormalities in the development of the skeleton and internal organs.
Congenital partial hypoplastic anemia of Josephs — Diamond — Blackfan is described in 1936 by Josephs (W. H. Josephs) and in 1938 by Diamond and Blackfen (L. K. Diamond, K. D. Blackfan). The underlying genetic defect has not been elucidated. The development of the disease in several children born from different mothers, but from one father, indicates the dominant nature of inheritance. A detailed picture of the disease is usually detected already in the 1st year of life: anemia of varying degrees is combined with deep erythro- and normoblastopenia against the background of a decrease in the number of myelokaryocytes (at the initial stages of the development of the disease, the number of bone marrow myelokaryocytes may not be changed). In some patients, other birth defects (delayed sexual and physical development) are detected, but anomalies in the development of the kidneys do not occur. Due to repeated blood transfusions, hemosiderosis often develops with portal cirrhosis of the liver.
Treatment – systematic blood transfusions (erythrocyte mass) in combination with corticosteroid hormones and vitamin B 12 . With the help of systematic blood transfusions, it was possible to bring sick children up to 8-15 years, after which spontaneous improvement occurred.
State educational institution of higher professional education
KAZAN STATE MEDICAL UNIVERSITY
Federal Agency for Health and Social Development
DEPARTMENT OF HOSPITAL PEDIATRICS WITH COURSES OF PP AND PDO
Head Department – Doctor of Medical Sciences, Professor Bulatov Vladimir Petrovich
Performed by a student of group 2607
Checked by the teacher
Doctor of Medical Sciences, Professor Volgina S.Ya.
KAZAN – 2013