Symptoms of aplastic anemia

Retrospective studies have established that the average interval from exposure to the etiologic agent to the onset of pancytopenia is 6-8 weeks.

Symptoms of aplastic anemia are directly related to the degree of reduction of 3 most important indices of peripheral blood - hemoglobin, platelets and neutrophils. The vast majority of patients with aplastic anemia seek medical attention due to bleeding, and life-threatening bleeding as the first clinical manifestation of the disease is very rare. In typical cases, we are talking about petechial rash, bleeding gums and easily occurring ecchymoses. Serious visceral bleeding - gastrointestinal, renal and intracranial - occurs later. Anemic syndrome is manifested by mild fatigue, tinnitus, a feeling of pulsation in the head, fatigue and other classic symptoms of anemia. As a rule, children tolerate even very severe anemia well. According to the literature, severe infections rarely act as the first symptoms of the disease, however, according to our data, this is not entirely true. Weight loss, splenomegaly, lymphadenopathy, and pain are not typical of aplastic anemia. The appearance of these symptoms forces one to look for another cause of pancytopenia.

In addition to a careful clinical examination, the minimum range of necessary diagnostic tests for suspected aplastic anemia includes:

• hemogram with determination of reticulocytes and manual calculation of the leukocyte formula;
• myelogram from 2-3 anatomically different points;
• bone marrow trephine biopsy;
• chromosome fragility test with diepoxybutane or mitomycin (mitomycin C);
• biochemical blood test.

A concordant decrease in the indices of derivatives of all three main bone marrow hematopoiesis lines (erythrocytes, granulocytes and thrombocytes) is typical for aplastic anemias, despite the different kinetics of mature blood elements. In most patients, the number of lymphocytes and monocytes is also decreased. The absolute number of reticulocytes is inadequate to the severity of anemia. An increase in fetal hemoglobin along with macrocytosis is typical for aplastic anemias. An increase in the activity of serum transaminases, with the exception of cases of hepatitis-associated aplastic anemias, is not typical. Relatively high reticulocytosis, an increase in bilirubin and lactate dehydrogenase indicate a concomitant syndrome - paroxysmal nocturnal hemoglobinuria.

The condition of the bone marrow in aplastic anemias should be assessed both by aspirate data from several points and by trephine biopsy data. The morphology of resident elements of erythro-, granulo- and megakaryocytopoiesis is assessed by the data of the puncture study. Dyserythropoiesis is a very common characteristic of aplastic anemias, and the detection of "megaloblastoid" erythroid elements, asynchrony of the maturation of the nucleus and cytoplasm of erythroblasts are also typical - these signs are very difficult to differentiate from erythroid dysplasia detected in myelodysplastic syndromes. Often, the puncture reveals an increase in the number of plasma cells and macrophages with signs of erythrocyte phagocytosis. The detection of leukemic blasts in the aspirate forces us to reconsider the diagnosis.

In 1976 and 1979, Bruce Camitta et al. identified a group of simple indicators of peripheral blood and bone marrow that determine the severity of the disease and the prognosis of patients with aplastic anemia.

Criteria for severe aplastic anemia

Bone marrow cellularity, as determined by trephine biopsy, is less than 25% (or <50% if non-lymphoid bone marrow cellularity is <30%) and 2 or more of the following:

• neutrophils less than 500/µl;
• platelets less than 20,000/µl;
• corrected reticulocytosis less than 40,000/μl (<1%).

Later, a super-severe form of aplastic anemia was identified, which is characterized by the same indicators as for severe, but with a neutrophil count of less than 200/μl. The remaining cases are classified as a non-severe form of aplastic anemia (moderate, moderate).

Congenital aplastic anemia

Constitutional aplastic anemia (Fanconi anemia)

It occurs with suppression of all hematopoiesis germs and congenital developmental anomalies. At least 900 cases of Fanconi anemia have been described. It is inherited in an autosomal recessive manner, and familial forms of the disease occur in brothers and sisters. It has been established that the group of patients with Fanconi anemia is heterogeneous in genetic terms - at least 5 different groups (the so-called complementation groups) are distinguished - A, B, C, D, E, for 3 of which the localization of the gene defect has been determined and for 2 a specific protein has been identified.

The disease is most often diagnosed at the age of 4-12 years, when hematological symptoms appear, but in some patients it may be observed already at birth.

Clinically characteristic are intrauterine growth retardation, decreased body weight (< 2500 g) and height of 45-48 cm at birth, with subsequent delay in physical development. Bone age is 2-5 years behind the passport age. The most typical congenital developmental anomalies for patients are: microcephaly, microphthalmia, strabismus, epicanthus, hypertelorism, aplasia or hypoplasia of the thumb and first metacarpal bone, absence of the radius, radioulnar synostosis, clubhand, syndactyly, hypoplasia of the hip joints, rib developmental anomalies, congenital heart defects, congenital anomalies of the urinary tract and kidneys, hearing loss. About 10-33% of patients do not have congenital developmental anomalies. Bronze-brown pigmentation of the skin is noted (due to melanin deposition in the cells of the basal layer of the epidermis), diffuse, increasing in places of natural folds, and "coffee with milk" spots. Trophic disorders of the skin, nails, and teeth are often observed. "Cold" diseases are frequent. Some patients have changes in the central nervous system in the form of isolation, "mental infantilism", and less often, debility. Parents complain of the child's pallor from birth, constantly decreased appetite, later children note headaches, weakness, decreased tolerance to physical activity. The liver and spleen are not enlarged.

The appearance of hematological changes is most often recorded at the age of 4-12 years; in boys, the appearance of hematological changes is usually recorded earlier than in girls. The average age of pancytopenia onset in boys is 7.9 years (from 0 to 32 years), in girls - 9 years (0-48 years). Often, hemorrhagic syndrome caused by thrombocytopenia appears first, in the form of spontaneous ecchymosis and petechial rash, periodic nosebleeds, then progressive anemia and leukopenia join. The disease can begin with isolated leukopenia or anemia, or a simultaneous onset with anemia and thrombocytopenia.

Pancytopenia is observed in the peripheral blood. Anemia is normochromic, characterized by anisocytosis with a tendency to macrocytosis, moderate poikilocytosis. Reticulocytes initially reach 2-2.5%, with the disease progressing, reticulocytosis decreases. Leukopenia is persistent and reaches its greatest severity in the terminal period (granulocytes make up to 0.1 x 10 ⁹ /l). Thrombocytopenia reaches a significant degree as the disease progresses (up to single platelets in a smear). ESR is usually increased.

In Fanconi anemia there is stress erythropoiesis, which is characterized by macrocytosis, high Hb F levels, high serum erythropoietin levels, and the presence of i-antigen.

Sternal punctate in the early stages of the disease is normo- or hypocellular. The number of blasts is within normal limits. The content of erythroid lineage cells is increased with a delay in their maturation and morphological abnormalities in the form of anisocytosis, basophilic puncturation in normoblasts, and sometimes the appearance of megaloblasts is noted. The granulocytic lineage is "narrowed", a delay in maturation at the stage of neutrophilic myelocytes and metamyelocytes is possible. The megakaryocytic lineage is significantly "narrowed" already in the early stages of the disease. As the disease progresses, pronounced hypocellularity of the bone marrow is noted with suppression of all lines and proliferation of adipose tissue. The number of reticular, plasma and mast cells in the bone marrow is increased. Bone marrow hypoplasia is confirmed by the results of trephine biopsy.

Among the biochemical indicators for aplastic anemia, an increase in the level of fetal hemoglobin to 15% (with a norm of 2%) is characteristic even before the development of cytopenia; as aplasia progresses, fetal hemoglobin reaches 45%.

It has been established that the cells of patients with Fanconi anemia are not capable of repairing DNA cross-links caused by so-called clastogens - diepoxybutane, mitomycin C, etc. This phenomenon is the basis of modern diagnostics of Fanconi anemia, and all patients with suspected Fanconi anemia should undergo a test with diepoxybutane.

The course of Fanconi anemia is characterized by periods of exacerbation and remission. Without treatment, 80% of patients die within 2 years of diagnosis of pancytopenia, and about 100% within 4 years. The cause of death, along with severe anemia, are the most serious manifestations of hemorrhagic syndrome - gastrointestinal bleeding, intracranial hemorrhage and the addition of various infections.

Patients with Fanconi anemia have a high risk of transformation into myelodysplastic syndrome, acute leukemia (especially myeloblastic or monoblastic), and malignant tumors of the gastrointestinal tract.

Hereditary aplastic anemia with general hematopoiesis disorder without congenital developmental anomalies (Estren-Dameshek anemia)

It is a total form of hereditary aplastic anemia, inherited autosomal recessively, occurs with pancytopenia, and is not accompanied by congenital malformations. The disease is extremely rare, hematological disorders are noted in early childhood. The prognosis is unfavorable.

Dyskeratosis congenita (Zinsser-Cole-Engmann syndrome)

The syndrome is characterized by signs of ectodermal dysplasia (pathological keratinization of individual cells of the spinous layer of the epidermis of the skin and mucous membranes) in combination with hematological changes (aplastic anemia develops in about 50% of patients). In 75% of cases, the syndrome is inherited recessively linked to the X chromosome and, accordingly, occurs in boys; in 25% of children with diseases it is inherited in an autosomal dominant manner (approximately the same number of patients have been described). The skin and its derivatives, mucous membranes are affected. There is multiple scattered hyperkeratosis with predominant localization on the face, neck, back, chest; atrophy of the skin of the palms and feet, palmar-plantar hyperhidrosis; impaired growth and dystrophy of the nails; hypotrichosis of the eyelashes; blockage of the lacrimal canals and lacrimation; leukoplakia of the mucous membranes of the oral cavity, mainly the tongue and gums; damage to the endocrine glands (nanism, underdevelopment of secondary sexual characteristics). Hematological changes are varied: pancytopenia, isolated anemia, thrombocytopenia, neutropenia. The age of onset of aplastic anemia in this syndrome can be quite variable, the average age of onset of AA is 15 years.

Unlike patients with Fanconi anemia, cells from patients with dyskeratosis congenita do not have increased sensitivity to cross-linking antigens, so these sometimes phenotypically similar syndromes can be differentiated based on the diepoxybutane test.

Shwachman-Diamond syndrome

Characterized by exocrine pancreatic insufficiency, dwarfism, metaphyseal chondrodysplasia, neutropenia, sometimes anemia, thrombocytopenia. Inherited in an autosomal dominant manner.

The disease manifests itself clinically at an early age and is characterized by signs of gastrointestinal tract damage and hematological changes. Diarrhea, steatorrhea, slow weight gain, and hypotrophy are noted. Changes in the skeletal system in the form of chondrodnasplasia of the metaphysis and the formation of orthopedic pathology, growth retardation are characteristic. Some patients may have galactosemia, which leads to hepatosplenomegaly, delayed psychomotor development. Recurrent respiratory diseases, otitis, abscesses, and osteomyelitis are characteristic. Some children experience a delay in the onset of puberty.

Blood tests from an early age show absolute neutropenia, the neutrophil count is less than 1 x 10 ⁹ /l. Mature neutrophils are characterized by hyposegmentation of nuclei, and a decrease in neutrophil chemotaxis is noted. Along with neutropenia, approximately 50% of patients have anemia with reticulocytopenia, 60-70% of children have thrombocytopenia, and approximately 25% of patients develop aplastic anemia. In the sternal puncture, the number of myelokaryocytes may be normal, decreased, or increased; a delay in neutrophil maturation at the metamyelocyte stage is noted. The prognosis is most unfavorable in early childhood, when about 25% of children die from infectious complications; a fatal outcome is also possible from hemorrhages in vital organs.

Hereditary aplastic anemia with selective erythropoiesis deficiency (Blackfan-Diamond anemia)

The incidence of the disease is 1:1,000,000 live births; 5-7:1,000,000 in France, 10:1,000,000 in Scandinavia, occurs in all ethnic groups, boys and girls are affected equally. The vast majority (75%) are sporadic cases; in some cases, autosomal dominant, autosomal recessive or X-linked inheritance is possible.

The first signs of the disease are detected in the first months or during the first year of life - 35% of patients with anemia at birth, 65% in the first 6 months of life and in 90% of cases the disease is diagnosed before the age of one year. The diagnosis of Blackfan-Diamond anemia in children over 2 years is unlikely. Children are usually born full-term with normal body weight and height, psychomotor development is normal. Paleness of the skin and mucous membranes is noted from the first days of life, but obvious clinical signs of hypoxia: lethargy or agitation, anxiety, drowsiness, refusal to eat, dyspeptic phenomena - appear when hemoglobin decreases to 60-30 g / l. Congenital malformations are less common (in 25% of cases) than in Fanconi anemia. Some patients have characteristic phenotypic features: tow-colored hair, snub nose, large upper lip, hypertelorism. As the disease progresses, the skin becomes waxy, and by the age of 5-6, due to the development of hemosiderosis, it becomes grayish, especially in the area of the neck, armpits, inguinal folds, and genitals. Hemorrhagic syndrome is absent. Hepatomegaly and splenomegaly are observed; in the course of the disease, the spleen contracts and the liver progressively enlarges. Bone age lags behind the passport age by 4-5 years, the rate of ossification is changed. The change of baby teeth is delayed, caries is often detected.

In the peripheral blood, normochromic macrocytic hypo- or aregenerative anemia (reticulocytes 0-0.1%) is usually severe. The number of leukocytes and platelets remains at a normal level during the first years of life; sometimes a tendency to thrombocytosis is noted. With a long course of the disease, moderate thrombocytopenia may develop. After the first decade of life, moderate neutropenia may also appear, probably due to a decrease in the clonal effectiveness of granulocyte precursors.

Biochemically, a high level of erythrocyte adenosine deaminase activity is noted; the level of fetal hemoglobin is normal or moderately elevated; the content of i-antigen in erythrocytes is increased; the content of erythropoietin in the serum is increased.

In the sternal puncture, the bone marrow is normocellular, with hypocellularity noted as the disease progresses. The erythroid lineage is sharply narrowed; the diagnostic criterion is the absence or small number of erythroblasts (less than 5% of nucleated cells) in the bone marrow. The myeloid and megakaryocytic lineages are unchanged. The number of reticular cells and lymphocytes is increased, while that of plasma cells is unchanged.

Blackfan-Diamond anemia is chronic, 80% of patients achieve remission with the use of corticosteroids; spontaneous remission has been described in 20% of patients. "Permanent hypoxia, impaired iron utilization, the need for vital transfusions of red blood cells steadily lead to hemosiderosis, which subsequently becomes the "killer" of the sick child." Transformation into myelodysplastic syndrome, acute leukemia (lymphoblastic, myeloblastic, promyelocytic, megakaryocytic), solid tumors (hepatoblastoma, rsteosarcoma, malignant fibrous histiocytoma), lymphogranulomatosis is possible.

Differential diagnosis

Differential diagnosis of Blackfan-Diamond anemia is carried out with other types of anemia, in which the number of reticulocytes in the peripheral blood decreases.

Anemia during the recovery period after hemolytic disease of the newborn.

Sometimes it can be combined with a decrease in the intensity of erythropoiesis. Aplastic crises, characterized by reticulocytopenia and a decrease in the number of erythrocyte precursors, can complicate different types of hemolytic disease. Such episodes are transient, in addition, signs of previous hemolytic disease are usually detected. The development of aplastic crises is associated with B19-parvovirus infection. The tactics of patient management are usually expectant: with a significant decrease in the hemoglobin level, blood transfusions are performed.

Transient erythroblastopenia of childhood

One of the most common forms of erythroid aplasia. The etiology of the disease is unknown. In previously healthy children aged 5 months to 6 years, most often at the age of 2 years, severe aregenerative anemia slowly develops, caused by a sharp decrease in red blood cells in the bone marrow.

The development of anemia may be preceded by a viral infection 1 to 2 months before, although the association of the disease with a specific pathogen has not been proven; parvovirus B19 is often used. The anamnesis and physical examination are uninformative; only pronounced pallor of the skin and mucous membranes is noticeable. In the peripheral blood, the Hb level is reduced to 30-80 g/l, reticulocytes are absent, the number of leukocytes and platelets is usually normal, but 10% of patients have neutropenia (<1.0 x 10 ⁹ /l) and 5% have thrombocytopenia (< 100 x 10 ⁹ /l). Laboratory tests reveal normal levels of erythrocyte adenosine deaminase and fetal hemoglobin activity; according to enzymatic characteristics, erythrocytes are classified as an aging population. The serum iron level is elevated. Transient erythroblastopenia is also supported by normal clinical blood test results before the disease. Sternal punctate shows a sharp narrowing of the erythroid lineage, no precursors, except for normocytes and erythrocytes. Bone marrow culture studies have revealed several pathogenetic mechanisms: the presence of stem cell inhibitors in the serum or abnormalities of the latter, expressed either in their number or in the ability to respond to erythropoietin. Autoimmune genesis of the disease is possible with damage to primary erythroid precursors, not mature erythrocytes. Spontaneous remission occurs several months after the onset of the disease. Blood transfusions may be required until recovery, corticosteroids are not used.

Secondary (acquired) aplasia of the erythroid lineage

They also manifest as anemia, accompanied by reticulocytopenia and a decrease in the number of erythrocyte precursors in the bone marrow. Secondary aplasia of the erythroid germ can be caused by viral infections (mumps, Epstein-Barr virus, parvovirus B19), and typ - ical pneumonia and bacterial sepsis; drugs (chloramphenicol, penicillin, phenobarbital, diphenylhydantoin); anti-erythrocyte antibodies; immunodeficiency; thymoma; malignant tumors.

Episodes of acute erythropoiesis failure may accompany a number of viral infections. In this case, the number of circulating reticulocytes is significantly reduced (less than 0.1%) and the level of iron in the serum increases. The number of erythrocyte precursors in the bone marrow is reduced. These episodes are usually stopped and do not leave any consequences. Most often, secondary erythroid aplasia is caused by parvovirus B19.

In all infants, the following studies are necessary for the diagnosis of erythroblastopenia:

1. Serum antibody content IgM and IgG (mother and child).
2. Viral DNA in blood serum.
3. Viral DNA in bone marrow.

These studies may help in differentiating erythroblastopenia due to parvovirus B19 infection and erythroblastopenia of other origins.

In the treatment of secondary erythroblastopenia, it is important to eliminate the cause of the disease - discontinuation of the drug, treatment of the underlying disease or thymectomy. If antierythroid antibodies are detected, corticosteroids are indicated, if they are ineffective - immunosuppressants (cyclophosphamide or azathioprine). In case of immunodeficiency, parvovirus infection can be chronic, then immunoglobulin is used intravenously.

Acquired aplastic anemia

The clinical picture of acquired aplastic anemias differs depending on the total or selective damage to hematopoiesis. In patients with acquired aplastic anemia, unlike hereditary forms, there are no congenital developmental anomalies, the physical and mental development of children is not changed, the bone age corresponds to the passport age.

Total forms of aplastic anemia are characterized by a combination of hemorrhagic, anemic and infectious-septic syndromes. Hemorrhagic syndrome caused by thrombocytopenia is expressed sharply: multiple ecchymoses and petechiae on the skin and mucous membranes, conjunctiva, recurrent nasal, gingival, uterine, gastrointestinal and renal bleeding, hemorrhages at injection sites. The immediate cause of death in such patients is most often hemorrhages in vital organs. Damage to the erythroid germ leads to the development of anemic syndrome, in which the patient experiences general weakness, decreased appetite, dizziness, increased fatigue, pale skin and mucous membranes, nail phalanges, changes in the cardiovascular system: enlargement of the heart borders, muffled tones, tachycardia, systolic murmur of varying intensity, extrasystole is possible, dyspnea. The presence of leukogranulocytopenia causes the development of infectious-septic syndrome: easy addition of infections of any localization, ulcerative-necrotic lesions of the skin, mucous membranes. Severe course of infections caused not only by pathogenic flora, but also by opportunistic and fungal pathogens is characteristic. Lymph nodes, liver, spleen are not enlarged. With selective damage to the erythroid germ, there are manifestations of only anemic syndrome.

All symptoms of the disease can manifest and increase more or less acutely.

Hematological changes in aplastic anemia consist of neutropenia (absolute neutrophil count less than 1.5 x 10 ⁹ /l), anemia (Hb < 110 g/l), thrombocytopenia (platelet count < 100 x 10 ⁹ /l) and reticulocytopenia that does not correspond to the severity of anemia. The myelogram shows a sharp decrease in cellularity, reduction of myeloid and erythroid lineages, variable lymphocytosis and absence of megakaryocytes. In patients with slow development of aplasia, areas of active hematopoiesis - "hot pockets" - may persist for a long time. A trephine biopsy reveals a sharp decrease in the hematopoiesis platform - fatty bone marrow dominates, hematopoietic elements are represented by residual foci of erythro- and myelopoiesis, megakaryocytes are practically not detected.

According to severity, acquired aplastic anemias are classified depending on the depth of cytopenia, reticulocytosis and residual cellularity of the bone marrow according to trephine biopsy data. The criteria for the severity of aplastic anemia developed by the International Group for the Study of Aplastic Anemia - the "Kamitta criteria" - are used:

1. granulocyte count less than 500 in 1 µl;
2. platelet count less than 20,000 in 1 µl;
3. reticulocyte count less than 40,000/µl (or less than 1% after correction for normal hematocrit).

Aplastic anemia is considered severe if any two of the above blood parameters are present in combination with decreased cellularity. If the hematological syndrome meets the criteria for severe aplastic anemia, but the granulocyte count is less than 200 in 1 μl - super-severe aplastic anemia. All other cases are characterized as non-severe aplastic anemia.

Differential diagnosis of acquired aplastic anemia is carried out mainly with acute leukemia, megaloblastic anemia, hypersplenism syndrome, and tumor metastases to the bone marrow.

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