Symptoms of aplastic anemia

Retrospective studies found that the average interval from the effect of the etiological agent before the occurrence of pancytopenia is 6-8 weeks.

Symptoms of aplastic anemia are directly related to the degree of reduction of 3 important parameters of peripheral blood - hemoglobin, platelets and neutrophils. The vast majority of patients with aplastic anemias turn to the doctor for 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 arising ecchymosis. Serious visceral hemorrhages - gastrointestinal, renal and intracranial - occur later. Anemic syndrome is manifested by easy fatigue, noise in the ears, a sensation of pulsation in the head, fatigue and other classic symptoms of anemia. As a rule, children can tolerate even very severe anemia. According to the literature, heavy infections are rarely the first symptoms of the disease, however, according to our data, this is not entirely true. Uncharacteristic for aplastic anemia, weight loss, splenomegaly, lymphadenopathy and pain. The appearance of these symptoms makes one seek another cause of pancytopenia.

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

• a hemogram with the definition of reticulocytes and a manual calculation of the leukocyte formula;
• myelogram of 2-3 anatomically different points;
• trepanobiopsy of the bone marrow;
• a sample for fragility of chromosomes with diepoxybutane or mitomycin (mitomycin C);
• blood chemistry.

For aplastic anemia, a typical concordant decrease in the indices of the derivatives of all 3 main sprouts of bone marrow hematopoiesis (erythrocytes, granulocytes and platelets), despite the different kinetics of mature blood elements. In most patients, the number of lymphocytes and monocytes is also reduced. The absolute number of reticulocytes is inadequate to the severity of anemia. The increase in fetal hemoglobin along with macrocytosis is typical for aplastic anemia. Increased activity of serum transaminases, except for cases of hepatitis-associated aplastic anemia, is not characteristic. Relatively high reticulocytosis, an increase in bilirubin and lactate dehydrogenase suggests a concomitant syndrome - paroxysmal nocturnal hemoglobinuria.

The condition of the bone marrow in aplastic anemia should be assessed both from aspirate data from several points and from trepanobiopsy data. According to the punctate study, the morphology of the resident elements of erythro-, granulo- and megakaryocytopoiesis is evaluated. Dyseritropoiesis is a very common characteristic of aplastic anemia, typically also the detection of the "megaloblasticity" of erythroid elements, the asynchrony of the maturation of the nucleus and the cytoplasm of erythroblasts - these signs are very difficult to differentiate from the erythroid dysplasia revealed in myelodysplastic syndromes. Often, the punctate reveals an increase in the number of plasma cells and macrophages with the phenomena of red cell phagocytosis. The detection of leukemia blasts in aspirates causes a revision of the diagnosis.

In 1976 and 1979 Bruce Camitta et al. A group of the simplest indicators of peripheral blood and bone marrow were identified, which determine the severity of the course of the disease and the prognosis of patients with aplastic anemia.

Criteria for severe aplastic anemia

Cellular marrow cell count, according to trepanobiopsy, is less than 25% (or <50% for the cellularity of non-lymphoid bone marrow elements <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, the superheavy form of aplastic anemia was isolated, for which the same indices are characteristic as for heavy, but with the number of neutrophils less than 200 / μl. The remaining cases are qualified as a mild form of aplastic anemia (moderate, moderate).

Congenital aplastic anemia

Constitutional aplastic anemia (Fanconi anemia)

It flows with the oppression of all germs of hematopoiesis and congenital anomalies of development. At least 900 cases of Fanconi anemia have been described. It is inherited by autosomal recessive type, family forms of the disease - in the case of brothers and sisters. It was established that the group of patients with Fanconi anemia is heterogeneous in genetic relation - at least 5 different groups (so-called complementation groups) are isolated - A, B, C, D, E, for 3 of which the localization of the genetic defect was determined and for 2 specific protein .

The disease is most often diagnosed at the age of 4-12 years, when there is hematological symptomatology, however in some patients it can be noted already at birth.

Clinically characterized by intrauterine growth retardation, weight loss (<2500 g) and growth of 45-48 cm at birth, the lag in physical development continues to lag further. Bone age is 2-5 years behind the passport age. The most common congenital malformations are microcephaly, microphthalmia, strabismus, epicanth, hypertelorism, aplasia or hypoplasia of the thumb and I of the metacarpal bone, absence of the radial bone, radiolucent synostosis, hip surgery, syndactyly, hipoplasia of the hip joints, abnormal development of the ribs, congenital malformations heart, congenital anomalies of the urinary tract and kidney, hearing loss. About 10-33% of patients do not have congenital malformations. Bronze-brown pigmentation of the skin (due to the deposition of melanin in the cells of the basal layer of the epidermis) is noted, diffuse, intensifying in places of natural folds, and spots of "coffee with milk". Often observed trophic disorders of the skin, nails, teeth. "Cold" diseases are frequent. In some patients there are changes in the central nervous system in the form of closure, "mental infantility," less common debility. Parents complain about the pallor of the child from birth, constantly reduced appetite, later the children notice a headache, weakness, a decrease in tolerance to physical exertion. The liver and spleen are not enlarged.

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

Peripheral blood is marked by pancytopenia. Anemia is normochromic, anisocytosis is typical with a tendency to macrocytosis, moderate poikilocytosis. Reticulocytes initially reach 2-2,5%, as the disease progresses, reticulocytosis decreases. Leukopenia is stable and reaches its highest expression in the terminal period (granulocytes are up to 0.1 x 10 ⁹ / l). Thrombocytopenia as the disease progresses reaches a significant degree (up to single platelets in the smear). ESR, as a rule, increased.

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

Sternal punctate in the early stages of the disease, normo- or hypo-cell. The number of blasts is within the norm. The content of erythroid germ cells is increased with a delay in their maturation and morphological disorders in the form of anisocytosis, basophilic puncture in normoblasts, and sometimes the appearance of megaloblasts. The granulocyte germ is "narrowed", maturation at the stage of non-trophic myelocytes and metamyelocytes is possible. The megakaryocytic germ is significantly narrowed already in the early stages of the disease. As the disease progresses, a marked hypochondria of the bone marrow is observed with oppression of all the sprouts and growth of adipose tissue. In the bone marrow the number of reticular, plasmatic and mast cells is increased. Hypoplasia of the bone marrow is confirmed by the results of trepanobiopsy.

From biochemical indicators for aplastic anemia, an increase in the level of fetal hemoglobin up to 15% (at a rate of 2%) even before the development of cytopenia is characteristic, as fetal hemoglobin progresses to 45%.

It has been established that cells of patients with Fanconi anemia are unable to repair cross-linking of DNA caused by so-called clastogens - diepoxybutane, mitomycin C, etc. This phenomenon is based on the modern diagnosis of Fanconi anemia and in all patients with suspicion of Fanconi anemia a test with diepoxybutane should be performed.

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

In patients with Fanconi anemia there is a high risk of transformation into myelodysplastic syndrome, acute leukemia (especially myeloblastic or monoblast), malignant GI tract.

Hereditary aplastic anemia with a common lesion of hemopoiesis without congenital developmental anomalies (anemia of Estrena-Dameshek)

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

Congenital dyskeratosis (syndrome of Cinser-Cole-Engman)

The syndrome is characterized by signs of ectodermal dysplasia (pathological keratinization of individual cells of the spiky layer of the epidermis of the skin and mucous membranes) in combination with hematologic changes (about 50% of patients develop aplastic anemia). In 75% of cases the syndrome is inherited recessively linked to the X-chromosome and, accordingly, occurs in boys; In 25% of children, patients are inherited in an autosomal dominant type (approximately the same number of patients are described). The skin and its derivatives, mucous membranes are affected. Multiple disseminated hyperkeratosis with predominant localization on the face, neck, back, chest is observed; atrophy of the skin of the palms and feet, palmar-plantar hyperhidrosis; dysplasia and nail dystrophy; gipotrihoz eyelashes; blockage of lacrimal canals and lacrimation; leukoplakia of the oral mucosa, mainly of the tongue and gums; defeat of the endocrine glands (nanism, underdevelopment of secondary sexual characteristics). Hematologic changes are various: pancytopenia, isolated anemia, thrombocytopenia, neutropenia. The age of debut of aplastic anemia in this syndrome can be very variable, the average age of AA debut is 15 years.

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

Syndrome Schwamman-Diamond

It is characterized by exocrine pancreatic insufficiency, dwarfism, metaphyseal chondrodesis, neutropenia, sometimes anemia, thrombocytopenia. It is inherited autosomal dominantly.

The disease is clinically manifested at an early age and is characterized by signs of gastrointestinal damage and hematological changes. There are diarrhea, steatorrhea, slowing of weight gain, hypotrophy. Characteristic changes in the bone system in the form of metodontic metformysis and formation of orthopedic pathology, growth retardation. Some patients may have galactosemia, which leads to hepatosplenomegaly, delayed psychomotor development. Characteristic are recurrent respiratory diseases, otitis, abscesses, osteomyelitis. Some children experience a delay in the onset of puberty.

In blood tests from early age there is absolute neutropenia, the number of neutrophils is less than 1 x 10 ⁹ / l. For mature neutrophils, hyposegmentation of the nuclei is characteristic, a decrease in neutrophil chemotaxis is noted. Along with neutropenia, approximately 50% of patients have anemia with reticulocytopenia, 60-70% of children have thrombocytopenia, about 25% of patients develop aplastic anemia. In the sternal punctate, the number of myelokaryocytes can be normal, reduced or elevated; delayed maturation of neutrophils in the metamyelocyte stage. The forecast is most unfavorable in early childhood, when about 25% of children die from infectious complications; A fatal outcome is also possible from hemorrhages to vital organs.

Hereditary aplastic anemia with selective lesion of erythropoiesis (Blackfellow-Diamond anemia)

The incidence of this disease is 1: 1 million live newborns; 5 - 7: 1 000 000 in France, 10: 1 000 000 in Scandinavia, is found in all ethnic groups, boys and girls get sick equally. The overwhelming majority (75%) are sporadic cases of the disease; in some cases, autosomal dominant inheritance, autosomal recessive or linked to the X chromosome is possible.

The first signs of the disease are detected in the first months or during the first year of life - in 35% of anemia patients at birth, in 65% in the first 6 months of life and in 90% of cases the disease is diagnosed up to a year. The diagnosis of anemia Blackfen-Diamond in children over 2 years is unlikely. Children, as a rule, are born full-term with normal body weight and height, psychomotor development is normal. Pale skin and mucous membranes have been observed since the first days of life, but obvious clinical signs of hypoxia: lethargy or agitation, anxiety, drowsiness, refusal to eat, dyspeptic phenomena - appear with a decrease in hemoglobin to 60-30 g / l. Congenital malformations are less common (in 25% of cases) than with Fanconi anemia. Some patients have characteristic phenotypic features: hair color of pakli, snub nose, big upper lip, hypertelorism. As the disease progresses, the skin becomes waxy, and by 5-6 years, due to the development of hemosiderosis, a greyish hue, especially in the region of the cervical, axillary, inguinal folds, genital organs. Hemorrhagic syndrome is absent. There are hepatomegaly, splenomegaly, in the dynamics of the disease the spleen is contracting, and the liver progressively increases. Bone age lags behind the passport for 4-5 years, the rate of ossification is changed. The change of milk teeth is late, caries often appear.

In peripheral blood, normochromic macrocytic hypo- or aregenerator anemia (reticulocytes 0-0.1%), as a rule, is of a severe degree. The number of leukocytes and platelets remains at a normal level during the first years of life; sometimes there is a tendency to thrombocytosis. With prolonged course of the disease, moderate thrombocytopenia may develop. After the first decade of life, moderate neutropenia may also appear, probably due to a reduction in the clonal efficacy of granulocyte progenitors.

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

In the sternal punctate, the bone marrow is normocellular, as the disease progresses, there is a note of hypocellularity. The erythroid sprout is sharply narrowed; the diagnostic criterion is the absence or small number of erythroblasts (less than 5% of nucleated cells) in the bone marrow. Myeloid and megakaryocytic sprouts are not changed. The number of reticular cells and lymphocytes is increased, plasma cells are not changed.

Bleken-Diamond anemia occurs chronically, in 80% of patients receive remission with corticosteroids; 20% of patients described spontaneous remission. "Constant hypoxia, a violation of iron utilization, the need for vital signs of transfusion of erythrocyte mass steadily leads to hemosiderosis, which later is a" killer "of a sick child." Possible transformation into myelodysplastic syndrome, acute leukemia (lymphoblastic, myeloblastic, promyelocytic, megakaryocytic), solid tumors (hepatoblastoma, rheosarcoma, malignant fibrous histiocyte), lymphogranulomatosis.

Differential diagnosis

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

Anemia during convalescence after hemolytic disease of newborns.

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. Similar episodes are transient, in addition, the signs of a previous hemolytic disease are usually revealed. The development of aplastic crises is associated with B19 parvovirus infection. Tactics of management of patients, as a rule, expectant: with a significant decrease in the level of hemoglobin, blood transfusions are carried out.

Transient erythroblastopenia of childhood

One of the most common forms of erythroid sprout aplasia. The etiology of the disease is not known. In healthy earlier children at the age of 5 months - 6 years, most often at the age of 2 years, a severe aregenerative anemia is slowly developing, caused by a sharp decrease in erythrocytes in the bone marrow.

The development of anemia in 1 to 2 months may be preceded by a viral infection, although the association of the disease with a particular pathogen has not been proven, it is often parvovirus B19. The anamnesis and physical research are not informative, attracts attention only expressed pallor of skin and mucous membranes. 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 (<1,0х10 ⁹ / l) and 5% have thrombocytopenia (<100 x 10 ⁹ / l). Laboratory reveals normal levels of erythrocyte adenosine deaminase and fetal hemoglobin activity; by enzymatic characteristics, red blood cells are referred to an aging population. The serum iron level is elevated. Transient erythroblastopenia is also supported by the normal results of the clinical analysis of blood before the disease. In the sternal point there is a sharp narrowing of the erythroid sprout, there are no precursors, with the exception of normocytes, erythrocytes. Cultural studies of the bone marrow have revealed several pathogenetic mechanisms: the presence in the serum of stem cell inhibitors or anomalies of the latter, expressed either in their numbers or in the ability to react to erythropoietin. It is possible autoimmune genesis of the disease with primary erythroid progenitors, and not mature erythrocytes. A few months after the onset of the disease, spontaneous remission occurs. Before the onset of recovery may require blood transfusion, corticosteroids are not used.

Secondary (acquired) erythroid spleen aplasia

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

Episodes of acute erythropoiesis deficiency can accompany a number of viral infections. This significantly reduces the number of circulating reticulocytes (less than 0.1%) and increases serum iron level. In the bone marrow the number of precursors of erythrocytes is reduced. These episodes, as a rule, stop and do not leave any consequences. Most often secondary aplasia of the erythroid sprout is caused by parvovirus B19.

In all patients with infarction in the diagnosis of erythroblastopenia, the following studies are needed:

1. The serum antibodies IgM and IgG (mother and child).
2. Viral DNA in the serum.
3. Viral DNA in the bone marrow.

These studies can help in the differentiation of erythroblastopenia when infected with parvovirus B19 and erythroblastopenia of another genesis.

In the treatment of secondary erythroblastopenia, it is important to eliminate the cause that caused the disease - drug withdrawal, treatment of the underlying disease or thymectomy. When anti-erythroid antibodies are detected, corticosteroids are shown, with their ineffectiveness - immunosuppressants (cyclophosphamide or azathioprine). When immunodeficiency parvovirus infection can be chronic, then use immunoglobulin intravenously.

Acquired aplastic anemia

The clinic of acquired aplastic anemia differs depending on the total or selective lesion of hemopoiesis. 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.

For the total forms of aplastic anemia is characterized by a combination of hemorrhagic, anemic and infectious-septic syndromes. Hemorrhagic syndrome caused by thrombocytopenia is expressed dramatically: multiple ecchymoses and petechiae on the skin and mucous membranes, conjunctiva, recurrent nasal, gingival, uterine, gastrointestinal and renal bleedings, hemorrhages at injection sites. The immediate cause of death in these patients are most often hemorrhages in vital organs. The defeat of the erythroid sprout leads to the development of anemic syndrome, in which the patient has general weakness, decreased appetite, dizziness, fatigue, pale skin and mucous membranes, nail phalanges, changes in the cardiovascular system: widening of the heart, muffled tones, tachycardia , systolic murmur of varying intensity, possible extrasystole, dyspnea. The presence of leukogranulocytopenia causes the emergence of an infectious-septic syndrome: easy attachment of infections of any location, ulcerative and necrotic lesions of the skin, mucous membranes. The severe course of infections caused not only by the pathogenic flora, but also by conditionally pathogenic and fungal pathogens is characteristic. Lymph nodes, liver, spleen are not enlarged. With selective lesion of the erythroid sprout there are manifestations of only anemic syndrome.

All the symptoms of the disease can manifest themselves and grow more or less sharply.

Hematologic changes in aplastic anemia consist of neutropenia (absolute number of neutrophils less than 1.5 x 10 ⁹ / L), anemia (Hb <110 g / l), thrombocytopenia (platelet count <100 x 10 ⁹ / l) and reticulocytopenia not corresponding severity of anemia. Myelogram marked a sharp decrease in cellularity, reduction of myeloid and erythroid sprouts, variable lymphocytosis and the absence of megakaryocytes. In patients with slow development of aplasia, the areas of active hematopoiesis - "hot pockets" - may persist for a long time. In trepanobioptate, a sharp decrease in the hematopoiesis base is found - the fatty bone marrow dominates, the hematopoietic elements are represented by residual foci of erythro- and myelopoiesis, and megakaryocytes are practically not detected.

The severity of acquired aplastic anemia is divided depending on the depth of cytopenia, reticulocytosis and residual cellularity of the bone marrow according to trepanobiopsy. The criteria for the severity of aplastic anemia, developed by the international group for the study of aplastic anemia, are used: "Camitta criteria":

1. the number of granulocytes is less than 500 in 1 μl;
2. the number of platelets is less than 20,000 in 1 μl;
3. the number of reticulocytes is less than 40,000 in 1 μl (or less than 1% after correction for normal hematocrit).

Aplastic anemia is considered severe if any two of the above blood levels are present in combination with reduced cell count. If the hematologic syndrome meets the criteria for severe aplastic anemia, but the number of granulocytes less than 200 in 1 μl is superheavy aplastic anemia. All other cases are characterized as a mild aplastic anemia.

Differential diagnosis with acquired aplastic anemia is mainly carried out with acute leukemia, megaloblastic anemia, a syndrome of hypersplenism, metastases of tumors in the bone marrow.

[1], [2], [3]