HYPOPLASTIC ANEMIA

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HYPOPLASTIC ANEMIA (Greek hypo-+ plasis formation, education; anemia; synonym: aplastic anemia, aregeneratorny anemia, hemorrhagic aleukia, myeloparesis, myelophthisis, panmyelophthisis, the progressing hypocytemia) — the disease of system of blood which is characterized by oppression of the hemopoietic function of marrow and shown insufficient formation of erythrocytes, leukocytes and thrombocytes (panhemocytopenia) or only one erythrocytes (partial G. and., eritroblastoftiz).

Classification

Distinguish the inborn (constitutional) and acquired forms G. and. Inborn G. and. meet rather seldom. Depending on the nature of oppression of a hemopoiesis allocate forms with defeat of all three sprouts (true G. and.) or only erythrogenesis (partial G. and.). Sometimes allocate G. to ampere-second with a hemolitic component, but some authors consider that it represents a hypoplastic stage of a paroxysmal night haemoglobinuria (see. Hemolitic anemia ).

History

In 1888 P. Ehrlich described a disease at the young woman, at Krom bleeding, fever, deep anemia and a leukopenia sharply developed (thrombocytes at that time did not count); on opening there were no signs of a hemopoiesis in marrow that P. Ehrlich explained with primary oppression of its function. The term «aplastic anemia» was offered for the first time by Shoffar (A. M. of Chauffard, 1904). Further aplastic anemia like Ehrlich was allocated, at a cut along with steadily progressing pancytopenia which is quite often complicated by sepsis, sharply expressed hemorrhages and the necrotic phenomena, histologically in marrow signs of a hemopoiesis did not come to light; the disease was observed at persons aged from 18 up to 20 years. The similar disease under the name «hemorrhagic aleukia» was described by Frank (E. Frank, 1915). With introduction to practice in 1927 by M. I. Arinkin of a puncture research of marrow there was an opportunity to distinguish true G. and. from the pancytopenias caused by leukemic or metastatic damage of marrow. In domestic literature the first descriptions of G. and. under the name «kliniko-hematologic syndrome» belong to G. P. Hosroyev (1913). And. as separate nozol, works of X are devoted to a form. X. Vladosa (1937), E. A. Kost (1952), I. A. Kassirsky and G. A. Alekseev (1962), F. E. Feinstein (1965), G. S. Mukhamedzyanova (1970), etc.

The statistics is in detail not studied. According to statistical data Moscow prozektur, G.'s frequency and. made in 1928 — 1932 0,009%, in 1945 — 1950 0,13%, in 1951 — 1956 0,25%. In the USA (according to the State of California, 1967) G.'s incidence and. made 2 cases on 1 million people, or 1:400000 — 1: 700 000. To the expressed dependence of incidence on a sex, age and ethnic origin it is not established.

The etiology

the Hypoplasia of a hemopoiesis can be caused by influence of various external factors which can be divided into two groups: 1) factors with the obligate myelotoxic effect proportional to the size of a dose — ionizing radiation, benzene and its derivatives (benzene anemia develops), antineoplastic drugs (chlorethylamines; fosforamida; antimetabolites — antagonists folic to - you, analogs of purines, pyrimidines, etc.; antimitotic means — colchicine, alkaloids of a periwinkle; antibiotics — Bruneomycinum, rubomitsin, adriamycin, Carminomycinum), inorganic compounds of arsenic, are oestrogenic, etc.; 2) factors with the optional myelotoxic effect found only in isolated cases — antibacterial, anticonvulsant, anti-thyroid, antihistaminic drugs, tranquilizers (aplastic post-medicamentous anemia develops), insecticides, etc.; the feedforward of development of G. of ampere-second by a dose and duration of use of drug in these cases is not noted. Rather exceptional cases of development of G. shall be carried to the second group and. at tuberculosis, pregnancy. And., connected with inclusion in food of the wintered grain (see the Aleukia alimentary and toxic), practically does not meet.

From factors with optional myelotoxic effect levomycetinum (chloramphenicol) is most dangerous an antibiotic. According to Vallerstein with sotr. (R. The lake of Wallerstein, 1969), at the persons accepting levomycetinum (see), an opportunity to ache with G. and. is 13 times higher, than at the population in general. Describe G. less often and. in connection with reception of organic compounds of arsenic (mafarsen, etc.), antimalarial drugs, derivative hydantoin, phenylbutazone, salts of gold.

The hypoplastic anemia caused by influence of various external factors is called myelotoxic anemia. Approximately in 50% of cases of G. and. it is not possible to establish a cause of illness — a so-called idiopathic form.

Constitutional G.'s etiology and. (syndrome, or anemia, Fankoni, partial G. and. Dzhozefsa — Daymonda — Blekfen and family G. and. Estrenum — Damesheka) it is connected most likely with inheritance of a gene from one of parents on recessive type. At a cytogenetic research Blum (G. E. Bloom) with sotr. (1966) found in patients various aberation chromosomes in the hemopoietic cells. Cases of the children who were born from interrelated marriages are described. Some authors note similarity of a syndrome of Fankoni with embryopathy (see), caused thalidomide (see).

Pathogeny

G.'s Development and. it can be connected or with damage of a stem cell, parent for granulo-, eritro-and a thrombocytopoiesis, or with the defect of its microenvironment (see the Hemopoiesis) interfering normal life activity of this cell. Detection of aberation chromosomes at inborn G. and., to lay down. efficiency of transplantation of marrow from enzygotic twins, and also the trace amount of stem cells revealed at cultivation of marrow of patients confirm the first assumption. Rarity of emergence of G. and. under the influence of the listed optional factors tells about a role individual, perhaps hereditary, predispositions. Participation of autoimmune mechanisms is supposed only at partial G. and., at a cut Krantts (S. Century of Krantz, 1973) and L. I. Idelson with sotr. (1976) found antibodies to kernels of erythrocytes. Apprx. 50% of cases of partial G. and. develops at the patients suffering from a high-quality thymoma; the reasons of it are still not clear. At G. and. deficit of factors of a hemopoiesis is not observed. On the contrary, contents them in blood is even increased owing to incomplete use of the erythropoietic fabric reduced on volume.

Hemorrhagic manifestations at G. and. are caused by disturbance of a hemostasis as a result of deep thrombocytopenia and defeat of a vascular wall. The hyperpermeability of a vascular wall has secondary character and is connected with a hypoxia, a lack of serotonin. Gistokhim, and immunomorfo l. researches reveal deep structural disturbances in a vascular wall.

Pathological anatomy

On opening find signs of an anemia and dystrophy of internals, a plentiful adiposity in hypodermic cellulose, an epicardium, an epiploon, multiple hemorrhages in skin, mucous membranes, serous covers, internals. Sometimes note massive hemorrhages in the brain or a muscle of heart which are a proximate cause of death. Marrow of flat bones of light pink or yellowish color, sometimes with dark red sites of hemorrhages. At a prelum of a bone from a cut surface bloody liquid, fat-rich flows down. Among fatty marrow sites of the remained hemopoietic fabric can be observed. The sizes of a spleen and limf, nodes are often reduced.

Fig. 1. Microdrug of a liver (hypoplastic anemia): the arrow specified adjournment of hemosiderin.
Fig. 2. Microdrug of a kidney (hypoplastic anemia): shooters specified adjournment of hemosiderin in an epithelium of tubules.

At microscopic examination marrow (see) various degree of its devastation comes to light. In case of an aplasia find only small accumulations of lymphocytes, plasmocytes and undifferentiated elements, single granulocytes and normoblasts in fatty marrow. At a hypoplasia find sites of the hemopoietic fabric slightly more often. Irregularity of distribution of the centers of a hemopoiesis not only in various sites of a skeleton, but also within the same bone is characteristic. The structure of a bone tissue is more often kept. Both for early, and adjournment of hemosiderin in a spleen, a liver (fig. 1) and marrow is characteristic of late phases of a disease, is more rare in kidneys (fig. 2), limf, nodes.

To frequent complications of G. and. carry fibrinous and hemorrhagic pneumonia and necrotic changes in mucous membranes and serous covers, skin, internals.

The current and symptoms

the Disease can flow sharply, subacutely or chronically. In - acute cases process begins with rough hemorrhagic diathesis (see. Hemorrhagic diathesis ), heavy general intoxication, infectious complications. Gradual increase of symptoms is more often observed. There are an adynamia, weakness, dizziness, bystry fatigue, an asthma at physical. to loading, sometimes ostealgia and area of heart. Wax-like pallor of skin without yellowness, an anemia of visible mucous membranes is noted. The hypodermic fatty tissue is kept. At development of deep thrombocytopenia (see) there are hemorrhages on skin, mucous membranes and an eyeground, nasal, gingival, uterine, intestinal, renal and other bleedings. During the progressing of process can take place nevrol, the symptomatology caused by hemorrhages in a brain. At partial G. and. bleeding is absent. The sizes limf, nodes, a spleen and a liver do not change.

Picture of blood. Anemia carries normokhromny, normotsitarny, macrocytic character is more rare. The polychromatophilia is absent, the number of reticulocytes is normal or reduced. The leukopenia can reach 1000 cells in 1 mkl less; it is caused generally by a granulocytopenia and is followed by a relative lymphocytosis. The absolute number of lymphocytes at a sharp leukopenia is also lowered. Thrombocytopenia with lengthening is noted bleeding time (see) and decrease in retraction of a blood clot (see Retraction). Plasma blood-coagulation factors (see. Coagulant system of blood ) do not change. Content of serumal iron is increased, the general iron-binding ability of serum is more often increased.

Partial G. and. it is characterized hron, normotsitarny anemia, it is frequent without leucio-and thrombocytopenia, with a deep reticulocytopenia.

Punctate of marrow, as a rule, scanty, head elements are presented generally by lymphocytes, not numerous granulocytes and normoblasts. Megacaryocytes are absent more often. Sometimes, despite an explicit pancytopenia, punctate is quite rich; it is connected with hit of a needle in the center of the remained hemopoiesis. In addition to purely quantitative deficit of erythroblastic elements, at G. and. note symptoms of their qualitative pathology (dizeritropoez), a megaloblastoidnost, atypical mitoses, multinucleosis (see. Dizeritropoetichesky anemia ). At partial G. and. punctate of marrow is rich with head elements, the leucio-thrombocytopoiesis is not broken, but the number of cells of a red row is quite often sharply reduced or they completely are absent.

Fig. 3. Microdrug of marrow of an ileal bone (hypoplastic anemia): sharp dominance of fatty marrow over hemopoietic. Marrowy cavities are filled with preferential fatty tissue, myeloid fabric is presented by small islands of black color; x 280.

Trepanobiopsiya of an ileal bone reveals sharp dominance of fatty marrow over hemopoietic (fig. 3), sometimes lack of the last.

The research with radioactive iron 59Fe gives the most exact total score of an erythrogenesis: the clearance of isotope from plasma is slowed down, it collects generally in a liver, inclusion of a tag in erythrocytes is slowed sharply down.

Complications

are the Main complications and a proximate cause of death of patients bleedings and infectious and inflammatory processes. Hemorrhages come to light at decrease in number of thrombocytes below a critical level (20 000 — 30 000 in 1 mkl), can be provoked even by insignificant injuries (subcutaneous injections etc.). Infections (pneumonia, etc.) develop at rather long and expressed (less than 500 in 1 mkl) decrease in number of neutrophils.

Any fever at sick G. and. it is, as a rule, connected with existence of the infectious center; many cases of development in them of an acute leukosis are described. Leukoses against the background of a hypoplasia of a beam or benzene origin concern to group miyeloblastny or miyelomonoblastny and are, probably, late result of leukemogenic action of the factor which caused anemia. Accession to G. is much less often observed and. a paroxysmal night haemoglobinuria though some authors treat in these cases of G. and. as hypoplastic stage of this form of hemolitic anemia.

The diagnosis

the Diagnosis is based on existence of a pancytopenia and punctate poor in nuclear cells or a trepanata of marrow in the absence of increase limf, nodes, a spleen and a liver. And. it is necessary to differentiate hl. obr. with pancytopenias of other origin. Detection in blood of young cells of a white or red row, even insignificant increase in a spleen always shall raise doubts in G.'s diagnosis and. In these cases it is possible to assume existence of aleukemic forms leukoses (see), cancer metastasises in marrow, multiple myeloma (see). The diagnosis is usually made on the basis of a research of punctate of marrow; besides, characteristic changes of proteins of serum and (or) urine are inherent in a multiple myeloma. The pancytopenia at a myelofibrosis (see the Osteomyelofibrosis) is followed, unlike G. and., increase and myeloid metaplasia of a spleen. Addison's anemia — Birmera (see. Pernicious anemia ) distinguishes from G. and. existence of a glossitis, nevrol, disturbances, an achlorhydria, the expressed megaloblastoz of marrow, good therapeutic effect of vitamin B 12 . The diagnosis of a paroxysmal night haemoglobinuria even in its early, hypoplastic, stages is confirmed by positive takes of saccharose and acid tests (see. Hemolitic anemia ). At subacute option lymphogranulomatosis (see) the pancytopenia is followed by fever, there is no sharp lymphocytosis, in a trepanata of marrow sometimes it is possible to find Berezovsky's cells — Shternberg. The pancytopenia owing to a hypersplenism is followed, as a rule, by increase in a spleen.

Treatment

Methods of radical treatment of G. and. does not exist, however to lay down. actions promote lengthening of life expectancy of patients. At identification etiol, a factor it is necessary to stop its further influence. For fight against anemia transfusions of blood or a packed red cells are shown; this measure shall not pursue the aim of full normalization of indicators of red blood — enough their maintenance at the level compatible to cardiovascular compensation. The number of transfusions shall be minimum for reduction of danger of a transfusion siderosis (at transfusion of 450 ml of blood 200 — 250 mg of iron are entered into an organism), hepatitis and other complications. In order to avoid an isosensitization antigens of leukocytes and thrombocytes it is reasonable to pour the washed erythrocytes. At repeated hemotransfusions development of an isosensitization by antigens of erythrocytes is frequent; in these cases blood for a transfusion is selected for indirect test of Koombs (see. Koombs reaction ).

In case of a combination of anemia to hemorrhagic diathesis transfusions of svezhetsitratny blood or direct hemotransfusions in a single dose not less than 500 ml are shown. The platelet concentrates received by means of a separator of blood cells from one donor or by centrifuging of a large number of the doses of blood taken from various donors have more expressed haemo static effect. Styptic action of trombokontsentrat is shown if the number of thrombocytes at the patient manages to be raised at least to 15 000 — 20 000 in 1 mkl blood. At repeated transfusions of the platelet concentrates which are especially received from blood of different donors the isosensitization to platelet antigens inevitably develops and decrease in a therapeutic effectiveness of transfusions is noted. Therefore it is desirable to use limited number of persons as donors, it is better than relatives, the most compatible on antigens of the HL — And system (see. Blood groups , leukocytic antigens).

Among medicines have property to stimulate an erythrogenesis only anabolic steroids (see). A condition of achievement of therapeutic effect consider duration of use of hormones in rather high dose necessary (e.g., methyltestosterone or Nerobolum on 1 — 2 mg on 1 kg of body weight a day inside within 3 — 4 months) [Mac-Kredi (K. V. of McCredie), 1969]. The first manifestation to lay down. efficiency of drugs there can be an improvement of indicators of peripheral blood. At emergence of signs of side effect (a delay of liquid, damage of a liver) hormones cancel. For G.'s treatment and. apply also corticosteroids (Prednisolonum of 0,5 — 1,0 mg on 1 kg of body weight or equivalent doses of other steroids) hl. obr. for the purpose of haemo static action (decrease in vascular permeability); for this purpose use also other, so-called sosudoukreplyayushchy means — ascorbic to - that, Rutinum, drugs of calcium. For the purpose of reduction of a hemosiderosis of bodies and fabrics it is possible to appoint drugs like desferal.

The numerous attempts of change by the patient of donor marrow made without due immunol, selection (only on the main erythrocyte antigens), were unsuccessful, t, e. came to the end with graft rejection owing to biol, incompatibility. Cases of original transplantation are not numerous. E. D. Thomas with sotr. (1974) carried out at four sick G. and. the successful change of the singenny marrow received from unioval twins of patients, which led to an absolute recovery; operation was performed without special preparation in view of antigenic identity of recipients and donors. However a similar opportunity is casuistic. Allogenic changes (on the Hl system — And) demand difficult training of recipients for prevention of graft rejection from the donors compatible (general irradiation or introduction Cyclophosphanum for the purpose of an immunosuppression), and also postoperative use of tsitostatik for suppression immunol, reactions «a transplant against the owner» (see. Incompatibility immunological ). From 24 sick G. and., described by Thomas with sotr., 12 lived St. 3 months; engraftment of a transplant at them was proved as a result of the analysis sex chromatin (see). At the patients who received earlier numerous hemotransfusions, chances of engraftment of a transplant in connection with formation of isoantibodies decrease. Complexity of a technique of bone marrow transplantation makes it available only for separate specialized institutions.

The issue of efficiency of a splenectomy is finally not resolved. At the expressed hemorrhages operation is contraindicated in connection with a high lethality. Possibly, is more reasonable splenectomy (see) at patients with the raised sequestration of thrombocytes and erythrocytes in the spleen proved by a tracer technique and at safety of the centers of a normal hemopoiesis in marrow.

Forecast. Predictively an adverse sign consider an acute onset of the illness. Forms with an acute current are usually steady against therapy and in several weeks come to an end with death. Disease long, months-long and even long-term is more often. Perhaps long absence a wedge, displays of a disease, however at patients signs of a defective marrowy hemopoiesis remain.

Prevention

the Faces which are professionally tied with influence of myelotoxic factors (sources of ionizing radiation, benzene production) shall be under constant dispensary observation. Performing cytostatic treatment concerning tumors and other diseases demands regular control of composition of blood and the timely termination at threat of a hypoplasia of a hemopoiesis. Use of potentially dangerous drugs, first of all levomycetinum (see), it has to be limited to direct indications and be under control of composition of blood. Prevention of hemorrhages at already developed G. and. includes hormonal suppression of a menstrual cycle at women with massive menorrhagias, replacement (whenever possible) injection to lay down. drugs peroral, shchazheniye of mucous membranes (exception of rough food, replacement of rigid toothbrushes with cotton plugs). For prevention of infectious complications at a deep granulocytopenia (see. Leukopenia ) suppression of an intestinal autoflora is recommended by not absorbed antibiotics, patients should be supported in conditions, aseptic or close to them, to monitor respect for personal hygiene.

Hypoplastic anemia at children

the Acquired forms G. and. at children proceed the same as at adults. Along with them at children's age also some inborn (constitutional) forms of a disease meet.

Fankoni's anemia (synonym: Fankoni's syndrome, inborn pancytopenia). It is described in 1927 under the name «family children's pernitsiozopodobny anemia». Since then it is published apprx. 200 observations. Anemia, as a rule, comes to light in the first years of life, occasionally later. Boys are ill twice more often than girls. The combination of a pancytopenia and a hypoplasia of marrow to other inborn defects — a brown xanthopathy in connection with adjournment of melanin, an atrophy of kidneys and spleens, absence or an underdevelopment of the I metacarpal or beam bones, the Delay intellectual, physical is characteristic. and sexual development, nanocephalia, microophthalmia. At cultivation of lymphocytes and fibroblasts of skin of patients numerous aberation chromosomes come to light. At relatives of patients often note leukoses.

Treatment — is appointed by systematic hemotransfusions (packed red cells). Forecast adverse.

Family hypoplastic anemia of Estrenum — Damesheka was for the first time described in 1947. The same changes from a hemopoiesis which are observed at Fankoni's anemia are inherent to it, but anomalies of a skeletogeny and internals are not observed.

Inborn partial hypoplastic anemia of Dzhozefs — Daymonda — Blekfenand it is described in 1936 by Dzhozefs (W. N of Josephs) and in 1938 Daymondom and Blekfen (L. To. Diamond, To. D. Blackfan). The genetic defect which is the cornerstone of a disease is not found out. The course of a disease at several children who were born from different mothers, but from one father testifies to the dominant nature of inheritance. The developed picture of a disease usually is found on the 1st year of life: anemia of various degree is combined with a deep eritro-and a normoblastopeniya against the background of reduction of quantity of myelocariocytes (at the initial stages of a course of a disease the quantity of myelocariocytes of marrow can be not changed). At a part of patients reveal other inborn defects (a delay sexual and physical. development), but anomalies of development of kidneys do not meet. Owing to repeated hemotransfusions the hemosiderosis with portal cirrhosis quite often develops (see. Cirrhoses of a liver ).

Treatment — systematic hemotransfusions (packed red cells) in combination with corticosteroid hormones and vitamin B 12 . By means of systematic hemotransfusions it was possible to finish sick children up to 8 — 15 years then there occurred spontaneous improvement.

See also Anemia .


Bibliography: Idelson L. I., D and d-kovsky N. A. and Ermilchen-k about G. V. Hemolitic anemias, M., 1975, bibliogr.; Kassirsky I. A. and Alekseev G. A. Clinical hematology, M., 1970; Mukhamedzyanova G. S. Hypoplastic anemias at children, M., 1970, bibliogr.; T about m and with E. D., etc. Problems of transplantation of marrow, in book: New in gematol., under the editorship of A. I. Vorobyov and Yu. I. Loriye, page 242, M., 1974, bibliogr.; Faynshteynf. AA. Aplastic and hypoplastic anemias, M., 1965, bibliogr.; Bloom G. E. and. lake of Chromosome abnormalities in constitutional aplastic anemia, New Engl. J. Med., v. 274, p. 8, 1966; D i a m o n d L. K. a. BlackfanK.D. Hypoplastic anemia, Amer. J. Dis. Child., v. 56, p. 464, 1938; E h r 1 i with h P. tJber einen Fall von Anamie, mit Bemerkungen tiber regenerative Veran-derungen des Knochenmarks * Charit6-Ann., 1886, t. 13, p. 300, 1888; F anconi G. Familiare infantile perniziosaartige Anamie (pernizioses Blutbild und Konstitution, Jb. Kinderheilk., Bd 117, S. 257, 1927; Josephs H. W. Anaemia of infancy and early childhood, Medicine (Baltimore), V. 15, p. 307, 1936; McCredieK. B. Oxymetholone in refractory anemia, Brit. J. Haemat., v. 17, p. 265, 1969; Wint-r o b e M. M. and. lake of Clinical hematology, Philadelphia, 1974, bibliogr.

Yu. I. Loriye, F. E. Feinstein.

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