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Hemophilia And - Practical hematology of children's age

Table of contents
Practical hematology of children's age
Embryonal hemopoiesis
Morfofunktsionalny characteristic of cells of marrow and peripheral blood
Marrow parenchyma cells
Peripheral blood of children of different age
The system of a hemostasis is normal
Etiology and pathogeny of leukoses
Acute leukoses
Acute leukoses - a preleukosis
Possibilities of a predictive assessment of a course of an acute lymphoblastoid leukosis at children
General principles of treatment of an acute leukosis
Chemotherapeutic drugs
Treatment of an acute lymphoblastoid leukosis
Treatment of myeloid forms of an acute leukosis
Infectious complications and symptomatic therapy of an acute leukosis
Consolidation and maintenance therapy of an acute leukosis
Immunotherapy
Remission and recurrence of an acute leukosis
Inborn leukosis
Neuroleukosis
Myelosis
Lymphogranulomatosis
Gematosarkoma
Macrofollicular lymphoma
Angioimmunoblastny lymphadenopathy
Leukemoid tests
Infectious lymphocytosis
Infectious mononucleosis
Leukemoid tests of different types
Dysfunctions of granulocytes
Leukopenias
Histiocytoses
Histiocytoses - an eosinophilic granuloma
Malignant histiocytosis
Family erythrophagocytal histiocytosis
Accumulation diseases
Nimann's illness — Peak
Angiopathies
Hemorrhagic vasculitis (Shenleyn's illness — Genokh)
Mayokki's purpura
Ataxy teleangiectasia
Entsefalotrigeminalny angiomatosis
Kortiko-meningealny diffusion angiomatosis
Cerebroretinal angiomatosis
Hypertrophic gemangiektaziya
Multiple and huge hemangiomas
Elastic fibrodisplaziya
Coagulopathies
Hereditary coagulopathies
Hemophilia And
Clinic of hemophilia
Treatment of hemophilia
Angiohemophilia
Cristmas disease (Kristmas's illness)
Hereditary deficit of factors of XI, XII, XIII and I
Dysfibrinogenemias
Hereditary deficit of factors of VII, X, V and II
Deficit K-vitaminozavisimykh of factors of coagulation
Syndrome of the disseminated intravascular coagulation
Clinic and diagnosis of the IDCS
Treatment of the IDCS
Thrombocytopenia
Idiopathic Werlhof's disease
Clinic and diagnosis of an idiopathic Werlhof's disease
Treatment of an idiopathic Werlhof's disease
Isoimmune Werlhof's disease
Transimmune Werlhof's disease of newborns
Trombogemolitichesky Werlhof's disease (syndrome Moshkovich)
Hereditary Werlhof's diseases
Trobotsitopatiya
Anemias
The anemias connected with blood loss
Chronic posthemorrhagic anemia
Iron deficiency anemias
Clinic and diagnosis of an iron deficiency anemia
Treatment of iron deficiency anemias
Sideroakhrestichesky, sideroblastny anemias
Megaloblastny anemias
Foliyevodefitsitny anemia
Hereditary forms of megaloblastny anemias
Hereditary dizeritropoetichesky anemias
The anemias connected with oppression of proliferation of cells of marrow
Hereditary hypoplastic anemias
Hemolitic anemias
Hemolitic anemias - an ovalocytosis, a hereditary stomatocytosis
Acanthocytosis, piknotsitoz
The hereditary hemolitic anemias connected with disturbance of activity of enzymes of erythrocytes
The hereditary hemolitic anemias connected with disturbance of structure or synthesis of hemoglobin
The acquired immune hemolitic anemias
Isoimmune hemolitic anemias
Treatment of a hemolitic illness of newborns
Autoimmune hemolitic anemias
List of references

Hemophilia is known since an extreme antiquity. The first medical scientific description of a disease was given by the Arab doctor from Cordoba to Alza-Garavi in 1100. In the middle of the 19th century A. A. Schmidt, professor of Yuryevsky university, showed that considerable delay of coagulability of blood is the cornerstone of a disease. Later it was confirmed with works of J. N of Wrighf (1906), T. Sahl (1910), etc. Long time hemophilia was considered as a uniform nosological form. However progress in studying of coagulant system of blood allowed to allocate several forms of a disease. Hemophilia And — the most often found coagulopathy caused by deficit of the VIII factor — anti-hemophilic globulin. Now it is shown that the VIII factor consists of several components: 1) koagulyantny part — VIIIk; 2) Villebrand's factor — VIII-FV and 3) the antigen connected with VI11-AG factor it is proteinaceous antigenic part of a factor of Villebrand. At hemophilia And the VIIIk component level whereas activity of VIII-FV and VI11-AG remains normal is sharply reduced. Also the so-called inhibitory forms of hemophilia And, are had by the caused development of the antibodies inhibiting the VIII factor, to be exact the VIIIk component.
Комбинация хромосом при гемофилии
Fig. 16. A combination of chromosomes at hemophilia and inheritance of a pathological gene (A. Delatre, 1972)
On the basis of studying of families in which have hemophilia the following conclusion is drawn: 1) hemophilia — a hereditary disease; 2) persons only of a male are ill; 3) women in a family are not ill, but can be conductors (conductors of this sign); 4) not all men in a family are ill; 5) men do not transmit a disease hereditarily to the children, and transfer through conductresses to grandsons; 6) hemophilia tends to quantitative reduction in succeeding generations.
Hemophilia And is the classical hereditary disease which is transmitted retsessivno, linked to X-chromosome (fig. 17).
About 25% of cases of hemophilia And are the sporadic forms caused not by hereditary transfer, but a new mutation of genes.
The gene of hemophilia is located on X-chromosome — Xh. Women have the sexual set provided by two X-chromosomes (XX). Therefore at conductresses, being heterozygous carriers of a sign (XXh), as a rule, clinical displays of a disease do not arise in connection with corrective influence of normal X-chromosome. Now it is proved, as at heterozygous carriers of a sign the level of a factor of VIII is lowered. Lack of clinical manifestations in most cases is explained by the fact that normal the level of a factor fluctuates in wide limits (from 50% to 200%) and even theoretical decrease at heterozygous carriers keeps rather high activity of the factor (25 — 100%) stopping hemorrhagic manifestations twice. It is known that bleedings at injuries and operations develop at decrease in a level of a factor the VIII lower than 20%, and spontaneous hemorrhagic manifestations — it is lower than 5%.

Схема наследования гемофилии
Fig. 17. Scheme of inheritance of hemophilia (A. Chapella and soavt., 1961)

Fig. 18. Distribution of conductors of hemophilia by means of family trees on proved, possible and potential
Распределение кондукторов гемофилии с помощью родословных
Men have the sexual set provided by X and Y chromosomes (XY). When receiving a pathological gene (XhY) there are clinical signs of a disease as Y chromosome does not contain a gene, is responsible for synthesis of the VIII factor and cannot compensate the available deficit.
By rules of the recessive, linked to X-chromosome inheritance, from marriage of the man sick with hemophilia, and the healthy woman healthy sons are born. They receive normal X-chromosome from mother, lose an abnormal gene and do not transmit a disease to the posterity. All girls who were born from this marriage are heterozygous carriers of an abnormal gene, reliable conductors of hemophilia which can develop at their sons.
From marriage of the healthy man with the woman — the reliable conductor of hemophilia with identical probability both sick, and healthy sons can be born. Also with identical probability the girls able are born to be or not to be heterozygous carriers of a gemofilichesky gene, in the latter case transfer of hemophilia by inheritance is interrupted in connection with loss of an abnormal gene (fig. 16). 3. S. Barkagan and E. Ya. Sukhoveeva (1969) described so-called kofaktorny, or autosomal and component, hemophilia at which deficit of a factor of VIII was inherited by the son from the father.
One of the possible reasons of so-called female hemophilia is caused by marriage of the man sick with hemophilia, with the woman — the reliable conductor of hemophilia. In this case at the birth of daughters they with identical chances can be heterozygous carriers and peredatchitsa of hemophilia or homozygous carriers with the expressed dslinichesky picture of hemophilia. Sons from this marriage have identical chances to be healthy or sick with hemophilia.
In the last decades, according to the conclusions of WHO, the number of patients with hemophilia and conductors of a Cristmas disease of population increased. And increase of hereditary forms of a disease, but not sporadic mutant forms is noted. It is explained by considerable reduction of child mortality from the hemophilia connected with efficiency of modern means of therapy. Patients with hemophilia live up to middle age, marry, give posterity which female half is peredatchitsa of hemophilia. Therefore medicogenetic consultation and detection of heterozygous bearers of an abnormal gene are actual. According to the standard scheme (G. M. Abdullaev, 1973) conductresses of hemophilia are divided into three groups whenever possible to descend an abnormal sign (fig. 18.).

Fig. 19. An arrangement of genes on X-chromosome
Расположение генов на Х-хромосоме
The proved conductors of hemophilia: a) daughters of patients with hemophilia; b) the women having not less than two sons sick with hemophilia; c) the women having the only son sick with hemophilia, and the daughter — the proved conductor; d) the women having not less than two daughters — the proved conductors; e) the women having the only son sick with hemophilia, in the presence in a family of the relatives sick with hemophilia.
Possible conductors: the women having the only son sick with hemophilia without family character of a disease. Potential conductors: the sisters of patients with hemophilia who do not have children yet.
For identification of conductresses in families where there are patients with hemophilia, conduct kliniko-genetic researches on the following scheme: 1. Studying of a genealogical family of a proband that allows to reveal the proved, possible and potential conductors of hemophilia. 2. Quantitative definition of a factor of VIII in blood conductresses of hemophilia that, according to a number of authors, is of great importance for identification of heterozygous carriers of a pathological gene. However there is a number of the difficulties connected with big fluctuations of indicators of norm (50 — 200%) therefore it is possible to judge authentically a heterozygous carriage only if stable reduction of a level of a factor lower than 45% is noted. 3. Immunological methods — research of procoagulant activity of the factor VIII possessing antigenic properties on reaction of immunoprecipitation (O. P. Plyushch and soavt., 1977).
Yu. N. Tokarev, G. A. Alekseev and O. P. The ivy (1977) was revealed by a number of the genetic markers important in definition of heterozygous carriers of hemophilia A. Gemofilichesky a gene is located on X-chromosome at a short distance from a gene of color-blindness (fig. 19). At inspection of the proved and possible conductors of hemophilia threshold disturbance of tsvetorazlichitelny ability more than at 60% of women whereas in the general female population the frequency of distribution of this pathology makes 0,5% is revealed. Disturbance of color sight can serve as a genetic marker for identification of the proved conductors of a Cristmas disease families of patients. Detection of heterozygous carriers and medicogenetic consultation are of great importance in prevention of appearance of patients with hemophilia, it is carried out in families of patients with hemophilia and their relatives and pursues such aims (O. P. Plyushch and soavt., 1977): 1) patients have to acquire character of a disease and a possibility of transfer it to the children; 2) in the presence of the sick child — to study clinical displays of a disease, an effect of complications and to get acquainted with modern methods of treatment of hemophilia; 3) to obtain necessary information on risk of the birth of the child, possible for a family, sick with hemophilia.
According to recommendations of Committee of WHO experts (1975) about genetics, the consultant can estimate to some extent risk and explain it to parents. But at the same time he should not draw the categorical conclusion about a possibility of continuation of posterity. The option belongs to parents. Especially the accuracy of an assessment depends on a number of factors which are not possible for defining by the time of consultation. Complex inspection of women allows to define heterozygous carriers of a gemofilichesky gene, but when receiving negative takes does not exclude a heterozygous carriage.
In modern conditions there is a possibility of sex determination of a fruit in early terms allowing at desire of parents to carry out artificial abortion. Parents have to know that from marriage of the man sick with hemophilia, and the healthy woman healthy boys are born. Therefore it is desirable to be limited to the birth of sons as girls surely will be heterozygous carriers. From the point of view of interruption of further distribution of hemophilia marriage without children at heterozygous women is ideal. The birth of sons has high degree of probability that the child will be a patient with hemophilia. Therefore if heterozygous women will have in a family only daughters, it will reduce probability of appearance of patients in posterity, but will not prevent their emergence.
In literature tens of cases of so-called female hemophilia are described (3. S. Barkagan, E. Ya. Sukhoveeva, 1969; E. M. Barrow and J. Century of Graham, 1975) which cannot be explained only with a homozygous carriage (XhXh). Allocate several main groups of female hemophilia: 1. A homozygous double carriage of a gemofilichesky gene (XhXh) — at the birth of girls from marriage of the man sick with hemophilia, and the conductress. 2. Clinical manifestations of a Cristmas disease to an easy form at some conductresses, heterozygous carriers of a gemofilichesky gene. Severe forms which are observed at heterozygous women are possible and are connected with an additional mutation of a gene responsible for synthesis of a factor of VIII in normal X-chromosome. 3. Existence of an incomplete set of gonosomes (HO). When receiving an abnormal gene (Xh0) the disease proceeds as well as at men from this family, in a severe form. 4. Testicular feminization: in sex cells the female set of chromosomes XX, and in somatic cells — man's XY is noted. 5. Deficit of a factor of VIII is inherited autosomal is prepotent. This clinical option is not an angiohemophilia. Both boys, and girls get sick.

Table 35. communication of a level of a factor VIII with clinical symptoms hemophilias (WHO, 1975)


Level of a factor of VIII, %

Clinical symptoms

50 — 200

Clinical symptoms are absent

20 — 50

As a rule, hemorrhagic manifestations are absent, bleedings happen only after big injuries or large surgeries

5-20

Long bleedings arise after small injuries and operations

1 — 5

Severe bleedings at insignificant injuries, are possible a hemarthrosis and spontaneous bleedings

0

Heavy bleedings, hemarthrosis, hematomas at microtraumas and arising spontaneously

The clinical picture of hemophilia is characterized by periodically arising bleeding having various localization (bleedings from mucous membranes, long bleedings at injuries, hemorrhages in joints, hematomas, a hamaturia etc.) . And hemorrhagic manifestations have a certain age evolution. Children are born already sick with hemophilia, but clinical symptoms of a disease in the period of a neonatality, as a rule, are absent. This phenomenon is tried to be explained with corrective effect of the women's milk containing thromboplastic factors. If hemophilia nevertheless is shown at the newborn, there can be heavy bleedings from an umbilical cord stump. At children of chest age long bleeding can arise during the cutting or a rupture of a bridle of language. Usually the first symptoms of hemophilia appear by the end of the 1st year or on 2 — the 3rd year of life. There is a certain interrelation of severity of hemophilia and time of emergence of clinical symptoms. Easy forms are shown at later age, cases of emergence of the first symptoms of a disease at the age of 20 — 23 are described. Severe forms already at early age give the developed clinical picture with an acute hemarthrosis. Weight of clinical manifestations at hemophilia is defined by a level of a factor of VIII in blood (tab. 35).
On the basis of this criterion on severity allocate several forms of hemophilia: a) the level of a factor of VIII is lower than 1% — a severe form; b) from 1 to 5% — moderately severe; c) from 5 to 10% — easy; d) it is higher than 10% — latent forms.
For practical purposes it is possible to use the classification offered 3 also. S. Barkagan (1980): a) a level of a factor of VIII from 0 to 1 — extremely severe form of hemophilia; b) from 1 to 2% — heavy; c) from 2 to 5% — moderately severe; d) it is higher than 5% — an easy form, but with possibility of heavy and even fatal bleedings at the injuries and surgical interventions which are carried out without sufficient replacement therapy.
At children of the first 3 years of life the disease has defined osobennostm, in particular there is no hemarthrosis. One of the first and characteristic symptoms of a Cristmas disease early age are bleedings from a mucous membrane of an oral cavity. They arise when traumatizing by various toys and objects which children often take in a mouth. During a teething not plentiful gingival bleedings are usually observed. At the same time, emergence of teeth is fraught with additional traumatization of a mucous membrane of an oral cavity — the language bites which are followed by long bleedings. Bleedings from a mucous membrane of a throat are very dangerous. They arise at children for the most insignificant reasons, for example at a tension of phonatory bands during crying, shout, cough. These bleedings as well as bleedings from mucous membranes of oral and nasal cavities, are fraught with threat of asphyxia, accumulation of blood and clots in upper respiratory tracts. It should be noted that medical manipulations can also cause heavy bleedings. Sometimes hemophilia is found when carrying out an injection concerning any somatic pathology or during inoculations. When at the child the motive sphere extends, he begins to rise, go, naturally, the possibility of traumatization increases. Children often fall and during this period the quantity of nasal bleedings increases, hematomas, generally on a face and a trunk develop. At disturbance of integrity of skin there are bleedings proceeding from several hours to many days obviously inadequate to an injury. Emergence of bleeding can be connected with any injury, but quite often at hemophilia spontaneous hemorrhagic manifestations which reason is not clear are observed. Hemorrhages in soft tissues, hematomas can be hypodermic, intramuscular, intermuscular. Hematomas arise in shoulder joints, a breast, a stomach, a neck etc. In some cases extensive hematomas squeeze peripheral nervous trunks or large arteries, causing sensitivity disturbance, paresis. At children of advanced age intramuscular hematomas arise under the influence of an injury, the awkward movement or is spontaneous (usually at severe forms of hemophilia). Clinically at hemorrhages in muscles the general state is broken, there is a pain syndrome, during a blood rassasyvaniye patients are in a fever, the subikterichnost of scleras is noted. Big hemorrhages lead to anemia. Most often hemorrhages happen in gastrocnemius, buttock, pectoral muscles, forearm muscles, sometimes in an iliolumbar muscle. Hematomas of cheeks are frequent. After three years when children begin to lead very much active lifestyle — to run, jump, participate in outdoor games, there is one of the most typical symptoms of hemophilia And — hemorrhages in joints — a hemarthrosis. At easy forms of a disease this symptom can be absent, at heavy — to appear at earlier age. In the further course of a disease in age aspect hemorrhages in joints prevail. On the frequency of clinical symptoms of hemophilia a hemarthrosis wins first place. Hemorrhages usually happen in knee, elbow, talocrural joints, is much more rare — in humeral, coxofemoral, radiocarpal and small joints of a brush and feet. The external reasons causing them are usually insignificant. At the first acute hemarthrosis blood can resolve completely over time. Clinically the hemarthrosis is characterized by fast increase in a joint in volume, morbidity, skin over it is strained, hyperemic, hot to the touch. At the proceeding hemorrhage pain amplifies, children spare an extremity, adopt the forced provision. The movements in a joint are sharply painful. During movements fluctuation can be defined. At a rassasyvaniye of blood there can be moderately expressed intoxication, fever, a leukocytosis, increase in SOE. Easy forms of an acute hemarthrosis come to an end with a blood rassasyvaniye in 7 — 12 days and recovery of function of a joint. More severe forms can proceed 3 — 4 weeks. At repeated hemorrhages in joints blood completely does not resolve. Gradually productive process which deforms a joint forms. Sometimes the inflammation of synovial membranes promoting the chronic course of process and dysfunction of a joint joins. Along with chronic arthritis the atrophy of the muscles supporting a joint develops.
Distinguish three forms of damage of joints at hemophilia: 1. An acute hemarthrosis — primary and recurrent, is most often observed at children. 2. Chronic destructive osteoarthroses. 3. A secondary rhematoid syndrome (for the first time described 3. S. Barkagan and L. P. Egorova, 1969).
Forming of a chronic destructive osteoarthrosis takes place several stages which differentiate on the basis of clinicoradiological data. Domestic hematologists adopted classification of E. Z. Novikova (1967) in which stages of damage of joints at hemophilia are allocated.
In the first, or early, stages the volume of a joint can be increased (with expansion of a joint crack) at the expense of hemorrhage. During the "cold" period function of a joint is not broken, but radiological it is possible to find a thickening and consolidation of a joint capsule. In the second stage there are typical changes in subchondral department of an epiphysis — regional uzura, education single, an oval form and small cellular destructions, a cyst. Osteoporosis is more expressed, the joint crack is kept, but can be moderately narrowed. Perhaps moderate depression of function of a joint that is shown by small restriction of amplitude of movements in it, gait disturbance, a hypotrophy of muscles.
In the third stage the joint is sharply increased, deformed, often is not equal and hilly to the touch, contrasts with the parts of an extremity forming it where the expressed hypotrophy of muscles is defined. Mobility of the affected joints to a greater or lesser extent is limited that is connected both with damage of the joint, and with change of muscles and sinews which are often shortened that leads to development of "horse foot" and other disturbances limiting function of an extremity. Radiological joints and joint surfaces are thickened, sharply deformed, an epiphysis is expanded at the expense of hyperostoses, a diaphysis is reduced, the joint crack is narrowed. Osteoporosis is expressed, easily there are intra joint changes. In a femur — signs of destruction of bone substance in the field of an intercondyloid pole. The patella is partially destroyed. Intra joint cartilages are destroyed, in a cavity of a joint find the mobile organized clots, splinters of cartilages.
In the IV stage function of a joint is almost completely lost, the joint crack is narrowed, the zarashchena konturirutsya badly by connecting fabric on the roentgenogram, often. The sclerosis of subchondral departments of a bone which is combined with a considerable uzuration and a cystosis of an epiphysis is expressed. Pathological intra joint changes are possible. Bone ankiloza are exclusively rare.



 
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