MINISTRY OF PUBLIC HEALTH OF UKRAINE
HIGHER STATE EDUCATIONAL ESTABLISHMENT OF UKRAINE
«UKRAINIAN MEDICAL STOMATOLOGICAL ACADEMY»
V.I. POKHYLKO, S.M. TSVIRENKO, YU.V. LYSANETS
AGE-RELATED FEATURES AND
PATHOLOGY OF BLOOD IN CHILDREN
MANUAL FOR STUDENTS OF HIGHER MEDICAL EDUCATIONAL INSTITUTIONS OF THE III-IV
ACCREDITATION LEVELS
Poltava 2017
МІНІСТЕРСТВО ОХОРОНИ ЗДОРОВ’Я УКРАЇНИ ВИЩИЙ ДЕРЖАВНИЙ НАВЧАЛЬНИЙ ЗАКЛАД УКРАЇНИ
«УКРАЇНСЬКА МЕДИЧНА СТОМАТОЛОГІЧНА АКАДЕМІЯ»
ПОХИЛЬКО В.І., ЦВІРЕНКО С.М., ЛИСАНЕЦЬ Ю.В.
ВІКОВІ ОСОБЛИВОСТІ ТА ПАТОЛОГІЯ КРОВІ У ДІТЕЙ
НАВЧАЛЬНИЙ ПОСІБНИК ДЛЯ СТУДЕНТІВ ВИЩИХ МЕДИЧНИХ НАВЧАЛЬНИХ ЗАКЛАДІВ III-IV РІВНІВ
АКРЕДИТАЦІЇ
Полтава 2017
UDC: 616+616.15]-053.2(075.8) ВВС: 57.33я73
The manual highlights the issues of embryogenesis, age-related features, semiotics of lesion, examination methods and diseases of hemic system in children.
The manual is intended for students of higher educational institutions of III-IV accreditation levels, and can be used by medical interns and primary care doctors.
Authors:
Doctor of Medical Sciences, Professor of the Department of Pediatrics No.1 with Propedeutics and Neonatology V.I. Pokhylko
Candidate of Medical Sciences, Acting Head of the Department of Pediatrics No.1 with Propedeutics and Neonatology S.M. Tsvirenko
Candidate of Philological Sciences, Senior Lecturer of the Department of Foreign Languages with Latin and Medical Terminology Yu.V. Lysanets
Reviewers:
O.S. Yablon’ ― Doctor of Medical Sciences, Professor, Head of the Department of Pediatrics No.1, Vinnytsya National M.I. Pirogov Memorial Medical University of Ministry of Public Health of Ukraine.
M.O. Honchar ― Doctor of Medical Sciences, Professor, Head of the Department of Pediatrics and Neonatology No.1, Kharkiv National Medical University.
TABLE OF CONTENTS
Foreword... 6
Unit 1. Embryogenesis of the Hematopoietic System... 7
Unit 2. Anatomical and Physiological Features of Blood Formation……… 11
Unit 3. Lesion Syndromes of the Hematopoietic System………...… 13
Unit 4. Methods for Examination of Patients with Blood System Lesions…... 15
Unit 5. Anemias in Children………... 18
Deficiency Anemias in Children………...…. 20
Iron Deficiency Anemias………...…. 20
Vitamin Deficiency Anemias………..…..…. 28
Hemolytic Anemias in Children………...…. 29
Hereditary Hemolytic Anemias Associated with a Defect in Erythrocyte Membrane Structure………..…… 30
Hereditary Anemias Associated with a Defect or Deficiency of Erythrocyte Enzyme Systems……….. 32
Anemias Caused by the Inherited Defect in Hemoglobin Metabolism 33 Sickle Cell Anemia……….. 36
Aplastic Anemia……….….... 38
Unit 6. Hemoblastoses………..… 41
Acute Leukemia………... 41
Chronic Myeloid Leukemia………..…. 49
Lymphogranulomatosis………... 51
Unit 7. Hemorrhagic Diatheses………..…... 57
Hereditary Coagulopathies………..…... 62
Acquired Coagulopathies………..…. 68
Angiopathies……….. 71
Thrombocytopenias……….….…. 73
Appendixes………..….. 77
Tests for Self-Check ………..………...… 83 The List of References ……….………..…...
Recommended Literature for Foreign Students……….
91 94
LIST OF ABBREVIATIONS
AA − aplastic anemia
ALT − alanine aminotransferase
APPT − activated partial thromboplastin time AST − aspartate aminotransferase
ATG − antithymocyte globulin
G-CSF − granulocyte colony stimulating factor ALL − acute lymphoblastic leukemia
AML − acute myeloid leukemia ARF − acute renal failure
HUS − hemolytic uremic syndrome
DIC − disseminated intravascular coagulation EBV − Epstein-Barr virus
ECG − electrocardiography IDA − iron deficiency anemia IDC − iron deficiency condition
TICS − total iron-binding capacity of serum SI − serum iron
ITP − idiopathic thrombocytopenic purpura CI − color indicator
LGM − lymphogranulomatosis (Hodgkin’s disease) LDH − lactate dehydrogenase
LICS − latent iron-binding capacity of serum LP − alkaline phosphatase
BW − body weight
SDG − succinate dehydrogenase CML − chronic myeloid leukemia CMV − cytomegalovirus
GIT − gastrointestinal tract
FOREWORD
Blood system is a concept that embraces the blood itself, the organs of hematopoiesis and destruction of blood cells. Blood system in children of different age periods is constantly changing, both in quantitative and qualitative terms.
Blood is the most important integrating system of the human body which provides stability of metabolism, exchange of metabolites and information between cells and tissues, performs plastic and protective functions of the body. The total amount of blood in a newborn in relation to body weight is 15%, in children aged 1 year
− 11%, in an adult − an average of 6-8%. Each day, this amount of blood passes through the heart more than 1000 times. However, only 40-45% of blood circulates in the bloodstream, since another part is located in the depot: the capillaries of the liver, the spleen and subcutaneous tissue − and is included into the bloodstream inhyperthermia, muscular work, blood loss, etc. Diseases of the blood system in children are quite common (16.6 cases per 1.000 of newly diagnosed diseases and 43.9 of all diseases).
This is due to anatomical and physiological immaturity of the blood organs and their high sensitivity to the unfavorable environment.
Differential diagnosis of blood pathology in children is impeded by significant anatomical and physiological characteristics as compared with adults, especially early in life. In recent years, significant clinical experience has been accumulated, issues of pathogenesis have been explored, new methods have been developed that allow us to diagnose diseases of the blood system more accurately, but it still requires knowledge and data. The present manual is designed for the effective study of blood diseases in children and involves the assimilation of issues on anatomical and physiological characteristics of the blood system, semiotics of lesions, methods for objective and laboratory tests, etiology, pathogenesis, clinical manifestations, diagnosis, treatment and rehabilitation of children with the most common diseases of blood and blood-forming organs.
The manual is intended for students of higher educational institutions of III-IV accreditation levels. The authors hope that this work will be useful to readers. All possible criticisms will be accepted with deep gratitude.
UNIT 1. EMBRYOGENESIS OF THE HEMATOPOIETIC SYSTEM
Hematopoiesis begins in the yolk sac on the 3rd week of embryogenesis. It contains stem cells that can give rise to all blood-forming buds. The formation of primary erythroblasts occurs within the vessels. After 6 weeks of fetal development, the first nuclear-free red blood cells are observed in the bloodstream. At the 3rd-4th week, the liver anlage occurs, and since the 5th-6th week, it becomes the principal organ of blood formation. During the hepatic hematopoiesis, erythropoiesis predominates, but starting from the 8th-10th week, the granulocyte precursors are also observed.
Hematopoiesis in the liver reaches its maximum at the 19th-20th week and is terminated at the end of antenatal period.
Starting from the 3rd month of fetal life, the anlage of spleen and bone marrow occurs. In the spleen, blood formation begins from the 12th week: red blood cells, granulocytes, megakaryocytes are produced. Since the 20th week, intensive lymphopoiesis begins, which lasts throughout the life. Spleen gradually loses the functions of universal blood formation organs, and starts producing B-lymphocytes and immunoglobulins. In lymphopoiesis, an important role also belongs to the thymus. It determines the differentiation of T-lymphocytes. The development of peripheral lymphoid tissue starts from the 4th month of fetal development.
In the bone marrow, hematopoiesis begins from the 13th-14th week and initially occurs in all bones. Pluripotent stem cells appear which are capable of producing lymphoid and myeloid elements. With the development of skeleton, the foci of hematopoiesis shift to flat spongy bones.
Bone marrow of a newborn constitutes 1.4% of its weight and fills the cavity of almost all long bones. During the growth of the child, the mass of bone marrow increases and amounts to 1.4 kg, but it is gradually replaced by fatty tissue in the tubular bones. In the flat bones, marrow is stored throughout the life. In adults, the weight of bone marrow is 4.6% of body weight, but the red marrow is only 50% of its total mass.
After the age of 30, hematopoiesis takes place only in the bone marrow of the sternum, ribs, and vertebral bodies. Differentiation and maturation time of erythroid cell is about
12 days, granulocytes − 13-14 days. Circulation time of different cells: red blood cells are in the bloodstream for 120 days, platelets − 10 days, neutrophils − about 10 hours.
Reserve capacities of cells in the bone marrow are also different: the number of mature neutrophils is by 10 times more than in the bloodstream; there is a 3-day supply of reticulocytes.
Young children are characterized by functional lability of blood and possible return to the embryonic type, when hematopoiesis appears in the liver, spleen, lymph nodes. The appearance of myeloid or lymphoid metaplasia in the bone marrow is typical under the influence of exogenous and endogenous factors due to the relatively high content of undifferentiated cells that are easily converted to myelo- or lymphoid series.
Children are also characterized by high regenerative ability, but rapid depletion of hemopoietic apparatus.
The process of hematopoiesis in accordance with the unitary theory is presented in the scheme of hematopoiesis by I.L. Chertkov and A.I. Vorobyev (1973, 1981), where hematopoiesis is seen as a series of successive cellular differentiations of a single stem cell (Figure 1). Depending on the type of final formation, formed elements of all cells of hematopoietic tissue are vertically divided into hematopoietic lineages (erythroid, myeloid and megakaryocytic). By the degree of differentiation (horizontally), the bone marrow cells are divided into 6 classes:
I − pluripotent progenitor cells (stem cells);
II − partly determined progenitor cells, which have a limited supply of information, namely lymphopoiesis progenitor cells and myelopoiesis progenitor cells;
III − unipotent poietic-sensitive progenitor cells that give rise to one of the lineages of blood formation, in other words, there are progenitor cells of erythropoiesis, myelopoiesis, thrombocytopoesis;
IV − morphologically recognizable proliferating cells that have certain morphological features;
V − maturing cells that are represented by all transitional forms;
VI − mature cells: red blood cells, granulocytes (neutrophils, eosinophils, basophils, monocytes) platelets.
Erythropoiesis. The morphology of red blood cells
Erythropoiesis is regulated by erythropoietin − a hormone of glycoprotein nature, 90% of which is produced in the kidneys (synthesized by cells of juxtaglomerular apparatus and epithelial cells of renal glomeruli), a small portion is synthesized by hepatocytes. The kidneys produce proerythropoietin, which does not have a specific activity. Proerythropoietin in plasma under the action of a specific enzyme erythrogenin is converted into active erythropoietin. There are other regulators of erythropoiesis.
Namely, androgens stimulate erythropoiesis (they increase the synthesis of erythropoietin). Vitamins and minerals also have the regulatory impact. The inhibitor of erythropoiesis − erythrocytic chalone, released from mature red blood cells − also takes part in the specific regulation. Its mechanism of action is to reduce the proliferative activity of erythron. In addition, in red blood cells, the erythrocytic anti-chalone has been detected, which stimulates erythropoiesis by feedback type.
Erythropoiesis under normal conditions undergoes the following steps: burst- forming unit → colony forming unit → erythroblast → pronormocyte → normocyte → erythrocyte. At the stage of normocyte, the denucleation of cells occurs. The remains in the erythrocyte nucleus are defined as Jolly bodies, Cabot’s ring bodies, azurophil granules. Under physiological conditions, along with the loss of the nucleus hemoglobin accumulates in the cytoplasm of the erythrocyte. The active part of the life cycle of red blood cells takes place within the peripheral blood, where they come from bone marrow at the reticulocytes stage. Reticulocyte is a nuclear-free erythrocyte containing basophilic component that is shown in a grid during staining. Production of reticulocytes in the bone marrow is 3 • 109 cells/kg per day. In the bone marrow, reticulocytes are stored for 36-44 hours, then they go into the blood, and mature there within 24-30 hours. The entire life cycle from erythroblast to reticulocyte is from 3-4 to 5-7 days.
The number of formed red blood cells depends on age. Before the child’s birth, the daily production of red blood cells is 3% of the total mass of circulating red blood cells. By the 5th day of life, the formation of red blood cells is reduced to 0.2% and on
the 10th day − to 0.1%. By 3 months of age, the production is 2% of the total mass of red blood cells and is kept at this level for the whole period of childhood.
Normally, a red blood cell has the shape of a biconcave disc of pink-red color which is lighter in the center. The average diameter of the erythrocyte is 7.2-7.5 µm, thickness − 2-2.5 µm. The discoid shape allows them to have a more extensive surface by 1.7 times than the spherical one, and it has a greater capacity for deformation in the capillaries. Normally, red blood cell can deform and pass through capillaries with lumen of 3 µm. This is due to the interaction between the proteins of membrane (segment 3, glycophorin) and cytoplasm (spectrums, ankyrin). Defects in these proteins cause morphological and functional changes in the erythrocyte.
Mature erythrocyte does not have cytoplasmic organelles and therefore is not able to synthesize proteins and lipids. The main way of energy metabolism in the erythrocyte is glycolysis. Glycolysis energy is used for active transport of cations through the cell membrane to maintain normal ratio between sodium and potassium ions in the red blood cells and plasma and to maintain the form of red blood cells.
The main function of red blood cells is the transport of oxygen from the lungs to the tissues, and carbon dioxide from the tissues to the lungs. This function is performed by hemoglobin (Hb) − a special protein found in red blood cells. Red blood cells play a certain role in hemostasis, they are involved in the formation of the primary hemostatic plug and transport the plasma factors of blood clotting, adsorbed on their surface.
Normally, the life span of red blood cells in adults is 110-120 days, the time of circulation in the bloodstream in term infants is 60-70 days, and in premature infants − 35-50 days. Under physiological conditions, the number of destroyed red blood cells is equal to the number of newly formed ones, therefore, their number remains constant. In
physiological conditions, the ageing RBCs are removed from circulation and are destroyed mainly in the spleen, liver and to a lesser extent − in the bone marrow. It is known that fraction of IgG serum contains antibodies against the old red blood cells.
Their attachment to the erythrocyte leads to the phagocytosis of the latter. Products released in the intracellular destruction of hemoglobin are amino acids (from globin), iron (from heme) which are used in the body to build hemoglobin. Heme after detachment from iron in microtomes is converted using hemoxygenase at first into biliverdin and then into bilirubin. Bilirubin is released into the blood, where it binds to albumin and is transported to the liver. In hepatocytes, it is conjugated with glucuronic acid by means of enzyme glucuronosyl transferase, thus transforming into direct bilirubin, which then enters the intestine with bile.
Normally, a part of red blood cells is destroyed in the bloodstream, Hb is connected to the haptoglobin in the irreversible complex, which due to its size does not penetrate the liver filter, and is enzymatically broken down in the liver. If intravascular hemolysis is significant and haptoglobin cannot bind all released Hb, its surplus goes to the kidneys, and the portion is excreted in the urine (hemoglobinuria), a part is reabsorbed in the proximal section of tubule, and a part of hemoglobin iron is deposited in the tubular epithelium in the form of ferritin and hemosiderin, and is slowly excreted with urine.
The structure, functions, biosynthesis features and types of hemoglobin
Hemoglobin is the main component of red blood cells (about 98% of red cell mass). By its chemical nature, Hb belongs to chromoproteins, and incorporates protein (globin) and iron-group (heme). Heme is a complex compound of iron and protoporphyrin IX. Heme structure is the same for all types of hemoglobin. Only the protein part − globin − is different. The main component of human hemoglobin − HbA (95-98% of blood hemoglobin) consists of two α-and two β-chains. Other normal types of human hemoglobin are НbА2 (2-2.5%) and HbF (0.1-2%).
In red blood cells of embryo, fetus, child and adult, one can define 6 types of hemoglobin: embryonic (Gower-1, Gower-2 and Portland); fetal hemoglobin (HbF) and adult types HbA1 and HbA2. From the 8th week of gestational age, hemoglobin HbF is
the dominant type, which constitutes 90% of the total amount in the fetus up to 6 months. HbF level gradually decreases, and by birth is about 70% of the total amount.
In the postnatal period, its level rapidly decreases, and at the age of 6-12 months only traces are detected.
UNIT 2. ANATOMICAL AND PHYSIOLOGICAL FEATURES OF BLOOD FORMATION
Blood in newborns
In the blood of newborns, there is a high content of red blood cells (5-7 • 1012/l) and hemoglobin (180-240 g/l). The main part of hemoglobin is HbF (80%). In addition, in the blood of some infants, abnormal forms of hemoglobin (Hb Baris, Lepore and others) can be observed. These hemoglobins have identical hemes and different structure of globin. Like НbF, they have high affinity to oxygen (easily attach it, but poorly give it away to the tissues). Therefore, the transport function of this hemoglobin is weak. Red blood cells in newborns have a higher hemoglobin content corresponding to a higher color indicator. At birth, it amounts to 1.1, indicating hyperchromia. These features are associated with fetal hypoxia during fetal development. After the birth, the oxygen supply becomes sufficient and red blood cells from НbF are destroyed.
Throughout the neonatal period, the level of red blood cells and hemoglobin is gradually reduced, and by the end of the first month of life, the number of erythrocytes equals to 4.7 • 1012/l, and hemoglobin − 156 g/l.
For newborns, anisocytosis (sizes of red blood cells vary between 3-13 µm), poikilocytosis (red blood cells of irregular and varying shape due to different elasticity of the membrane), polychromatophilia (different color) are typical. Numerous reticulocytes (8-42 ‰) are characteristic. By the end of the 1st week of life, their number is reduced to 7-10 ‰. The average life span of red blood cells in the neonatal period is less than in adults. At the 2nd-3rd day after birth, it is 12 days. Red blood cells have a lower osmotic resistance: hemolysis in hypotonic NaCl solution is observed at higher concentrations of NaCl, than in adults.
Platelet count significantly ranges from 140 • 109/l to 450 • 109/l.
At birth, physiological leukocytosis is observed: 11-33 • 109/l. Maximum rates of leukocytosis are observed in the first hours after birth, then during the 1st week of life, the number of leukocytes gradually decreases to 10 • 109/l. Further, there is again a gradual increase in the number of leukocytes to 12 • 109/l. The leukocyte formula at
birth is dominated by neutrophils − 60-70%, there is a shift of myelocytes to the left.
The amount of lymphocytes at birth is 20-30%. By the end of the 1st day of life, neutrophil count is gradually reduced, while the amount of lymphocytes increases. By the 5th-7th day of life, there is the first intersection of neutrophils and lymphocytes curves when their percentage is equal and amounts to 43-45%.
Later on, during the neonatal period in the peripheral blood, the lymphocytes count increases and the amount of neutrophilic granulocytes decreases. At the end of neonatal period, promyelocytes and myelocytes disappear from the peripheral blood and generally only segmented ones are left, as well as a small percentage of stab neutrophils.
The amount of monocytes after birth is up to 10%, and during the first two weeks, a slight increase is observed. The amount of eosinophilic granulocytes after birth may be 1-10%, but in the first days of life it reaches the usual level. Erythrocyte sedimentation rate in infants is 2-3 mm/hr.
Factors affecting the features of the peripheral blood in newborns:
1) insufficient oxygen supply of the fetus with compensatory increase of erythropoiesis;
2) changes in the biochemical composition of the blood;
3) termination of hormonal influence of the mother’s blood;
4) relative blood thickening;
5) absorption of decay products from embryonic tissues;
6) massive bacterial invasion after birth;
7) the nature of feeding (lactotrophic);
8) a higher content of red blood cells than in adults.
Blood in infants
Hb level and the amount of red blood cells reach the physiological minimum at the age of 3 months. Red blood cells are thus reduced to 3.0 • 1012/l, hemoglobin − to 90 g/l, reticulocytes − to 1-2 ‰. This confirms the hypothesis that the physiological decline in red blood cells is based on the physiological immaturity of erythroid lineage of bone marrow (erythropoietin deficiency, poor development of receptors in the progenitor
cells to erythropoietin, intense disintegration of red blood cells containing fetal hemoglobin (HbF).
In the 2nd half year of life, Hb content is increased to 110-120 g/l, erythrocyte count to 4.0-4.5 • 1012/l, reticulocytes − to 5-10 ‰. However, iron deficiency anemia may develop in some infants due to the intense growth and insufficient exogenous supply with iron.
Platelet count is 180-350 • 109/l.
The number of leukocytes ranges within 10-12 • 109/l. From the age of 4-6 months, the leukocyte formula is dominated by lymphocytes (60-65%), neutrophil granulocytes amount to 25-30%. Among neutrophilic granulocytes, segmented forms make up the bulk of it. Eosinophilic granulocytes and monocytes do not significantly change in quantitative proportion.
ESR is 6-8 mm/hr.
Blood in children above the age of 1 year
At the end of the first year, the number of red blood cells, white blood cells and platelets is relatively constant and composition of peripheral blood gradually acquires features of an adult. After the age of 1 year, red blood cells amount to 4.0-5.0 • 1012/l, Hb − 120-160 g/l, reticulocytes 4-10 ‰. The diameter of red blood cells reaches the adult values until 5-6 years of age. Color index is 0.85-1.05.
Platelet count is within 180-320 • 109/l.
The qualitative changes of white blood cells count take place. After the age of 1 year, the number of lymphocytes begins to decrease, while the number of neutrophils increases. During this process at the age of 5-6-years, their equal amount is again observed (the second intersection). The final composition of the blood is established in prepubertal age: neutrophil percentage − 60-65%, lymphocytes − 25-30%. In healthy children over 1 year of age, plasma cells disappear from the peripheral blood.
UNIT 3. LESION SYNDROMES OF THE HEMATOPOIETIC SYSTEM
The main syndromes of blood system are:
- anemic;
- hemorrhagic;
- leukemoid reaction;
- lymphoproliferative;
- sideropenic.
Clinical signs of anemic syndrome:
1) asthenic-neurotic syndrome (drowsiness, adynamia, reduced intelligence and emotion, delay in the psycho-motor development);
2) epithelial syndrome (dystrophy and atrophy of barrier tissues − skin and mucous membranes, their inflammatory changes), taste disturbance;
3) immunodeficiency syndrome − frequent ARVI, intestinal disease, early formation of chronic foci of infection;
4) hypoxic syndrome − malaise, disturbance of consciousness, headaches, muscle pain;
5) cardiovascular syndrome − tachycardia, weakened heart tones, functional systolic murmur;
6) changes in the respiratory system − tachypnea;
7) hepatolienal syndrome − moderate enlargement of liver and spleen.
The triad of hemolytic anemia is as follows: hepatolienal syndrome, jaundice, anemia.
Clinical manifestations of hemorrhagic syndrome depend on the type of bleeding:
a) hematomal − occurs in coagulopathies (hemophilia A, B, C, Christmas disease); it is characterized by large, painful intramuscular hematomas and hemarthroses.
b) petechial-spotted − occurs is the pathology of platelets (thrombocytopathies, thrombocytopenia, thrombocytopenic purpura, Glanzmann thrombasthenia, leukemia).
The skin spontaneously or after minor trauma develops punctulated hemorrhages
(petechiae) and larger ones − ecchymosis. Bleeding from the mucous membranes is characteristic. Bleeding in internal organs is also possible.
c) mixed − occurs in the pathology of factors of plasma and platelet links of homeostat (Willebrand disease).
d) vascular purpuric − is associated with pathology of vascular wall of primary (immunocomplex systemic vasculitis) and secondary genesis (acute infectious diseases, rheumatism). It is observed in hemorrhagic vasculitis, vitamin K deficiency, infectious and toxic shock.
e) microangiomatous − is observed in Rendu-Osler disease; resulting from reduced resistance and easy destruction of the vessel wall due to its focal (local) thinning and as a result of weak stimulation in these areas of platelet aggregation and coagulation, in hereditary telangiectasias; it is accompanied by persistent recurrent nasal, gastrointestinal, renal bleeding that occur in damaged telangiectasia.
Leukemoid response syndrome − is a clinical and hematological syndrome, accompanied by changes in the blood and blood-forming organs that resemble leukemia or other tumors of the hematopoietic system, but are always reactive in nature, do not transform into the tumor, which they resemble. They are more common in children aged 3-7 years; they occur more often in boys than in girls.
The reasons are as follows: a) the admission into the blood of endotoxin from the affected intestine, which is a powerful stimulant of granulocytopoiesis (neutrophilic type of leukemoid reaction);
b) massive collapse of cancer cells stimulates myelopoiesis with the release of leuko- and thrombopoietins;
a) infectious processes that are accompanied by a strong immune response, causing leukemoid reaction of lymphatic or monocytic type.
Types of leukemoid reactions:
1. Pseudoblastic reactions occur in neonates with a genetic defect in chromosome, at resolution of immune agranulocytosis; cells similar to blasts in the bone marrow are observed.
2. Promyelocytic reactions occur in toxinfection, allergic dermatitis, atresolution of immune agranulocytosis; a large percentage of promyelocytes is revealed in the points of the bone marrow without inhibition of platelet and erythrocytic lineages.
3. Neutrophilic reactions in septic conditions, in acute blood loss combined with toxinfection; neutrophilic leukocytosis with stab shift is observed.
4. Eosinophilic reactions − in helminthiasis, tumors, allergies, collagenoses, organ eosinophilias (lesions of lung, pleura), eosinophilic leukocytosis (20%), increased number of eosinophils in the bone marrow are observed.
5. The reactions of two or three myelopoiesis lineages − in cancer (hypernephroma), sepsis, cancer metastases in the bone marrow, acute immune hemolysis; neutrophilic leukocytosis, thrombocytosis, erythrocytoma, myelomia (myelocytes, erythrokaryocytes) are observed.
6. Lymphocytic − in infectious mononucleosis, viral infections, yersiniosis; the increase in peripheral blood lymphocyte count and the emergence of infectious mononucleosis cells (blast-transformed lymphocytes) are observed.
7. Monocyte-macrophage − in tuberculosis, rheumatism, yersiniosis, parasitic invasions; it is manifested by monocytosis in peripheral blood and monocyte- macrophage infiltrates (granulomas) in affected tissues (lymph nodes, spleen).
UNIT 4. METHODS FOR EXAMINATION OF PATIENTS WITH BLOOD SYSTEM LESIONS
Complaints: pallor, increased fatigue, headache, dizziness, loss of appetite, irritability; frequent hemorrhages; arthralgia; abdominal pain; fever; taste disturbances.
Anamnesis: genetic anamnesis; adverse pregnancy course, childbirth; diseases in infancy; pathology of the digestive tract; inadequate care; adverse hygiene-and-sanitary conditions.
Examination: color, hemorrhages; enlarged lymph nodes, liver and spleen;
increased joints (hemarthrosis), abdomen, swelling, defects.
Palpation: clinical examination of externally accessible lymph nodes, abdominal and thoracic areas (in their significant increase).
There are the following groups of lymph nodes: occipital; postaural;
submandibular; submental; anterior cervical or tonsillar; posterior cervical;
supraclavicular; subclavian; axillary; cubital; inguinal; popliteal. Palpation of lymph nodes should be sliding, systemic on both sides. One should characterize their size, number, mobility, relationship to surrounding tissue and with each other, tenderness. In healthy children, not more than 3 groups of lymph nodes (submandibular, axillary, inguinal) are palpated. The size from a lentil to a pea is considered normal (II-III degree). Consistency is elastic, palpation is not painful.
On objective examination, tubular bones and sternum are percussed, defining their painfulness, chest (increased mediastinal lymph nodes), abdomen (enlarged liver and spleen).
The study of hematopoietic system includes:
The study of peripheral (capillary) blood and study of bone marrow (myelogram).
Laboratory examination methods of hematopoietic system:
1) Complete blood count;
2) Osmotic resistance of erythrocytes;
3) ABO blood group system and the system of Rh;
4) Coagulogram;
General rules for the collection of blood for analysis.
a) at the same time of the day, usually in the morning;
b) on an empty stomach or one hour after a light breakfast;
c) before any medical procedures;
d) the child should be calm;
e) before morning exercises or other physical activities.
Assessment of blood Red blood cell count
Normal fluctuations in the red blood cells count are:
- In children under 6 years: 3.66 • 1012/l − 5.08 • 1012/l;
- Boys above the age of 7 years and older: 4.00 • 1012/l − 5.12 • 1012/l;
- Girls above the age of 7 years and older: 3.99 • 1012/l − 4.41 • 1012/l.
Increased values − in absolute and relative erythrocytoses:
- absolute − in hypoxic conditions (chronic lung disease, congenital heart disease);
- relative (when plasma volume is reduced while maintaining the amount of red blood cells) − with thickening of the blood (excessive sweating, vomiting, diarrhea, burns, growing swellings).
Reduced values: due to the deficiency of iron, protein and vitamins.
Hemoglobin contents
The optimal level of Hb in the capillary blood for children up to 6 years is higher than 120 g/l, for children over the age of 6 years − higher than 130 g/l.
Increased values: in diseases that are manifested by increase in the amount of red blood cells (primary and secondary erythrocytoses, congenital heart defects, cardiopulmonary failure); in blood thickening (dehydration, burns, vomiting, intestinal obstruction); due to physiological reasons (in the residents of highland areas, after increased physical activity).
Reduced values: in all types of anemia.
Color index (CI) reflects the relative content of Hb in erythrocytes. Normal values of CI are 0.85 − 1.05. The value of CI is important to determine the form of
anemia. Based on this value, anemias are divided into three types: hypochromic (CI is less than 0.85); normochromal (CI is within the normal range, i.e., from 0.85 to 1.05);
hyperchromic (CI is more than 1.05).
The average content of Hb in the erythrocyte (mean corpuscular hemoglobin) (MCH) is the indicator that characterizes absolute hemoglobin content in one erythrocyte.
Normal rates of MCH are 24-33 picograms (pg).
The average concentration of Hb in the erythrocyte (mean corpuscular hemoglobin concentration) (MCHC) is the indicator that reflects the degree of erythrocyte’s saturation with hemoglobin.
Normal values of MCHC are 30-38%.
The average volume of red blood cells (mean corpuscular volume) (MCV) Normal values of mean corpuscular volume are 75-95 µm3.
The average diameter of erythrocytes is 7.2-7.5 μm.
White blood cells
White blood cells perform protective functions, providing phagocytosis of microbes, foreign substances, decay products of cells, participating in the immune responses.
The normal white blood cells count is 4-9 • 109/l (the amount of leukocytes in the age aspect is discussed in Unit 2).
Increased values (leukocytosis):
Absolute leukocytosis − in infants − 12-15 • 109/l (neutrophils 60%), children from the age of 2 weeks to 2 years − 8-13 • 109/l. Daily fluctuations (the content increases in the afternoon): in acute inflammatory and infectious diseases, acute and chronic leukemia, malignant tumors, burns, after blood loss (posthemorrhagic leukocytosis), in the postoperative conditions.
Reduced values (leukopenia) are observed in malnutrition (food deficiency), they are rarely hereditary; can be detected in certain viral and bacterial infections (influenza, viral hepatitis, sepsis, measles, malaria, rubella, mumps, tuberculosis, AIDS).
Leukocyte count is the index, which includes determining the 5 major types of white blood cells (neutrophils, eosinophils, basophils, lymphocytes, monocytes) that perform different functions in the body and represents their ratio (expressed as a percentage). WBC is counted by laboratory doctor via microscopy method of 100 cells in the blood smear or automatic hematology analyzer. It is important to remember that automatic meter does not divide the subpopulation of neutrophils into stab and segmented ones, which is a requirement for counting leukocyte formula under the microscope.
Normally, white blood cells are distributed in the following proportions:
basophils − 0-1%, eosinophils − 0.5-5%, stab neutrophils − 1-6%, segmented neutrophils − 47-72%, lymphocytes − 19-38%, monocytes − 2-11%. In infants above the age of 2 weeks up to 4-5 years, lymphocytes amount is up to 50-60%. Up to 12 years of age, lymphocytes reduce to 25-48%, by 15 years − approach the adult rate.
In newborns, blood is characterized by 60-65% of neutrophils and 25-30% of lymphocytes. Starting from the 2nd day of life, the amount of neutrophils reduces and lymphocytes count increases. At the 5th-6th day, the first intersection occurs, when the amount of neutrophils and lymphocytes is the same. Further, the amount of lymphocytes increases to 60-65%. Subsequently, there is a gradual decrease in the amount of lymphocytes and increase of neutrophils count. At the age of 5-6 years, the second intersection occurs, then leukocyte count gradually approaches the formula of adults.
Thrombocytes are blood platelets, cells non-nuclear with the diameter of 2-4 µm, of irregular rounded shape. They play an important role in blood clotting. The normal platelet count is 180 • 109-320 • 109/l.
Increased values are observed in polycythemia, asphyxia, traumas, inflammation, anemia due to blood loss, after surgery.
Reduced values (thrombocytopenia) below 150 • 109/l are observed in thrombocytopenic purpura, infectious diseases, poisoning, leukemia.
Corpuscular volume (hematocrit − Нt) (ratio of formed elements volume to plasma volume). The normal hematocrit is 0.41-0.53 for men, and 0.36-0.46 − for
women. Hematocrit in neonates is about 20% higher, and in young children − about 10% lower than in adults.
The features of myelogram in healthy children
In the bone marrow of children under 3 years of age, there are significantly more lymphocytes, on average 6-16.5% (40%), while in children above the age of 3, their content is 2-8%.
In the myelogram of children under 3 years of age, there are significantly more granulocyte cells (60%) than in children above the age of 3 (35-40%).
Young children are characterized by lower content (5-10%) of myelocytes and metamyelocytes, while in older children and adults, the content of them is higher (15- 20%).
An important myelogram indicator is the ratio of elements of myeloid and red blood cells, called myeloerythroblastic ratio (M/E). In neonates, M/E ratio is 1.2 : 1; in infants − 2 : 1; in children above the age of 10 years − 3 : 1; in adults − 3.5-4 : 1.
UNIT 5. ANEMIAS IN CHILDREN
Anemia is a pathological condition characterized by a decrease in hemoglobin per unit of blood volume (less than 110 g/l in children under the age of 6 years and less than 120 g/l in children above the age of 6 years). Anemia is the most common group of blood diseases in children, of diverse etiology and pathogenesis. It can occur as an underlying disease and a syndrome of various diseases (systemic blood diseases, systemic connective tissue disease, and others). In this regard, oxidation processes in the body are disrupted and hypoxia develops.
According to WHO, 20% of the planet population suffer from iron deficiency anemia (IDA). The share of hemolytic anemia is about 11.5%. Aplastic anemia is observed much less frequently (10.6 per 1000 000 of child population per year), but is has a malignant course.
Classification of anemias
By the mechanism of development, anemias are divided into 4 groups:
I. Posthemorrhagic anemias (due to external or internal blood loss):
1. Acute.
2. Chronic.
II. Anemia due to insufficient erythropoiesis:
1. Hereditary aplastic anemias:
A. Pancytopenia (in conjunction with birth defects − Fanconi anemia, without congenital anomalies − Estren-Dameshek anemia);
B. With the partial damage of erythroid lineage (Blackfan-Diamond syndrome).
2. Acquired aplastic anemia:
A. With pancytopenia (acute, subacute, chronic forms);
B. With the partial damage of erythropoiesis, including transient erythroblastemia in neonates.
3. Dyserythropoietic anemias (hereditary and acquired).
4. Sideroblastic anemias (hereditary and acquired).
5. Deficiency anemia (due to deficiency of specific factors).
A. Megaloblastic anemias
a) folic acid deficiency (lack of folic acid in the nutrition or malabsorption);
b) vitamin B12-deficiency (malabsorption or transport disruption);
c) orotic aciduria.
B. Microcytic anemias:
a) iron;
b) copper-iron;
c) in lead poisoning.
6. Physiological anemia in neonates.
7. Early anemia of premature infants.
III. Hemolytic anemias:
1. Hereditary:
A. Membranopathies:
a) deficiency or disruption in the structure of protein membrane (microspherocytosis, ovalocytosis, elliptocytosis, stomatocytosis et al.);
b) disruption of lipid membrane (acanthocytosis et al.).
B. Fermentopathies (disruption of enzyme activity of pentose-phosphate pathway, glycolytic cycle, metabolism of nucleotides, glutathione).
C. Defects of structural globin chains (hemoglobin S, C, D, et al., unstable hemoglobins) and synthesis of globin chains (thalassemia), mixed forms.
2. Acquired:
A. Immunopathologic (isoimmune − hemolytic disease of the newborns, transfusion of incompatible blood, autoimmune, hapten, drug-induced).
B. Infections (bacterial, viral, parasitic).
C. Vitamin-deficient (B-vitamin-deficient anemia in premature infants).
D. Toxic (poisoning by heavy metals and other chemical compounds, oxidants).
E. Paroxysmal nocturnal hemoglobinuria.
F. DIC of different etiologies and mechanical damage of red blood cells.
IV. Anemias of mixed genesis:
A. In acute infections, sepsis.
B. In burns.
C. In tumors and leukemia.
D. In endocrinopathies.
The classification given above takes into account only the leading pathogenetic factor. In many cases, anemia can be attributed to several groups. Chronic posthemorrhagic anemia is iron deficiency by pathogenesis. In chronic infections and inflammatory diseases, the demand for iron in reticulo-endothelial cells increases and iron deficiency anemia also develops, while treatment with iron in this case has a minimal effect on hematopoiesis.
Clinical manifestations of anemia
Clinical course of anemia depends on the etiology, rate of its progression and adaptive capacities of the child. Due to reduction in hemoglobin, symptoms caused by tissue hypoxia occur. Patients complain of fatigue, drowsiness, tinnitus, dizziness, decreased performance, drowsiness or insomnia. Along with general symptoms of anemia, each option has its own specific symptoms: sideropenic syndrome − in iron deficiency anemia, jaundice − in hemolytic anemia, neurological disorders − in B12- deficiency anemia, hemorrhagic syndrome − in aplastic anemia.
An important role in the differential diagnosis of anemic belongs to anamnestic data. In collecting the history, one should clarify the following issues:
- The occurrence and rate of anemia progression (usually hereditary anemia is manifested at an early age, anemia with the course of crises over the years can also indicate a hereditary process);
- Information about the pregnancy of the mother, nutrition, presence of preeclampsia, the threat of termination, medications during pregnancy, industrial hazard, bad habits;
- The nature and dates of delivery;
- The possibility of chronic hemorrhage (bleeding);
- The presence of anemia, jaundice in the maternal and paternal lines, health condition of other children in the family;
- The nature of the child’s feeding, especially in the first year of life;
- The possibility of the child’s contact with various toxins and poisons (mercury, lead, benzine, pesticides, etc.).
The child’s objective examination displays the signs typical of anemias of different genesis.
The skin and mucous membranes
Pale skin and mucous membranes are the typical manifestations of anemia of non-hemolytic nature. Pale skin combined with icterus is typical of hemolytic anemia.
Pale skin along with hemorrhagic rash (petechiae, purpura) indicates anemia combined with thrombocytopenia (hypo- and aplastic anemia). Dryness, trophic disorders of the skin and its appendages are most characteristic for iron deficiency anemia. Smoothing of lingual papillae occurs in megaloblastic anemia.
Lymphatic system. Severe lymphadenopathy is not characteristic of anemia as an underlying disease and suggests the diagnosis of anemia syndrome in other diseases, such as leukemia, lymphoma, or infectious diseases (tuberculosis, AIDS, toxoplasmosis, etc.).
Cardiovascular system. Tachycardia, the appearance of systolic murmur of functional nature, muffled heart tones, expanded boundaries of the heart to the left indicate the severe and prolonged course of anemia.
The organs of gastrointestinal tract. Hepatosplenomegaly is characteristic of hereditary and autoimmune hemolytic anemia with a prolonged course.
Nervous system. Ataxia, paresthesia, clonus, appearance of pathological reflexes are typical of B12-deficiency anemia.
Deficiency anemias in children
80% of hematological diseases account for deficiency anemias. In modern classification, deficiency anemias are divided into:
1) primarily iron deficiency, 2) primarily vitamin deficiency, 3) primarily protein deficiency.
There has recently been a redistribution of deficiency anemias toward poly- deficiency, which is especially important for children during the first 3 years of life.
Iron deficiency conditions (IDC − ICD-10: D50) are most often observed in childhood.
Classification of iron deficiency anemias (IDA):
1. By the form: alimentary; posthemorrhagic; due to increased consumption of iron; disrupted transport of iron (atransferrinemia) and others.
2. By the stage: pre-latent iron deficiency; latent iron deficiency; iron deficiency anemia.
3. By the severity: mild anemia (Hb 110 − 91 g/l); medium severity anemia (Hb 90 − 71 g/l); severe anemia (Hb 70 − 51h/l); extremely severe (Hb less than 50 g/l).
The relevance of the problem of iron deficiency in children goes beyond the phenomenon of anemia. In addition to hemoglobin, the iron is found as a part of many enzyme systems which provide tissue respiration and immune reactions; iron also takes part in the biosynthesis of collagen and DNA.
According to WHO statistics, approximately 1 billion of people in the world suffer from iron deficiency. Iron deficiency anemia and iron deficiency conditions (IDC) have always been common among children and adolescents.
Causes of IDC.
Antenatal:
- Disorders of utero-placental circulation (toxicosis, threatened miscarriage, somatic and infectious diseases of the mother);
- Feto-maternal and feto-placental bleeding;
- Prematurity, multiple pregnancy;
- Deep and prolonged iron deficiency in pregnancy.
Intranatal:
- Fetoplacental transfusion;
- Intrapartum bleeding.
Postnatal:
- Insufficient intake of iron from food (early artificial feeding, dairy-and- vegetarian diet, unbalanced diet);
- Increased need for iron in children (premature infants; neonates with high birth weight; children of the second half year and the second year of life, prepubertal and pubertal age);
- Increased loss of iron through bleeding, disorder of intestinal absorption (malabsorption syndrome, chronic bowel disease);
- Disrupted metabolism of iron in the body due to hormonal changes in the transport of iron.
In children with IDC, Hb content in the blood is not beyond the age norm and is usually located at the lower limits: 110-118 g/l − in children during the first 5 years of life; 120-128 g/l − in children above the age of 5 years (as recommended by WHO). In this regard, one can observe the disappearance of reserve iron and reduction of its content in the tissues. In IDC, further depletion of tissue iron continues and the reduction of hemoglobin iron begins, leading to anemia.
The main localizations of iron in the body are: 1) Hb of erythrocytes; 2) brain cells; 3) myoglobin of muscles, liver, spleen, bone marrow; 4) enzymes of oxidizing group.
Iron in the body is represented in the form of heme and non-heme compounds (Table 2).
Heme compounds of iron.
Hemoglobin (translated as “blood corpuscle”) is a complex protein-pigment complex which is found in erythrocytes. It transports oxygen from the lungs to the tissues and carbon dioxide from the tissues to the lungs.
Heme is a complex compound of pigment protoporphyrin with ion of ferrous iron.
Heme is a non-protein molecule of Hb. It is also a part of myoglobin and enzymes (cytochromes, catalase, etc.). Iron, which is included in these compounds, is called heme iron. Heme iron is much better absorbed by the body than ionized one or iron, which is not a part of protoporphyrin compounds. Protoporphyrin is a pigment, which is synthesized in the body from succinic acid and glycine and has the affinity for ions of ferrous iron.
Myoglobin is a pigment heme-containing proteid that is found in muscle tissue.
Myoglobin transports oxygen and is deposited in muscle tissue.
Catalase is aheme-containing enzyme that catalyzes the redox reaction, whereby the disintegration of hydrogen peroxide to form oxygen and water occurs. The physiological role of catalase is to protect the body from excess peroxides.
Cytochromes are heme-containing proteids, which provide tissue respiration.
Peroxidases are heme-containing enzymes that catalyze the oxidation of compounds using hydrogen peroxide. Their physiological role consists in protecting the body from excess peroxides.
Non-heme iron compounds
Xanthine oxidase is the enzyme that catalyzes the oxidation of xanthine, hypoxanthine and aldehydes with the absorption of oxygen and the formation of urinary and carboxylic acid, xanthine.
Acetyl-coenzyme-A dehydrogenate is the enzyme that catalyzes the oxidation of macroergic compounds of acetyl coenzyme A, participates in the metabolism of fatty acids.
Succinate-dehydrogenase is the enzyme that catalyzes the reverse reaction of oxidation of succinic acid into fumaric. It participates in the citric acid cycle.
NAD-H dehydrogenase is the enzyme that is involved in restoring NADP, catalyzes the transfer reaction of hydrogen atoms.
Transferrin, ferritin and hemosiderin are non-heme compounds of iron, taking a direct part in the metabolism of iron.
The functions of iron in the body. The main function of iron is the transport of oxygen and participation in oxidative processes (using 72 enzymes that contain iron).
Iron plays an important role in maintaining the high level of immune resistance of the body. Adequate iron content in the body promotes the proper functioning of factors of nonspecific defense, cellular and local immunity. Indirect stimulating effect of iron on myeloperoxidase and enzyme systems by Н2О2 generation contributes to the maintenance of phagocytosis activity at the required “protective” level. Iron through the system of ribonucleotide reductase supports the normal proliferation and mitotic activity
of T-lymphocytes. Regulation of the expression of class II surface antigens of the major histocompatibility complex on T-cells occurs in the obligatory participation of iron enzymes. In sideropenia, the number of T-lymphocytes is reduced by 50%, their functionality is disrupted, the synthesis of secretory component of IgA in the mucus of nasopharynx and digestive tract is disturbed, which impairs the barrier function. The phagocytic activity of neutrophils is disrupted as well.
According to new data, after Hb of erythrocytes, the largest amount of iron is found in the cells of the brain. Iron deficiency in them leads to the disruption of neuropsychiatric features, reduced performance of intelligence quotient (IQ), delayed formation of logical thinking, language deterioration, learning deviations in the child’s psyche.
Many authors believe that simultaneously with the development of sideropenia and its progression, the glucocorticoid and androgen functions of adrenal glands are impaired.
Thus, IDC leads to the profound dysfunction of four major systems: the blood, the nervous, immune and adaptive systems. In addition, in iron deficiency, degenerative changes develop in the epithelium of the skin, mucous membranes of the mouth, gastrointestinal tract, the respiratory tract. Clinically it is manifested by dryness of the skin, dryness, fragility and hair loss. Peeling and brittle nails are observed, less frequently – celonychia, angular stomatitis, atrophy of lingual papillae, glossitis, dysphagia, and chronic gastroduodenitis develop. The amount of gastric juice, its acidity, the activity of gastric and pancreatic enzymes are reduced, the absorption of amino acids, vitamins, trace elements is disrupted.
In other words, iron deficiency leads to enteropathy and is accompanied by malabsorption syndrome. An important aspect of sideropenic enteropathy is the intestinal bleeding with the volume is 0.5-2.0 ml/day. The role of these bleedings in the exacerbation of iron deficiency in children is significant. Enteropathy is clinically manifested by the decrease in appetite.
Diagnostics of IDC. Pre-latent iron deficiency in the body is characterized by the depletion of tissue iron stores. Levels of transport fund of iron and Hb are within the age
norms. In children with the decreased tissue iron stores, its absorption from the food is not increased, but decreased. It is associated with the reduction of enzyme activity of ferrum absorption in the child’s intestine.
Latent iron deficiency develops against the background of depletion of tissue iron stores and is characterized by the reduction of the deposited iron and transport pool without reducing Hb and development of anemia.
Iron deficiency anemia is the clinically manifested iron deficiency condition. It develops only in depleted iron stores of the body. Hb concentration reduces and anemic hypoxia develops. Enzyme activity of tissue respiration is inhibited, and degenerative processes in tissues develop.
Symptoms of IDC: sideropenic; generally anemic.
In young children, the following symptoms predominate:
1) pale skin;
2) growth delay or weight loss;
3) frequent ARVI.
In 10% of infants with IDC, hepato- or splenomegaly is found.
In older children (7-12 years), the skin-and-epithelial syndrome is in foreground:
dry skin; peeling skin on the elbows and knees; darkened and brittle hair; atrophy of lingual papillae (“varnished” tongue); cracked tongue, painful cracks in the corners of the mouth (angular stomatitis).
One simple test to identify the IDC isbeeturia symptom (pink color of urine after consumption of red beet salad). The reason is that with a sufficient amount of iron, the liver can completely desaturate the beet colors by enzymes that iron contains.
The peculiarities of clinical manifestations of IDC in teenagers include dizziness, syncope, hypotension. Clinical course of IDC is similar to vegetative dystonia since the asthenia syndrome is distinct (weakness, shortness of breath on exertion, fatigue, headache, inability to focus, reduced academic performance). On the ECG of these children, the degenerative changes in the heart muscle are determined (sideropenic myopathy). It can be suspected at the lowered voltage of QRS complex and the T wave,
in tachycardia. Phonocardiogram (PCG) indicates the weakening of the papillary muscles.
Laboratory criteria for IDC diagnosis:
Microscopic changes in red blood cells undergo the following steps:
- isolated microcytes appear among the red blood cells;
- anisocytosis occurs (erythrocytes of various sizes);
- hypochromia of red blood cells;
- poikilocytosis (erythrocytes of various shapes);
- basophilic stippling of red blood cells;
- normoblastosis.
Laboratory parameters that characterize the status of iron metabolism
Iron metabolism in the body is characterized by the parameters of the transport fund and iron stores parameters. Iron transport fund is determined by the following factors: serum iron (SI), total iron-binding capacity of serum (TIBC), latent iron-binding capacity of serum (LIBC), ratio of transferrin saturation (RTS).
Serum iron (SI) is the amount of non-heme iron in serum. Non-heme serum iron is a part of transferrin and ferritin serum.
Age-standardized values of serum iron:
- In neonates: 5.0-19.3 µmol/l;
- In infants over the age of 1 month: 10.6-33.6 µmol/l.
Total iron-binding capacity of serum (TIBC) is an indicator that characterizes the total amount of iron that can bind with plasma transferrin.
Normal values of TIBC are 40.6-62.5 µmol/l.
Latent iron-binding capacity of serum (LIBC) is an indicator that reflects the mathematical difference between the values of TIBC and SI: LIBC = TIBC − SI
In the norm, the value should not be less than 47 µmol/l.
The ratio of transferrin saturation (RTS) is an indicator that indicates the proportion of TIBC to SI:
RTS = (SI: TIBC) 100%
Normally, RTS value should not be less than 17%.
SI in normal conditions is ⅓ of TIBC. When SI reduces, TIBC increases. This is due to the increase in the LIBC values. At the same time, the coefficient of transferrin saturation is reduced due to decreased proportion of “transferrin bound to iron”.
The indicators of body iron stores
Body iron stores are characterized by the parameters of desferal test and serum ferritin levels.
Desferal test is based on the ability of desferal to form compounds with iron, which is a part of hemosiderin, ferritin and is excreted in the urine. By daily urinary excretion of these complexes, the iron stores in the body are assessed. Normally, the desferal test result is 0.3 − 0.4 mg/day.
Serum ferritin characterizes the iron stores in the body.
Normal levels of serum ferritin in infants are 175 mg/l, in children aged from 1 to 14 years − 32-36 mg/l. Regardless of age, the serum ferritin below 10-12 µg/l is considered the criterion of iron stores depletion.
Treatment of IDC
Important elements of treatment are: elimination of etiologic factors, clinical nutrition (for infants − breastfeeding, and in the absence of milk in the mother − adapted infant formula fortified with iron, early introduction of complementary foods, meat, especially beef, innards (meat by-products), oatmeal and buckwheat groats, fruit and vegetable mash, hard cheese, reduced intake of phytates, phosphates, tannin, calcium that impair iron absorption), pathogenetic treatment with iron.
Correction of iron deficiency in mild anemia is carried out mainly by good nutrition, adequate period of staying outdoors. Prescription of iron supplements at the level of hemoglobin 100 g/l and above is not indicated.
Classification of iron supplements I. Monocomponent.
1. Iron sulphate: hemofer prolongatum, ferrogradumet, conferon.
2. Iron fumarate: cheferol.
3. Iron chloride: hemofer.
II. Combined.
1. With folic acid: feromed, fefol.
2. With serine: aktiferrin.
3. With ascorbic acid: sorbifer durules, ferroplex.
4. With ascorbic acid and mucoproteasa: tardyferon.
5. With folic acid, calcium, vitamins C and B: vi-fer, natabsk.
6. With folic acid and amino acids: irravit, irradian.
7. With vitamins of group B and nicotinic acid: fesovit.
It is advisable to prescribe trivalent iron preparations due to their optimal absorption and lack of side effects.
Calculation of daily doses of iron preparations
Daily therapeutic doses of oral iron supplements in medium and severe IDC are as follows:
- up to 3 years − 3-5 mg/kg/day of elemental iron;
- from 3 to 7 years − 50-70 mg/day of elemental iron;
- above the age of 7 years − 100 mg/day of elemental iron.
The daily dose of iron supplements is given to a child in three ways. Treatment should start with ½-¼ of a therapeutic dose, gradually (for 7-14 days) bringing it to the full therapeutic one. This reduces the risk of side effects in ferrotherapy; in case of their development, it allows time to detect the initial signs and take appropriate actions.
When prescribing iron supplements, one should observe the following rules:
1. They should be taken in the intervals between meals, to prevent the formation of insoluble salts, unable to be absorbed from food components.
2. It is advisable to combine them with the prescription of ascorbic acid (0.1 g), which increases the absorption of iron.
3. It is advisable to start therapy with a single dose to identify the body’s tolerance to iron supplements which can prevent adverse reactions, the full daily dose is prescribed only at the end of the week after the initiation of treatment.
4. Treatment must be controlled by studies of peripheral blood with calculation of reticulocyte count before treatment and two weeks after treatment.
Parenteral administration of iron preparations is indicated only: in the syndrome of impaired intestinal absorption and after major resection of the small intestine, nonspecific ulcerative colitis, chronic enterocolitis and severe dysbacteriosis, intolerance to oral medications.
Recovery of normal Hb − is only a part of IDC treatment. After normalization of Hb, it is necessary to restore iron levels in the muscles, nervous system, and depot. For treatment of infants under the age of 1 year, it is needed to use the liquid form. Children above the age of 1 year can be prescribed any iron supplements.
After 2.5-3 weeks of iron preparations intake, one should evaluate the effectiveness of treatment.
Criteria of treatment effectiveness:
1) development of the reticulocytes crisis on the 12th-14th days of treatment (increase in young cells to 20-100 ‰ at the rate of 4-8 ‰);
2) normalization of the morphological features of erythrocytes (elimination of anisocytosis, poikilocytosis);
3) daily increase in hemoglobin by 2 g/l or more;
4) improvement and normalization of the laboratory evidence of iron balance in the body;
5) improvement or normalization of ECG and PCG;
6) disappearance or significant weakening of abnormal murmurs in the heart;
7) improvement in the clinical presentation: reduced muscle weakness, improved memory, elimination of paresthesias in the extremities and others.
Parenteral iron supplements should be used only by highly specific indications, due to the high risk of local and systemic adverse reactions.
The daily dose of elemental iron for parenteral administration is:
- infants aged 1-12 months − up to 25 mg/day.
- infants aged 1-3 years − 25-40 mg/day.
- above the age of three years − 40-50 mg/day.
The course dose of elemental iron is calculated by the formula:
WT • (78-0.35 • Hb), where WT − body weight (kg), Hb − hemoglobin (g/l)
The toxicity of iron supplements. The range between therapeutic and toxic dose of iron is large, therefore iron poisoning during the treatment is rare, but it should be taken into account. The poisoning by iron preparations may be caused by their use in large quantities, wrong dose of parenteral administration. In addition, children may face increased sensitivity to iron (even at low doses). Poisoning is manifested by the following criteria: ceaseless vomiting; recurrent diarrhea; general growing dehydration;
ulceration of the mucous membrane of the digestive tract and the appearance of blood in fecal masses; increase of pronounced pallor; development of soporose condition;
gradual symptoms of shock and coma.
If there are signs (or history) of the intake of excessive doses of iron, one should:
1. Conduct the gastric lavage with a short period of time by 2% aqueous solution of soda.
2. After the gastric lavage, it is necessary to drink 100-150 ml of soda solution. It promotes the formation of iron carbonate, which is very poorly absorbed. After that, gastric lavage should be conducted once again.
3. Give almagel, thereby preventing the necrotic effect of iron salts on the mucosa of the gastrointestinal tract.
4. Anti-shock treatment by generally accepted method.
Since 50-100% of premature babies develop late anemia, from the 20-25 days of life at gestational age of 27-32 weeks, in body weight 800-1600 g (in reducing the concentration of hemoglobin below 110 g/l, and erythrocyte count below 3.0 • 1012/l, reticulocytes less than 10 ‰), apart from iron supplementation (3-5 mg/kg/day) and sufficient protein supply (3-3.5 g/kg/day), erythropoietin is prescribed s/q, 250 units/kg/day three times a week for 2-4 weeks with vitamin E (10-20 mg/kg/day) and folic acid (1 mg/kg/day).
Diet in anemia
The diet of the child must be balanced so as to include foods rich in iron (Table 4). Iron, which is included in products containing heme (e.g., meat) is better absorbed than iron, which is a part of ferritin (liver) or hemosiderin (fish). Culinary processing does not affect the properties of heme iron, therefore there is no need to give the child
