Anaemias

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prepared by M.D., PhD., Associate Professor, Marta R. Gerasymchuk,
Department of pathophysiology,
Ivano-Frankivsk National Medical University, Ukraine

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  • Нормальні значенняЕритроцити (RBC),х 1012/л m - 4-5,1; f - 3,7-4,7Гемоглобін (HGB), г/л m - 130-160; f - 120-140Гематокрит (HCT), % m - 40-48; f - 36-42Середній об'єм еритроцитів (MCV), мкм3 m - 80-94, f - 81-99Середній вміст гемоглобіну в еритроциті (MCH), пг 27-31Середня концентрація гемоглобіну в еритроциті (МСНС), % 33-37Анізоцитоз еритроцитів (RDW), % 11,5-15,5Ретикулоцити, % 0,5-1,2Лейкоцити (WBC), х109/л 4-9Тромбоцити (PLT), х109/л 180-320ШОЕ (ESR), мм/год m - 1-10; f - 2-15
  • Derivation
    The MCV can be conceptualized as the total volume of a group of cells divided by their number. For a real world sized example, imagine you had 10 small jellybeans with a combined volume of 10 µL. The mean volume of a jellybean in this group would be 10 µL / 10 jellybeans = 1 µL / jellybean. A similar calculation works for the MCV.
    1. You measure the RBC index in cells/µL. Take the reciprocal (1/RBC index) to convert it to µL/cell.
    1/5E6 (cells/µL) = 2E-7 (µL/cell).
    2. The 1 µL is only made of a proportion of red cells (e.g. 45%) with the rest of the volume composed of plasma. Multiply by the hematocrit to take this into account.
    2E-7 (µL/cell) * 0.4 (hematocrit has no units) = 8E-8 µL/cell.
    3. Finally convert the units of uL to fL by multiplying by 10^9. The result would look like this.
    8E-8 µL/cell* (1E9 fL / 1 µL) = 80 fL/cell
    Note: The shortcut proposed above just makes the units work out: 10*40/5=80
  • Note the “spiculated” appearance of the outer table of the skull due to extreme erythroid hyperplasia! How is this different from a myeloma skull?
  • ACD, anemia of chronic disease; AD, autosomal dominant; AIHA, autoimmune hemolytic anemia; AR, autosomal recessive; ATP adenosine triphosphate: BPG, bisphosphoglycerate; DAF, decay accelerating factor; EBV, Epstein-Barr virus; EPO, erythropoietin; G6PD, glucose-6-phosphate dehydrogenase; GSH, glutathione; Hb, hemoglobin; HbAS, sickle cell trait; HbSS. homozygous for sickle cell disease; Hct, hematocrit; OBC, oxygen-binding curve; Rh HDN. Rhesus hemolytic disease of the newborn; SLE, systemic lupus erythematosus: XR, X-linked recessive
  • ACD, anemia of chronic disease; AD, autosomal dominant; AIHA, autoimmune hemolytic anemia; AR, autosomal recessive; ATP adenosine triphosphate: BPG, bisphosphoglycerate; DAF, decay accelerating factor; EBV, Epstein-Barr virus; EPO, erythropoietin; G6PD, glucose-6-phosphate dehydrogenase; GSH, glutathione; Hb, hemoglobin; HbAS, sickle cell trait; HbSS. homozygous for sickle cell disease; Hct, hematocrit; OBC, oxygen-binding curve; Rh HDN. Rhesus hemolytic disease of the newborn; SLE, systemic lupus erythematosus: XR, X-linked recessive
  • ACD, anemia of chronic disease; AD, autosomal dominant; AIHA, autoimmune hemolytic anemia; AR, autosomal recessive; ATP adenosine triphosphate: BPG, bisphosphoglycerate; DAF, decay accelerating factor; EBV, Epstein-Barr virus; EPO, erythropoietin; G6PD, glucose-6-phosphate dehydrogenase; GSH, glutathione; Hb, hemoglobin; HbAS, sickle cell trait; HbSS. homozygous for sickle cell disease; Hct, hematocrit; OBC, oxygen-binding curve; Rh HDN. Rhesus hemolytic disease of the newborn; SLE, systemic lupus erythematosus: XR, X-linked recessive
  • Anaemias

    1. 1. 1.1. EryhtropoiesisEryhtropoiesis 2.2. Erythrocytosis and erythropenia.Erythrocytosis and erythropenia. 3.3. Anaemia. Classifications of anaemias.Anaemia. Classifications of anaemias. 4.4. Etiology and pathogenesis of acuteEtiology and pathogenesis of acute and chronic posthemorrhagic anaemia.and chronic posthemorrhagic anaemia. 5.5. Etiology and pathogenesis ofEtiology and pathogenesis of hemolytic anaemias.hemolytic anaemias. 6.6. Anaemias with disorders ofAnaemias with disorders of erythropoesis.erythropoesis.
    2. 2. ActualityActuality  Alterations of erythrocyteAlterations of erythrocyte function involve either insufficient or excessive numbers of erythrocytes in the circulation or normal numbers of cells with abnormal components.  AnemiasAnemias are conditions in which there are too few erythrocytes or an insufficient volume of erythrocytes in the blood.  PolycythemiasPolycythemias are conditions in which erythrocyte numbers or volume is excessive.  Each of these conditions has many causes and is a pathophysiologic manifestation of a variety of disease states.
    3. 3. Eryhtropoiesis is a process of structural, metabolic and functional differentiation from polypotent cell to the differentiated erythrocytes. Life-span of erythrocyte is 100-130 days. Than they destroy mainly in a spleen, liver and marrow. The norm amount of erythrocytes in peripheral blood is 3,7- 4,7×1012/l for women, 4,2-5,2×1012/l - for men. Haemoglobin accordingly - 120-140 g/l and 135-165 g/l. The color index (degree of saturation of erythrocytes by hemoglobin) is 0.85-1.05 Production of erythrocytes: Erythropoiesis
    4. 4. Red blood cell count Male: 4.32-5.72 trillion cells/L* (4.32-5.72 million cells/mcL**) Female: 3.90-5.03 trillion cells/L (3.90-5.03 million cells/mcL) Hemoglobin Male: 13.5-17.5 grams/dL***(135-175 grams/L) Female: 12.0-15.5 grams/dL (120-155 grams/L) Hematocrit Male: 38.8-50.0 percent Female: 34.9-44.5 percent White blood cell count 3.5-10.5 billion cells/L (3,500 to 10,500 cells/mcL) Platelet count 150-450 billion/L (150,000 to 450,000/mcL**) The following are normal complete blood count results for adults: * L = liter ** mcL = microliter *** dL = deciliter Index Normal Value Mean cell volume (MCV) = (hematocrit × 10)/ (red cell count × 10⁶) 90 ± 8 fL Mean cell hemoglobin (MCH) = (hemoglobin × 10)/(red cell count × 10⁶) 30 ± 3 pg Mean cell hemoglobin concentration = (hemoglobin × 10)/hematocrit, or MCH/MCV 33 ± 2%
    5. 5.  1. Mean corpuscular volume (1. Mean corpuscular volume (MCVMCV) =) = PCV in L/LPCV in L/L RBC count/LRBC count/L  2. Mean corpuscular haemoglobin (2. Mean corpuscular haemoglobin (MCHMCH) =) = Hb/LHb/L RBC count/LRBC count/L  3. Mean corpuscular haemoglobin concentration3. Mean corpuscular haemoglobin concentration Hb/dlHb/dl MCHCMCHC == PCV in L/LPCV in L/L Erythrocyte Volume Hemoglobin Content Normal Normocytic Normochromic Increased Macrocytic (higher mean corpuscular volume [MCV]) Hyperchromic (higher mean corpuscular Hb concentration [MCHC]) Decreased Microcytic (lower MCV) Hypochromic (lower MCHC) (femto- is 10−15 ) (pico- is 10−12 ) (deci- is 10−1 )
    6. 6. Normally, MCV is expressed in femtoliters (fL, or 10−15 L), and [RBC] is the quantity expressed in millions per microliter (106 / μL). The normal range for MCV is 80–100 fL. For example, if the Hct = 42.5% and [RBC] = 4.58 million per microliter (4,580,000/μL), then Use of volume-sensitive automated blood cell counters, such as the Coulter counter. In this type of apparatus, the red cells pass one-by-one through a small aperture and generate a signal directly proportional to their volume. Other automated counters measure red blood cell volume by means of techniques that measure refracted, diffracted, or scattered light To calculate MCV, the hematocrit (Hct) isTo calculate MCV, the hematocrit (Hct) is divided by the concentration of RBCs ([RBC])divided by the concentration of RBCs ([RBC]) HIGHHIGH LOWLOW Pernicious anemiaPernicious anemia,, MCV up to 150 fLMCV up to 150 fL Vit B12Vit B12 and/orand/or folic acidfolic acid deficiencydeficiency AlcoholismAlcoholism, as are, as are  CGTCGT & a ratio of AST:ALT of& a ratio of AST:ALT of 2:12:1 Iron deficiency, MCVIron deficiency, MCV  60-7060-70 fL due to dietary intake, GITfL due to dietary intake, GIT or menstrual blood lossor menstrual blood loss ChronicChronic diseasedisease Thalassemia,Thalassemia, sideroblasticsideroblastic anemiaanemia
    7. 7. The system of red blood (erythron) is presented: a)by the organs of hemopoiesis (mainly, by marrow); b)by blood; c)by the organs of hemodieresis (basic by spleen). The spleen and liver can also resume their foetal haematopoietic role in certain pathologic conditions and is called extramedullary haematopoiesis. In the bone marrow, developing blood cells are situated outside the marrow sinuses, from where after maturation they enter the marrow sinuses, the marrow microcirculation and thence released into circulation.
    8. 8. Erythropoietin MechanismErythropoietin Mechanism Imbalance Reduces O2 levels in blood Erythropoietin stimulates red bone marrow Enhanced erythropoiesis increases RBC count Normal blood oxygen levels Stimulus: Hypoxia due to decreased RBC count, decreased availability of O2 to blood, or increased tissue demands for O2 Imbalance Start Kidney (and liver to a smaller extent) releases erythropoietin Increases O2-carrying ability of blood
    9. 9. a)a) increase (increase (erythrocytosis)erythrocytosis) Various changes are in the system ofVarious changes are in the system of erythronerythron, which arise, which arise up in physiology terms and at pathological processes,up in physiology terms and at pathological processes, can be accompanied running the number ofcan be accompanied running the number of erythrocytes in blood:erythrocytes in blood: ErythrocytosisErythrocytosis is multiplying the amount ofis multiplying the amount of erythrocytes higher as norm.erythrocytes higher as norm. Distinguish the followings types of erythrocytosis:Distinguish the followings types of erythrocytosis: A. PrimaryA. Primary (independent forms of illness):(independent forms of illness): 1)1) erythremiaerythremia [polycythemia vera, Osler's disease, Vaquez' disease],[polycythemia vera, Osler's disease, Vaquez' disease], 2)2) «familiar»«familiar» (inherited) erythrocytosis.(inherited) erythrocytosis. B. SecondaryB. Secondary (symptoms of other illnesses or(symptoms of other illnesses or pathological processes):pathological processes): 1)1) absoluteabsolute,, 2)2) relativerelative.. b)b) diminishing (diminishing (anemiaanemia))
    10. 10. ErythremiaErythremia is a disease of tumor nature, which relative to the group ofis a disease of tumor nature, which relative to the group of chronic hemoblastosis.chronic hemoblastosis. The amount of erythrocytes is multiplied considerable inThe amount of erythrocytes is multiplied considerable in peripheral blood. Reticulocytes, neutrophiles, monocytes,peripheral blood. Reticulocytes, neutrophiles, monocytes, platelets increase also. Haemoglobin grows also. Inplatelets increase also. Haemoglobin grows also. In marrow are signs ofmarrow are signs of tumor hyperplasia of myeloid linestumor hyperplasia of myeloid lines.. Displays:Displays: a)a) multiplying viscosity of blood;multiplying viscosity of blood; b)b) aggregation and agglutination of erythrocytes,aggregation and agglutination of erythrocytes, c)c) diffuse thrombosis which leads to violation ofdiffuse thrombosis which leads to violation of microcirculation and results in capillarotrophicmicrocirculation and results in capillarotrophic insufficiency.insufficiency.  •• Family erythrocytosisFamily erythrocytosis usually have inheritedusually have inherited  character, also accompanied multiplying mass ofcharacter, also accompanied multiplying mass of  circulating erythrocytes and volume of blood.circulating erythrocytes and volume of blood.  •• Primary (absolute) erythrocytosisPrimary (absolute) erythrocytosis connect with increasing the amount ofconnect with increasing the amount of stimulators of erythropoiesis (in particular, erythropoietin) and arise up:stimulators of erythropoiesis (in particular, erythropoietin) and arise up: a)a) at chronic hypoxia of different origin;at chronic hypoxia of different origin; b)b) at the local ischemia ofat the local ischemia of kidneys,kidneys, c)c) some types of tumors of kidneys or liver.some types of tumors of kidneys or liver.  •• Second (relative) erythrocytosisSecond (relative) erythrocytosis is linked with:is linked with: a)a) hemoconcentration -hemoconcentration - diminishing of volume of plasma of blood indiminishing of volume of plasma of blood in conditions loss of liquid (diarrhea, vomit, plasmorrhea at burn illness)conditions loss of liquid (diarrhea, vomit, plasmorrhea at burn illness) b)b) by a redistribution of blood –by a redistribution of blood – supply exit of the deposited erythrocytessupply exit of the deposited erythrocytes (stress, acute hypoxia, increase the amount of catecholamines).(stress, acute hypoxia, increase the amount of catecholamines).
    11. 11. Hematological attributes of anemias areHematological attributes of anemias are subdivided on quantitative and qualitativesubdivided on quantitative and qualitative N = 36-48%N = 36-48% AnemiasAnemias are diminishing of amount of erythrocytes and/orare diminishing of amount of erythrocytes and/or hemoglobin in unit of volume of blood with the high-qualityhemoglobin in unit of volume of blood with the high-quality (morphologic and functional) changes of erythrocytes.(morphologic and functional) changes of erythrocytes. Hematological attributes of anemias are subdivided onHematological attributes of anemias are subdivided on quantitativequantitative andand qualitativequalitative.. 1. The quantitative displays include:1. The quantitative displays include: 1)1) reductionreduction of the maintenance of erythrocytesof the maintenance of erythrocytes in unit ofin unit of blood volume:blood volume: •inin menmen isis lower than 4×10lower than 4×101212,, •inin womenwomen isis lower than 3,5×10lower than 3,5×101212 in 1L of blood;in 1L of blood; 2)2) reduction of hemoglobinreduction of hemoglobin concentrationconcentration:: inin menmen isis lower than 130 g/llower than 130 g/l,, • inin womenwomen isis lower than 120 g/llower than 120 g/l;; 3)3) reduction of hematocrit (Htc),reduction of hematocrit (Htc), also known as packed cell volume (PCV) or erythrocyte volume fraction (EVF) in men is lower than 0,43 (43%), in women is lower than 0,40 (40%);in men is lower than 0,43 (43%), in women is lower than 0,40 (40%); 4)4) change of achange of a color indexcolor index – is– is not lower thannot lower than 0,850,85 andand
    12. 12. 2. Qualitative attributes of anemias are presence in2. Qualitative attributes of anemias are presence in blood of:blood of:  1)1) regenerativeregenerative, but not mature forms of erythrocytes;, but not mature forms of erythrocytes;  2)2) degenerativedegenerative changes of erythrocytes;changes of erythrocytes;  3) cells of3) cells of pathological regenerationpathological regeneration..  Regenerative forms of erythrocytesRegenerative forms of erythrocytes (cells of physiological(cells of physiological regeneration) are young immature cells of red blood sproutregeneration) are young immature cells of red blood sprout appearance of which in peripheral blood testifies to amplificationappearance of which in peripheral blood testifies to amplification of regeneration of cells erythroid lines in red bone marrow orof regeneration of cells erythroid lines in red bone marrow or increase of medullar barrier permeability.increase of medullar barrier permeability. 11). Regenerative forms include:). Regenerative forms include: a)a) reticulocytesreticulocytes are nuclear-free cells of brown-green colorare nuclear-free cells of brown-green color with the black including (granules). In a norm their maintenance in blood is 0,2-with the black including (granules). In a norm their maintenance in blood is 0,2- 2%. During the increased regeneration of cells of red line of blood their amount2%. During the increased regeneration of cells of red line of blood their amount can grow to 50%;can grow to 50%; b)b) polychromatophilespolychromatophiles are nuclear-free cells with a cyanotic tint whichare nuclear-free cells with a cyanotic tint which distinguishes them from mature erythrocytes;distinguishes them from mature erythrocytes; c)c) normoblastsnormoblasts (acidophilic polychromatophilic, basophilic) are nuclear(acidophilic polychromatophilic, basophilic) are nuclear precursors of erythrocytes. In a norm in peripheral blood are absent, containedprecursors of erythrocytes. In a norm in peripheral blood are absent, contained only in red bone marrow. Sometimes, at hyperregenerative anemias, in blood itonly in red bone marrow. Sometimes, at hyperregenerative anemias, in blood it is possible to find erythroblasts (precursors of normoblasts).is possible to find erythroblasts (precursors of normoblasts). ReticulocytesReticulocytes
    13. 13. Changes of erythrocytes, which testify about inferiority of these cells, named degenerative. Such changes are characterized by the following phenomena: а) anisocytosis – change in the size of the erythrocytes. Occurrence of macrocytes and microcytes; b) poikilocytosis – change in the form of the erythrocytes. In conditions of a pathology may occur pear-shaped, extended, sickle-cell, oval erythrocytes, and also erythrocytes with the spherical form (spherocytes); c) change in the staining of the erythrocytes, that depends on the contents of hemoglobin in them. Erythrocytes, intensively colored, are named hyperchromatic, with pale staining – hypochromatic. d) presence of pathological inclusions. They include Jolly’s bodies are the rests of nuclear substance; Cabot’s rings – the rests of  nuclear environment having the form of ring or  eight; basophilic granularity – the rests basophilic substances of cytoplasm significative of toxic defeat of red bone marrow. 3). Cells of pathological regeneration3). Cells of pathological regeneration occur when there is changed ofoccur when there is changed of erythropoesis from erythroblastic to megaloblastic:erythropoesis from erythroblastic to megaloblastic: аа) megaloblasts) megaloblasts are  big cells with basophilic, polychromatophilic or acidophilicare  big cells with basophilic, polychromatophilic or acidophilic cytoplasm, containing large, located usually eccentrically nucleus with soft chromatin gridcytoplasm, containing large, located usually eccentrically nucleus with soft chromatin grid ((diameter of 12-15 mkmdiameter of 12-15 mkm),), ;; b) megalocytesb) megalocytes – denuclearized cells which are formed during maturing of– denuclearized cells which are formed during maturing of megaloblasts. They usually intensively stained, some the oval form, non an brighten up inmegaloblasts. They usually intensively stained, some the oval form, non an brighten up in the central part (the central part (diameter of 10-12 mkm and morediameter of 10-12 mkm and more)).. Occurrence of the specified cells in red bone marrow and blood is typical forOccurrence of the specified cells in red bone marrow and blood is typical for megaloblastic anemias, in particular of the B12-deficiency anemia.megaloblastic anemias, in particular of the B12-deficiency anemia.
    14. 14. AnisocytosisAnisocytosis AnisocytosisAnisocytosis MicrocytosisMicrocytosis MacrocytosisMacrocytosis MegalocytosisMegalocytosis
    15. 15. ShuistocytesShuistocytes DacriocytesDacriocytes EliptocytesEliptocytes SpherocytesSpherocytes Drepa-Drepa- nocytesnocytes PoikilocytosisPoikilocytosis
    16. 16. Anemia: a condition in which the blood is deficient in red blood cells, in hemoglobin, or in total volume – see APLASTIC ANEMIA, HYPERCHROMIC ANEMIA, HYPOCHROMIC ANEMIA, MEGALOBLASTIC ANEMIA, MICROCYTIC ANEMIA, PERNICIOUS ANEMIA, SICKLE-CELL ANEMIA; compare OLIGOCYTHEMIA
    17. 17. Symptom checkerSymptom checker
    18. 18. Symptom checkerSymptom checker ADULT SYMPTOMS Because a low red blood cell count decreases oxygen delivery to every tissue in the body, anemia causes many signs and symptoms.
    19. 19. CLASSIFICATION OF ANEMIASCLASSIFICATION OF ANEMIAS CriteriaCriteria Types of anemiaTypes of anemia RangeRange I. By etiologyI. By etiology 1. Hereditary1. Hereditary 2. Acquired2. Acquired II. By pathogenesisII. By pathogenesis 1. Posthemorrhagic1. Posthemorrhagic 2. Hemolytical2. Hemolytical 3. Diserythropoietic3. Diserythropoietic III. By the type ofIII. By the type of hemopoiesishemopoiesis 1. Normoblastic1. Normoblastic 2. Megaloblastic2. Megaloblastic IV. By regeneratoryIV. By regeneratory ability of bone marrowability of bone marrow 1. Regeneratory1. Regeneratory 2. Hyperregeneratory2. Hyperregeneratory 3. Hyporegeneratory3. Hyporegeneratory 4. Aregeneratory4. Aregeneratory 5. Aplastic5. Aplastic 0,2-1%0,2-1% More than1%More than1% Less than 0,2%Less than 0,2% 0%0%
    20. 20. CriteriaCriteria Types of anemiaTypes of anemia RangeRange V. By color indexV. By color index 1. Normochromic1. Normochromic 2. Hyperchromic2. Hyperchromic 3. Hypochromic3. Hypochromic 0.85-1.050.85-1.05 more than 1.05more than 1.05 less than 0.85less than 0.85 VI. By the sizes ofVI. By the sizes of erythrocyteserythrocytes 1. Normocytary1. Normocytary 2. Microcytary2. Microcytary 3. Macrocytary3. Macrocytary 4. Megalocytary4. Megalocytary 7.2-8.3 mcm7.2-8.3 mcm less than 7.2 mcmless than 7.2 mcm 8.3-12 mcm8.3-12 mcm more than 12-15 mcmmore than 12-15 mcm VII. By the clinicalVII. By the clinical coursecourse 1. Acute1. Acute 2. Chronic2. Chronic
    21. 21. Classifications of anemiasClassifications of anemias Pathogenetic classification:Pathogenetic classification: АА. Posthemorrhagic anemias:. Posthemorrhagic anemias: a)a)acute posthemorrhagic anemia;acute posthemorrhagic anemia; b)b) chronic posthemorrhagic anemia.chronic posthemorrhagic anemia. B.B. Hemolytic anemias:Hemolytic anemias: 1.1. Acquired:Acquired: аа) toxic-hemolytic;) toxic-hemolytic; b) immune;b) immune; c) mechanical;c) mechanical; d) acquired membranopathy.d) acquired membranopathy. CC. Anemias as a result of erythropoiesis disorders. Anemias as a result of erythropoiesis disorders (Dyserythropoietic).(Dyserythropoietic). 1. Deficient:1. Deficient: аа)) iron deficient;iron deficient; b)b) B12-deficient;B12-deficient; c)c) protein deficient.protein deficient. 2. Hypo-, aplastic.2. Hypo-, aplastic. 3. Metaplastic.3. Metaplastic. 4. Dysregulative.4. Dysregulative. 2.2. Hereditary:Hereditary: аа) hereditary membranepathy;) hereditary membranepathy; b) enzymopathy;b) enzymopathy; c) hemoglobinopathy.c) hemoglobinopathy.
    22. 22. Morphology ofMorphology of remaining erythrocytesremaining erythrocytes Name and Mechanism of AnemiaName and Mechanism of Anemia Primary CausePrimary Cause Macrocytic- normochromic anemia: large, abnormally shaped erythrocytes but normal hemoglobin concentrations Pernicious anemia: lack of vitamin B12 (cobalamin) for erythropoiesis; abnormal deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) synthesis in the erythroblast; premature cell death Folate deficiency anemia: lack of folate for erythropoiesis; premature cell death Congenital or acquired deficiency of intrinsic factor (IF); genetic disorder of DNA synthesis Dietary folate deficiency Microcytic- hypochromic anemia: small, abnormally shaped erythrocytes and reduced hemoglobin concentration Iron deficiency anemia: lack of iron for Hb production; insufficient Hb Sideroblastic anemia: dysfunctional iron uptake by erythroblasts and defective porphyrin and heme synthesis Thalassemia: impaired synthesis of α- or β-chain of hemoglobin A; phagocytosis of abnormal erythroblasts in the marrow Chronic blood loss; dietary iron deficiency, disruption of iron metabolism or iron cycle Congenital dysfunction of iron metabolism in erythroblasts, acquired dysfunction of iron metabolism as a result of drugs or toxins Congenital genetic defect of globin synthesis
    23. 23. MORPHOLOGIC CLASSIFICATION OFMORPHOLOGIC CLASSIFICATION OF ANEMIASANEMIAS Morphology ofMorphology of remaining erythrocytesremaining erythrocytes Name and Mechanism of AnemiaName and Mechanism of Anemia Primary CausePrimary Cause Normocytic- normochromic anemia: normal size, normal hemoglobin concentration Aplastic anemia: insufficient erythropoiesis Posthemorrhagic anemia: blood loss Hemolytic anemia: premature destruction (lysis) of mature erythrocytes in the circulation Sickle cell anemia: abnormal hemoglobin synthesis, abnormal cell shape with susceptibility to damage, lysis, and phagocytosis Anemia of chronic disease: abnormally increased demand for new erythrocytes Depressed stem cell proliferation resulting in bone marrow aplasia Acute or chronic hemorrhage that stimulates increased erythropoiesis, which eventually depletes body iron Increased fragility of erythrocytes Congenital dysfunction of hemoglobin synthesis Chronic infection or inflammation; malignancy
    24. 24. The characteristic of posthemorrhagic anemiasThe characteristic of posthemorrhagic anemias Posthemorrhagic anemiaPosthemorrhagic anemia is an anemia which develops as a result ofis an anemia which develops as a result of hemorrhage. There arehemorrhage. There are two typestwo types of anemias of this groupof anemias of this group according to theaccording to the character of hemorrhagecharacter of hemorrhage:: 1)1) acuteacute posthemorrhagic andposthemorrhagic and 2)2) chronicchronic posthemorrhagic anemia.posthemorrhagic anemia. Acute posthemorrhagic anemiaAcute posthemorrhagic anemia develops as a result of the massive externaldevelops as a result of the massive external or internal (in the cavities of human body) bleeding.or internal (in the cavities of human body) bleeding. Etiology:Etiology: a)a) various traumas;various traumas; b)b) bleeding from a gastro-intestinal tract [alimentary canal];bleeding from a gastro-intestinal tract [alimentary canal]; c) c) gynecological pathology and others.gynecological pathology and others. PathogenesisPathogenesis of acute posthemorrhagic anemia consists of tree periods:of acute posthemorrhagic anemia consists of tree periods: 1)1) Reflex vascular periodReflex vascular period - develops at once after- develops at once after hemorrhagehemorrhage.. Accompanied:Accompanied: a)a) by the spasm of vessels; by the spasm of vessels; b)b) by the redistribution of blood;by the redistribution of blood; c)c) exit of deposited erythrocytes.exit of deposited erythrocytes. Analysis of peripheral bloodAnalysis of peripheral blood : Er, Hb, color index, Ht – all is a near norm.: Er, Hb, color index, Ht – all is a near norm. 2)2) Hydremic period after 2-3 daysHydremic period after 2-3 days - there is compensation of circulating- there is compensation of circulating plasma volume:plasma volume: a)a) diminishing of excretion by kidneys;diminishing of excretion by kidneys; b)b) increase transport intertissue liquid and lymph to a lumen of vessels.increase transport intertissue liquid and lymph to a lumen of vessels. Analysis of peripheral bloodAnalysis of peripheral blood : Er and Hb are lesser as norm, color index, Ht: Er and Hb are lesser as norm, color index, Ht is near the norm, may be decreasing.is near the norm, may be decreasing. 3)3) Regenerative (bone-marrow) periodRegenerative (bone-marrow) period is on 5-7 days.is on 5-7 days. Analysis of peripheral bloodAnalysis of peripheral blood : Er, Hb, color index are decreasing. Increase: Er, Hb, color index are decreasing. Increase amount of Ht. May appearance normoblasts.amount of Ht. May appearance normoblasts. Complete renewal of basic indexes of red blood after acuteComplete renewal of basic indexes of red blood after acute hemorrhagehemorrhage isis
    25. 25. Chronic posthemorrhagic anemiaChronic posthemorrhagic anemia Chronic posthemorrhagic anemiaChronic posthemorrhagic anemia runs across on the type ofruns across on the type of asiderotic [iron-deficiency] anemia and develops as a resultasiderotic [iron-deficiency] anemia and develops as a result of small, but protracted repeated hemorrhage at:of small, but protracted repeated hemorrhage at: a)a) different diseases (ulcerous illness, pathology of kidneys,different diseases (ulcerous illness, pathology of kidneys, breathing organs, gynaecological pathology);breathing organs, gynaecological pathology); b)b) at pathology of vessels;at pathology of vessels; c)c) at violations of thrombocyte-vascular and coagulativeat violations of thrombocyte-vascular and coagulative hemostasis.hemostasis. DuringDuring chronic posthemorrhagic anemiachronic posthemorrhagic anemia after theafter the loss of ironloss of iron hematologic attributes of iron deficiency anemia develop:hematologic attributes of iron deficiency anemia develop: ► concentration of hemoglobin and color index decrease;concentration of hemoglobin and color index decrease; ► in blood smear there are degenerate forms of erythrocytes (micro- andin blood smear there are degenerate forms of erythrocytes (micro- and poikilocytosis, hypochromy);poikilocytosis, hypochromy); ► quantity of erythrocytes and hematocrit may remain without changes.quantity of erythrocytes and hematocrit may remain without changes.
    26. 26. Petechiae of the gastric mucosaPetechiae of the gastric mucosa Ecchymosis Metrorrhagia Ruptured esophageal varix
    27. 27. Hemolytical anemias Acquired (secondary) Hereditary or congenital (primary) immune toxic mechanical membranopathy enzymopathy Hb-pathy alloimmune transimmune heteroimmune autoimmune 1.Protein dependent - mykrospherocytosis - stomatocytosis - Ovalocytosis etc. 2.Lipid dependent - acantocytosis 1.Glycolysis -hexokinase - Piruvatkinase etc. 2.Pentosphosphate cycle - G-6-PhDH etc. 3. Glutathione system - glutathionsynthetase - GSH-reductase - GSH-peroxidase 1.Thalassemia • α- thalassemia • β -thalassemia 2.Dysorder of globin chains primary structure • sickle cell anemia etc. membranopathy
    28. 28. The characteristic  of hemolytic anemiasThe characteristic  of hemolytic anemias Hemolytic anemias arise up as a result of destroying (to hemolysis) of erythrocytes.Hemolytic anemias arise up as a result of destroying (to hemolysis) of erythrocytes. ► T y p e s ofT y p e s of Hemolytic anemias:Hemolytic anemias: ► I. By origin:I. By origin: 1)1) Acquired (secondary).Acquired (secondary). 2)2) Inherited or innate (primary);Inherited or innate (primary); Intravascular hemolysisIntravascular hemolysis arises up in the vessels of bloods under the action ofarises up in the vessels of bloods under the action of hemolytic factors which damage erythrocytes, in particular:hemolytic factors which damage erythrocytes, in particular: a)a) physical factors (mechanical trauma, ionizing radiation, ultrasound, temperature);physical factors (mechanical trauma, ionizing radiation, ultrasound, temperature); b)b) chemical agents (hemolytic poisons);chemical agents (hemolytic poisons); c)c) biological factors (exciters of infectious diseases, toxins, enzymes);biological factors (exciters of infectious diseases, toxins, enzymes); d)d) immune factors (antibodies).immune factors (antibodies). Mechanisms of intravascular hemolysis.Mechanisms of intravascular hemolysis. ► I.I. MechanicalMechanical hemolysishemolysis - arises up as a result of mechanical destruction of- arises up as a result of mechanical destruction of erythrocytes (at squashing [crushing] of erythrocytes in the vessels of foot).erythrocytes (at squashing [crushing] of erythrocytes in the vessels of foot). ► II.II. OsmoticOsmotic hemolysishemolysis - arises up subject to the condition, when osmotic pressure- arises up subject to the condition, when osmotic pressure into erythrocytes more than osmotic pressure of plasma of blood → increaseinto erythrocytes more than osmotic pressure of plasma of blood → increase moving of water inside of erythrocyte → enlargement → rapture of membrane.moving of water inside of erythrocyte → enlargement → rapture of membrane. ► IIIIII.. OxidizingOxidizing hemolysishemolysis - develops as a result of FOL and albumens of plasmatic- develops as a result of FOL and albumens of plasmatic membrane of erythrocytes. That led to increase permeability of membrane ofmembrane of erythrocytes. That led to increase permeability of membrane of erythrocytes → than osmotic mechanism.erythrocytes → than osmotic mechanism. ► IV.IV. DetergentDetergent hemolysishemolysis – connect with to dissolution of lipidic components of– connect with to dissolution of lipidic components of membrane of erythrocytes by detergents. This type ofmembrane of erythrocytes by detergents. This type of hemolysishemolysis is caused byis caused by bilious acids (bilious syndrome), liposoluble chemical agents, some toxins ofbilious acids (bilious syndrome), liposoluble chemical agents, some toxins of bacteria (lecithinase).bacteria (lecithinase). ► V.V. Complement-dependentComplement-dependent hemolysishemolysis – conditioned destruction (by a perforation)– conditioned destruction (by a perforation) of membrane of erythrocytes by active complement. This mechanism lies in basisof membrane of erythrocytes by active complement. This mechanism lies in basis of immuneof immune hemolysishemolysis.. II. By the mechanisms of hemolysis:II. By the mechanisms of hemolysis: 11)) anemias with intravascular hemolysis;anemias with intravascular hemolysis; 2)2) anemias with intracellularanemias with intracellular hemolysis.hemolysis.
    29. 29. IntravascularIntravascular hemolysishemolysis is accompanied theis accompanied the exit of hemoglobin from cells in plasma ofexit of hemoglobin from cells in plasma of blood, where it connect with the albumenblood, where it connect with the albumen (haptoglobin).(haptoglobin).  1)1) The complex of hemoglobinThe complex of hemoglobin -haptoglobin-haptoglobin phagocytes by macrophages and causes productionphagocytes by macrophages and causes production and excretion erythropoietin → stimulatesand excretion erythropoietin → stimulates erythropoiesis.erythropoiesis.  2)2) Albuminous part of haemoglobinAlbuminous part of haemoglobin chip off tochip off to amino acid, and from a heme will appear bilirubin whichamino acid, and from a heme will appear bilirubin which contacts with albumins and enters into bloodcontacts with albumins and enters into blood (unconjugated [indirect] bilirubin). Hemolytic jaundice(unconjugated [indirect] bilirubin). Hemolytic jaundice develops.develops.  3)3) Part of unconnected from haptoglobinPart of unconnected from haptoglobin hemoglobin is filtered by kidneys →hemoglobin is filtered by kidneys → appearanceappearance of hemoglobin in urines (hemoglobinuria) andof hemoglobin in urines (hemoglobinuria) and "obstructions" of nephrons of kidney with development"obstructions" of nephrons of kidney with development of signs of acute kidney insufficiencyof signs of acute kidney insufficiency..
    30. 30. IntracellularIntracellular hemolysishemolysis develops as a result ofdevelops as a result of absorption and overcooking of erythrocytesabsorption and overcooking of erythrocytes by macrophages.by macrophages.  Reasons:Reasons: a)a) appearance ofappearance of imperfect erythrocytesimperfect erythrocytes which delay in thewhich delay in the venous sinus of spleen ("splenic filter"), where theyvenous sinus of spleen ("splenic filter"), where they contact with macrophages;contact with macrophages; b)b) appearance on theappearance on the surface of erythrocytessurface of erythrocytes of chemicalof chemical groups, capable specifically to co-operate with thegroups, capable specifically to co-operate with the receptors of macrophages;receptors of macrophages; c)c) hypersplenismhypersplenism is increasing phagocytic activity ofis increasing phagocytic activity of macrophagesmacrophages of spleen.of spleen.  Increased phagocytosisIncreased phagocytosis of erythrocytes causes theof erythrocytes causes the followings changes:followings changes: a)a) production and excretion of erythropoietinproduction and excretion of erythropoietin b)b) increase unconjugated [indirect] bilirubin. Hemolyticincrease unconjugated [indirect] bilirubin. Hemolytic jaundice developsjaundice develops c)c) proliferation of macrophages. That lead toproliferation of macrophages. That lead to splenomegaly.splenomegaly.
    31. 31. MacrophageMacrophage phagocytosesphagocytoses Globin chainsGlobin chains amino acidsamino acids HemeHeme Iron (stored)Iron (stored) ProtoporphyrinProtoporphyrin UnconjugatedUnconjugated bilirubinbilirubin (Jaundice)(Jaundice) Principal features : anemia & jaundice; Hemoglobinemia & hemoglobinuria are not observed Principal features : Hemoglobinemia , hemoglobinuria, jaundice & hemosiderinuria
    32. 32. TYPES EXAMPLES Microangiopathic Platelet thrombi Hemolytic uremic syndrome Thrombotic thrombocytopenic purpura Fibrin thrombi Disseminated intravascular coagulation; HELLP syndrome: H - hemolytic anemia; EL - elevated transaminases; LP – low platelets; associated with preeclampsia Macroangiopathic Aortic stenosis (most common cause) Prosthetic heart valves
    33. 33. I.I. Acquired hemolytic anemiasAcquired hemolytic anemias Depending on the reasons of development is allocated the followingDepending on the reasons of development is allocated the following kinds of  acquired hemolytic anemias.kinds of  acquired hemolytic anemias.  1.         1.          ToxicToxic hemolytic anemias.hemolytic anemias. InfectiousInfectious hemolytic anaemias.hemolytic anaemias.  2.         2.          ImmuneImmune hemolytic anemias.hemolytic anemias.  3.         The anemias caused by3.         The anemias caused by mechanical damagemechanical damage ofof erythrocytes.erythrocytes.  4.         4.          Acquired membranopathyAcquired membranopathy .. 11.. Toxic hemolytic  anemiaToxic hemolytic  anemia may be  caused by:may be  caused by:  аа)) exogenousexogenous  chemical agents: phenylhydrasin, lead, copper salts, chemical agents: phenylhydrasin, lead, copper salts, arsenous hydrogen etc.;arsenous hydrogen etc.;  b)b) endogenousendogenous  chemical factors: bile acids, products formed at  chemical factors: bile acids, products formed at burn desease, uraemia;burn desease, uraemia;  c) poisons of c) poisons of  biological originbiological origin : snake, beer, poison of some kinds: snake, beer, poison of some kinds of spiders, number of infectious agents, in particular, hemolyticof spiders, number of infectious agents, in particular, hemolytic streptococcus, malarial plasmodium, toxoplasma, leishmania.streptococcus, malarial plasmodium, toxoplasma, leishmania. Infectious hemolytic anaemiasInfectious hemolytic anaemias - caused a number of infectious- caused a number of infectious agents, in particular, by a hemolytic streptococcus, malaria,agents, in particular, by a hemolytic streptococcus, malaria, toxoplasmosis and others.toxoplasmosis and others.
    34. 34. 2. Immune Hemolytic Anemias2. Immune Hemolytic Anemias Immune hemolytic anemiasImmune hemolytic anemias arise due to participation of specific immunearise due to participation of specific immune mechanisms.mechanisms. They are caused by interaction of humoral antibodies with theThey are caused by interaction of humoral antibodies with the antigenes fixed on a surface of erythrocytesantigenes fixed on a surface of erythrocytes (II type of allergic reactions)(II type of allergic reactions) and dividedand divided on:on:  1) Isoimmune1) Isoimmune, reason of which is:, reason of which is:  a) receipt from outside of antibodies against own erythrocytes (hemolytic illness ofa) receipt from outside of antibodies against own erythrocytes (hemolytic illness of babies);babies);  b) entering organism of erythrocytes against which there are antibodies in plasmab) entering organism of erythrocytes against which there are antibodies in plasma (transfusion of incompatible is after a group or Rh of blood).(transfusion of incompatible is after a group or Rh of blood).  2) Autoimmune2) Autoimmune - conditioned education in the organism of antibodies against own- conditioned education in the organism of antibodies against own erythrocytes.erythrocytes. Reasons: primary changes of erythrocytes (appearance ofReasons: primary changes of erythrocytes (appearance of autoantigen), changes in the immune system (abolition of immunological toleranceautoantigen), changes in the immune system (abolition of immunological tolerance and appearance of "prohibitive" clones of lymphocytes).and appearance of "prohibitive" clones of lymphocytes).  3) Heteroimmune3) Heteroimmune - arise up during fixing on the surface of erythrocytes of foreign- arise up during fixing on the surface of erythrocytes of foreign antigens (haptens),antigens (haptens), in particular, medicinal preparations (penicillin,in particular, medicinal preparations (penicillin, sulfonamidessulfonamides) or) or viruses.viruses.  Hemolytic illness of newbornsHemolytic illness of newborns arises up as a result of hemolysis of erythrocytes ofarises up as a result of hemolysis of erythrocytes of embryo and baby, caused the antibodies of mother.embryo and baby, caused the antibodies of mother. Most often meet 2th variants ofMost often meet 2th variants of this illness: a) rhesus incompatibility and b) AB0- incompatibility.this illness: a) rhesus incompatibility and b) AB0- incompatibility.  Rhesus-incompatibilityRhesus-incompatibility - develops in the case of pregnancy of Rh(-)mother- develops in the case of pregnancy of Rh(-)mother Rh(+)fetus (more frequent in case of the repeated pregnancy).Rh(+)fetus (more frequent in case of the repeated pregnancy). At first there isAt first there is immunization of mother Rh+Er of fetus, which can get in the organism of motherimmunization of mother Rh+Er of fetus, which can get in the organism of mother during births or at the defects of placenta. In reply to the receipt of Rh+Er in theduring births or at the defects of placenta. In reply to the receipt of Rh+Er in the organism of mother antibodies are synthesized against to the D-antigen. Theseorganism of mother antibodies are synthesized against to the D-antigen. These antibodies (IgG) are able to penetrate through a placenta in the organism of fetusantibodies (IgG) are able to penetrate through a placenta in the organism of fetus and to cause hemolysis of erythrocytes.and to cause hemolysis of erythrocytes.  AB0- incompatibilityAB0- incompatibility - arises up in instances where mother have 0(I), and fetus – A(II)- arises up in instances where mother have 0(I), and fetus – A(II) or B(III).or B(III).
    35. 35. TYPE OF IMMUNETYPE OF IMMUNE HEMOLYTIC ANEMIAHEMOLYTIC ANEMIA EXAMPLESEXAMPLES AutoimmuneAutoimmune Warm antibodies (IgG) Cold antibodies (IgM) Chronic lymphocytic leukemia Primary or idiopathic (no underlying cause) Secondary (e.g., SLE) Primary or idiopathic Secondary:  Mycoplasma pneumoniae (anti-l antibodies) Infection: mononucleosis (anti-I antibodies) Warm and cold immune hemolytic anemia Drug-induced Drug adsorption (e.g., penicillin): IgG antibody directed against the drug attached to the RBC membrane Immunocomplex (e.g., quinidine): drug-IgM immunocomplex deposits on the RBC causing intravascular hemolysis Autoantibody induction (e.g., α-methyldopa): drug alters Rh antigens on RBCs causing synthesis of autoantibodies against Rh antigens AlloimmuneAlloimmune Hemolytic transfusion reaction ABO hemolytic disease of newborn Rh hemolytic disease of newborn SLE, systemic lupus erythematosus.
    36. 36. ABO Blood GroupABO Blood Group • Anti-A and anti-B antibodies are produced when an antigen is absent from the cell membrane • Type A plasma contains anti-B antibodies • Type B plasma contains anti-A antibodies • Type AB plasma contains no antibodies, universal recipient • Type O plasma contains anti-A and anti-B antibodies, universal donor
    37. 37. Rh Blood GroupRh Blood Group  Rh positiveRh positive indicates presence of antigenindicates presence of antigen D, one of the Rh antigensD, one of the Rh antigens  Rh negativeRh negative indicates absence of Antigenindicates absence of Antigen DD  Rh antigens, like A and B antigens areRh antigens, like A and B antigens are inherited and present from birthinherited and present from birth  Anti-D antibodies are not producedAnti-D antibodies are not produced until after an individual is sensitizeduntil after an individual is sensitized to antigen Dto antigen D
    38. 38. 33.. The anaemias caused by mechanicalThe anaemias caused by mechanical damage of erythrocytesdamage of erythrocytes Anaemias, conditioned by mechanical damage of erythrocytes:Anaemias, conditioned by mechanical damage of erythrocytes: 1)1) Mechanical hemolysis after prosthesis of vessels or valves of heart.Mechanical hemolysis after prosthesis of vessels or valves of heart. 2)2) March hemoglobinuria – trauma of erythrocytes in capillaries of feetMarch hemoglobinuria – trauma of erythrocytes in capillaries of feet during protracted march.during protracted march. 44.. Acquired membranopathy.Acquired membranopathy. Acquired membranopathyAcquired membranopathy arise due to the acquired defectsarise due to the acquired defects of erythrocytes membranes. As an example may be paroxysmal nightlyof erythrocytes membranes. As an example may be paroxysmal nightly hemoglobinuria (hemoglobinuria ( illness of Markiafavi-Mikeliillness of Markiafavi-Mikeli ) is a somatic mutation of) is a somatic mutation of erythropoietic cells with defects of membrane.erythropoietic cells with defects of membrane. It is considered that disordersIt is considered that disorders of membranes are connected withof membranes are connected with changes of  ratio of fat acids which are part of theirchanges of  ratio of fat acids which are part of their phospholipidsphospholipids. Erythrocytes of  abnormal population get ability to fix complement and. Erythrocytes of  abnormal population get ability to fix complement and hemolyse. The erythrocytes of anomalous population obtain ability to fix complementhemolyse. The erythrocytes of anomalous population obtain ability to fix complement which is pre-condition ofwhich is pre-condition of complement-depended hemolysiscomplement-depended hemolysis, and, and diminishing of pHdiminishing of pH environment is a factor which provokes intravascularenvironment is a factor which provokes intravascular hemolysishemolysis. This feature explains. This feature explains the destruction of erythrocytes is observed more frequent at night (in the night-timethe destruction of erythrocytes is observed more frequent at night (in the night-time рНрН of blood some diminishes).of blood some diminishes). ► The picture of bloodThe picture of blood of acquired hemolytic anemias is characterized byof acquired hemolytic anemias is characterized by reduction of erythrocytes quantity and hemoglobin. The color index inreduction of erythrocytes quantity and hemoglobin. The color index in norm, however may be higher than 1 unit that is connected withnorm, however may be higher than 1 unit that is connected with extraerythrocytic hemoglobin. In blood smear the significant amountextraerythrocytic hemoglobin. In blood smear the significant amount regenerative forms of erythrocytes is found out:regenerative forms of erythrocytes is found out: reticulocytes,reticulocytes, polychromatophils, normocytes.polychromatophils, normocytes.
    39. 39. ІІ.ІІ. Hereditary hemolytic anemiasHereditary hemolytic anemias 1.1. Membranopathies.Membranopathies. Defects of erythrocytes  membranes are in  basis of this Defects of erythrocytes  membranes are in  basis of this  anemias group.anemias group. 2.2. Enzymopathies.Enzymopathies. Anemias of this group are caused by disorder  of erythrocytesAnemias of this group are caused by disorder  of erythrocytes enzymes .enzymes . 3.3. Hemoglobinopathies.Hemoglobinopathies. Arise after qualitative changes of hemoglobin.Arise after qualitative changes of hemoglobin. Hereditary membranopathiesHereditary membranopathies may be caused by two groups of defects erythrocyticmay be caused by two groups of defects erythrocytic membranes:membranes: 1.1. MembranopathiesMembranopathies, caused by disorders of membrane proteins:, caused by disorders of membrane proteins: аа)) microspherocytic anemia Minkovsky-Shoffar’s;microspherocytic anemia Minkovsky-Shoffar’s; b)b) ovalocytic hemolytic anemia;ovalocytic hemolytic anemia; ► Anemia Minkovsky-Shoffar’sAnemia Minkovsky-Shoffar’s is hereditary, endoerythrocyticis hereditary, endoerythrocytic (membranopathy) hemolytic anemia with endocellular hemolysis. Type of(membranopathy) hemolytic anemia with endocellular hemolysis. Type of inheritance – autosomal dominant. Hereditary defect mentions membraneinheritance – autosomal dominant. Hereditary defect mentions membrane proteins of erythrocytes,proteins of erythrocytes, in particularin particular spectrinspectrin. Therefore permeability. Therefore permeability of erythrocytic membranes for ions sodium isof erythrocytic membranes for ions sodium is considerably increased.considerably increased. Sodium and waterSodium and water pass from plasma inside of erythrocytes.pass from plasma inside of erythrocytes. At passing in the sinus of spleen theyAt passing in the sinus of spleen they lose part of erythrocytes membrane andlose part of erythrocytes membrane and turn into microspherocytes.turn into microspherocytes. Life expectancy of erythrocytes decreasesLife expectancy of erythrocytes decreases untilluntill 8-12 (10-14) days instead of 120.8-12 (10-14) days instead of 120.
    40. 40. Schematic representation of the red cell membrane cytoskeleton andSchematic representation of the red cell membrane cytoskeleton and alterations leading to spherocytosis and hemolysis. Mutations weakeningalterations leading to spherocytosis and hemolysis. Mutations weakening interactions involvinginteractions involving αα-spectrin,-spectrin, ββ-spectrin, ankyrin, band 4.2, or band 3-spectrin, ankyrin, band 4.2, or band 3 all cause the normal biconcave red cell to lose membrane fragments andall cause the normal biconcave red cell to lose membrane fragments and adopt a spherical shape. Such spherocytic cells are less deformable thanadopt a spherical shape. Such spherocytic cells are less deformable than normal and therefore become trapped in the splenic cords, where they arenormal and therefore become trapped in the splenic cords, where they are phagocytosed by macrophages.phagocytosed by macrophages.
    41. 41. 2. Hereditary enzymopathies Hereditary enzymopathies arise due to defect of erythrocytes fermental systems:  1) deficiency of enzymes pentose cycle.deficiency of enzymes pentose cycle. The most widespread enzymopathy is glucose-6- phosphatedehydrogenase deficiency anemia, caused by absence or significant decrease (reduction) of glucose-6-phosphatedehydrogenase activity;  2) deficiency of enzymes of glycolysis.deficiency of enzymes of glycolysis. The most widespread is deficiency of pyruvatekinase which results to disorders of energy provision Na-K-pumps of plasmatic membranes. Erythrocytes thus turn into spherocytes which are exposed to phagocytosis by macrophages;  3) deficiency of enzymes of glutathion cycledeficiency of enzymes of glutathion cycle (glutathionsynthetase, glutathionreductase, glutathionperoxidaza) results in oppression antioxidant systems of erythrocytes, barrier properties of erythrocytic membranes to ions and osmotic hemolysis;  4) deficiency of utilizationdeficiency of utilization АТАТP enzymes.P enzymes. An example is deficiency of albuminous components Na-K-pump of erythrocytic membranes. Thus concentration of sodium that results them to hemolysis is increased in a cell. As metabolic reactions in erythrocytes are interdependent, quite often the blockade of one of links brings to violation of vital important functions cells over in connection with the deficit of energy or ionic disbalance. On the whole it: a) reduces viability of erythrocytes, b) multiplies their sensitiveness to the action of unfavorable factors which over brings to development of hemolysis. Hereditary hemolytic anemia. Reticulocytoses
    42. 42. 33.. Hemoglobinopathies - related to violations ofHemoglobinopathies - related to violations of synthesis of molecule of haemoglobin.synthesis of molecule of haemoglobin. Sickle-cell anemia The molecules of haemoglobin are heterogeneous of the adult healthy man. 95 % factionThe molecules of haemoglobin are heterogeneous of the adult healthy man. 95 % faction of haemoglobin, which is reflected a letter A, makes (“standard”) (from word "adult").of haemoglobin, which is reflected a letter A, makes (“standard”) (from word "adult"). About 3,5-4 % it is haemoglobin on faction of A2 and 1-1,5% - on haemoglobin of F (fetus).About 3,5-4 % it is haemoglobin on faction of A2 and 1-1,5% - on haemoglobin of F (fetus). Every faction consists of 574 amino acid which form polypeptidic chains. The molecule ofEvery faction consists of 574 amino acid which form polypeptidic chains. The molecule of haemoglobin consists of 4 polypeptidic chains which are reflected by letter of the Greekhaemoglobin consists of 4 polypeptidic chains which are reflected by letter of the Greek alphabet:alphabet: α,β,γ,δα,β,γ,δ.. Basic forms: 1)Basic forms: 1) drepancytic anemia [sickle-cell, Herrick's, sicklemiadrepancytic anemia [sickle-cell, Herrick's, sicklemia]] 2) thalassemia.2) thalassemia. Qualitative and quantitative changes of hemoglobin lay in basis of development ofQualitative and quantitative changes of hemoglobin lay in basis of development of hereditaryhereditary hemoglobinopathies.hemoglobinopathies. The most widespreadThe most widespread clinical form isclinical form is sickle-cellsickle-cell anemiaanemia at which inat which in β-chain of a molecule ofβ-chain of a molecule of hemoglobin glutaminehemoglobin glutamine acid is replaced onacid is replaced on valine (HbS).valine (HbS).
    43. 43. Spleen in sickle cell anemia (low power). Red pulp cords and sinusoids are markedly congested; between the congested areas, pale areas of fibrosis resulting from ischemic damage are evident. B, Under high power, splenic sinusoids are dilated and filled with sickled red cells. (Courtesy of Dr. Darren Wirthwein, Department of Pathology, University of Texas Southwestern Medical School, Dallas, TX.) Pathophysiology of sickle cell anemiaPathophysiology of sickle cell anemia
    44. 44. SCD is characterized by its presentation: 1- Vaso-occlusive crises 2- Sequestration crises 3- Hemolytic crises 4- Aplasic crises Crewcut appearance
    45. 45. Thalassemias.Thalassemias. In contrast to sickle cell anemia, the thalassemias resultIn contrast to sickle cell anemia, the thalassemias result from absent or defective synthesis of the α or thefrom absent or defective synthesis of the α or the β chains of hemoglobin. Theβ chains of hemoglobin. The β-thalassemias represent a defectβ-thalassemias represent a defect in β-chain synthesisin β-chain synthesis, and the, and the α-thalassemiasα-thalassemias represent a defectrepresent a defect in α-chain synthesisin α-chain synthesis. The defect is inherited as a mendelian. The defect is inherited as a mendelian trait, and a person may be heterozygous for the trait and havetrait, and a person may be heterozygous for the trait and have a mild form ofa mild form of the disease or be homozygous and have thethe disease or be homozygous and have the severe form of the disease. Likesevere form of the disease. Like sickle cell anemia, the thalassemiassickle cell anemia, the thalassemias occur with high degree of frequency inoccur with high degree of frequency in certain populations.certain populations. TheThe β-thalassemiasβ-thalassemias, sometimes called, sometimes called Cooley’s anemiaCooley’s anemia oror Mediterranean anemia,Mediterranean anemia, are most common in the Mediterraneanare most common in the Mediterranean populations ofpopulations of southern Italy and Greece, and thesouthern Italy and Greece, and the α-thalassemias are most common amongα-thalassemias are most common among Asians. Both α- andAsians. Both α- and β-thalassemias are common in Africans and blackβ-thalassemias are common in Africans and black Americans.Americans. Thalassemia HemoglobinHemoglobin PolypePolype ptidesptides HemoglobinHemoglobin A1 (Adult)A1 (Adult) 22αα 22ββ HemoglobinHemoglobin A2A2 22αα 22δδ HemoglobinHemoglobin F (Fetal)F (Fetal) 22αα 22γγ
    46. 46. TypeType HbHb Hb-Hb- electrophoresiselectrophoresis GenotypeGenotype Clinical SyndromeClinical Syndrome α-THALASSAEMIAS 1. Hydrops foetalis 3-10 gm/dl Hb Barts (γ4) (100%) Deletion of four γ-genes Fatal in utero or in early infancy 2. Hb-H disease 2-12 gm/dl HbF (10%), HbH (2-4%) Deletion of three α-genes Haemolytic anaemia α-Thalassaemia trait 10-14 gm/dl Almost normal Deletion of two α-genes Microcytic hypochromic blood picture but no anaemia β-THALASSAEMIAS 1. β- Thalassaemia major < 5 gm/dl HbA (0-50%), HbF(50-98%) βthal/βthal Severe congenital haemolytic anaemia, requires blood transfusions 2. β- Thalassaemia intermedia 5-10 gm/dl Variable Multiple mechanisms Severe anaemia, but regular blood transfusions not required β-Thalassaemia minor 10-12 gm/dl HbA2 (4-9%), HbF (1-5%) βA/βthal Usually asymptomatic
    47. 47. 2-The clinically significant haemoglobinopathies are listed in following Table
    48. 48. ANEMIAANEMIA PATHOGENESISPATHOGENESIS DISCUSSIONDISCUSSION Reticulocytosis < 3% Acute blood loss Loss of whole blood Initial Hb and Hct normal Infusion of normal saline uncovers anemia Signs of volume depletion (c,g„ absolute neutrophilic leukocytosis) commonly present; positive tilt test Early iron deficiency Decreased iron stores Normocytic before microcytic Iron studies abnormal (  serum ferritin) Early ACD Iron trapped in macrophages by hepcidin Normocytic before microcytic Iron studies abnormal (  serum ferritin) Aplastic anemia Suppression or deficiency of myeloid stem cells Pancytopenia Hypocellular marrow Chronic renal failure Deficiency of EPO Presence of burr cells
    49. 49. ANEMIAANEMIA PATHOGENESISPATHOGENESIS DISCUSSIONDISCUSSION Reticulocytosis ≥ 3% Hereditary spherocytosis AD disorder Defect in ankyrin Extravascular hemolysis Increased osmotic fragility Treat with splenectomy Hereditary elliptocytosis AD disorder Defect in spectrin and band 4.1 Extravascular hemolysis Elliptocytes > 25% Paroxysmal nocturnal hemoglobinuria Loss of anchor for DAF in myeloid stem cell Complement destruction of hematopoietic cells Intravascular hemolysis Defect on hematopoietic cells Pancytopenia Positive sugar water test (screen) and acidified serum test (confirmatory test) Sickle cell anemia AR disorder Valine substitution for Glutamic acid β-globin chain Extravascular hemolysis HbAS: HbA 55-60%; HbS 40-45% HbSS: HbS 90-95%; HbF 5-10%; no HbA C6PD deficiency XR disorder Deficiency GSH causes oxidant damage to Hb and RBC membrane Intravascular hemolysis Heinz body preparation: screen during active hemolysis Enzyme assay: confirmatory test when hemolysis subsides
    50. 50. ANEMIAANEMIA PATHOGENESISPATHOGENESIS DISCUSSIONDISCUSSION Reticulocytosis ≥ 3% Pyruvate kinase deficiency AR disease  ATP synthesis Extravascular hemolysis  2,3.BPG right shifts OBC Dehydrated RBCs with thorny projections (echinocytes) Acute blood loss Loss of whole blood Reticulocytosis 5-7 days  Hb, Hct, RBC count Warm AIHA IgG with or without C3b Extravascular hemolysis Positive direct Coombs' test SLE most common cause Cold AIHA IgM with C3b Extravascular or Intravascular hemolysis Association with Mycoplasma pneumoniae; EBV Positive direct Coombs' test Drug-induced Immune hemolytic anemia Drug hapten; penicillin Extravascular hemolysis Immunocomplex: quinidine Intravascular hemolysis Autoantibody: methyldopa Positive direct Coombs' test
    51. 51. ANEMIAANEMIA PATHOGENESISPATHOGENESIS DISCUSSIONDISCUSSION Reticulocytosis ≥ 3% Alloimmune hemolytic anemia Antibodies against foreign RBC antigens Extravascular hemolysis Hemolylic transfusion reaction ABO and Rh HDN Positive direct Coombs' test Micro- and macroangiopathic hemolytic anemia Mechanical destruction of RBCs with formation of schistocytes Intravascular hemolysis Calcific aortic stenosis most common cause Chronic hemoglobinuria causes iron deficiency Malaria Transmitted by female Anopheles mosquito Intravascular hemolysis Rupture of RBCs corresponds with fever ACD, anemia of chronic disease; AD, autosomal dominant; AIHA, autoimmune hemolytic anemia; AR, autosomal recessive; ATP adenosine triphosphate: BPG, bisphosphoglycerate; DAF, decay accelerating factor; EBV, Epstein-Barr virus; EPO, erythropoietin; G6PD, glucose-6-phosphate dehydrogenase; GSH, glutathione; Hb, hemoglobin; HbAS, sickle cell trait; HbSS. homozygous for sickle cell disease; Hct, hematocrit; OBC, oxygen-binding curve; Rh HDN. Rhesus hemolytic disease of the newborn; SLE, systemic lupus erythematosus: XR, X-linked recessive
    52. 52. The reasons of anemias with disorders of erythropoiesis mayThe reasons of anemias with disorders of erythropoiesis may be:be: ► 1)1) disorder of formation of erythrocytesdisorder of formation of erythrocytes : deficiency of: deficiency of hemopoietic cells due to their damage or replacement,hemopoietic cells due to their damage or replacement, disorder of cells maturation of hemopoiesis (disorders of DNAdisorder of cells maturation of hemopoiesis (disorders of DNA resynthesis), defects of erythrocytes maturing and theirresynthesis), defects of erythrocytes maturing and their output(exit) into blood flow (deficiency erythropoiesis);output(exit) into blood flow (deficiency erythropoiesis); ► 2)2) disorders of hemoglobin synthesisdisorders of hemoglobin synthesis : deficiency of: deficiency of iron, disorder of synthesis porphyrines (hereditary disordersiron, disorder of synthesis porphyrines (hereditary disorders of enzymes, poisonings by lead, deficiency of vitamin B6,of enzymes, poisonings by lead, deficiency of vitamin B6, frustration of albuminous chains synthesis of hemoglobinfrustration of albuminous chains synthesis of hemoglobin molecules).molecules). Anemias as a resultAnemias as a result of erythropoiesis disorderof erythropoiesis disorder
    53. 53. Deficiency anemiasDeficiency anemiasIrondeficiency anemiaIrondeficiency anemia arises as a result of:arises as a result of: 1)1) Insufficient receipt of ironInsufficient receipt of iron with organism:with organism:  аа) an) an alimentary anemiaalimentary anemia in the infants (feeding with cow or goat milk);in the infants (feeding with cow or goat milk);  b)b) disorder of iron absorbtiondisorder of iron absorbtion (resection of stomach, intestines, gastritises, enteritis);(resection of stomach, intestines, gastritises, enteritis); 2)2) HemorrhageHemorrhage. It is the most widespread reason of iron deficiency in organism;. It is the most widespread reason of iron deficiency in organism; 3)3) Strengthened use of ironStrengthened use of iron – pregnancy, lactation.– pregnancy, lactation. Insufficiency of iron in organism results in disorder of ferriferous proteins synthesis andInsufficiency of iron in organism results in disorder of ferriferous proteins synthesis and consequently to the following disorders:consequently to the following disorders:  1) disorder of heme synthesis,1) disorder of heme synthesis,  2) disorder of cytochromes formation and tissue hypoxia,2) disorder of cytochromes formation and tissue hypoxia,  3) decrease of catalase activity hemolysis of erythrocytes and development of3) decrease of catalase activity hemolysis of erythrocytes and development of dystrophic changes in cells,dystrophic changes in cells,  4) reduction of synthesis myoglobin and decrease (reduction) of resistance to hypoxia.4) reduction of synthesis myoglobin and decrease (reduction) of resistance to hypoxia. Decrease of hemoglobin concentration in peripheral blood andDecrease of hemoglobin concentration in peripheral blood and reduction of color indexreduction of color index are typical for iron deficiency anemia. The quantity of erythrocytes decreases a little.are typical for iron deficiency anemia. The quantity of erythrocytes decreases a little. In blood smear the quantity regenerative forms of erythrocytes (reticulocytes,In blood smear the quantity regenerative forms of erythrocytes (reticulocytes, polychromatophils) decreases and their degenerative forms (anulocytes, microcytosis,polychromatophils) decreases and their degenerative forms (anulocytes, microcytosis, poikilocytosis).poikilocytosis). Iron refractory anemiaIron refractory anemia results from disorder of iron inclusion in heme at decrease ofresults from disorder of iron inclusion in heme at decrease of enzymes activity, which catalase synthesis of porphyrines and heme. The reasons mayenzymes activity, which catalase synthesis of porphyrines and heme. The reasons may be:be:  1) genetic down turn of decarboxylase activity of coproporphyrinogen – the enzyme1) genetic down turn of decarboxylase activity of coproporphyrinogen – the enzyme providing one of final stages of heme synthesis (it is inherited recessively, is linked toproviding one of final stages of heme synthesis (it is inherited recessively, is linked to the X-chromosome);the X-chromosome);  2) reduction of the maintenance pyridoxalphosphate – the active form of vitamin B6 and2) reduction of the maintenance pyridoxalphosphate – the active form of vitamin B6 and as a result of this iron is not taken from mitochondria of erythroblasts and is not includedas a result of this iron is not taken from mitochondria of erythroblasts and is not included in heme;in heme;  3) lead blockade of sulfhydryl groups of the enzymes participating in synthesis of heme.3) lead blockade of sulfhydryl groups of the enzymes participating in synthesis of heme.
    54. 54. (M = males; F = females)
    55. 55. Iron Deficiency AnaemiaIron Deficiency Anaemia  Symptoms:Symptoms:  weakness, fatigue, or lack of stamina  shortness of breath  headache – frontal  difficulty concentrating  irritability, apathy  dizziness  pale skin  craving substances that are not food (pica)  Signs:Signs:  rapid heart beat  brittle nails (also spoon nails)  cracked lips (angular stomatitis)  smooth sore tongue (Glossitis)  decreased appetite (especially in children)  decreased rate of growth  delay in skills like walking, talking .. and relatively later  Blue scleraBlue sclera
    56. 56. Glossitis. Tongue of individual with iron deficiency anemia has bald, fissured appearance caused by loss of papillae and flattening. Koilonychia. The nails are concave, ridged, and brittle. A siderocyte containing Pappenheimer bodies, a normal sideroblast and a ring sideroblast.
    57. 57. CLASSIFICATIONCLASSIFICATION CAUSESCAUSES DISCUSSIONDISCUSSION Blood lossBlood loss Gastrointestinal loss Menorrhagia Meckel's diverticulum (older children) PUD (most common cause in adult men) Gaslritis (e.g., NSAID) Hookworm infestation Polyps/colorectal cancer (most common cause in adults > 50years of age); positive stool for blood Most common cause in women < 50 years of age IncreasedIncreased utilizationutilization Pregnancy/lactation Infants/children Daily iron requirement in pregnancy is 3.4 mg and 2,5-3 mg in lactation Net loss of 500 mg of iron if not on iron supplements Iron required for tissue growth and expansion of blood volume DecreasedDecreased intakeintake Prematurity Infants/children Elderly Loss of iron each day fetus is not in utero Blood loss from phlebotomy Most common cause of iron deficiency in young children Restricted diets with little meat (lack of hemic iron) DecreasedDecreased absorptionabsorption Celiac sprue Post-gastric surgery Absence of villous surface In the duodenum Rapid transit; absent acid, which helps in iron reabsorption IntravascularIntravascular hemolysishemolysis Microangiopathic hemolytic anemia PNH Chronic loss of Hb in urine leads to iron deficiency
    58. 58. Iron deficiency anemiaIron deficiency anemia Normal tongue Iron deficiency anemia: bald tongue with atrophied papillae and angular inflammation
    59. 59. 2.76 Iron deficiency anemia with bald tongue and angular stomatitis 2.77 Iron and vitamin B 12 deficiency: glossitis with angular stomatitis 2.78 Undernutrition with multiple vitamin and iron deficiency: bald, fiery tongue 2.79 Peutz-Jeghers syndrome: mucosal lentigines and pigmentation
    60. 60. TESTTEST IRONIRON DEFICIENCYDEFICIENCY ANEMIA OFANEMIA OF CHRONICCHRONIC DISEASEDISEASE αα-THAL/-THAL/ββ-- THALTHAL MINORMINOR LEADLEAD POISONINGPOISONING MCV     Serum iron   Normal  TIBC   Normal  Percent saturation   Normal  Serum ferritin   Normal  RDW  Normal Normal Normal RBC count     Hb electrophoresis Normal Normal Α-Thal. trait: normal _ Ringed sideroblasts None None None Present Coarse basophilic stippling None None None Present Hb – hemoglobin; MCV - mean corpuscular volume; RDW - red blood cell distribution width; Thal – thalassemia; TIBC - total iron-binding capacity
    61. 61. B12-(folate)deficiency anemiaB12-(folate)deficiency anemiaThe reasons of vitamin B12 insufficiency in an organism:The reasons of vitamin B12 insufficiency in an organism: 1.1. Exogenous (alimentary) insufficiency –Exogenous (alimentary) insufficiency – insufficient receipt in an organism with foodinsufficient receipt in an organism with food stuffs. May develop in small children as a result feeding goat milk or dry dairy mixes.stuffs. May develop in small children as a result feeding goat milk or dry dairy mixes. 2.2. Disorders of vitamin B12 absorbtion:Disorders of vitamin B12 absorbtion: аа)) disorder of formation and secretion of gastromucoprotein (internal Castle’s factor).disorder of formation and secretion of gastromucoprotein (internal Castle’s factor). It happens atIt happens at hereditary caused disorders, an atrophy of a mucous membrane of stomach, autoimmune damages ofhereditary caused disorders, an atrophy of a mucous membrane of stomach, autoimmune damages of parietal cells of stomach mucous, due to gastrectomy or removal of more than two thirds of stomach;parietal cells of stomach mucous, due to gastrectomy or removal of more than two thirds of stomach; b)b) disorder of small intestine function:disorder of small intestine function: chronic diarrheas (celiac disease, sprue), resection of the bigchronic diarrheas (celiac disease, sprue), resection of the big parts of intestine;parts of intestine; c)c) competitive use of vitamin B12 by helmints and microflora of intestines (competitive use of vitamin B12 by helmints and microflora of intestines (diphyllobothriasisdiphyllobothriasis).). 3.3. Disorder of transcobalamines formation in liver.Disorder of transcobalamines formation in liver. 4.4. Disorder of vitamin B12 deposition in liver.Disorder of vitamin B12 deposition in liver. 5.5. Increased use of vitamin B12 (at pregnancy).Increased use of vitamin B12 (at pregnancy). Deficiency of vitamin B12 results in development of the frustration connected with formation disorderDeficiency of vitamin B12 results in development of the frustration connected with formation disorder of its two coenzyme forms: methylcobalamine and 5-desoxyadenosilcobalamine. In a red bone marrowof its two coenzyme forms: methylcobalamine and 5-desoxyadenosilcobalamine. In a red bone marrow erythroblastic type of hemopoiesis is replaced on megaloblastic, inefficient erythropoesis increases, lifeerythroblastic type of hemopoiesis is replaced on megaloblastic, inefficient erythropoesis increases, life expectancy of erythrocytes is shortened. The anemia with the expressed degenerate shifts not only in aexpectancy of erythrocytes is shortened. The anemia with the expressed degenerate shifts not only in a bone marrow, but also in blood develops. Changes in cells of myeloid and megacariocytic lines arebone marrow, but also in blood develops. Changes in cells of myeloid and megacariocytic lines are shown by reduction of leukocytes quantity and thrombocytes, expressed by atypia of cells (hugeshown by reduction of leukocytes quantity and thrombocytes, expressed by atypia of cells (huge neutrophils, megacaryocytes with degenerative changes in a nucleus). Occurrence of atypic mitosis andneutrophils, megacaryocytes with degenerative changes in a nucleus). Occurrence of atypic mitosis and huge cells of epithelium digestive tract results in development of inflammatory-atrophic processes inhuge cells of epithelium digestive tract results in development of inflammatory-atrophic processes in mucous membrane of its parts (mucous membrane of its parts (glossitis, stomatitis, esophagitis, achylic gastritis, enteritisglossitis, stomatitis, esophagitis, achylic gastritis, enteritis).). As a result of theAs a result of the second coenzyme forms insufficiencysecond coenzyme forms insufficiency of vitamin B12 –of vitamin B12 – 5-desoxyadenosilcobalamine5-desoxyadenosilcobalamine in organismin organism propionic and methylmalonic acids, which are toxic for nervous cellspropionic and methylmalonic acids, which are toxic for nervous cells. Besides fatty acids. Besides fatty acids with the changed structure are synthesised in nervous fibres results in disorder formation of myeline andwith the changed structure are synthesised in nervous fibres results in disorder formation of myeline and to damage of axones.to damage of axones. The degeneration of back and lateral columns of a spinal cord developsThe degeneration of back and lateral columns of a spinal cord develops ((funicular myelosisfunicular myelosis), cranial and peripheral nerves are damaged.), cranial and peripheral nerves are damaged. TheThe color index is increasedcolor index is increased, that is explained by the big saturation of cells by, that is explained by the big saturation of cells by hemoglobin. The phenomenon of degeneration erythrocytes is typical: anisocytosishemoglobin. The phenomenon of degeneration erythrocytes is typical: anisocytosis (macrocytosis), poikilocytosis (occurrence of the oval form cells), pathological inclusions(macrocytosis), poikilocytosis (occurrence of the oval form cells), pathological inclusions (Jolly’s bodies, Cabot’s rings).(Jolly’s bodies, Cabot’s rings).
    62. 62. Megaloblastic anemiaMegaloblastic anemia
    63. 63. CLASSIFICATIO N CAUSES DISCUSSION Decreased intake Pure vegan diet Malnutrition Breast-fed infants of pure vegans may develop deficiency May occur in elderly patients Malabsorption  Intrinsic factor  Gastric acid  Intestinal reabsorption Autoimmune destruction of parietal cells (i.e., pernicious anemia) Cannot activate pepsinogen to release vitamin B12 Crohn's disease or celiac disease involving terminal ileum (destruction of absorptive cells) Bacterial overgrowth (bacterial utilization of available vitamin B12) Fish tapeworm Chronic pancreatitis (cannot cleave off R- binder)Increased utilization Pregnancy/lactation Deficiency is more likely in a pure vegan
    64. 64. Pathogenesis of vitamin BPathogenesis of vitamin B1212 deficiency anaemiadeficiency anaemia Deficit of vitamin B12 Deficit of methylcobalamin – coenzyme form of vitamin B12 Deficit of tetrahydrofolic acid Deficit of 5,10-methyltetrahydrofolic acid (coenzyme type of folic aside) Deficit of thymidynphosphate Delay of DNA synthesis Inhibition of erythropoiesis
    65. 65. CLASSIFICATION CAUSES DISCUSSION Decreased intake Malnutrition Infants/elderly Chronic alcoholics Goat milk Decreased intake most common cause of folate deficiency Malabsorption Celiac disease Bacterial overgrowth Deficiency usually occurs in association with other vitamin deficiencies (fat and water soluble) Drug inhibition 5-Fluorouracil Methotrexate, trimethoprim- sulfamethoxazole Phenytoin Oral contraceptives, alcohol Inhibits thymidylate synthase Inhibit dihydrofolate reductase Inhibits Intestinal conjugase Inhibit uptake of monoglutamate in jejunum Alcohol also inhibits the release of folate from the liver Increased utilization Pregnancy/lactation Disseminated malignancy Severe hemolytic anemia Increased utilization of folate in DNA synthesis
    66. 66. Occurrence in blood and red bone marrow of   pathological regeneration cells – megaloblasts, megalocytes is the most typical feature of this anemia. B12-(folate)deficiency anemia. Blood B12-(folate)deficiency anemia. Red bone marrow
    67. 67. Such syndromes  are observed forSuch syndromes  are observed for B12-(folate)deficiency anemia:B12-(folate)deficiency anemia:  1. Hematologic syndrome:1. Hematologic syndrome: аа) anemia; b) leukopenia; c) thrombocytopenia.) anemia; b) leukopenia; c) thrombocytopenia.  2. Damages of the digestive tract which are2. Damages of the digestive tract which are shown by development inflammatory –atrophicshown by development inflammatory –atrophic changes in mucous membrane.changes in mucous membrane.  3. Damages of the central and peripheral3. Damages of the central and peripheral nervous system: funicular myelosis, degenerationnervous system: funicular myelosis, degeneration of peripheral nerves.of peripheral nerves.
    68. 68. LABORATORY/LABORATORY/ CLINICAL FINDINGCLINICAL FINDING PERNICIOUPERNICIOU S ANEMIAS ANEMIA OTHER VITAMINOTHER VITAMIN B12B12 DEFICIENCIESDEFICIENCIES FOLATEFOLATE DEFICIENCYDEFICIENCY Achlorhydria Present Absent Absent Autoantibodies Present Absent Absent Chronic atrophic gastritis Present Absent Absent Gastric carcinoma risk  None None Hypersegmented neutrophils Present Present Present Mean corpuscular volume    Neurologic disease Present Present None Pancytopenia Present Present Present Plasma homocysteine    Serum gastrin level  Normal Normal
    69. 69. Hypoplastic anemiasHypoplastic anemias  Hypoplastic (Hypoplastic (ааplastic)plastic) anemia is characterized byanemia is characterized by oppression hemopoietic functions of red bone marrowoppression hemopoietic functions of red bone marrow and shown by insufficient formation of erythrocytes,and shown by insufficient formation of erythrocytes, granulocytes and throrombocytes or only erythrocytes.granulocytes and throrombocytes or only erythrocytes.  There are acquired and is hereditary caused forms ofThere are acquired and is hereditary caused forms of hypoplastic anemia. The type of hereditary ishypoplastic anemia. The type of hereditary is autosomal-recessive type of inheritance concerns.autosomal-recessive type of inheritance concerns.  TheThe acquired formsacquired forms may be caused by the followingmay be caused by the following reasons:reasons: 1)1) physical factorsphysical factors (ionizing radiation);(ionizing radiation); 2)2) chemical agentschemical agents (benzene, lead, steams of mercury,(benzene, lead, steams of mercury, medical products: cytostatic agents, chloramphenicol,medical products: cytostatic agents, chloramphenicol, sulfanilamids);sulfanilamids); 3)3) biological factorsbiological factors (virus of hepatites).(virus of hepatites).  Essential formsEssential forms of anemia, which reason is notof anemia, which reason is not established belongs to acquired anemias.established belongs to acquired anemias.
    70. 70. CLASSIFICATlON EXAMPLES AND DISCUSSION Idiopathic Approximately 50-70% of cases are idiopathic Drugs  Most common known cause of aplastic anemia  Dose-related causes are usually reversible (e.g., alkylating agents)  Idiosyncratic reactions are frequently irreversible (e.g., chloramphenicol) Chemical agents Toxic chemicals in industry and agriculture (e.g., benzene, insecticides-DDT, parathion) Infection May involve all hematopoietic cell lines (pancytopenia) or erythroid cell line alone (pure RBC aplasia) Examples—EBV; CMV; parvovirus; non-A, non-B hepatitis, HCV Physical agents Whole-body ionizing radiation (therapeutic or nuclear accident) Miscellaneous Thymoma (may be associated with pure RBC aplasia) Paroxysmal nocturnal hemoglobinuria CMV, cytomegalovirus; EBV, Epstein-Barr virus; HCV, hepatitis C.
    71. 71. Hypoplastic anemias  Reduction of erythrocytes maintenance and concentration of hemoglobin when color index is within the limits of norm is characterised for the peacture of peripheral blood. Regenerative of erythrocytes (reticulocytes, polychromatophils) as a role are not found in a blood smear.The maintenance of granulocytes (especially neutrophils) and thrombocytes decreases.The quantity of lymphocytes may remain without changes.  In a red bone marrow the quantity of hemopoietic cells decreases with increase of maintenance of fatty tissue (picture of devastation red bone marrow). Because of iron is not used for the purposes hemopoiesis, its maintenance in erythroblasts and extracelulary is increased.  Appearence of hypoplastic anemias are connected with reduction of three kinds formation of form blood elements: erythrocytes, granulocytes and thrombocytes. It results in development of the following clinical syndromes: 1. The anemia and connected to it hypoxic syndrome. 2. Hemorrhagic syndrome. 3.The inflammatory processes caused by infectious agents (pneumonia, otitis, pyelitis etc.).
    72. 72. Metaplastic anemiasMetaplastic anemias TheThe metaplastic anemiametaplastic anemia is the result of hemopoieticis the result of hemopoietic tissue replacement on tissues: leucosis cells, connectivetissue replacement on tissues: leucosis cells, connective tissue (fibrosis), metastasises of tumor.tissue (fibrosis), metastasises of tumor. Dysregulative anemiasDysregulative anemias Dysregulative anemiasDysregulative anemias arise as a result ofarise as a result of erythropoiesis regulation disorders (infringement of ratioerythropoiesis regulation disorders (infringement of ratio between erythropoietins and inhibitors of erythropoiesis duebetween erythropoietins and inhibitors of erythropoiesis due to insufficiency of kidneys, damage of strome elements –to insufficiency of kidneys, damage of strome elements – microenvironments of erythropoietins cells, hypofunction ofmicroenvironments of erythropoietins cells, hypofunction of hypophysis, thyroid gland).hypophysis, thyroid gland).
    73. 73. 1- Pallor1- Pallor  looked forlooked for  in the skin in general, at palms, morein the skin in general, at palms, more precise in the palmar creasesprecise in the palmar creases  at the conjunctiva of the eyesat the conjunctiva of the eyes  Mouth mucosaMouth mucosa  nail bedsnail beds 2- Jaundice as in Haemolysis2- Jaundice as in Haemolysis  Skin, Eye Sclera, MucousSkin, Eye Sclera, Mucous MembraneMembrane 3- Hyperpigmentation, café au-lait spots3- Hyperpigmentation, café au-lait spots  Fanconi AnaemiaFanconi Anaemia
    74. 74. 1- Frontal Bossing1- Frontal Bossing  ThalassaemiaThalassaemia 2- Microcephaly2- Microcephaly  Fanconi AnaemiaFanconi Anaemia
    75. 75. 1- Glossitis1- Glossitis  Vit. B12 deficiency, Fe deficiencyVit. B12 deficiency, Fe deficiency 2- Angular stomatitis2- Angular stomatitis  Fe deficiency anemiaFe deficiency anemia
    76. 76. Chest:Chest: Chest PainChest Pain MurmerMurmer  Severe anemia, EndocarditisSevere anemia, Endocarditis Rapid BreathingRapid Breathing Rapid Heart RateRapid Heart Rate
    77. 77. Abdomen:  Abdominal pain  Hepatomegaly, Splenomegaly
    78. 78. Extremities:Extremities:  brittle nails, Spoon Nailsbrittle nails, Spoon Nails  Iron deficiencyIron deficiency
    79. 79. Nerves:Nerves:  Ataxia, PeripheralAtaxia, Peripheral neuropathy (Vitamin B12)neuropathy (Vitamin B12)
    80. 80. Neuropathy:Neuropathy: (A)erythema(A)erythema chronicumchronicum migransmigrans (Lyme(Lyme disease),disease), (B)Reynaud's(B)Reynaud's phenome-phenome- non,non, (C) purpuric(C) purpuric rash (eg,rash (eg, vasculitis)vasculitis) andand (D)depigmen-(D)depigmen- tationtation (leprosy).(leprosy).
    81. 81. General:General:  Poor weight gain or Weight lossPoor weight gain or Weight loss  Short StatureShort Stature  ThalassaemiaThalassaemia  Sickle cell diseaseSickle cell disease
    82. 82. 1. General and clinical pathophysiology/ Edited by Anatoliy V. Kubyshkin – Vinnytsia: Nova Knuha Publishers – 2011. 2. Robbins and Cotran Pathologic Basis of Disease 8th edition / Kumar, Abbas, Fauto 2006. – Chapter 12. 3. Essentials of Pathophysiology: Concepts of Altered Health States (Lippincott Williams & Wilkins), Trade paperback (2003) / Carol Mattson Porth, Kathryn J Gaspard. – Chapter 13. 4. Russell J. Greene. Pathology and Therapeutics for Pharmacists. A basis for clinical pharmacy practice / Russell J. Greene, Norman D. Harris // IL 60030-7820, 3rd edition, USA. – 2008. – Chapters 11. 5. Corwin Elizabeth J. Handbook of Pathophysiology / Corwin Elizabeth J. – 3th edition. Copyright В. – Lippincott Williams & Wilkins – 2008. – Chapters 12. 6. Copstead Lee-Ellen C. Pathophysiology / Lee-Ellen C. Copstead, Jacquelyn L. Banasik // Elsevier Inc, 4th edition. – 2010. 7. Pathophysiology, Concepts of Altered Health States, Carol Mattson Porth, Glenn Matfin. – New York, Milwaukee. – 2009. 8. Silbernagl S. Color Atlas of Pathophysiology / S. Silbernagl, F. Lang // Thieme. Stuttgart. New York. – 2000. 9. Gozhenko A.I. Pathophysiology / A.I. Gozhenko, I.P. Gurcalova // Study guide for medical students and practitioners. Edited by prof. Zaporozan, OSMU. – Odessa. – 2005.

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