Anaemias

1.1. EryhtropoiesisEryhtropoiesis2.2. Erythrocytosis and erythropenia. Erythrocytosis and erythropenia. 3.3. Anaemia. Classifications of anaemias.Anaemia. Classifications of anaemias.4.4. Etiology and pathogenesis of acute Etiology and pathogenesis of acute

and chronic posthemorrhagic anaemia.and chronic posthemorrhagic anaemia.5.5. Etiology and pathogenesis of Etiology and pathogenesis of

hemolytic anaemias.hemolytic anaemias.6.6. Anaemias with disorders of Anaemias with disorders of

erythropoesis.erythropoesis.

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.

Polycythemias Polycythemias 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.

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- 4,71012/l for women, 4,2-5,21012/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

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 ContentNormal Normocytic NormochromicIncreased Macrocytic (higher mean

corpuscular volume [MCV])Hyperchromic (higher mean corpuscular Hb concentration [MCHC])

Decreased Microcytic (lower MCV) Hypochromic (lower MCHC)

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 certainpathologic 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.

Erythropoietin MechanismErythropoietin MechanismImbalance

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

a)a) increase ( increase (erythrocytosis)erythrocytosis)

Various changes are in the system of Various changes are in the system of erythronerythron, , which arise up in physiology terms and at which arise up in physiology terms and at pathological processes, can be accompanied pathological processes, can be accompanied running the number of erythrocytes in blood: running the number of erythrocytes in blood:

ErythrocytosisErythrocytosis is multiplying the amount of is multiplying the amount of erythrocytes higher as norm. erythrocytes higher as norm.

Distinguish the followings types of Distinguish the followings types of erythrocytosis:erythrocytosis:

A. PrimaryA. Primary (independent forms of illness): (independent forms of illness): 1)1) erythremiaerythremia [polycythemia vera, Osler's [polycythemia vera, Osler's disease, Vaquez' disease], 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))

ErythremiaErythremia is a disease of tumor nature, which relative to the group is a disease of tumor nature, which relative to the group of chronic hemoblastosis. of chronic hemoblastosis.

The amount of erythrocytes is multiplied considerable in peripheral blood. The amount of erythrocytes is multiplied considerable in peripheral blood. Reticulocytes, neutrophiles, monocytes, platelets increase also. Haemoglobin Reticulocytes, neutrophiles, monocytes, platelets increase also. Haemoglobin grows also. In marrow are signs of grows also. In marrow 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 of diffuse thrombosis which leads to violation of

microcirculation and results in capillarotrophic insufficiency. microcirculation and results in capillarotrophic insufficiency.

• • Family erythrocytosisFamily erythrocytosis usually have inherited character, also usually have inherited character, also accompanied multiplying mass of circulating erythrocytes and volume of accompanied multiplying mass of circulating erythrocytes and volume of blood.blood.

• • Primary (absolute) erythrocytosisPrimary (absolute) erythrocytosis connect with increasing the amount connect with increasing the amount of stimulators of erythropoiesis (in particular, erythropoietin) and arise up: of 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 of kidneys, at the local ischemia of 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 in diminishing 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 [repartition] of blood – by a redistribution [repartition] of blood – supply exit of the supply exit of the

deposited erythrocytes (stress, acute hypoxia, increase the amount of deposited erythrocytes (stress, acute hypoxia, increase the amount of catecholamines).catecholamines).

Hematological attributes of anemias are Hematological attributes of anemias are subdivided on quantitative and qualitativesubdivided on quantitative and qualitative

AnemiasAnemias are diminishing of amount of erythrocytes and/or are diminishing of amount of erythrocytes and/or hemoglobin in unit of volume of blood with the high-quality hemoglobin 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 on Hematological attributes of anemias are subdivided on quantitativequantitative and and qualitativequalitative..

1. The quantitative displays include:1. The quantitative displays include:1)  1)  reductionreduction of the maintenance of erythrocytes of the maintenance of erythrocytes  in unit of blood volume:  in unit of blood volume:•in in menmen is is lower than 4×10lower than 4×101212, , •in in womenwomen is is lower than 3,5×10lower than 3,5×101212 in 1L of blood; in 1L of blood;2)  2)  reduction of hemoglobinreduction of hemoglobin concentration concentration – in – in menmen is is lower than 130 g/llower than 130 g/l, , • in in womenwomen is is lower than 120 lower than 120

g/lg/l;;3)  3)  reduction of hematocrit (Htc) reduction of hematocrit (Htc) – in men is lower than 0,43 (43%), – in men is lower than 0,43 (43%), N = 36-48% N = 36-48% in women is lower than 0,40 (40%);in women is lower than 0,40 (40%);•4)  4)  change of a change of a color index color index – is – is not lower thannot lower than 0,85 0,85 and and not higher than not higher than

1,151,15..

2. Qualitative attributes of anemias are presence in blood of:2. Qualitative attributes of anemias are presence in 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 of 3)  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 sprout   regeneration) are young immature cells of red blood sprout   appearance of which in peripheral blood testifies to amplification appearance of which in peripheral blood testifies to amplification of regeneration of cells erythroid lines in red bone marrow or of 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 color are 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 amount 2%. 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 which are 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, contained precursors of erythrocytes. In a norm in peripheral blood are absent, contained only in red bone marrow. Sometimes, at hyperregenerative anemias, in blood it is only in red bone marrow. Sometimes, at hyperregenerative anemias, in blood it is possible to find erythroblasts (precursors of normoblasts).possible to find erythroblasts (precursors of normoblasts).

ReticulocytesReticulocytes

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 occur when there is changed of erythropoesis from erythroblastic to megaloblastic:changed of erythropoesis from erythroblastic to megaloblastic:

аа) megaloblasts ) megaloblasts are  big cells with basophilic, polychromatophilic or are  big cells with basophilic, polychromatophilic or acidophilic cytoplasm, containing large, located usually eccentrically nucleus acidophilic cytoplasm, containing large, located usually eccentrically nucleus with soft chromatin grid with soft chromatin grid ((diameter of 12-15 mkmdiameter of 12-15 mkm),), ;;

b) megalocytes b) 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 megaloblasts. They usually intensively stained, some the oval form, non an brighten up in the central part (brighten up in 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 Occurrence of the specified cells in red bone marrow and blood is typical for megaloblastic anemias, in particular of the B12-deficiency anemia.for megaloblastic anemias, in particular of the B12-deficiency anemia.

AnisocytosisAnisocytosis

AnisocytosisAnisocytosis

MicrocytosisMicrocytosis

MacrocytosisMacrocytosis

MegalocytosisMegalocytosis

ShuistocytesShuistocytes DacriocytesDacriocytes

EliptocytesEliptocytes

SpherocyteSpherocytess

Drepa-Drepa-nocytesnocytes

PoikilocytosisPoikilocytosis

NORMAL BLOODNORMAL BLOOD ANEMIC BLOOD ANEMIC BLOOD

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

Symptom checkerSymptom checker

Symptom checkerSymptom checkerADULT SYMPTOMS

Because a low red blood cell count decreases oxygen delivery to every tissue in the body, anemia causes many signs and symptoms.

CLASSIFICATION OF ANEMIASCLASSIFICATION OF ANEMIAS

CriteriaCriteria Types of anemiaTypes of anemia RangeRange

I. By etiologyI. By etiology 1. Hereditary 1. Hereditary 2. Acquired2. Acquired

II. By pathogenesisII. By pathogenesis1. Posthemorrhagic1. Posthemorrhagic2. Hemolytical2. Hemolytical3. Diserythropoietic 3. Diserythropoietic

III. By the type of III. By the type of hemopoiesishemopoiesis

1. Normoblastic1. Normoblastic2. Megaloblastic2. Megaloblastic

IV. By regeneratory IV. By regeneratory ability of bone marrowability of bone marrow

1. Regeneratory1. Regeneratory2. Hyperregeneratory2. Hyperregeneratory3. Hyporegeneratory3. Hyporegeneratory4. Aregeneratory4. Aregeneratory5. Aplastic5. Aplastic

0,2-1%0,2-1%More than1%More than1%Less than 0,2%Less than 0,2%0%0%

CriteriaCriteria Types of anemiaTypes of anemia RangeRange

V. By color indexV. By color index1. Normochromic 1. Normochromic 2. Hyperchromic2. Hyperchromic3. Hypochromic3. Hypochromic

0.85-1.050.85-1.05more than 1.05more than 1.05less than 0.85less than 0.85

VI. By the sizes of VI. By the sizes of erythrocyteserythrocytes

1. Normocytary1. Normocytary2. Microcytary2. Microcytary3. Macrocytary3. Macrocytary4. Megalocytary 4. Megalocytary

7.2-8.3 mcm7.2-8.3 mcmless than 7.2 mcmless than 7.2 mcm8.3-12 mcm8.3-12 mcmmore than 12-15 mcmmore than 12-15 mcm

VII. By the clinical VII. By the clinical coursecourse

1. Acute1. Acute2. Chronic2. Chronic

Classifications of anemiasClassifications of anemiasPathogenetic 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.

Morphology of Morphology 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 deathFolate 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, abnormallyshaped 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 cycleCongenital dysfunction of iron metabolism in erythroblasts, acquired dysfunction of ironmetabolism as a result of drugs or toxinsCongenital genetic defect of globin synthesis

MORPHOLOGIC CLASSIFICATION OF MORPHOLOGIC CLASSIFICATION OF ANEMIASANEMIASMorphology of Morphology of

remaining erythrocytesremaining erythrocytes Name and Mechanism of AnemiaName and Mechanism of Anemia Primary CausePrimary Cause

Normocytic-normochromic anemia: normal size, normal hemoglobinconcentration

Aplastic anemia: insufficient erythropoiesis

Posthemorrhagic anemia: blood loss

Hemolytic anemia: premature destruction (lysis) of mature erythrocytes in the circulationSickle cell anemia: abnormal hemoglobin synthesis,abnormal cell shape with susceptibility to damage,lysis, and phagocytosisAnemia of chronic disease: abnormally increased demand for new erythrocytes

Depressed stem cell proliferation resulting in bone marrow aplasiaAcute or chronic hemorrhage that stimulates increased erythropoiesis, which eventually depletes body ironIncreased fragility of erythrocytes

Congenital dysfunction of hemoglobin synthesis

Chronic infection or inflammation; malignancy

The characteristic of posthemorrhagic The characteristic of posthemorrhagic anemiasanemias

Posthemorrhagic anemiaPosthemorrhagic anemia is an anemia which develops as a result of is an anemia which develops as a result of hemorrhage. There are hemorrhage. There are two typestwo types of anemias of this group of anemias of this group according to the according to the character of hemorrhagecharacter of hemorrhage: : 1)1) acuteacute posthemorrhagic and posthemorrhagic and

2)2) chronicchronic posthemorrhagic anemia. posthemorrhagic anemia.Acute posthemorrhagic anemiaAcute posthemorrhagic anemia develops as a result of the massive external develops 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 acute Complete renewal of basic indexes of red blood after acute hemorrhagehemorrhage is is

observed on 30-35 days.observed on 30-35 days.

Chronic posthemorrhagic anemiaChronic posthemorrhagic anemiaChronic posthemorrhagic anemia Chronic posthemorrhagic anemia runs across on the type of runs across on the type of

asiderotic [iron-deficiency] anemia and develops as a result of asiderotic [iron-deficiency] anemia and develops as a result of small, but protracted repeated hemorrhage at: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 coagulative at violations of thrombocyte-vascular and coagulative

hemostasis.hemostasis.

DuringDuring chronic posthemorrhagic anemiachronic posthemorrhagic anemia after the after the loss of iron loss 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- in blood smear there are degenerate forms of erythrocytes (micro-

and poikilocytosis, hypochromy); and poikilocytosis, hypochromy); ► quantity of erythrocytes and hematocrit may remain without changes.quantity of erythrocytes and hematocrit may remain without changes.

Petechiae of the gastric mucosaPetechiae of the gastric mucosa Ecchymosis

Metrorrhagia

Ruptured esophageal varix

Hemolytical anemias

Acquired (secondary) Hereditary or congenital (primary)

immune

toxic mechanical membranopathy

enzymopathy

Hb-pathy

alloimmunetransimmuneheteroimmuneautoimmune

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

The characteristic  of hemolytic anemiasThe characteristic  of hemolytic anemiasHemolytic 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 of T 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 of hemolytic arises up in the vessels of bloods under the action of hemolytic factors which damage erythrocytes, in particular: 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. Mechanical Mechanical 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. Osmotic Osmotic hemolysishemolysis - arises up subject to the condition, when osmotic pressure into - arises up subject to the condition, when osmotic pressure into

erythrocytes more than osmotic pressure of plasma of blood → increase moving of erythrocytes more than osmotic pressure of plasma of blood → increase moving of water inside of erythrocyte → enlargement → rapture of membrane. water inside of erythrocyte → enlargement → rapture of membrane.

► IIIIII. . Oxidizing Oxidizing 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 of membrane of erythrocytes. That led to increase permeability of membrane of erythrocytes → than osmotic mechanism.erythrocytes → than osmotic mechanism.

► IV.IV. Detergent Detergent hemolysishemolysis – connect with to dissolution of lipidic components of – connect with to dissolution of lipidic components of membrane of erythrocytes by detergents. This type of membrane of erythrocytes by detergents. This type of hemolysishemolysis is caused by bilious is caused by bilious acids (bilious syndrome), liposoluble chemical agents, some toxins of bacteria acids (bilious syndrome), liposoluble chemical agents, some toxins of bacteria (lecithinase).(lecithinase).

► V.V. Complement-dependent Complement-dependent hemolysishemolysis – conditioned destruction (by a perforation) of – conditioned destruction (by a perforation) of membrane of erythrocytes by active complement. This mechanism lies in basis of membrane of erythrocytes by active complement. This mechanism lies in basis of immune 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 intracellular anemias with intracellular hemolysis.hemolysis.

Intravascular Intravascular hemolysishemolysis is accompanied the is accompanied the exit of hemoglobin from cells in plasma of exit of hemoglobin from cells in plasma of blood, where it connect with the albumen blood, where it connect with the albumen (haptoglobin). (haptoglobin).

1)1) The complex of hemoglobin-haptoglobin The complex of hemoglobin-haptoglobin phagocytes by macrophages and causes production phagocytes by macrophages and causes production and excretion erythropoietin → stimulates and excretion erythropoietin → stimulates erythropoiesis.erythropoiesis.

2)2) Albuminous part of haemoglobin Albuminous part of haemoglobin chip off to chip off to amino acid, and from a heme [haem] will appear amino acid, and from a heme [haem] will appear bilirubin which contacts with albumins and enters bilirubin which contacts with albumins and enters into blood (unconjugated [indirect] bilirubin). into blood (unconjugated [indirect] bilirubin). Hemolytic jaundice develops.Hemolytic jaundice develops.

3)3) Part of unconnected from haptoglobin Part of unconnected from haptoglobin hemoglobin is filtered by kidneys → hemoglobin is filtered by kidneys → appearance appearance of hemoglobin in urines (hemoglobinuria) and of hemoglobin in urines (hemoglobinuria) and "obstructions" of nephrons of kidney with "obstructions" of nephrons of kidney with development of signs of acute kidney insufficiencydevelopment of signs of acute kidney insufficiency. .

Intracellular Intracellular hemolysishemolysis develops as a develops as a result of absorption and overcooking of result of absorption and overcooking of erythrocytes by macrophages. erythrocytes by macrophages.

Reasons:Reasons:

a)a) appearance of appearance of imperfect erythrocytesimperfect erythrocytes which delay in which delay in the venous sinus of spleen ("splenic filter"), where the venous sinus of spleen ("splenic filter"), where they contact with macrophages; they contact with macrophages;

b)b) appearance on the appearance on the surface of erythrocytessurface of erythrocytes of of chemical groups, capable specifically to co-operate chemical groups, capable specifically to co-operate with the receptors of macrophages; with the receptors of macrophages;

c)c) hypersplenism hypersplenism is increasing phagocytic activity of is increasing phagocytic activity of macrophagesmacrophages of spleen.of spleen.

Increased phagocytosisIncreased phagocytosis of erythrocytes causes the of erythrocytes causes the followings changes:followings changes:

a)a) production and excretion of erythropoietinproduction and excretion of erythropoietin b)b) increase unconjugated [indirect reacting] increase unconjugated [indirect reacting]

bilirubin. Hemolytic jaundice developsbilirubin. Hemolytic jaundice develops c)c) proliferation of macrophages. That lead to proliferation of macrophages. That lead to

splenomegaly.splenomegaly.

MacrophageMacrophagephagocytosesphagocytoses

Globin chains Globin chains amino acids amino acids

HemeHemeIron (stored)Iron (stored)

Protoporphyrin Protoporphyrin Unconjugated Unconjugated

bilirubin bilirubin (Jaundice)(Jaundice)

Reduced haptoglobin levelsReduced haptoglobin levels(acute Intravascular hemolysis)(acute Intravascular hemolysis)

Intravascular Intravascular hemolysis hemolysis

Hb • haptoglobin Hb • haptoglobin complexcomplex Removed by macrophagesRemoved by macrophages

Unbound free Hb (haptoglobin depleted)Unbound free Hb (haptoglobin depleted)

HemoglobinuriaHemoglobinuriaRenal tubules reabsorbtion Renal tubules reabsorbtion

Excreted as HbExcreted as Hb Possible ironPossible irondeficiencydeficiency

HemosiderinuriaHemosiderinuria(chronic intravascular hemolysis)(chronic intravascular hemolysis)

TYPES EXAMPLESMicroangiopathic

Platelet thrombi Hemolytic uremic syndromeThrombotic thrombocytopenic purpura

Fibrin thrombiDisseminated 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

I.I. Acquired hemolytic anemiasAcquired hemolytic anemiasDepending on the reasons of development is allocated the Depending on the reasons of development is allocated the

following kinds of  acquired hemolytic anemias.following kinds of  acquired hemolytic anemias.

1.         1.         Toxic Toxic hemolytic anemias.hemolytic anemias. Infectious Infectious hemolytic anaemias.hemolytic anaemias. 2.         2.         ImmuneImmune hemolytic anemias. hemolytic anemias. 3.         The anemias caused by 3.         The anemias caused by mechanical damagemechanical damage of of

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  chemical agents: phenylhydrasin, lead, copper

salts, arsenous hydrogen etc.;salts, 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, hemolytic of 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 - caused a number of infectious agents, in particular, by a hemolytic streptococcus, infectious agents, in particular, by a hemolytic streptococcus, malaria, toxoplasmosis and others.malaria, toxoplasmosis and others.

2. Immune Hemolytic Anemias2. Immune Hemolytic AnemiasImmune hemolytic anemiasImmune hemolytic anemias arise due to participation of specific immune arise due to participation of specific immune

mechanisms. mechanisms. They are caused by interaction of humoral antibodies with the They 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 and divided on: divided on:

1) Isoimmune1) Isoimmune, reason of which is: , reason of which is: a) receipt from outside of antibodies against own erythrocytes (hemolytic illness of a) receipt from outside of antibodies against own erythrocytes (hemolytic illness of

babies); babies); b) entering organism of erythrocytes against which there are antibodies in plasma b) 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 of Reasons: primary changes of erythrocytes (appearance of autoantigen), changes in the immune system (abolition of immunological tolerance autoantigen), 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 of arises 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 of Most 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 is At first there is immunization of mother Rh+Er of fetus, which can get in the organism of mother immunization 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 the during 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. These organism of mother antibodies are synthesized against to the D-antigen. These antibodies (IgG) are able to penetrate through a placenta in the organism of fetus antibodies (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).

TYPE OF IMMUNE TYPE OF IMMUNE HEMOLYTIC ANEMIAHEMOLYTIC ANEMIA EXAMPLESEXAMPLES

AutoimmuneAutoimmuneWarm antibodies (IgC)

Cold antibodies (IgM)

Chronic lymphocytic leukemia

Primary or idiopathic (no underlying cause)Secondary (e.g., SLE)Primary or idiopathicSecondary: 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 membraneImmunocomplex (e.g., quinidine): drug-IgM immunocomplex deposits on the RBC causing intravascular hemolysisAutoantibody induction (e.g., α-methyldopa): drug alters Rh antigens on RBCs causing synthesis of autoantibodies against Rh antigens

AlloimmuneAlloimmuneHemolytic transfusion reaction ABO hemolytic disease of newborn Rh hemolytic disease of newborn

SLE, systemic lupus erythematosus.

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 anti-A and anti-B

antibodies, universal recipient• Type O plasma contains no antibodies,

universal donor

Rh Blood GroupRh Blood Group Rh positiveRh positive indicates presence of indicates presence of

antigen D, one of the Rh antigensantigen D, one of the Rh antigens Rh negativeRh negative indicates absence of indicates absence of

Antigen DAntigen D Rh antigens, like A and B antigens are Rh antigens, like A and B antigens are

inherited and present from birthinherited and present from birth Anti-D antibodies are not produced Anti-D antibodies are not produced

until after an individual is until after an individual is sensitized to antigen Dsensitized to antigen D

33. . The anaemias caused by The anaemias caused by mechanical damage of erythrocytesmechanical damage 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 March hemoglobinuria – trauma of erythrocytes in capillaries of

feet during protracted march. feet during protracted march. 44. . Acquired membranopathy.Acquired membranopathy.

Acquired membranopathyAcquired membranopathy arise due to the acquired defects arise due to the acquired defects of erythrocytes membranes. As an example may be paroxysmal of erythrocytes membranes. As an example may be paroxysmal nightly hemoglobinuria (nightly hemoglobinuria (illness of Markiafavi-Mikeliillness of Markiafavi-Mikeli) is a somatic ) is a somatic mutation of erythropoietic cells with defects of membrane.mutation of erythropoietic cells with defects of membrane. It is It is considered that disorders of membranes are connected with changes of  considered that disorders of membranes are connected with changes of  ratio of fat acids which are part of their phospholipids. Erythrocytes of  ratio of fat acids which are part of their phospholipids. Erythrocytes of  abnormal population get ability to fix complement and hemolyse. The abnormal population get ability to fix complement and hemolyse. The erythrocytes of anomalous population obtain ability to fix complement erythrocytes of anomalous population obtain ability to fix complement which is pre-condition of complement-depended hemolysis, and diminishing which is pre-condition of complement-depended hemolysis, and diminishing of pH environment is a factor which provokes intravascular of pH environment is a factor which provokes intravascular hemolysishemolysis. This . This feature explains the destruction of erythrocytes is observed more frequent feature explains the destruction of erythrocytes is observed more frequent at night (in the night-time 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 of acquired hemolytic anemias is characterized by reduction of erythrocytes quantity and hemoglobin. The color by reduction of erythrocytes quantity and hemoglobin. The color index in norm, however may be higher than 1 unit that is index in norm, however may be higher than 1 unit that is connected with extraerythrocytic hemoglobin. In blood smear the connected with extraerythrocytic hemoglobin. In blood smear the significant amount regenerative forms of erythrocytes is found out: significant amount regenerative forms of erythrocytes is found out: reticulocytes, polychromatophils, normocytes.reticulocytes, polychromatophils, normocytes.

ІІ.ІІ. Hereditary hemolytic Hereditary hemolytic anemiasanemias

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 Anemias of this group are caused by disorder  of erythrocytes enzymes .erythrocytes 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 may be caused by two groups of defects

erythrocytic membranes: erythrocytic membranes: 1.1. MembranopathiesMembranopathies, caused by disorders of membrane , caused by disorders of membrane

proteins: 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, endoerythrocytic is hereditary, endoerythrocytic

(membranopathy) hemolytic anemia with endocellular hemolysis. (membranopathy) hemolytic anemia with endocellular hemolysis. Type of inheritance – autosomal dominant. Hereditary defect Type of inheritance – autosomal dominant. Hereditary defect mentions membrane proteins of erythrocytes,mentions membrane proteins of erythrocytes, in particular in particular

spectrin. Therefore permeability spectrin. Therefore permeability of erythrocytic membranes for ions sodium is of erythrocytic membranes for ions sodium is considerably increased. considerably increased. Sodium and water Sodium and water pass from plasma inside of erythrocytes. pass from plasma inside of erythrocytes. At passing in the sinus of spleen they At passing in the sinus of spleen they lose part of erythrocytes membrane and lose part of erythrocytes membrane and turn into microspherocytes. turn into microspherocytes. Life expectancy of erythrocytes decreases Life expectancy of erythrocytes decreases untilluntill 8-12 (10-14) days instead of 120. 8-12 (10-14) days instead of 120.

Schematic representation of the red cell membrane cytoskeleton and alterations Schematic representation of the red cell membrane cytoskeleton and alterations leading to spherocytosis and hemolysis. Mutations weakening interactions leading to spherocytosis and hemolysis. Mutations weakening interactions involving involving αα-spectrin, -spectrin, ββ-spectrin, ankyrin, band 4.2, or band 3 all cause the normal -spectrin, ankyrin, band 4.2, or band 3 all cause the normal biconcave red cell to lose membrane fragments and adopt a spherical shape. Such biconcave red cell to lose membrane fragments and adopt a spherical shape. Such spherocytic cells are less deformable than normal and therefore become trapped spherocytic cells are less deformable than normal and therefore become trapped in the splenic cords, where they are phagocytosed by macrophages.in the splenic cords, where they are phagocytosed by macrophages.

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 utilization deficiency  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 oflinks 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

33. . Hemoglobinopathies - related to Hemoglobinopathies - related to violations of synthesis of molecule of violations of synthesis of molecule of

haemoglobin.haemoglobin.

Sickle-cell anemia

The molecules of haemoglobin are heterogeneous of the adult healthy man. 95 % faction The 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 of Every 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 Greek haemoglobin consists of 4 polypeptidic chains which are reflected by letter of the Greek alphabet:alphabet: α,β,γ,δ α,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 of Qualitative and quantitative changes of hemoglobin lay in  basis of development of hereditary hereditary hemoglobinopathies. hemoglobinopathies. The most widespread The most widespread clinical form is clinical form is sickle-cell sickle-cell anemiaanemia at which in at which in β-chain of a molecule of β-chain of a molecule of hemoglobin glutamine hemoglobin glutamine acid is replaced onacid is replaced onvaline (HbS). valine (HbS).

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

SCD is characterized by its presentation:

1- Vaso-occlusive crises2- Sequestration crises3- Hemolytic crises4- Aplasic crises

Crewcut appearance

Sickle Cell Disease (SCD)Sickle Cell Disease (SCD)

Thalassemias.Thalassemias. In contrast to sickle cell anemia, the thalassemias result from In contrast to sickle cell anemia, the thalassemias result from absent or defective synthesis of the α or theabsent or defective synthesis of the α or the β chains of hemoglobin. The β chains of hemoglobin. The β-β-thalassemias represent a defectthalassemias represent a defect in β-chain synthesisin β-chain synthesis, and the , and the α-thalassemias α-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 of the a mild form of the disease or be homozygous and have thedisease or be homozygous and have the severe form of the disease. Like sickle severe form of the disease. Like sickle cell anemia, the thalassemiascell anemia, the thalassemias occur with high degree of frequency in certain occur with high degree of frequency in certain populations.populations. The The β-thalassemiasβ-thalassemias, sometimes called , sometimes called Cooley’s anemiaCooley’s anemia or or Mediterranean anemia, Mediterranean anemia, are most common in the Mediterraneanare most common in the Mediterranean populations of populations of southern Italy and Greece, and thesouthern Italy and Greece, and the α-thalassemias are most common among α-thalassemias are most common among Asians. Both α- andAsians. Both α- and β-thalassemias are common in Africans and black β-thalassemias are common in Africans and black Americans.Americans.

Thalassemia

HemogloHemoglobinbin

PolypPolypeptideptid

esesHemoglobiHemoglobin A1 n A1 (Adult)(Adult)

22αα

22ββ

HemoglobiHemoglobin A2 n A2

22αα 22δδ

HemoglobiHemoglobin F (Fetal)n F (Fetal)

22αα

22γγ

TypeType Hb Hb Hb-Hb-

electrophoreselectrophoresisis

GenotypeGenotype Clinical SyndromeClinical Syndrome

α-THALASSAEMIAS1. Hydrops foetalis 3-10 gm/dl Hb Barts (g4)

(100%) Deletion of four α-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 bloodtransfusions not required

β-Thalassaemia minor

10-12 gm/dl

HbA2 (4-9%),HbF (1-5%) βA/βthal Usually asymptomatic

2-The clinically significant haemoglobinopathies are listed in following Table

ANEMIAANEMIA PATHOGENESISPATHOGENESIS DISCUSSIONDISCUSSIONReticulocytosis < 3%

Acute blood loss Loss of whole blood

Initial Hb and Hct normalInfusion of normal saline uncovers anemiaSigns of volume depletion (c,g„ absolute neutrophilic leukocytosis) commonly present; positive tilt test

Early iron deficiency Decreased iron storesNormocytic before microcyticIron studies abnormal ( serum ferritin)

Early ACDIron trapped in macrophages byhepcidin

Normocytic before microcyticIron studies abnormal ( serum ferritin)

Aplastic anemiaSuppression or deficiency of myeloid stem cells

PancytopeniaHypocellular marrow

Chronic renal failure Deficiency of EPO Presence of burr cells

ANEMIAANEMIA PATHOGENESISPATHOGENESIS DISCUSSIONDISCUSSIONReticulocytosis ≥ 3%Hereditaryspherocytosis

AD disorderDefect in ankyrinExtravascular hemolysis

Increased osmotic fragilityTreat with splenectomy

Hereditary elliptocytosis

AD disorderDefect in spectrin and band 4.1Extravascular hemolysis

Elliptocytes > 25%

Paroxysmal nocturnalhemoglobinuria

Loss of anchor for DAF in myeloid stem cellComplement destruction ofhematopoietic cellsIntravascular hemolysisDefect on hematopoietic cells

PancytopeniaPositive sugar water test (screen) and acidifiedserum test (confirmatory test)

Sickle cell anemia AR disorderValine substitution for Glutamic acid β-globin chainExtravascular hemolysis

HbAS: HbA 55-60%; HbS 40-45%HbSS: HbS 90-95%; HbF 5-10%; no HbA

C6PD deficiency XR disorderDeficiency GSH causes oxidantdamage to Hb and RBC membraneIntravascular hemolysis

Heinz body preparation: screen during active hemolysisEnzyme assay: confirmatory test when hemolysis subsides

ANEMIAANEMIA PATHOGENESISPATHOGENESIS DISCUSSIONDISCUSSIONReticulocytosis ≥ 3%Pyruvate kinasedeficiency

AR disease ATP synthesisExtravascular hemolysis

2,3.BPG right shifts OBCDehydrated RBCs with thorny projections(echinocytes)

Acute blood loss Loss of whole bloodReticulocytosis 5-7 days

Hb, Hct, RBC count

Warm AIHA IgG with or without C3bExtravascular hemolysis

Positive direct Coombs' testSLE most common cause

Cold AIHA IgM with C3bExtravascular or Intravascularhemolysis

Association with Mycoplasma pneumoniae; EBVPositive direct Coombs' test

Drug-induced Immune hemolytic anemia

Drug hapten; penicillinExtravascular hemolysisImmunocomplex: quinidine Intravascular hemolysisAutoantibody: methyldopa Entravascular hemolysis

Positive direct Coombs' test

ANEMIAANEMIA PATHOGENESISPATHOGENESIS DISCUSSIONDISCUSSIONReticulocytosis ≥ 3%Alloimmune hemolyticanemia

Antibodies against foreign RBCantigensExtravascular hemolysis

Hemolylic transfusion reactionABO and Rh HDNPositive direct Coombs' test

Micro- andmacroangiopathichemolytic anemia

Mechanical destruction of RBCs with formation of schistocytesIntravascular hemolysis

Calcific aortic stenosis most common causeChronic hemoglobinuria causes iron deficiency

Malaria Transmitted by female Anopheles mosquitoIntravascular 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

The reasons of anemias with disorders of erythropoiesis The reasons of anemias with disorders of erythropoiesis may be: may be:

► 1) 1) disorder of formation of erythrocytesdisorder of formation of erythrocytes: : deficiency of hemopoietic cells due to their damage or deficiency of hemopoietic cells due to their damage or replacement, disorder of cells maturation of replacement, disorder of cells maturation of hemopoiesis (disorders of DNA resynthesis), defects of hemopoiesis (disorders of DNA resynthesis), defects of erythrocytes maturing and their output(exit) into erythrocytes maturing and their output(exit) into blood flow (deficiency erythropoiesis); blood flow (deficiency erythropoiesis);

► 2) 2) disorders of hemoglobin synthesisdisorders of hemoglobin synthesis: deficiency : deficiency of iron, disorder of synthesis porphyrines (hereditary of iron, disorder of synthesis porphyrines (hereditary disorders of enzymes, poisonings by lead, deficiency disorders of enzymes, poisonings by lead, deficiency of vitamin B6, frustration of albuminous chains of vitamin B6, frustration of albuminous chains synthesis of hemoglobin molecules).synthesis of hemoglobin molecules).

Anemias as a result Anemias as a result of erythropoiesis disorderof erythropoiesis disorder

Deficiency anemiasDeficiency anemias                      Irondeficiency 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 and Insufficiency 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 of dystrophic 3) decrease of  catalase activity hemolysis of erythrocytes and  development of dystrophic

changes in cells, 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 and reduction  of  color index are Decrease of  hemoglobin concentration in peripheral blood and reduction  of  color index are

typical for iron deficiency anemia. The quantity of erythrocytes decreases a little.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 of enzymes results from disorder   of iron inclusion in heme at decrease of enzymes activity, which catalase synthesis of porphyrines and heme. The reasons may be: activity, which catalase synthesis of porphyrines and heme. The reasons may be:

1) genetic down turn of decarboxylase activity of coproporphyrinogen – the enzyme 1) genetic down turn of decarboxylase activity of coproporphyrinogen – the enzyme providing one of final stages  of heme synthesis (it is inherited recessively, is linked to the providing one of final stages  of heme synthesis (it is inherited recessively, is linked to the X-chromosome); X-chromosome);

2) reduction of the maintenance pyridoxalphosphate – the active form of vitamin B6 and as 2) 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 included in a result of this iron is not taken from mitochondria of erythroblasts and is not included in heme; 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.

(M = males; F = females)

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

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, anormal sideroblast and a ring sideroblast.

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 infestationPolyps/colorectal cancer (most common cause in adults > 50years of age); positive stool for bloodMost common cause in women < 50 years of age

IncreasedIncreasedutilizationutilization

Pregnancy/lactation

Infants/children

Daily iron requirement in pregnancy is 3.4 mg and 2,5-3 mg in lactationNet loss of 500 mg of iron if not on iron supplementsIron required for tissue growth and expansion of blood volume

DecreasedDecreasedintakeintake

Prematurity

Infants/children

Elderly

Loss of iron each day fetus is not in uteroBlood loss from phlebotomyMost common cause of iron deficiency in young childrenRestricted diets with little meat (lack of hemic iron)

DecreasedDecreasedabsorptionabsorption

Celiac spruePost-gastric surgery

Absence of villous surface In the duodenumRapid transit; absent acid, which helps in iron reabsorption

IntravascularIntravascularhemolysishemolysis

Microangiopathic hemolytic anemiaPNH

Chronic loss of Hb in urine leads to iron deficiency

Iron deficiency anemiaIron deficiency anemia

Normal tongue

Iron deficiency anemia: bald tongue with atrophied papillae and angular inflammation

2.76Iron

deficiency anemia with bald tongue and angular stomatitis

2.77Iron and vitamin B

12 deficiency: glossitis with

angular stomatitis

2.78Undernutrition with multiple vitamin

and iron deficiency: bald, fiery tongue

2.79 Peutz-Jeghers

syndrome: mucosal lentigines and pigmentation

TESTTEST IRON IRON DEFICIENCYDEFICIENCY

ANEMIA OF ANEMIA OF CHRONICCHRONICDISEASEDISEASE

αα-THAL/-THAL/ββ--THAL THAL MINORMINOR

LEAD LEAD POISONINGPOISONING

MCV Serum iron Normal TIBC Normal Percent saturation Normal

Serum ferritin Normal RDW Normal Normal NormalRBC count Hb electrophoresis

Normal Normal Α-Thal. trait: normal _

Ringed sideroblasts None None None PresentCoarse basophilic stippling

None None None PresentHb – hemoglobin; MCV - mean corpuscular volume; RDW - red blood cell distribution width;

Thal – thalassemia; TIBC - total iron-binding capacity

B12-(folate)deficiency B12-(folate)deficiency anemiaanemiaThe 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 food insufficient 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 at It happens at

hereditary caused disorders, an atrophy of a mucous membrane of stomach, autoimmune damages of hereditary 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 big chronic 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 disorder of Deficiency 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 marrow its two coenzyme forms: methylcobalamine and 5-desoxyadenosilcobalamine. In a red bone marrow erythroblastic type of hemopoiesis is replaced on megaloblastic, inefficient erythropoesis increases, life erythroblastic 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 a expectancy 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 are shown bone 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 (huge neutrophils, 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 and huge cells of 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 in mucous epithelium  digestive tract results in development of inflammatory-atrophic processes in mucous membrane of its parts (glossitis, stomatitis, esophagitis, achylic gastritis, enteritis). As a result of the membrane of its parts (glossitis, stomatitis, esophagitis, achylic gastritis, enteritis). As a result of the second coenzyme forms  insufficiency of vitamin B12 – 5-desoxyadenosilcobalamine in organism second coenzyme forms  insufficiency of vitamin B12 – 5-desoxyadenosilcobalamine in organism propionic and methylmalonic acids, which are toxic for nervous cells. Besides fatty acids with the changed propionic and methylmalonic acids, which are toxic for nervous cells. Besides fatty acids with the changed structure are synthesised in nervous fibres results in disorder formation of myeline and to damage of structure are synthesised in nervous fibres results in disorder formation of myeline and to damage of axones.axones. The degeneration of back and lateral columns of a spinal cord develops The degeneration of back and lateral columns of a spinal cord develops (funicular (funicular myelosismyelosis), cranial and peripheral nerves are damaged.), cranial and peripheral nerves are damaged.

The color index is increased, that is explained by the big saturation of cells by The color index is increased, that is explained by the big saturation of cells by hemoglobin. The phenomenon of degeneration erythrocytes is typical: anisocytosis hemoglobin. 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).

CLASSIFICATION CAUSES DISCUSSION

Decreased intake

Pure vegan diet

Malnutrition

Breast-fed infants of pure vegans may develop deficiencyMay 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 B12Crohn's disease or celiac disease involving terminal ileum (destruction of absorptive cells)Bacterial overgrowth (bacterial utilization of available vitamin B12)Fish tapewormChronic pancreatitis (cannot cleave off R- binder)

Increased utilization

Pregnancy/lactation

Deficiency is more likely in a pure vegan

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

CLASSIFICATION CAUSES DISCUSSION

Decreased intake

MalnutritionInfants/elderlyChronic alcoholicsGoat milk

Decreased intake most common cause of folate deficiency

MalabsorptionCeliac diseaseBacterial overgrowth

Deficiency usually occurs in association with othervitamin deficiencies (fat and water soluble)

Drug inhibition

5-FluorouracilMethotrexate, trimethoprim-sulfamethoxazolePhenytoinOral contraceptives, alcohol

Inhibits thymidylate synthaseInhibit dihydrofolate reductase

Inhibits Intestinal conjugaseInhibit uptake of monoglutamate in jejunumAlcohol also inhibits the release of folate from the liver

Increased utilization

Pregnancy/lactationDisseminated malignancySevere hemolytic anemia

Increased utilization of folate in DNA synthesis

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

Such syndromes  are Such syndromes  are observed for B12-observed for B12-

(folate)deficiency anemia:(folate)deficiency anemia: 1. Hematologic syndrome: 1. Hematologic syndrome: аа) anemia; b) leukopenia; c) ) anemia; b) leukopenia; c)

thrombocytopenia.thrombocytopenia. 2. Damages of the digestive tract which 2. Damages of the digestive tract which

are shown by development inflammatory –are shown by development inflammatory –atrophic changes in mucous membrane.atrophic changes in mucous membrane.

3. Damages of the central and peripheral 3. Damages of the central and peripheral nervous system: funicular myelosis, nervous system: funicular myelosis, degeneration of peripheral nerves.degeneration of peripheral nerves.

LABORATORY/LABORATORY/CLINICAL FINDINGCLINICAL FINDING

PERNICIOUPERNICIOUS ANEMIAS ANEMIA

OTHER VITAMIN OTHER VITAMIN B12 DEFICIENCIESB12 DEFICIENCIES

FOLATE FOLATE DEFICIENCYDEFICIENCY

Achlorhydria Present Absent AbsentAutoantibodies Present Absent AbsentChronic atrophic gastritis Present Absent Absent

Gastric carcinoma risk None None

Hypersegmented neutrophils Present Present Present

Mean corpuscular volume

Neurologic disease Present Present NonePancytopenia Present Present PresentPlasma homocysteine

Serum gastrin level Normal NormalUrine methylmalonic acid Normal

Megaloblastic anemiaMegaloblastic anemia

Hypoplastic anemiasHypoplastic anemias Hypoplastic  (Hypoplastic  (ааplastic)plastic) anemia is characterized by anemia is characterized by

oppression hemopoietic functions of red bone marrow oppression 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 of There are acquired and is hereditary caused forms of hypoplastic anemia. The type of hereditary is hypoplastic anemia. The type of hereditary is autosomal-recessive type of inheritance concerns.autosomal-recessive type of inheritance concerns.

The The acquired formsacquired forms may be caused by the following may 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 not of anemia, which reason is not

established belongs to acquired anemias.established belongs to acquired anemias.

CLASSIFICATlON EXAMPLES AND DISCUSSIONIdiopathic 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)

InfectionMay 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.

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.).

Metaplastic anemiasMetaplastic anemiasThe The metaplastic anemiametaplastic anemia is the result of hemopoietic is the result of hemopoietic

tissue replacement on tissues: leucosis cells, connective tissue replacement on tissues: leucosis cells, connective tissue (fibrosis), metastasises of tumor.tissue (fibrosis), metastasises of tumor.

Dysregulative anemiasDysregulative anemiasDysregulative anemiasDysregulative anemias arise as a result of arise as a result of

erythropoiesis regulation disorders   (infringement of ratio erythropoiesis regulation disorders   (infringement of ratio between erythropoietins and inhibitors of erythropoiesis due between 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 of microenvironments of erythropoietins cells, hypofunction of hypophysis, thyroid gland).hypophysis, thyroid gland).

1- Pallor 1- Pallor looked for looked for in the skin in general, at palms, more in 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 Haemolysis 2- Jaundice as in Haemolysis Skin, Eye Sclera, Mucous Skin, Eye Sclera, Mucous MembraneMembrane

3- Hyperpigmentation, café au-lait spots 3- Hyperpigmentation, café au-lait spots Fanconi Anaemia Fanconi Anaemia

1- Frontal Bossing 1- Frontal Bossing Thalassaemia Thalassaemia2- Microcephaly 2- Microcephaly Fanconi Anaemia Fanconi Anaemia

1- Glossitis 1- Glossitis Vit. B12 deficiency, Fe deficiency Vit. B12 deficiency, Fe deficiency2- Angular stomatitis 2- Angular stomatitis Fe deficiency anemia Fe deficiency anemia

Chest:Chest: Chest PainChest Pain Murmer Murmer Severe anemia, Endocarditis Severe anemia, Endocarditis Rapid Breathing Rapid Breathing Rapid Heart RateRapid Heart Rate

Abdomen: Abdominal pain Hepatomegaly, Splenomegaly

Extremities: Extremities: brittle nails, Spoon Nails brittle nails, Spoon Nails Iron deficiencyIron deficiency

Nerves: Nerves: Ataxia, Peripheral Ataxia, Peripheral neuropathy (Vitamin B12)neuropathy (Vitamin B12)

Neuropathy: (A) erythema chronicum migrans (Lyme disease), (B) Reynaud's phenome-non, (C) purpuric rash (eg, vasculitis) and (D) depigmen-tation (leprosy).

General: General: Poor weight gain or Weight lossPoor weight gain or Weight loss Short Stature Short Stature Thalassaemia Thalassaemia Sickle cell diseaseSickle cell disease

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