Аnemia I

Disorders in the formation of erythrocytes

 Pathophysiological classification of
anemia
Аnemias occur as a consequence:

• Disorders in the formation of Er

• Increased breakdown of Er
• Acute or chronic blood loss
 Pathophysiological classification of anemia

Disorder in the formation Er:

• Disrupt the reproduction and differentiation of hematopoietic stem cell (aplastic

anemia)

• Disorder of reproduction and differentiation of unipotent stem cell destined for

erythropoiesis

• Disorder or reproduction and differentiation of morphologically recognized

precursors of erythropoiesis(megaloblastic anemia)

• Disorder of hemoglobin synthesis(iron, chем and globin)

• Unknown or multifactorial cause (chronic diseases,eating disorder)

 Disorders in the formation of erythrocytes:

Disorder in the formation Er:

• Disrupt the reproduction and differentiation of hematopoietic stem cell

(aplastic anemia)

• Disorder of reproduction and differentiation of unipotent stem cell

destined for erythropoiesis

• Disorder or reproduction and differentiation of morphologically

recognized precursors of erythropoiesis(megaloblastic anemia)

• Disorder of hemoglobin synthesis(iron, chем and globin)

• Unknown or multifactorial cause (chronic diseases,eating disorder)

 Disorder of proliferation and differentiation of
hematopoietic stem cells
• Aplastic anemia

• Characterized by bone marrow hypoplasia or aplasia and consequent

pancytopenia.

• The defect is at the level of the pluripotent stem cell:

– A decrease in the absolute number of progenitors

– There is an adequate number of progenitors but no colony proliferation
in vitro

• With a lack of hematopoietic tissue the proliferation of fatty tissue occurs

(fatty bone marrow)
 Classification of aplastic anemias

• Congenital aplastic anemia

• Acquried aplastic anemia
- primary (idiopathic)
- secondary
 Congenital aplastic anemia

Rare anemias (Fanconi,anemias as part of genetic syndromes)

Fanconi anemia

‒ Is inherited in an autosomal recessive manner,

‒ Anemia is accompanied by disturbances in the structure of

the kidneys and bone system.
 Acquried aplastic anemia

• Primary idiopathic

• Secondary

- caused by ionizing radiation,

-caused by drugs and chemical substances,

- caused by infections (viruses,fungi,TBC) ,

- caused by infiltration of bone marrow by malignant cell,

- diseases mediated by immune mechanisms.

 Pathogenesis of aplastic anemia
Direct damage

viruses, drugs Stem cell Аplastic anemia

radiation, Progenitor cell
chemical
substances
Indirect damage
Immune mechanisms (caused by T-lymphocyts)

Cytokines ( IFNg , TNF):

• they suppress the proliferation of stem cell and hematopoietic
progenitors
• they induce apoptosis of stem cell
 Clinical picture of aplastic anemia
• Symptoms are related to the lack of erythrocyte,leukocytes and platelets:

– Malaise and tiredness,

– Petechiae
– Tendency to infections

• Physical findings:
– pallor,
– petechiae,
– Feverishness

The most alarming severe bleeding from the digestive tract and
genitourinary tract and bleeding into the CNS.
 Clinical picture of aplastic anemia

Bleeding into the mucous membrane

of the oral cavity

Bleeding about thrombocytopenia

 Clinical picture of aplastic anemia

Bleeding in the retina in patients with

aplastic anemia and Ulcerations on the buccal mucosa
thrombocytopenia
 Laboratory characteristics

• Blood:
• anemia (normocytic normochromic or macrocytic anemia)
• thrombocytipenia
• neutropenia
• Bone marrow:bone marrow aspiration and biopsy,scant
cellularity,hypoplasia,fatty infiltration
 Disorders in the formation of erythrocytes

Disorder in the formation Er:

• Disrupt the reproduction and differentiation of hematopoietic stem cell (aplastic

anemia)

• Disorder of reproduction and differentiation of unipotent stem cell destined for

erythropoiesis

• Disorder or reproduction and differentiation of morphologically recognized

precursors of erythropoiesis(megaloblastic anemia)

• Disorder of hemoglobin synthesis(iron, chем and globin)

• Unknown or multifactorial cause (chronic diseases,eating disorder)

 Disorder of reproduction and differentiation of
unipotent stem cells

• Disturbance at the level of unipotent stem cells destined for erythropoiesis

• Isolatet aplastic anemia: etiology

• Viral infections (antibodies against unipotent stem cells

– Erythropoietin deficiency(in kidney dieseases)

– Effect of cytokines that inhibit erythropoiesis (in chronic infections and

tumors)
 Disorders in the formation of erythrocytes

Disorder in the formation Er:

• Disrupt the reproduction and differentiation of hematopoietic stem cell (aplastic

anemia)

• Disorder of reproduction and differentiation of unipotent stem cell destined for

erythropoiesis

• Disorder or reproduction and differentiation of morphologically recognized

precursors of erythropoiesis(megaloblastic anemia)

• Disorder of hemoglobin synthesis(iron, chем and globin)

• Unknown or multifactorial cause (chronic diseases,eating disorder)

 Anemia about disorders in DNK
synthesis(megaloblastic anemia)

• A common biochemical feature:

– Nucleotide synthesis disorder(DNK)

-Minor changes in RNK and protein synthesis.

• It is most often manifested as anemia disorders occur in all

proliferating cells.There are megaloblasts in the bone marrow and
macrocytes in the blood.Most of the cells perish in the bone
marrow,and the cells in the blood have a shorter lifespan.
 Anemia about disorders in DNK
synthesis(megaloblastic anemia)

The most common cause is a deficiency of vitamins essential for DNK

synthesis

– B12 (cobalamin) and

– Folate
 Vitamin B12
• In humans cobalamin is produced by colonic bacteria but distally from the
site of absorption.

• In food it is usually in the from of coenzymes non-specifically bound to

proteins

• An average non-vegeterian diet with5-7µg B12/day

• In food it is most abundant in:

• liver (>10µg/100g)
• fish,milk, meat and eggs (1-10µg/100g)
 Vitamin B12

• It is found in the human body in the form of coenzymes.

• In an adult the vitamin reserve is 2-5mg,of wich 1mg is in the liver.

• It is used up daily 0.1% B12 (1.3µg)

• It takes 3-4 years to consume cobalamin stores in vitamin B12

malabsorption.
 Etiopathogenesis of vitamin B12 deficiency

• Reduced intake (vegetarians, infants of mothers with pernicious anemia)

• Imparied absorption:

- Atrophic gastritis
- Gastrectomy
- Celiac disease
- Regional enteritis
- Infiltration of the small intestine
- Parasites
- Blind coil syndrome and diverticulosis
- Hereditary trascobalamine II deficiency
- Increased needs for B12
 Folate

• Folate is synthesized by plants and microorganisms

• A natural source of folate:

– vegetables (spinach,broccoli, beans)

– fruits( bannana, melon, lemon)
– Cereals, liver

• Folates are thermolabile (destructions in >15min cooking)

• Recommended entry:

– Male and female: 400µg, - children 300-400 µg

– Pregnant women: 600µg,
– Nursing mothers: 500 µg,
 Absorption of folate

• They are absorbed in the small intestine (pH 5,5)in the presence of Zn. Small
intestine has a high capacity to absorb folate.

• Polymorphism of intestinal enzymes:some people have reduced folate

absorption.

• After 1-2h folates reach their "peak" in plasma, and enterohepatic

circulation begins (90µg).
 Etiopathogenesis of folate deficiency
• Reduced intake

• Increased needs (pregnancy, growth, hemolysis, malignant diseases,

hemodialysis,exfoliative skin diseases).

• Folate malabsorption (celiac disease, drugs - phenytoine, barbiturates).

• Folic acid metabolism disorder(methotrexate prevents the conversion of

folic acid into its active form).
 Anemia about disorders in DNK
synthesis(megaloblastic anemia)

• Megaloblastic (megaloblasts in the bone marrow) and macrocytic

(macrocytes in peripherial blood), normochromic anemia.
Morphological changes in megaloblastosisabout
vitamin B12 and folate deficiency
• Peripheral smear • Bone marrow

• Increased MCV • Increased cellularity

• Hypersegmentation PMN • Proliferation of all lineages

Abnormal erythropoiesis:
• Thrombocytopenia acidophillic megaloblasts

• Abnormal leukopoiesis :
hypersegmented PMN
 Bone marrow

• MGGx1000
 Disorders in the formation of erythrocytes:

Disorder in the formation Er:

• Disrupt the reproduction and differentiation of hematopoietic stem cell

(aplastic anemia)

• Disorder of reproduction and differentiation of unipotent stem cell

destined for erythropoiesis

• Disorder or reproduction and differentiation of morphologically

recognized precursors of erythropoiesis(megaloblastic anemia)

• Disorder of hemoglobin synthesis(iron, chем and globin)

• Unknown or multifactorial cause (chronic diseases,eating disorder)

 Disorder of hemoglobin synthesis

• Lack of iron

• Disorder of hem synthesis

• Disorder of globin synthesis

 Iron metabolism

• Fe is an essential element of all cells

• It is easily oxidized and reduced in many metabolic processes. In mammals, its

main role is oxygen transport.

– It forms a complex with heme in hemoglobin

• Hemoglobin synthesis depends on the amount of iron in the body.

 Iron metabolism

• The level of iron in the blood is kept within very narrow limits (10-30
mmol/L) and thus two harmful phenomena are avoided

Accumulation Lack

/siderosis/ /hyposiderosis/
 Iron metabolism

• Spare iron – ferritin and hemosiderin

• Section with the most variable iron values

Depends on the amount of iron absorption and loss

• Ferritin is the main compound for the physiological accumulation of iron,

a complex of apoferritin and iron is formed

• Hemosiderin forms agregates of ferritin,releases iron more easily, is

found in monocyte-macrophage cells,spleen,bone marrow and Kupffer
cells.
 Iron homeostasis in humans

• There is not a single organ that regulates the excretion of iron from the body.

• Iron homeostasis is achieved only by regulating the amount of iron absorbed in

the digestive organs.
 Iron homeostasis in humans

Iron is lost in small amounts:

• Desquamation of the cells of the gastrointestinal tract

• Desquamation of epidermal cells,

• Desquamation of the epithelium of the renal tubules and removing

hair,nails and secretions but also through menstrual and gastrointestinal
bleeding.
 Absorption of iron
• Iron is absorbed in the duodenum and proximal jejunum by the active
process of endocytosis. Iron from food is quickly absorbed from myoglobin
and hemoglobin usabillity ½ 1/3.

• Non-heme iron is reduced to a soluble ferrous from by the enzyme

ferroreductase.

• Iron is transported across the membrane of the epithelial cells of the digestive
tract with help of DMT1 (divalent methyl transporters).
 Iron homeostasis in humans

Ferritin regulates the transfer of iron from the epithelial cell of the
gastrointestinal tract into the bloodstream:

• ,, Hunger” of epithelial cells for iron /hypochromic anemia/  

apoferritin, apotransferrin  Fe3+ + apotransferrin  transfer of iron
into the circulation /FeTf/

– Reoxidation Fe2+-----Fe3+ in supported by feroxidase

• Excess iron in the body  apoferritin+ Fe  ferritin  desquamation

of epithelial cells  elimination of excess iron
 Iron homeostasis in humans

• Iron from transferrin binds to receptors on the surface of

erythroblasts endocytosed and reaches mitochondria,incorporated
into protoporphyrin III wich is essential for heme syntesis.
 It is important to stand out:

Iron is an important element of all cells in the body, it participates in

many oxydo-reduction processes, It is most important role is to
transport oxygen in hemoglobin.

• The total amount of iron in the body is 3,2-5 gr.

• Iron deficiency is hyposiderosis , iron overload is siderosis.

• There is no mechanism for excreting excess iron from the body.

• Homeostasis is possible only by regulating absorption from

gastrointestinal tract where ferritin is the main factor.

• Iron from foods of animal origin is better utilized than from food of
plant origin.
Sideropenic anemia
 Еpidemiology

• Sideropenic or hypochromic anemia is the most widespread

disease on Earth.

• Half a billion people suffer from iron deficiency.

• In developing countries 40-70% of population has some iron

deficiency. In the USA 1/3 of women have almost completely
depleted iron reserves.
 Iron requirements
• Requirements for iron:
– 1mg Fe male
– 1,4 mg woman in the reproductive period

• Woman loses :
– 680-800mg of iron each time she gives birth
– and 140 mg during breastfeeding

• Newborns who are fed with mother”s milk get enough iron only up to the
fourth month of age then the needs increaseа 1,5 mg/kg ТТ.
 Causes of iron deficiency

• There are three main groups of causes of iron deficiency :

Increased needs for iron Decreased

Increased loss of iron
or hemapopoiesis intake,absorption or
utilization of iron
 Increased needs for iron or
hemapopoiesis

• Rapid growth of a child or adolescent

• Pregnancy
• Erythropoietin therapy
 Increased loss of iron
Genital tract in women
Gastrointestilan tract • menometrorrhagia
• hiatus hernia • Postpartum bleeding
• Esophageal varices
• Peptic ulcer Respiratory tract
• Drugs: Pulmonary hemosiderosis
NSAIL,corticosteroids,alcohol
• tumors Urinary tract
• Ulcerative colitis • hematuria
• Telangiectasias • Chronic dialysis
• Angiodysplasias • Chronic hemoglobinuria or
• Diverticulosis hemosidenuria
• Hemorrhoids (paroxysmal noctural
• Helminthiasis hemoglobinuria)
• (Schistosoma mansoni, Other
• Blood donation
Trichuris trichiura)
• Self harm
Decreased intake, absorption or utilization of iron

• Аtrophic gastritis

• Celiac disease

• Partial gastrectomy

• Vegetarian diet
 Degrees of iron deficiency

• There are three degrees of iron deficiency i the

body:
1. Reduced iron reserves
2. Decreased concentration of iron in the blood
3. Dyserythrocytopoiesis with poikilocytosis
 Reduced iron reserves

• Iron requirements or loss exceed the ability to absorb from food.

• Physiological mechanisms : menstruation,pregnancy,rapid growth in

adolescents,inadequate iron intake

• Blood loss greater than 10-20 ml per day exceeds the body”s absorption
capacity. The iron deficit is compensated from RES. The serum level of ferritin
or hemosiderin in the bone marrow is reduced, but as long as iron stores exist
and are mobile iron will be within the reference values.

• At this stage, the morphology and properties of erythrocytes are normal.

 Reduced ferremia, HB, HCT
The decrease in stored iron quickly leads to a decrease in iron
concetration in the blood. TIBC and protoporphyrin levels in
erythrocytes increase.

• When the level of serum ferritin is less than15µg/l,there is no

storage of iron in the bone marrow, the level of iron in the blood
soon drops.

• When transferrin saturation drops to 15-20% , hemoglobin synthesis

also decreases.

• Mycrocytic, hypochromic erythrocytes appear

• Hemoglobin and hematocrit gradually decrease and anemia occurs

about iron deficiency.
 Dyserythrocytopoiesis with poikilocytosis

If the anemia is moderate, hemoglobin of 10-13 gr/dl, the bone marrow

remains hypoproliferative.

When hemoglobin drops to 7-8 gr/dl , hypochromic and microcytosis

become more pronounced,with poikilocytosis in wich erythrocytes are
target,cigar or pencil shaped ----ineffective erythrocytopoiesis

• In the bon marrow preerythroid hyperplasia occur rather than

hypoproliferation.
 Peripheral smear Bone marrow: painting on iron - normal

Bone marrow: painting on iron – in hypochromia

 Clinical picture
Anemia symptoms:
• fatigue
• drowsiness
• Reduced concentration
• Pale skin
• Blue sclera
• palpitations
• headache and tinnitus

Signs of iron deficiency :

• Fissures at the corners of the lips
• and concave nail plate ,glossitis and dysphagia
Clinical picture
 Мicrocytic anemia

Меgaloblastic anemia Sideroblastic anemia

 Аnemia about disorders of heme synthesis
(sideroblastic anemia)

• Iron + protoporphyrin = heme

• Sideroblastic anemia:

• Disorder of protoporphyrin synthesis about to reduced synthesis d-

aminolevulinic acid from glycin and succinyl CoA

• Disturbance of incorporation of iron in chem ( deficiency of heme

synthesis ) .
 Аnemia about disorders of heme synthesis
(sideroblastic anemia)
• Heme concetration regulates the synthesis of d-aminolevulinic acid (a
negative feedback loop)

– Heme deficiency – increased formation d-aminolevulinic acid

– Heme synthesis –inchibition synthesis d-аminolevulinic acid

• Disruption of synthesis leads to increased formation of intermediate products

(enzyme deficiency) (porphyria)

• Iron accumulates in erythroblasts , most often in the form ferritin,sideroblasts

are formed,wich live shorter and have mitochondrial damage.
 Аnemias caused by disruption of globin
synthesis
• Hemoglobin:
– А1: HbA1= HbAa2b2
– А2 (2-3%):, HbA2= HbAa2d2
– F:, HbF= HbAa2g2

• HEMOGLOBINOPATHIES
– Quantitative (thalassemia)
– Qualkitative
 Аnemias caused by disruption of globin
synthesis : talassemia
• These anemias are the result of a hereditary disorder in the synthesis of one
on more polypeptide chains,they are inherited in an autosomal dominant
manner.

• Division of talassemia:

– Аlpha talassemia (a disorder in the synthesis of the alpha chain in

people of the yellow race, this disorder usually leads to the death of the
fetus).

– Beta talassemia (beta chain synthesis disorder,Cooley”s

anemia ,Mediterranean anemia,southern Italy,Greece,HBA1
deficiency, HBA2 and HBF are synthesized.
 Аnemias caused by disruption of globin
synthesis : talassemia
• Synthesis of abnormal hemoglobin

• The lifespan of erythrocytes is shortened,abnormal hemoglobin is deposited in

the form of inclusions and damages the cell membrane.

• Аnemia: hypochromic and microcytic

• In beta talassemia the affinity of hemoglobin for oxygen is high,the

dissociation curve is shifted to the left and hypoxia worsens .
 Аnemias caused by disruption of globin synthesis:
sickle cell anemia
• Qualitative disorder in globin synthesis

– Аbnormal globin chains: disorder in the sequenec of amino acids in the

alpha or beta chain.

• About 300 genetically determined variants of hemoglobin are know,they do not

significantly affect its function of binding and releasing oxygen.Just one wrong
amino acid can cause serious disorders like sickle cell anemia , sickle cell disease.
• On the beta chain at position 6 is valin instead of glutamic acid.
Аnemias caused by disruption of globin synthesis:
sickle cell anemia
• This anemia occurs in the population of Central Africa, in blacks or in their
descendants. In areas with high prevalence of malaria.

• Heterozygotes are protected from most severe forms of malaria,wich is

called a selective advantage. Homozygotes have the hardest form of the
disease.
Аnemias caused by disruption of globin synthesis:
sickle cell anemia
• After the release of oxygen in its deoxy form hemoglobin S polymerizes
and the erythrocyte acquires a sickle shape.

• The change in shape is initially reversibile and later becomes irreversibile.

• The change in shape damages the erythrocyte membarne,erythrocytes

easily lose K+ and water, calcium accumulates in them,lose elasticity and
have shorter lifespan.
Аnemias caused by disruption of globin synthesis:
sickle cell anemia
• Altered erythrocytes easily aggregate and thus close small blood
vessels,especially in organs with slow blood flow such as the splen.

• This leads to the infarct of organs that are real and severe pain.

• Repeated thrombosis of blood vessels of the spleen leads to autosplenectomy.

• In a state of hypoxia, occlusion occurs in other organs as well.