Bone marrow
Red
Yellow
Bone
Fat
Reticulin
Haematopoiesis –
red, white, platelets
lymphoid
Normal red cells
Central pale area
Red cells
Men
• Hemoglobin (g/l)
140-180
• Hematocrit (%)
40-52
• Red cell count (1012/l) 4.5-6.5
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Women
120-160
36-48
3.9-5.6
Reticulocyte count (%)
0.5-1.5
Mean cell volume (fl)
80-95
Mean corpuscular hemoglobin (pg)
27-33
Mean corpuscular hemoglobin concentration (gm/dL) 33-37
Red cells
pathological conditions:
I. decrease in the circulating red cell mass
(poss. with structural abnormalities)
very common - anaemia
II. increase in the circulating red cell mass
less common
polycythemia =erythrocytosis=polyglobuly
Polycythemia
=increased concentration of red cells
• RELATIVE - decreased plasma volume
dehydration, stress
• ABSOLUTE
primary – neoplastic= polycythemia vera
= myeloproliferative neoplasm
secondary - increased erythropoietin stimulation
Appropriate
reactive – low levels of oxygen in the PB
(heart disease, high altitude)
Inappropropriate
Red cells
• Normal: uniform in size and shape
• Pathologic: variation in size, shape, inclusions
• Variation
• size - anisocytosis
• Shape – poikilocytosis
Red cells - functions
• Deliver oxygen to the tissues
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Anemia - reduction
of the total number of red cells
amount of hemoglobin
circulating red cell mass
Consequences of anemia - symptoms
• ???????????
Dg. of anemia - history
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Age of onset
Duration of illness
Prior therapy of anemia
Suddennes or severity of anemia
Chronic blood loss
Hemolytic episodes
Toxic exposures
Dietary history
Family history, racial background
Underlying diseases
Anemia – consequences, symptoms
• Fatigue, syncope, dyspnea
• Impairment of organ function due to
hypoxia
• Pallor, postural hypotension )decreased
blood volume)
• Heart murmurs, heart failure . Increased
cardiac output
Anemia
• Not a diagnosis per se
• Look for an underlying problem
• History, physical examination
Anaemia
decrease in the total circulating red cell mass
(hematocrit, hemoglobin concentration)
Classification: A. underlying mechanism
blood loss
M
A
increased destruction
Y
decreased production
C
B. morphology of erythrocytes
O
size (micro-, macro-, normocytic)
M
B
shape (spherocytosis, stomato-,...)
I
N
color (degree of hemoglobinization:
E
normo- hypo-, hyperchromic)
Blood loss
•acute or chronic
•internal or external
Acute
• Hypovolemia – shock
• Anemia – normocytic normochromic
• Shift of water – hemodilution –↓ hematocrite
• Compensatory increase of red cell production
• Reticulocytes
• Chronic → loss of iron→ iron deficiency
• hypochromic sideropenic anemia
Iron deficiency anemia
mechanism: blood loss, decreased
production
body iron = functional + storage
F - 2g, M - 6g
inadequate intake for metabolic demands
Lack in diet or low absorption
most common nutritional disorder in the world
2. Increased requirement (children, pregn., lact)
!!!3. Chronic blood loss!!! - GIT, GYN
most important cause of iron deficiency
Hypochromic microcytic
sideropenic anemia
Small hemoglobinization
(narrow Hb rim -periphery)
Small red cells
Iron deficiency
Scattered fully hemoglobinized
cells - blood transfusion
PB: ery pale + small
BM: erythroid hyperplasia, loss of iron
alopecia, koilonychia, atrophy of tongue,
gastric mucosa
Plummer-Vinson (Kelly-Patterson) syndrome:
siderop.an., atrophic glossitis, esophageal
webs
Iron deficiency anaemia
Pallor
conjunctiva
skin
pale
palmar
creases
Iron deficiency anaemia
koilonychia
nails concave (or flat), ridged, brittle
Iron deficiency anaemia
angular cheilosis
fissuring and ulceration; pallor
Iron deficiency anaemia
flattening and loss of papillae
bald, fissured tongue
Causes of hypochromic anemia
1. Disorders of iron metabolism
2. Disorders of heme synthesis
3. Disorders of globin synthesis (thalassemia)
Ad 1. Iron deficiency
• Blood loss
• Poor intake - growth, pregnancy, lactation
• Malabsorption
• Chronic infections or inflammatory states
• neoplasia
Anaemia
decrease in the total circulating red cell mass
(hematocrit, hemoglobin concentration)
Classification: A. underlying mechanism

blood loss
→
increased destruction
decreased production
Increased destruction
=lysis of red cells=hemolysis
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•
intravascular – rare - mechanical injury – artificial
valves or microthrombi, exogenous toxic agents,
complement fixation (transfusion of mismatched
blood)
extravascular - more common, when red cells
considered foreign or less deformable
Hemolytic anemia
Abnormality:
 intracorpuscular or extracorpuscular
 hereditary (intra) or acquired (extra)
Hemolytic anemia
• premature destruction of red cells
• accumulation of the products of the hemoglobin
catabolism
• BM – increased erythropoiesis, extreme:
extramedullary hematopoiesis
• PB: reticulocytosis
• high bilirubin –gallstones; jaundice, blr in urine
• chronic duration: hemosiderosis
Main clinical symptoms
anemia, splenomegaly, jaundice; gallstones
Haemolytic anaemia
splenomegaly and jaundice
Haemolytic anaemia
jaundice
normal
Increased destruction of ery=hemolysis
I. Intrinsic (intracorpuscular) causes
A. hereditary
• membrane – cytoskeleton, lipid synthesis
• enzymes – deficiencies - G6PD, glutathione
synthetase, pyruvate kinase
• hemoglobin - deficient synthesis of globin,
structurally abnormal Hb
B. acquired
• membrane defect: paroxysmal nocturnal
hemoglobinuria
• II. Extrinsic (extracorpuscular) causes
• antibodies, trauma, infection, chemical injury
sequestration
Examples of hemolytic anemia
• Membrane defects –
• Proteins underlying the red cell membrane
• Shape, stability, flexibility
Hereditary spherocytosis (peripheral smear)
anisocytosis and several dark-appearing spherocytes with no
central pallor. Howell-Jolly bodies (small dark nuclear remnants)
Hereditary spherocytosis
AD (AR, sporadic);most common her. hemol. A.
Membrane defect – cytoskeleton – protein spectrin
(and ankyrin) deficiency
Round erythrocyte= spherocyte, less deformable
Vulnerable to spleen sequestration and destruction
Main clinical symptoms
anemia, splenomegaly, jaundice; gallstones
Chronic hemolytic anemia (mild to normal)
Acute anemic episodes:
aplastic crisis (parvovirus)
hemolytic crisis
Splenic sinus
A red cell squeezing from the red pulp cordsinto the sinus lumen.
Note the degree of deformability required for red cells to pass
through the wall of the sinus.
Red cell membrane cytoskeleton
Alterations leading to spherocytosis and hemolysis
Mutations weakening interactions involving α-spectrin, β-spectrin, ankyrin
band 4.2, or band 3 cause the normal biconcave red cell to
lose membrane fragments and become spherical
spherocytic cells: less deformable than normal, become trapped in the
Pathophysiology
of hereditary spherocytosis
Haemolytic anaemia: reticulocytes
precip. RNA
Hereditary elliptocytosis
Usually mild, rarely severe
Hemolytic anemia
• Intracorpuscular
• Enzyme deficiencies
G6PD deficiency
enzymes protecting the red cell against the oxidative stress
G6PD deficiency → loss of protection → oxidant injury
infections, drugs, beans (favism)
→ hemolysis; otherwise normal
morphologic changes of chronic HA rarely present
hundreds of genetic forms of G6PD
common pathologic alleles: G6PDA-, G6PD Mediterranean
X-linked→ males homozygous, women heterozygous
Mediterranean, Middle East, Africa
Protection against malaria
G6PD deficiency
• Clinical and laboratory findings
• Episode of acute hemolytic anemia in
anotherwise healthy person; neonatal jaundice
• following oxid. injury – drug (antimal. –
primaquine,; sulfoamides, nitrofurantoin,
nalidixic acid; TNT, , infections, food
• Variable severity
Enzyme deficiency: G6PD deficiency
effects of oxidant drug exposure (PB)
Red cells with precipitates of denatured globin (Heinz bodies)
splenic macrophages pluck out these inclusions → "bite cells"
Increased destruction of ery=hemolysis
I. Intrinsic causes
A. hereditary
membrane – cytoskeleton, lipid synthesis
enzymes – deficiencies - G6PD, glutathione
synthetase, pyruvate kinase
→hemoglobin – abnormal
quantity (deficient synthesis of globin)
quality (structurally abnormal Hb)
Sickle cell anemia (PB)
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Shape: sickle
Hereditary hemoglobinopathy
Structurally abnormal hemoglobin HbS
abnormal physiochemical properties
B-globin – 6th position,
Molecular defect: point mutation
valine for glutamic acid
Sickle cell anemia
Hemolysis, microvascular occlusion
Sickle cell anemia
• Oxyg. HbS: liquid
• Deoxyg.:viscous gel →fibers
HbS - aggregation and polymerization
• Sickle shape; Initially: reversible (with
oxygenation)
• Repeated: irreversible sickling
• Membrane damage
Rate and degree of sickling
1. Amount of HbS
Heterozygotes: HbS and HbA – only sickle cell trait
(sickling when marked hypoxia)
Homozygotes: severe anemia
2. Hemoglobin concentration
the higher, the worse
3. Fall in pH → deoxygenation
Sickle cell anemia - clinical manifestation
1. chronic hemolytic anemia (ery survival 20 days)
chronic hyperbilirubinemia, Hbemia, jaundice,
gallstones
aplastic crisis
2. occlusion of small vessels
→ thrombosis, ischemia, necrosis
painful crises
3. splenomegaly
4. increased susceptibility to infections
5. activation of the bone marrow,
extramedullary haematopoiesis
Diagnosis
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Clinical, laboratory – blood smear
HbS - electrophoresis
Clinical course variable
Therapy symptomatic
Thalassemia
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Deficient synthesis of globin chains
Globin chain absent or amount reduced
β - major, minor (more common), intermedia
β +,0
Homo/heterozygous
• α +,0
Scleral jaundice
Haemolytic autoimmune anaemia
Pathogenesis of β-thalassemia major
aggregates of unpaired
α-globin chains not
visible
Blood transfusions
correct the anemia
reduce
the stimulus for marrow
expansion,
but add to systemic iron
overload
Thalassemia major:
gallbladder - bilirubin gallstones
Immunohemolytic anemia
• Antibodies
• Coombs test
Raynaud phenomenon
autoimmnune haemolytic anaemia
Erythroblastosis fetalis
Decreased production of red cells
Deficiency of vital substrates
disorders of proliferation and differentiation

stem cells

erythroblasts
Impaired:
 DNA synthesis – B12, folic acid – megaloblastic
 hemoglobin synthesis
- heme
(lack of iron)

- globin
Others: anemia of chron. dis., AA, PRCA
Megaloblastic anemia
• impaired DNA synthesis
• characteristic morphologic changes
blood (macrocytes), bone marrow (megaloblasts)
• Deficiency of vit. B12
• Folic acid
Megaloblastic anaemia
Vitamin B12
absorption
Deficiency of vit. B12
1. Decreased intake – diet, vegetarianism
2. Impaired absorption
Intrinsic factor deficiency – pernicious anemia,
gastrectomy
Malabsorption
Intestinal dis., resection of ileum
Parasitic uptake, bacterial overgrowth
3. Increased requirement
pregnancy, hyperthyroidism, disseminated cancer
Vit. B12 deficiency
• BM and blood, CNS, (pernicious: GIT)
• GIT: beefy tongue – atrophic glossitis
• CNS – spinal cord - myelin degenaration
laterodorsal tracts – balance, motoric,
sensitive
• Pernicious: stomach: chronic gastritis,
intestinal metaplasia, higher risk of
carcinoma
Pernicious anemia
• Older people
• Autoimmune Ab
• Poss. with autoimmune thyroiditis, adrenalitis
Megaloblastic anaemia
Acute leukaemia
Diffferential diagnosis
Megaloblastic anaemia
hypersegmented neutrophils
(macropolycyte)
Megaloblastic anaemia pernicious
lemon-yellow appearance
pallor (anaemia)
+ jaundice (ineffective
erythropoiesis)
Pernicious anaemia (38 ys.)
premature greying, blue eyes, vitiligo
Beefy tongue
atrophic glossitis
(Hunter)
vit. B12 deficiency
Pernicious anaemia
Dorsolateral spinal cord demyelination
Folate deficiency
• Decreased intake
• Increased requirements
• Impaired use
• Relative deficiency
• Megaloblastic anemia; no neurological symptoms
• Cheilosis, glossitis, dermatitis
Anemia of chronic disease
*Infections
*immunologic
*neoplasms
Mechanism: defect in reutilization of iron
(transfer, cytokines)
! abundant storage iron
Anemia: normo, normo or hypo, micro
Aplastic anemia
• Failure or suppression of myeloid stem cell
• PANCYTOPENIA
• primary OR secondary - drugs , chemicals
infections
irradiation
inherited – Fanconi
Or cause unknown…
BM: hypocellular, PB: pancytopenia,
symptoms
spleen normal
Special subgroup: pure red cell anemia
Aplastic anemia
Markedly hypocellular marrow
contains mainly fat cells.