Hematopathology (Lecture II)

Hematopathology
lecture part II
- diseases of red blood cells
Miroslav Kovařík, PharmD, PhD.

Overview
- erythrocytes
erythrocytes count:
• men: 4.19 – 5.75 · 1012 erythrocytes/l of blood
• women: 3.54 – 5.18 · 1012 erythrocytes/l of blood
hemoglobin concentration:
• men: 130 – 170 g/l of blood
• women: 120 – 160 g/l of blood
Overview
- hemoglobin variants
Overview
- erythropoiesis
erytropoietic factors:
• erythropoietin – hormone secreted in kidneys (90 %) and liver (10 %)
– increased synthesis: hypoxia, thyroid hormones, androgens
– decreased synthesis: glucocorticoids, estrogens
• interleukins (IL-1, IL-3)
• amino acids – globin synthesis
• iron – hemoglobin synthesis
• vitamin B6 (pyridoxine) – heme synthesis
• vitamin B9 (folic acid) – important for nucleic acid synthesis during cell division
and maturation
• vitamin B12 (cobalamin) – maturation of erythrocytes, for absorption in gut is
necessary intrincic factor produced in stomach
• vitamin B2 (riboflavine) – normal function and survival of erythrocytes
• vitamin C (ascorbic acid) – iron metabolism
Erythrocytes morfology variations
size:
• normocytic – diameter 7.2 µm
• mikrocytic – diameter less than 6.7 µm
• makrocytic – diameter higher than 7.7 µm
• anisocytosis – increased variation in size
color:
• normochromic
• hypochromic
• hyperchromic
• anisochromic – unequal color
• polychromatic – bazophilic color
Erythrocytes morfology variations
shape:
normal – round, biconcave (discoid)
poikylocytes – abnormally shaped
• acanthocytes (spur/spike cells) – spiked cell membrane
• codocytes (target cells) – maldistribution of hemoglobin
• spherocytes – round shape
• schistocytes – fragments of erythrocytes
• drepanocytes – sickle cells
• anulocytes – central pallor

Anemia
definition:
• decrease of hemoglobin concentration
– in male: less than 140 g/l
– in women: less than 120 g/l (WHO limit: less than 110 g/l)
• usually in same time decrease of hematocrit and erythrocyte
count
clinical features:
• general symptoms
– signs of tissue hypoxia
– signs of compensatory mechanisms
• specific symptoms
Anemia
compensatory mechanisms:
• shift of hemoglobin dissociation curve to the right → ↓ hemoglobin
oxygen affinity
• ↑ cardiac output by means of tachycardia
• ↑ erythropoiesis
• ↑ lung ventilation
• redistribution of blood flow from not vitally important tissues to tissues
more sensitive to oxygen
signs:
• ↓ oxygen transport to tissues → fatigue, dyspnea, angina pectoris, organ
failure
• ↓ plasma volume → pallor, postural hypotension
• ↑ cardiac output → palpitation, heart murmurs, tachycardia
→ anemic syndrome
Anemia
classification:
1) morphological: according the shape and color of erythrocytes
2) patophysiological:
• erytropoiesis defect
– DNA synthesis defect
– hemoglobin synthesis defect
– erythropoietin insufficiency
– hemopoietic stem cell deficiency
• increased loss of erythrocytes
– posthaemorrhagic
– hemolytic
Video - Anemia of decreased red cell production
Video - anemia of increased red cell destruction (loss)
Forms of anemia
Prevalence of anemia
Megaloblastic anemia
(DNA synthesis disorder)
• insuficiency of folic acid (vitamin B9) and cobalamin (vitamin B12)
→ failure of DNA synthesis and cell cycle slowdown →
megaloblasts formation (huge erythrocytes with immatured
nucleus) → shortened lifespan → anemia
(DNA synthesis disorder)
• folic acid – transport of one-carbon residues – thymin synthesis:
– N5, N10 – methylenetetrahydrofolate → deoxythymidylate
• cobalamin – transfer of homocysteine to methionine +
regeneration of tetrahydrofolate from methyl-tetrahydrofolate
- etiology
folic acid insufficiency:
• inadequate dietary intake (elderly people, alcoholism)
• malabsorption (gluten enteropathy, bowel inflammation)
• increased consumption (pregnancy)
• increased loss (dialysis)
• drugs (cholestyramine, methotrexate, fluorouracil, trimethoprim)
- etiology
cobalamin insufficiency (pernicious anemia):
• inadequate dietary intake (strict vegetarian diet)
• intrinsic factor insufficiency (atrophic gastritis, post resection state, antibodies)
• malabsorption (resection and inflammation of terminal ileum)
• defect of transcobalamin II
- pernicious anemia
clinical features – specific signs:
• pale skin (yellowish tint)
• glossitis (swollen tongue)
• decreased homocysteine degradation →
hyperhomocysteinemia – risk factor of atherosclerosis,
trombosis and ischemic heart disease
• lack of methionine (for choline and phospholipids formation)
→ demyelination of nerve fibers, axon degeneration,
neuronal cell death → dementia, psychosis
Anemia due to hemoglobin
synthesis disorder
classification:
• disorder of protoporphyrin synthesis – porphyria →
sideroblastic anemia
• disorder of heme synthesis due to lack of iron → sideropenic
anemia
• disorder of globin synthesis – sickle cell anemia, thalassemia
Porphyria
• usually inherited (mostly autosomal dominant) disorder of
heme synthesis – defects of enzymes needed at various steps
→ lack of heme
→ accumulation and increased excretion of porphyrins and
their precursors
– early steps – neurotoxicity of early precursors (aminolevulinic acid and
porphobilinogen) → periodic acute attacks of neurovisceral symptoms:
abdominal pain, neurologic deficits, psychiatric symptoms and red urine
– final steps – accumulation of protoporphyrins in skin → photosensitivity
Porphyria
Sideropenic anemia
- lack of iron
• most common type of anemia
• easily treated disorder with an excellent outcome
Etiology:
• increased loss of iron (bleeding, blood donation)
• insufficient dietary intake
• malabsorption (achlorhydria, inflammation, iron chelators)
• disrupted recycling (chronic infections)
• increased demand (pregnancy, growth period)
Sideropenic anemia
- etiology
Sideropenic anemia
- etiology
Sideropenic anemia
- etiology
Sideropenic anemia
- clinical features
• mikrocytic hypochromic anemia
• pallor of skin and mucous
membranes
• abnormalities of epithelial
tissues:
– esophageal webbing
– koilonychia
– glossitis
– angular stomatitis
– gastric atrophy
Sideropenic anemia
- clinical features
decrease of concentration, palpitation soft fragile nails, dry skin

dizziness, headache
fatigue, sleepiness menstruation disorder frayed ending of hair, alopecy

Posthaemorrhagic anemia
• loss of blood after trauma or vascular integrity damage
• acute loss of blood → hypovolemia/hypovolemic shock →
normochromic anemia
• chronic loss of blood (e. g. gastric ulcer) → cumulated loss of
iron → hypochromic anemia
Hemolytic anemia
• premature destruction of erythrocytes – hemolysis
• anemia develop when bone marrow not cover the losses of
erythrocyte
• possible variations in erythrocyte shape
• in chronic state hepato- and splenomegaly
Hemolytic anemia
signs of increased destruction:
• shortened erythrocyte life span
• increased plasmatic levels of iron, hemoglobin and bilirubin
• hemoglobinuria
signs of increased erythropoiesis:

• increased number of erythrocyte precursors in bone marrow
• retikulocytosis
• nuclear form of erythrocytes in peripheral blood
Hemolytic anemia
- classification
cause in defect erythrocyte – corpuscular (inherited):
• membrane disorders – spherocytosis, eliptocytosis,
paroxysmal nocturnal hemoglobinuria
• hemoglobin synthesis defect (hemoglobinopathy) – sickle cell
disease, thalassemia
• enzymes defects – deficiency of glucose-6-phosphate
dehydrogenase or pyruvate kinase
cause in surroundings – extracorpuscular (acquired):
• antibodies against erythrocytes (drugs, autoimmunity)
• mechanical damage (artificial valves in the heart)
• infection (malaria)
• excessive destruction (hypersplenism)
• chemicals (lead, copper)
Hemolytic anemia
- clinical features
jaundice pallor hepatomegaly,

splenomegaly
Hereditary spherocytosis
• most common inherited disorder of erythrocyte membrane
• associated with a variety of mutations that lead to defects in
erythrocyte membrane proteins
(spectrin, ankyrin, band 3 or protein 4.2)
→ cytoskeleton instability → spherical shape of erythrocytes
→ increased destruction mainly in spleen
• splenectomy is standard treatment
• clinical features: jaundice, splenomegaly, bilirubin gallstones
Hereditary spherocytosis
Video - how hereditary spherocytosis causes anemia

Sickle cell anemia
• genetic disorder resulting from the presence of a mutated
form of hemoglobin – hemoglobin S (HbS)
• mutation of hemoglobin β-chain gene → valine instead of
glutamate in position 6
• deoxy conditions – marked ↓ in solubility and ↑ viscosity and
polymer formation x in presence of oxygen liquid state
• membrane damage after recurrent episodes of sickling →
cells are no longer capable of resuming the biconcave shape
upon reoxygenation
Sickle cell anemia
Video - sickle cell disease

Sickle cell anemia
• symptoms usually do not develop until the age of 6-12 months
because of high levels of circulating fetal hemoglobin
• after infancy in erythrocytes: 90 % HbS, 2 – 10 % hemoglobin F
(HbF) and a normal amount of minor fraction of adult
hemoglobin (HbA2), adult hemoglobin (HbA) is absent
• heterozygous carriers
– asymptomatic (no anemia) – only about 40 % of HbS
– protection again malaria
• high prevalence in endemic malaria areas
• high mortality (especially in the early childhood years)
Sickle cell anemia
- distribution
distribution of sickle cell anemia historical distribution of malaria

Sickle cell anemia
clinical features:
• hemolytic anemia
• painful vaso-occlusive crisis
• multiple organ damage from microinfarcts
(heart, skeleton, spleen, kidneys and central nervous system)
Thalassemia
• hereditary disorder characterized by reduced or absent
production of 1 or more of the globin chains
• one of the world’s most common single-gene disorders
• most often of African, Asian, Mediterranean or Middle Eastern
descent (higher prevalence in endemic malaria areas)
Thalassemia
- types of hemoglobin
α-thalassemia
• deficient expression of 1 or more of the 4 α-globin genes on
chromosome 16 → absent or reduced synthesis of α-globin chains
– deletion of 1 α-globin gene → asymptomatic
– deletion of 2 α-globin genes → mild hemolytic anemia
– deletion of 3 α-globin genes → formation of unstable aggregates of β-globin
tetramers – hemoglobin H (HbH) with high affinity for oxygen → moderate
hemolytic anemia
– deletion of all 4 α-globin genes (hydrops fetalis/ α-talassemia major) → no
production of hemoglobin → incompatible with extrauterine life
Video - pathophysiology of alpha thalassemia

β-thalassemia
• mutations of 1 or both β-globin genes on chromosome 11 →
absent or reduced synthesis of β-globin chains
– heterozygous state (1 functional gene) – β-thalassemia minor → mild to
moderate microcytic anemia
– homozygous state (no functional gene) – β-thalassemia major → severe,
transfusion-dependent anemia
• excess unpaired α -globin chains aggregate to form precipitates →
damage of erythrocyte membranes → intravascular hemolysis
• premature destruction of erythroid precursors → ineffective
erythropoiesis → erythroid hyperplasia, bone abnormalities (chipmunk
faces) and extramedullary hematopoiesis → hepato- and splenomegaly
• increased risk of iron overload (long-term transfusional therapy)
Video - pathophysiology of beta thalassemia

β-thalassemia
β-thalassemia
chipmunk facies
Glucose-6-phosphate
dehydrogenase (G6PD) deficiency
• G6PD enzyme is part of the pentose monophosphate shunt – only
source for NADPH in erythrocytes (maintaining glutathione in its
reduced form – scavenger for dangerous oxidative metabolites) →
in persons with G6PD deficiency, oxidative stresses can denature
hemoglobin and cause intravascular hemolysis
Glucose-6-phosphate
dehydrogenase (G6PD) deficiency
• most common enzyme deficiency in humans (400 million people)
• high prevalence in persons of African, Asian and Mediterranean
descent
• X-linked recessive disorder
(males usually manifest the abnormality and females are carriers)
• degree of G6PD deficiency determines the clinical expression:
– minimally reduced enzyme levels → asymptomatic
– greater degree of deficiency → episodes of brisk hemolysis triggered by
infections or oxidative stress (self-limiting within 8 to 14 days)
– severe deficiency → chronic hemolysis

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Hematopathology

Miroslav Kovařík, PharmD, PhD.

poikylocytes – abnormally shaped

• acanthocytes (spur/spike cells) – spiked cell membrane

• codocytes (target cells) – maldistribution of hemoglobin

• spherocytes – round shape

• schistocytes – fragments of erythrocytes

• drepanocytes – sickle cells

• anulocytes – central pallor

decrease of concentration, palpitation soft fragile nails, dry skin

fatigue, sleepiness menstruation disorder frayed ending of hair, alopecy

signs of increased erythropoiesis:

jaundice pallor hepatomegaly,

Video - how hereditary spherocytosis causes anemia

Video - sickle cell disease

distribution of sickle cell anemia historical distribution of malaria

Video - pathophysiology of alpha thalassemia

Video - pathophysiology of beta thalassemia

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