Download PATHOPHYSIOLOGY OF RED BLOOD CELLS Zsófia Mezei, MD

Mezei_RBC_2017
Mezei_RBC_2017
PATHOPHYSIOLOGY OF RED BLOOD CELLS
Zsófia Mezei, MD., 2017.
3./ Hemoglobinopathies
a./qualitative alterations: differences in aminoacid composition
Gel or crystal formation tendency of hemoglobin
sickle cell anemias/drepanocytosis/ HgbS ((226gluval)
hemoglobin C disease Hgb C ((226glulis)
Unstable hemoglobin: Hereditary Heinz-body anemia
Hemoglobin E
Hemoglobin easily oxidisable to methemoglobin
Methemoglobinemias
b./ quantitative: disordered synthesis of complete hemoglobin chains
-thalassemias:
 Thalassemia minor
 Thalassemia intermedia
 Thalassemia major/Cooley’s anaemia
-thalassemias:
Silent carrier
Thalassemic characteristics
Hemoglobin H (β4)
Hemoglobin Barts / hydrops fetalis (γ4)
II./ EXTRACORPUSCULAR HEMOLYTIC ANEMIAS:
1./ Immune hemolytic anemias
a./ isoimmunisation/alloimmunisation:
b./ autoimmune hemolytic anemiák (AIHA):
Warm autoimmune hemolytic anemias:
Drug-induced AIHA:
Type 1:
Hapten mechanism
Type 2:
Immune complex mechanism
Type 3:
Protein binding to RBC surface
Type 4:
Autoantibody induction and binding
Cold autoimmune hemolytic anemias
- primary
- secondary
Bithermic autoimmune hemolytic anemias
- paroxysmal cold hemoglobinuria
2./ Non-immune hemolytic anemias
ANEMIAS
DEFINITION:
GENERAL SIGNS AND SYMPTOMS:
Caused by hypoxia and its compensating mechanisms:
CLASSIFICATION:
A./ INEFFECTIVE ERYTHROPOIESIS/DECREASED RED BLOOD CELL PRODUCTION
I./ Normochromic-normocytic anemias:
Damaged bone marrow, EPO or cytokine deficiency
1./ APLASTIC OR HYPOPLASTIC ANEMIAS
2./ MYELOPHTHISIS
3./ HYPOPROLIFERATIVE ANEMIAS
4./ PURE RED CELL APLASIA
II./ Macrocytic hyperchromic / megaloblastic anemias:
Cbl, IF or folate deficiency
1./ PERNICIOUS ANEMIA
2./ OTHER MEGALOBLASTIC ANEMIAS
III./ Microcytic, hypo(micro)chromic anemias
Disturbed iron metabolism and hem or globin synthesis
1./ IRON DEFICIENCY ANEMIAS
2./ IRON TRANSPORT DEFICIENCY ANEMIAS
3./ IRON UTILIZATION AND REUTILIZATION ANEMIAS
a./ SIDEROBLASTIC ANEMIAS
Hereditary:
DALA synthase disorder
Uroporphyrinogen syntase disorder
Impaired ferrochelatase
Acquired:
b./ HEMOGLOBINOPATHIES
4./ ANEMIAS ASSOCIATED WITH CHRONIC DISEASES
B./ HEMOLYTIC ANEMIAS / ANEMIAS WITH EXCESSIVE HEMOLYSIS
I./ INTRACORPUSCULAR HEMOLYTIC ANEMIAS:
1./ RBC membrane defects
Hereditary:
a./ Hereditary spherocytosis
b./ Hereditary elliptocytosis
c./ Hereditaty pyropoikilocytosis
d./ Stomatocytosis or hydrocytosis
e./ Abetalipoproteinemia (acanthocytosis)
Acquired: Paroxysmal nocturnal hemoglobinuria (PNH)
2./ RBC enzyme deficiencies
Pentose phosphate pathway -glucose-6-phosphate dehydrogenase
Glycolytic pathway (Embden-Meyerhof pathway) - pyruvate kinase
Nucleotide metabolism
- pyrimidine 5’ nucleotidase
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C./ ANEMIAS CAUSED BY/FOLLOWING BLOOD LOSS
1./Anemia following to acute blood loss
2./Anemia following to chronic blood loss
D./ ABNORMAL DISTRIBUTION OF BLOOD
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NORMAL VALUES
ANEMIAS
- 4.5-5.3 x 1012/L = 4.5-5.3 million/L
- 4.1-5.1 x 1012/L = 4.1-5.1 million/L
HEMATOCRIT / Htk:
- 0.37-0.49 L/L
- 0.36-0.46 L/L
HEMOGLOBIN / Hb:
- 8.1-11.2 mmol/L
(13.0-18.0 g/dL)
- 7.4-9.9 mmol/L
(12.0-16.0 g/dL)
IRON / Fe:
- 5.4-28.7 mol/L
TOTAL IRON BINDING CAPACITY /TIBC: - 40.8-76.7 mol/L
FERRITIN:
Men
- 30-300 g/L
Women
- 10-200 g/L
FOLATE:
- 7.0-39.7 nmol/L
B12:
 184 pmol/L
RETICOLOCYTE COUNT:
5-15 among 1000 RBCs
MEAN CORPOSCULAR HEMOGLOBIN (MCH):
- 25-35 pg/cell
MEAN CORPOSCULAR HEMOGLOBIN CONCENTRATION (MCHC):
- 310-370 g/L
MEAN CORPOSCULAR VOLUME (MCV)
- 78-102 fL
RBC COUNT:
Men
Women
Men
Women
Men
Women
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ERYTHROPOIESIS
ERYTHRON: The total mass of circulating RBCs, their precursors and the tisues
(bone marrow) that produce them.
BONE MARROW:
ERYTHROID CELLS:
Proerythroblast (E1)
Basophilic erythroblast (E2)
Polychromatic erythroblast (E3)
Polychromatic normoblast (E4)
Oxyphilic normoblast (E5)
Reticulocyte (contains remnants of nuclei only; stained supravitally)
RATIO OF ERYTHROPOIESIS AND GRANULOPOESIS:
1:3
REGULATION IF RBC FORMATION:
Erythropoietin (EPO):
produed by kidneys; its physiological stimulus is O2
deficiency
Cytokines/ growth factors
CYCLE OF RBC FORMATION:
Proerythroblasts turn to reticulocytes in 5 days /as an effect of EPO in 2 days/
Reticulocytes turn to erythrocytes in 1-2 days
Lifespan of RBCs
120 days
SUBSTANCES REQUIRED FOR RBC FORMATION: Iron, B6, B12, folate and erythropoietin
ERYTHROID CELLS FOUND IN CIRCULATION PHYSIOLOGICALLY:
Reticulocyte
Erythrocyte- without nucleus
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MORPHOLOGICAL DIFFERENCES OF RBCs:
distorted and shrinked RBC with multiple spiny
cytoplasmic projections
pyruvate kinase deficiency
ANISOCYTE:
RBC with different size but normal shape
in all anemias
ANULOCYTE:
Annular(ring)-shaped RBC with decreased MCH
hypochromic anemia
BASOPHILIC STIPPLING:
in increased abnormal erythropoiesis
lead poisoning
thalassemia
DACRYOCYTE:
tear-shaped RBC
osteomyelofibrosis
ELLIPTOCYTE:
egg-shaped RBC
hereditary elliptocytosis
FRAGMENTOCYTE/SCHISTOCYTE: split / RBC fragment
HUS, TTP, heart valve implant
HEINZ BODY:
denatured hemoglobin
G-6-PD deficiency
methemoglobinemia
HOWELL-JOLLY BODY:
nuclear remnants
asplenia
MACROCYTE:
large RBC but normal in size
hyperchromic anemia
MEGALOCYTE:
large and egg-shaped RBC
hyperchromic anemia
MICROCYTE:
small RBC but normal in size
hypochromic anemia
NORMOCYTE:
RBC with diameter 7-8 m; doughnut-shaped with light center
POIKILOCYTOSIS:
RBCs showing abnormal variations in shape
in severe anemias
SICKLE CELL:
lunular RBC (sicle shaped) due to abnormal Hgb
sickle cell anemia
SPHEROCYTE:
spheric form small RBC
lacking central pallor
spherocytosis
without light center
TARGET CELL:
RBCs with bullseye appearance
thalassemias
ACANTHOCYTE:
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ANEMIAS
CLASSIFICATION:
DEFINITION:
Anemia is a condition where the oxygen-carrying capacity of RBCs is impaired.
This might be induced by:
- decreased absolute RBC count
- reduced hemoglobin content, corresponding to age and sex
- abnormal hemoglobin
A./
I./ Normochromic-normocytic anemias:
GENERAL SIGNS AND SYMPTOMS:
Caused by hypoxia and its compensating mechanisms:
Nervous system:
headache, tinnitus, vertigo, syncope, insomnia,
concentration difficulty and impaired vision
Urinary system:
microscopic hematuria, mild proteinuria, salt and
water retention and elevated erythropoietin synthesis
Circulatory system:
tachycardia and angina
Respiratory system: hyperventilation
Discoloration of skin and visible mucous membranes:
Depending on type of anemia:
- white:
iron deficiency anemia
- yellow: hemolytic anemia
- gray:
tumor anemia
Skin appendages:
- hair:
split ends and hair loss
- nail:
INEFFECTIVE ERYTHROPOIESIS/CONDITIONS WITH DECREASED RED BLOOD
CELL PRODUCTION
cracked, koilonychias (spoon nails)
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Definition:
Reduced RBC count and oxygen carrying capacity of RBCs without
morphologic and staining abnormalities
Normocytic:
normal
Mean corpuscular volume / MCV
Normochromic: normal
normal
Mean corpuscular hemoglobin / MCH
Mean corpuscular hemoglobin
concentration/MCHC
Types:
1./ APLASTIC OR HYPOPLASTIC ANEMIAS
Definition:
Anemia that results from a loss of hematopoietic stem
cell population and decrease of early blood cell precursor
count
EPO level is normal or increased
Aplastic anemia is part of pancytopenia caused by hypoplasia of
bone marrow.
Causes
1./ unknown – 50-65 % of cases are idiopathic
2./ known
a./ hereditary:
chromosomal abnormlaity
b./ acquired:
radiation
chemicals
- benzene
drugs: side effect: dose-dependent manner
idiosyncratic effect
- unexpected
- dose-independent
autoimmune mechanisms
infections: hepatitis, HIV, Epstein-Barr virus
hypersplenia
Clinical signs and symptoms:
1./peripheral blood smear:
a./ anemia: normocytic, normochromic
(due to ↓ RBC production of bone marrow)
↓ reticulocyte count
therapy (Fe, folate, B12) resistant
general signs and symptoms of anemia
b./ neutropenia: leukopenia (↓ leukocyte count)
- infections and sepsis
c./ thrombocytopenia (↓ PLT count)
- hemorrhages
2./ empty bone marrow (bone marrow poor in cells)
site of hematopoiesis is replaced
by lipids
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2./ MYELOPHTHISIS
Definition:
Infiltration and replacement of normal hematopoietic
cells by ’non-hematopoietic’ cells
EPO level is normal or increased
Cause:
Infiltration of bone marrow by: a./ connective tissue
b./ lipid
c./ tumor cells
Clnical signs and symptoms:
General signs and symptoms of anemia
Signs and symptoms of underlying disease
Hepatosplenomegaly
(extramedullar hematopoiesis/due to myeloid metaplasia)
Peripheral blood smear:
RBC:
normocytic anemia
(but ocasionally size and morphologic
differences occur, which shortens
lifespan of RBCs and in this case
reticulocytosis occurs)
in case of extramedullar RBC formation
nucleated red blood cells might appear in
the circulation
WBC:
normal, ↓ or 
PLT:
the count is often low, giant, bizarre
shape cells might occur
3./ HYPOPROLIFERATIVE ANEMIAS
Definition: absent or deficient EPO or
diminished response to EPO and/or cytokines
Cause:
Renal diseases:
amyloidosis, diabetes nephropathy and uremia
Decreased metabolism:
hypothyroidism and hypopituitarism
Conditions with protein loss
Clinical signs and symptoms:
peripheral blood smear: normocytic, normochromic RBCs
reticulocytopenia
general signs and symptoms of anemia
signs and symptoms of underlying disease
4./ PURE RED CELL APLASIA
Definition:
Selective destruction of erythroid precursors
EPO level is normal or increased
Cause:
viral infection, immune processes,
drugs and toxins
Clinical signs and symptoms:
usually mild,
depending on degree of underlying disease and anemia
variable cellularity of bone marrow
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II./ Macrocytic hyperchromic or megaloblastic anemias:
Definition:
Reduced RBC count and oxygen carrying capacity.
Large ( MCV) and strong staining (MCH, MCHC)
Cells are found in circulation and bone marrow as well
Cause:
Vitamin B12 deficiency or inadequate utilization
Folate deficiency or inadequate utilization
VITAMIN B12:
PHYSIOLOGY
Cobalamin (Cbl) is essential, found in animal products only
Way of absorption:
Cbl from food, bound to protein, is
dissociated from food protein by gastric hydrochloric acid and pepsin
Cbl binds to R protein found in saliva and gastric juice and transported
to duodenum,
where B12 is dissociated from R protein by pancreatic digestive
enzymes and
binds to intrinsic factor (IF) produced by gastric parietal cells
The complex is absorbed via attachment to special receptors located in
the ileum
Cbl in circulation:
bound to transcobalamin I (blood) storage
bound to transcobalamin II
transported with blood to
receptors of consuming and
storage organs
bound to transcobalamin III
reach liver, bile and intestine and defecated
DEFICIENCY OR INADEQUATE UTILIZATION OF VITAMIN B12 :
A./ Decreased B12 uptake:
vegetarians
B./ Vitamin B12 malabsorption:
1./ Disorders of IF metabolism:
a./Decrease of IF synthesis:
Hereditary: - inability to synthetise IF or
- IF is functionally inadequate
Acquired: - gastrectomy or
- injury of gastric parietal cells
cell mediated autoimmune process
or caused by auto antibodies
produced against microsomal
fraction of gastric mucosal cells
consequence:
atrophic gastritis
histamine refractory achylia
gastrica (HCl production cannot be
stimulated by histamine)
- ↑ risk for stomach cancer
b./impaired B12 binding capacity of IF- due to blocking Ab
c./impaired binding of IF-B12 complex to ileal receptors
because this is inhibited by autoAb against the complex
2./ pancreatic gland disorders
3./ disorders of ileum: inflammation, surgiacl resection
4./ increased B12 consumption:
vermis and bacteria consume B12
5./ Drugs: p-amynosalicylic acid, colchicine, neomycin
C./ Transcobalamin II deficiency  protein synthesis – liver diseases
 protein loss
- nephrosis
D./ Increased need: pregnancy, following to blood loss
Aim:
Technique:
SCHILLING TEST
This test is used to determine whether Se B12 deficiency is caused by:
malabsorption or IF deficiency
Schilling I.
- B12 storages of the patinet has to be filled by parenterally administered B12 (1000 g)
- Then (after 1 hour and within 6 hours following to administration) radioactive B12 is
given orally to the patient
- 24-hour urine collection
- Amount of voided isotope is determined from the 24-hour collected urine:
normally ≥ 9 % ; if the result < 5 % decreased B12 absorption is
determined when renal function is normal
Schilling II.
- B12 storages of the patinet has to be filled by parenterally administered B12 (1000 g)
- Then (1-6 h following to administration) radioactive B12 +IF is given orally to the patient
- 24-hour urine collection
- The amount of voided isotope is determined in rate (in percentage) of transported activity
If amount of voided B12 isotope normalizedIF deficiency is the cause
If the voided B12 isotope remains abnormal, malabsorption is the cause
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FOLATE
PHYSIOLOGY OF FOLATE
Synthetised in plants and damaged by cooking
Transports C1 portions (methyl and formyl group) and has an
importan role in synthesis of
homocysteine
methyonine
DNA
DEFICIENCY OR UTILIZTAION DISORDER RFOLATE
A./ Insufficient uptake:
alcoholists, adolsecents and children
B./ Malabsorption:
in inflammatory bowel diseases
drugs (phenytoine, barbiturate, ethanol)
C./ Disorders of metabolism:
dihydrofolate reductase inhibitors
(methotrexate, trimethoprim), alcohol,
enzyme defects
D./ Cytotoxic substances: interfere with DNA ynthesis
(purine, pyrimidine or folate antagonists,
antimetabolites, alkyling agents)
E./ Increased need: pregnancy, children
Tumors  hematopoiesis
Types:
1./ Pernicious anemia /Biermer’s anemia/
macrocytic anemia caused by autoimmune processes
2./ Pernicious like anemia / other macrocytic anemia
caused by B12 and folate deficiency
Pathomechanism:
Methylcobalamin (MeCbl) deficiency
Cause impaired DNA synthesis, thus
-maturation of nucleus is slow and cell cycle is prolonged
(lifespan of cells increase)
RNS synthesis continues, thus
- cytoplasma increases; i.e. megaloblastic hematopoiesis
occurs
- RBC precursors are megaloblastic
- RBCs are vulnerable
-  cell lysis→  Se ncBi and urea
Affect all (currently dividing) cell lines, thus
leukopenia, large WBC with hypersegmented nucleus
(over-matureated) and
thrombocytopenia might occur as well
Impaired methionine synthesis
-decreased methionine synthase activity
-decreased methionine level might be responsible for
nervous sytem symptoms
Adenosylcobalamin (AdoCbl) deficiency
Disordered myelin synthesis and repair occurs.
Accumulated propionyl-CoA damages myelin sheath
This cause degenaretive processes in:
Cerebral white matter
Peripheral nerves
Posterior and lateral horn of spinal cord
Optic nerves
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Clinical signs and symptoms:
Peripheral blood smear:
RBC: macrocytic
hyperchromic
- large size
MCV  100 fl
- strong staining MCH35pg/sejt,
MCHC370g/l
ovalocytosis – egg-shaped cells
anisocytosis – exceedingly variable RBC diameters
widened Price-Jones curve and shifted to the right
Poikilocytosis – variable RBC shape
 osmotic resistance of RBCs – hemolysis
 reticulocyte count
WBC: hypersegmented (showing more than 5 nuclear lobes)
Leukopenia
PLT: thrombocytopenia
Bone marrow:
(MPO=myeloperoxidase)
Hypercellular bone marrow
Megaloblastic erythropoiesis
Erythroid hyperplasia (high RBC precursor count)
 myeloid/erythroid (norm. WBC/RBC: 3:1) ratio
Gastrointestinal signs
Hunter’s glossitis:
red and painful toung with atrophic
papillae
Histamine refractory achylia gastrica – perdispose to gastric cc
Narvous system:
Presented in vitamin B12 deficiency only
(folate deficiency cause nervous system injury in fetus only):
Polyneuropathy
Disorders of peripheral sensing:
Disturbed:
- touching sensation
- heat sensation,
Memory disorder
Depression
Funicular myelosis, degenaration of myelin sheath:
1./ Posterior fascuculi of spinal cord
- spinal ataxia
- cause wide-based gait
2./ Corticospinal tract
spastic paresis and corticospinal signs
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III./ Microcytic, hypo(micro)chromic anemias
Definition:
Reduced RBC count and oxygen carrying capacity
Small/MCV and poorly staining/MCH, MCHC RBCs
are presented in circulation
Types:
1./ IRON DEFICIENCY ANEMIA
Definition:
ineffective erythropoiesis caused by iron
deficiency
IRON
Need:
PHYSIOLOGY
1 mg/day (adult men)
Absorption:
Absorbed in duodenum and in proximal jejunum.
Heme iron is absorbed in a better way than nonheme iron.
Absorption of non-heme iron is assisted by:
gastric hydrocholic acid,
ascorbic acid
Iron is absorbed via acative transport.
If transferrin saturated, iron absorption ceases and
the non-absorbed unrequired iron leaves the body
via the faces.
Apoferritin synthetised in mucosal cells takes up
iron. From ferritin iron gets to the carrier plasma
protein transferrin. Transferrin is a beta-globulin
synthethised by the liver.
Iron distribution:
Only small amount of ferritin is found in serum.
There is a close relation between Se ferritin and iron
storage of the body.
Low Se ferritin - A sign of iron deficiency in
all cases
High Se ferritin concentration is not always
caused by the increased iron storages.
Inflammation can induce high ferritin level as
well, because ferritin is an acute phase protein.
Hemosiderin is a degraded storage form of
ferritn, difficult to use for hematopoiesis.
Primarily iron is stored in mononuclear phagocytic
cells (machrophages) of spleen, liver and bone
marrow. Iron released during cell lysis is reused in
hematopoiesis. Iron reuse covers 97% of daily iron
need.
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CAUSES OF IRON DEFICIENCY:
Usually caused my multiple factors simultaneously
Insufficient intake:
not enoug or not the adequate form (ferri or ferro)
Malabsorption (impaired absorption):
1./ Decreased hydrochloric acid production
2./ Increased bowel motility
3./ Transport disorders
Hereditary
Acquaired
Increased loss:
occult hemorrhage (GI hemorrhage, menstrual)
chronic intravascular hemolysis:
iron deficiency occur due to hemoglobinuria and
hemosiderinuria
Increased need
pregnancy, growth
Development of iron deficiency anemia:
Stage 1/
Pre-latent: Decreased iron storage
Normal: Se Hb and iron
Decreased: Se ferritin < 20 ng/mL
Increased: transferrin concentration
(↑ TIBC/total iron binding capacity refers to
this)
Stage 2/ Latent:
Empty iron storage
Cannot guarantee
iron neded to erythroid bone marrow
Decreased:
Se iron
Increased:
Se transferrin
Se ferritin receptor concentration increases
>8.5 mg/L
Stage 3/
Manifest: Microcytic hypochromic anemia
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Clinical signs and symptoms:
General signs and symptoms of anemia
Koilonychia: concave, cracked and dry nails
Angular cheilosis:
fissure and ulcer of labial
comissure
Plummer-Vinson syndrome: iron deficiency anemia
dysphagia
glossitis
Peripheral blood smear:
RBC microcytic: small diameter of RBC ( MCV)
anisocytosis: varable RBC diameters
widened Price-Jones curve and
shifted to the left
hypochromic: poorly staining RBCs
(MCH, MCHC)
planocytes: thin RBCs
anulocytes: ring-shaped RBCs
decreased reticulocyte count
Bone marrow:
Serum:
Numerous young RBCs (normoblasts)
iron 
ferritin (↓ RBC ferritin as well)
TIBC (total iron binding capacity) 
transferrin saturation 
2./ IRON-TRANSPORT DEFICIENCY ANEMIAS
Koilonychia
Definition:
Iron from storages cannot reach site of erythropoiesis.
Glossitis
Cause:
transferrin deficeinecy: - synthesis (e.g. liver diseases)
-  loss (e.g. nephrosis)
defective transferrin molecule
Angular cheilosis
Dysphagia
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3./ IRON UTILIZATION AND REUTILIZATION ANEMIAS
Definition: Inadequate or abnormal intracellular iron utilization for
hemoglobin synthesis, in spite of the fact that amount of
iron is sufficient or increased in mitochondria of erythroid
precuror cells.
Types:
a./ SIDEROBLASTIC ANEMIAS
Definition: Impaired formation of hem porfirin structure
Thus iron cannot be built into the structure of
heme.
Cause:
Hereditary: Disorders of enzymes required for heme
prophyrin synthesis:
DALA synthase defect
uroporphyrinogen synthase defect
ferrochelatase defect
Acquired: Vitamin B6 deficiency (DALA cofactor)
Intoxication:
- lead, inhibits heme synthesis
- antituberculotics and alcohol disturb
pyridoxine metabolism or formation of
active pyridoxine-5-phoshate from
pyridoxine
- chloramphenicol and chemotherapeutic
agents
Associated with neoplastic and
inflammatory diseases (cc, leukemia and
RA)
Clinical signs and symptoms:
Peripheral blood smear:
RBC: microcytic,
Price-Jones curve widened, shifted to the left
Siderocytes: iron granules in RBC cytoplasm
elevated: Se iron, ferritin,
Transferrin saturation
decreased: TIBC (total iron binding capacity)
Bone marrow: hypercellular
ringed sideroblasts
The
ring
is
fromed
by
mitochondrial iron deposits, as
there is the initial and last step of
heme synthesis
 intramedullary death of RBCs
b./ HEMOGLOBINOPATHIES
thalassemias (see hemolytic anemias)
microcytic, hypochromic anemia
but elevated Se iron and ferritin
decreased Se transferrin
(i.e. there is a large quantity of iron storages)
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Bone marrow
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4./ ANEMIAS ASSOCIATED WITH CHRONIC DISEASES
Cause:
acute and chronic inflammation
(virus, bacteria, parasites, fungi)
tumor (hematological, solid tu)
autoimmune diseases (RA, SLE and vasculitis)
chronic renal disease and nephritis
Pathomechanism:
a./ Impaired iron metabolism (defective iron reutilization):
Cytokines are released from activated T-cells and
monocytes by pathogens: INF, TNF, IL-1, IL-6, IL-10
Cytokines  iron uptake and store of RES cells, due to:
 of ferritin synthesis  thus  iron storage of RES
 erythrophagocytosis
 DMT1 expression of macrophages, and thus
 iron uptake of a macrophages
 transferrin-mediated uptake of iron by
macrophages
 ferropontin expression of macrophages and thus
 iron export of macrophages
 hepcidin expression and thus
 iron export of macrophages and
 duodenal iron absorption
b./ Impaired erythropoies because cytokines
- inhibit
proliferation and
differentiation of RBC precurors
-  EPO production and acativity
-  EPO receptor expression in progenitor cells
-  ROS activity, direct cytotoxic
to progenitor cells and EPO producing cells
Clinical signs and symptoms:
symptoms of underlying diseases (infection, inflammation, tu)
Moderate microcytic anemia
Se iron decreased
Se ferritin and RBC ferritin normal
Anemia associated with
chronic diseases
Iron
Transferrin
Transferrin saturation
Ferritin
Solubile transferrin receptor

 - normal

normal - 
normal
Cytokine level

Iron deficiency anemia





normal
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C./ HEMOLYTIC ANEMIAS / ANEMIAS WITH EXCESSIVE HEMOLYSIS
SITE OF HEMOLYSIS:
DEFINITION:: Decreased RBC count and oxygen carrying capacity despite effective
erythropoiesis, as lifespan of RBCs are decreased
HEMOLYISIS::
Iron, LDH1, Potassium and Hgb released from RBCs:
Iron bound to apotransferrin
-  Se iron
LDH1
-  Se LDH1
Potassium
-  Se K
Hgb bound to haptoglobin
- ↓ Se haptoglobin
One part of free hemoglobin that remained in plasma is excreted by
kidneys
- hemoglobinuria
Other part is transformed to hematin and bound to hemopexin (only
after haptoglobin is saturated)
- Se hemopexin 
Carried to RES by hemopexin
In RES biliverdin and then bilirubin is formed and gets to plasma
-  Se ncBi.
Nonconjugated Bi (ncBi) is carried by albumin to the liver, where that
is conjugated (cBi) by glucuronate and becomes water soluble
cBi reaches the bowels, where Ubg is formed; one part of Ubg is
reabsorbed in the circulation
One part of Ubg that reached circulation gets back to liver and other
part is voided
-  urinary Ubg
The unabsorbed Ubg is transformed to stercobilin in bowels, this
determines color of faces
- pleiochromic faces
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RED BLOOD CELL MEMBRANE
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CAUSES AND TYPES OF HEMOLYTIC ANEMIAS
I. INTRACORPUSCULAR HEMOLYTIC ANEMIAS:
1./ RBC membrane defects
# HEREDITARY
a./ Hereditary spherocytosis
Definition: hereditary RBC membrane defect
Cause:
abnormal RBC cytoskeleton caused by a genetic
disorder
autosomal recessive:
↓ binding ability of  spectrin to 4.1protein and actin
autosomal dominant:
unstable ankyrin that leads to
↓ incorporation of spectrin to membrane
Pathomechanism:
Cytoskeletal defect cause:
 ion permeability of RBC membrane,
thus ic. Na+ and water 
that leads to development of spherocyte
(ball-shaped RBC)
Deformed RBCs are
- filtered by spleen and
- lifespan of RBCs ↓ because continuous shape
changes use up much energy
Clinical signs and symptoms:
Most of the patients suffer from a lifelong
but moderate normochromic anemia
Cahnges in hemoglobin level
RBC:
Spherocyte (ball-shaped), these red cells
lack central pallor
Their osmotic resistance 
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Normal
osmotic
resistance
Decreased
ozmotic
resistance
Signs of hemolysis with intermittent and variable jaundice
and splenomegaly
Gall stones
Congenital disorders: polydactylia, gothic palate
b./ Hereditary elliptocytosis
Definition:
>20 % of circulating RBC are elliptocytes
Forms/Types:
- general form: numerous elliptocytes with
mild hemolysis
- spherotic form: spherocytes and elliptocytes with
moderate anemia
- stomatocytic form:
accompanied with RBC antigen alteration that
is protective against malaria
Pathomechanism:
- abnormal  spectrin chain leads to impaired spectrin
dimer-dimer interaction
- in spherocytic form amount of 4.1 protein is decreased
- impaired ankyrin-anion transporter bound
Clinical signs and symptoms:
asymptomatic or well compensated
normal osmotic resistance
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c./ Hereditary pyropoikilocytosis:
Definition: thermosensitive RBCs
Pathomechanism:
impaired spectrin dimer-dimer interaction
caused by abnormal  spectrin chain
Clinical signs and symptms:
RBC: fragments, microspherocytes
Hairy cells, decreased MCV
Mild hemolytic anemia
e./ Acanthocytosis Abetalipoproteinemia
Cause:
Genetic disorder, recessive
apo B-48 and 100 deficiency
Pathomechanism
impaired transport of TG to blood
Clinical signs and symptoms:
Decreased lipid absorption:
Steatorrhoea
Decreased Se chylomicron
(postprandial lipidaemia cannot be
detected)
Se total lipid
Se VLDL (not produced)
Acanthocytes in peripheral blood smear:
dark and shrinked RBCs with
collapsed and irregular cavity and
wide spike projections
this is accompanied with relatively high
sphingomyelin
content
of
RBC
membrane; this makes the cell rigid
severe hemolytic anemia
ataxic neuropathy
retinitis pigmentosa
mental retardation
d./ Stomatocytosis o hydrocytosis
Pathomechanism:
Exact structural defect is unknown.
Increased membrane permeability to
Na ions and K ions as well
Na+ carries water, cells become swollen and
susceptible to osmotic and mechanic lysis
Clinical signs and symptoms:
Erythroid hyperplasia and thus mild anemia.
RBC: stomatocytes:
fish mouth-like pallor in the middle of cells
uniconcave cells, increased MCV, hemolysis
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II. INTRACORPUSCULAR HEMOLYTIC ANEMIAS:
1./ RBC membrane defect
# HEREDITARY
# ACQUIRED
Paroxysmal nocturnal hemoglobinuria (PNH):
Definition: Acquired clonal disorder of hemopoietic stem cell
Cause:
X-linked somatic mutation of
phosphatidylinositol glycan–A (PIG-A) gene
in hematopoietic stem cells
Pathomechanism:
First step: X-linked somatic mutation of phosphatidylinositol
glycan– A (PIG-A) gene in stem cells and thus
glycosylphosphatidyl inositol (GPI) anchor protein
becomes impaired on hemopoietic stem cell surface
Second step:
Immunological selection of hemopoietic stem cells
with deficient GPI anchor
The selection is initiated by suppressive cytokines
(i.e.transforming growth factor β - TGF-β) that
diminish hematopoiesis.
These abnormal cells survive and proliferate
Increased proliferation increase the chance of further
genetic mutations
Third step: Abnormal GPI anchor appear in phenotype
(in all circulating cells)
RBCs are more sensitive to lytic effect of complement
because abnormal GPI anchor cannot bind:
complement regulatory proteins:
- DAF (CD55 /decay-accelerating factor/) that
accelerate C3 convertase degradation
- MIRL (CD59 /membrane inhibitor of reactive
lysis) that prevent C9 polymerisation and sinking
into membrane
This protein is found on PLTs as well.
Activated complement might cause platelet
aggregation and hypercoagulabilty; i.e. thrombosis.
Increased cell lysis might cause an elevation in Se
TF level, which might cause
increased platelet aggregation and
hypercoagulability
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Clinical signs and symptoms:
chronic intravascular hemolyis with acute attacks
(causes: infection, stress, drugs, sleeping, ↓ pH)
hemoglobinuria, hemosiderinuria, splenomegaly
venous thrombosis:
- in intraabdominal veins:
(in portal and mesenterial veins and in
hepatic vein) that cause splanomegaly
and abdominal pain
- Thrombi in cerebral veins might cause death
of the patient
Prognosis:
aregenerative crisis
infection
embolisation
uremia
death within 10 years from set up of
diagnosis
Peripheral blood smear:
Normocytic normochromic anemia
granulocytopenia
thrombocytopenia
Bone marrow:
hypercellular in early phase
hypocellular in a later phase
PCV/Packed Cell Volume/HCT/Hematocrit
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2./ RBC enzyme deficiencies
# CONGENITAL
Pentose phosphate pathway
glucose-6-phosphate dehydrogenase (G6PD)=Fabism
Cause: G6PD gene on chromosome X
Patients: male and homozygous female
Altering signs and symptoms:
heterozygous female
(resistance against malaria)
Pathomechanism:
G-6-PD deficiency
G6PD catalyzes NADP+NADPH+ formation
NADPH is a cofactor of glutathione reductase
↓ amount of reduced glutathione
glutathione is protective against
oxidative stress
↓ RBC protection against oxidativesterss
Oxidative stress might be induced by:
drugs:
antimalarial
sulphonamides
sulphones
analgetics
nitrofurans
vitamin K derivatives
Fava bean:
Contains reductive compounds
(isouracil and divicin), hydrogen
peroxide is formed by them
The following parts might be oxidized:
Heme iron:
Methemoglobin is formed,
inadequate for O2 transport
Globin:
Heinz-bodies are formed, these are
products
from
oxidative
degeneration of Hgb, which are
bound to the membrane
RBCs that contain Heinz-bodies
are rigid and detected and
destructed by RES
- ↑ cation permeability of
membrane, thus cause hydrated and
deformed RBCs
Membrane proteins:
e.g. spectrin, this leads to
decreased RBC deformation
Lipids:
cause acute iv. haemolysis
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Clinical signs and symptoms:
Induce:
oxidants high body temperature
Acute viral and
bacterial infection
Diabetic acidosis
General signs and symptoms of hemolytic
anemia:
Hemolysis (jaundice)
Enhanced erythropoiesis
(Reticulocytosis)
Anemia
RBC: Heinz-bodies
Bite cells (caused by removal of Heinzbodies by spleen)
Complication: hemoglobinuria
Acute renal failure
Acute hemolysis in G6PD deficiency
„bite” cell or keratocyte (arrow)
two „blister cells” (arrow),
polychromatic macrocytes and irregularly contracted cell
(arrowhead)
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Glycolytic pathway (Embden-Meyerhof pathway)
Pyruvate kinase (PK)
Cause:
AR enzyme deficiency
Pathomechanism:
Physiological role of PK:
pyruvate synthesis with
ATP formation, which ir required for
- K+-Na+ pump
Ca++ pump of RBC membrane
- maintenance of deformation
Signs and symptoms:
Hemolysis
- in homozygous only
- in heterozygous not
Splenomegaly
RBC:
normocytic
Akantocytes (contracted spiky RBCs)
Aplastic crisis might occur (e.g. in parvovirus infection)
Nucleotide metabolism
Pyrimidine 5’ nucleotidase
Cause:
AR, Manifest in homozygous-hemolytic anemia
Pathomechanism:
Due to enzyme deficiency:
There is no RNA degradation of reticulocytes,
5x increase of RBC nucleotide pool:
↑ pyrimidine and ↓ adenosine nucleotide
undegraded ribosomes accumulate and
aggragate
Signs and symptoms: hemolysis, basophilic stippling in mature
RBCs, splenomegaly
Pyruvate kinase deficiency after splenectomy
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PHYSIOLOGY OF GLOBIN SYNTHESIS:
Chromosome 16 (α, ζ) and 11 (β, δ, ε, γ) are responsible for synthesis
of globin chains.
Formation site and type of globin chain changes periodically.
3./ Hemoglobinopathies
a./qualitative alterations: Differences in aminoacid structure
A./ Gel or crystal formation tendency of hemoglobin
1./ SICKLE CELL ANEMIAS / DREPANOCYTOSIS
Cause:
Point mutation of chromosome 11
Hgb S is formed: Hgb S ((226gluval), site of
glutamate is occupied by valin in  chain
Heterozygous - RBCs  50% Hgb S
Homozygous - RBCs 70–98% Hgb S (other F)
Pathomechanism:
Hemoglobin consists of 4 globin chains.
Cromosome 16 is responsible for formation of 2 alpha chains and chromosome 11 is
responsible for formation of other 2 beta chains.
Solubility of oxy-Hgb S is normal
Solubility of reduced-Hgb S is decreased, thus
these precipitate
When size of the aggregate reaches a critical
level, explosive gel formation starts, because
the aggregate acts as a core and tube-like fibers
are formed by adhesion of core and reducedHgbS-teramers. This cause formation of sickle
cells, i.e. menisocytosis
gel fromation is:
enhanced by:
- hypoxia
- pH ↓  stability of reduced-HgbS
- 2,3-DPG   stability of reduced-HgbS
-increased redued-HgbS cc ( 16 g/dl)
- mechanical effects; e.g. shearing stress 
- RBC dehydration ( MCHC)
- deceleration of speed
(because a given time is required for gel
formation)
suppressed by:
- increase in amount of HgbF
- increase in amount of HgbA
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Signs and symptom:
Chr. hemolysis
Blood
Characteristics of sickle cells:
Principal Mechanisms responsible for
potassium and water loss in sickle red cells
Defect in membrane salt and water transport:
1./ Na+-K+-ATPase is activated
2./ K+-Cl- cotransporter is activated
3./ Gárdos-type K+ channel is activated
RBC is dehydrated
of MCHC is increasing the polymerisation
that cause irreversible sickling
(sickle form remains after reoxygenisation)
Spontaneous Heinz-body formation
Membrane protein (glycophorin and
ankyrin) precipitation
IgG, IgA, IgM and complemts
factors are attached to them
Macrophages are activated
RES detects (and filters) affected RBCs
iv. hemolysis occurs that might cause
anemia
- anemia
Heinz-bodies
Howell-Jolly-bodies
(nuclear chromatin remnants in
cytoplasm, spleen is unable to
filter them)
Sickle cell in Na-metabisulphite
preparation
Jaundice
Bone marrow: - erythroid hyperplasia
Symptoms due to vascular occlusion
Splenic vein thrombosis
-hyposplenia
Pain
-muscle, bone, abdominal
Ulcus cruris
Liver: Congestive hepatopathy
-caused by heart failure
Hepatitis
-caused by frequent transfusions
Hepatic lesions
-caused by hepatic sinusoidal
occlusion
-caused by overburdened
Kupffer cells
Sudden hepatomegaly
-caused by sequestration
Cholelitiasis
Respiratory:
Pulmonal embolisation
Lung infarction
Urogenital:
urine concentration ability 
Hematuria
Papillary necrosis
decreased GFR
RTA
Priapism and impotence
Ophthalmic:
Retinopathy
Hyaloid hemorrhage
Neurologic:
Thrombosis
Ischemic cerebral events
Acute attacks
Acute life-theratening events
Hemolytic crisis
Elicited by: -infection, cold,  Hgb level, ↓ pH
Signs:-pain, portal and renal vessel occlusion
Aplastic crisis
Elicited by -Parvovirus infection
Signs
-rapidly decreasing Hgb, Htk,
Reticulocyte
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2./ HEMOGLOBIN-C DISEASE
Cause:
Gene defect caused by point mutation,
Hgb C ((226glulis) is produced
glu = glutamate, lys = lysine
Glutamate is replaced with lysine in -chain
Pathomechanism:
HgbC- interacts with K+-Cl- transporter
- its activity remain in mature RBCs
- K+ is lost by RBC and RBC is dehydrated,
MCHC is increased
oxyHgbC is aggregated and crystallized but
dissolved during deoxygenisation and
do not cause occlusion
Signs:
RBC membrane becomes rigid by HgbC:
Fragmentocytes,
Microspherocytes,
Target cells might be formed (80 % of RBCs)
Homozygous: mild hemolysis, compensated
splenomegaly -moderate
Heterozygous: asymptomatic
Hemoglobin C crystals are hexagonally shaped rods that occur
in the red cell cytoplasm of patients with homozygous
hemoglobin C. These crystals may also be extracellular
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B./ Unstable hemoglobin
1./ HEREDITARY HEINZ-BODY ANEMIAS
Definition: Aminoacid change caused by a point mutation that results in
unstable hemoglobin molecule.
There are numerous individual variants
Pathomechanism:Effects of aminoacid change:
Heme group of hemoglobin molecule is lost,
- Configuration of heme binding site is changed,
- Bounds between  and  chains are weaken or
- Structure of subunit is weaken
Consequences: In oxydative stress Hgb molecule is broken up and
precipitates
Heinz-bodies are formed
They are precipitated, denaturated hemoglobin due
to oxidative injury. They are usually eccentrically
placed and attach to the membrane.
(They are may be seen in G6PD, α thalassemia,
unstable hemoglobins and in splenectomised patients
also.)
RBC membrane becomes defected
RES detects/filters
Hemolysis
Signs:
Chr. and partially compensated hemolysis
Splenomegaly
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2./ HEMOGLOBIN E
Definition:
ponit mutation, gene defect,
unstable Hgb molecule is formed,
Glutamate is replaced by lysisn in position 26 of 
Hgb 2 226GluLys
Pathomechanism:
Mutation occurs in 1-1 bound and thus the
oxydative stress makes the molecule unstable
Signs:
Heterozygous:
Normal Hgb, Microcytosis, No splenomegaly
Electrophoresis: 70% Hgb A, 25% E, 5% A2 or F
Homozygous: Mild anemia, Low MCV, microcytosis,
Traget cell, No reticulocytosis, chr. hemolysis
Electrophoresis: Hgb E only
C./ Hemoglobin easily oxidisable to methemoglobin
METHEMOGLOBINEMIAS:
Definition:
Methemoglobin is an oxidation product of hemoglobin
that contains ferri iron
Ferri ion containing heme of methemoglobin is
unable to bind oxygen.
Ferro heme in hemoglobin tetramer is unable to
carry oxygen either, because its oxygen binding
capacity is increased and cannot deliver oxygen
(oxygen dissociation curve is shifted to the left).
Normally rate of methemoglobin is 0.5 %, which is
reduced by NADH-cytochrom-b5 reductase
Types:
Hereditary:
a./ Hemoglobinopathy -Haemoglobin M
Pathomechanism:
Genetically defected  and  chains.
Histidine, which has a role in formation
of iron binding, is replaced by tyrosine.
Stable bound is formed between heme
iron and aminoacid side chain, thus
inability of oxygen binding and
resistance cytochrome-b5 reductase.
Signs:
cyanosis
minimal hemolysis
when compensated might be
symptomatic due to:
- polycythemia and
- increased 2,3 DPG level
b./ Cytochrome-b5 reductase deficiency or defect
Aquired - oxidants:
Causes: Exogenous: nitrite, nitrate pollution
Endogenous: bacteria (enteritis, sepsis)
Signs:Children: nervous system defects
Occur when there is 40 % methemoglobin
50 %: cyanosis, hypoxia; 70-80 %: life-threatening
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b./quantitative alterations: disorders of entire globin chain synthesis
THALASSEMIAS
Definition A genetic defect that cause imbalance between synthesis
of the globin chains
Pathomechanism:
The unpaired chains are accumulated in erythropoietic stem
cells and are toxic causing ineffective erythropoiesis.
Types:
 THALASSEMIA
Definition:
Genetic defect of  globin chain synthesis is located
in chromosome 11
Cause:
Defected perparation of mRNS-transcript in nucleus
- Early termination of translation
- Gene deletion
Pathomechanism:
In adults  chain can be replaced by  and  chain
Thus in -thalassemia the amount of:
Hgb A2 ( 22) and
Hgb F ( 22) increase
Excessive unpaired  chains aggregate and
precipitate that leads to:
decreased ATP synthesis
potassium leakage
decreased sialic acid content of
membrane
IgGs against blood group antigens are produced and
macrophages bind them - rigid and deformed RBCs
Ca++ transport defect occur, thus ic Ca++ level
incerases
 chain aggregates are bound to membrane
cytoskeleton and cause:
apoptosis of erythropoietic stem cells in bone
marrow and
rigidity and instability of RBCs,
K+-Cl- cotransporter becomes defected, thus
RBCs become dehydrated
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Clinical menifestations:
1./  -thalassaemia minor:
heterozygous
mild anemia, or anemia is not presented
peripheral blood:
RBC –microcytic, hypochromic, basophilic stippling
splenomegaly (rare)
2./  -thalassemia intermedia:
various genetic background
moderately severe
definite anemia
hepatosplenomegaly
3./  -thalassemia major (Cooley’s anemia):
homozygoous
severe hemolytic anemia
jaundice, hepatosplenomegaly
impaired growth
increased susceptibility to infections
peripheral blood smear: nucleated RBCs
basophilic stippling
(rRNS aggregates)
 chain aggregates
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 THALASSEMIA
Definition: Genetic defect of  globin chain synthesis is located
in chromosome 16
Cause: gene translocation, point mutation
Clinical manifestations:
1./ Silent carrier syndrome:Genotype: /
One α gene is absent
2./ Thalassememic nature:
2  genes are absent
either homozygous
or heterozygous
Homozygous -thalassemia:
genotype: -/-
Heterozygous -thalassemia:
genotype: --/
Normal HgbA2 level
anemia is presented or not, hypochromic,
microcytic RBCs
3./ Hemoglobin-H disease
3  genes are absent; genotype: --/- /
Hgb H (ß4) is formed
Hgb H is unstable and precipitates
in vivo: compensated hemolysis occur
splenomegaly
RBC
microcytic
hypochromic
target cells
Heinz-bodies (precipitated Hgb H)
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4./ Hemoglobin Barts or hydrops fetalis:
 chain is not produced at all; genotype: (--/--)
 chain cannot be raplaced by other chains
4 (Hemoglobin Barts)
Characteristics:
-high oxygen affinity
-unstable
-aggregate in oxidative stress
- aggregates might bind to RBC membrane:
- severe hemolysis
- ineffective erythropoiesis (small degree)
Might cause overhydration of RBCs
Might lead to intrauterin death
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II. EXTRACORPUSCULAR HEMOLYTIC ANEMIAS:
Cause of hemolysis is located outside RBCs
1./ Immune hemolytic anemias
a./ isoimmunisation/alloimmunisation:
- transfusion of incompatible blood
ABO
(incomplete Ab / IgM)
- Rh incompatibility: (complete Ab / IgG)
hemolytic disease of neonates
(morbus haemolyticus neonatorum)
Rh (-) mother produces antibodies against Rh (+) RBCs of
fetus. When maternal and fetal circulation contact,
maternal antibodies harm fetal RBCs
KERNICTERUS
Pathomechanism:
Lipid soluble ncBi penetrates to central nervous
system because blood-brain-barrier is immature. In
CNS ncBi is deposited to basal ganglions that are
rich in lipids. This leads to neurological defects.
Clinical signs:
apathy, hypotoniciy, encephalopathy, rigidiy,
chorea, hardness of hearing
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b./ autoimmune hemolytic anemias /AIHA/:
Definition: autoantibodies are produced against self RBCs
Types:
Detection: Coombs test
A./ WARM AUTOIMMUNE HEMOLYTIC ANEMIAS:
Direct Coombs test:
Used for detection of RBCs covered by IgG.
The test is positive if Coombs serum that contain
anti-IgG and anticomplement cause agglutination of
RBCs.
Indirect Coombs test:
Used for detection of free antibodies in serum.
The test is positive if normal RBCs (not covered by
antibodies), which are given to the examined serum,
agglutinate in the presence of Coombs serum.
Causes:
Primary/Idiopathic/genetic susceptibility
Secondary: associated to other diseases
(SLE, RA, CLL,
infection/ CMV, HIV)
Drugs
Pathomechanism:
At body temperature IgGs are bound to RBCs
These marked RBCs are detected by spleen
and destroyed via phagocytosis.
(extravascular hemolysis)
Signs:
RBC: Spherocyte
RBCs are covered by IgG and C3
Direct antiglobulin test is positive
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Drug induced autoimmune hemolytic anemias:
Type 1:
Hapten-mediated mechanism:
Cause: im. high dose of penicillin or
tetracyclin
Mechanism:
Type 2 allergic reaction
The drug binds to RBC membrane as
a hapten, thus becomes a complete
antigen and IgG is produced against
them, which binds to complete Ag
RES filter/detect them
RBC hemolysis
Type 2
Immuncomplex-mediated
mechanism „innocent bystander”:
Cause:
Kinidine, p-aminosalicylate,
phenacetin, NSAID
Mechanism
Type 3 allergic reaction
Drugs, as hapten, bind to plasma
proteins and become complete
antigen. IgM is produced against this
antigen that binds to the antigen.
Immuncomplexes are formed that
nonspecifically cover RBCs, PLTs
and glomerular endothelium and thus
deposits are formed.
IgM activates complement (C) and
cause RBC hemolysis
Type 3 Attachment of proteins to RBC
surface
Cause:
Cephalothin
Mechanism:
non-immunologic process:
Cause nonsepcific connection of
different proteins
(IgG,
IgM,
complement, tissue factor, albumin)
to cell surface
Rarely cause hemolysis
Type 4
Autoantibody induction and
attachemnt:
Cause:
Methyldopa, levadopa,
procainamide, ibuprofen, diclofenac
in high doses and prolonged
administration
Mechanism:
Autoimmune disease due to defect of
immune system
T-supresor cell is inhibited by drugs
and B-cell is activated, and IgG
against Rh is produced
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B./ COLD AUTOIMMUNE HEMOLYTIC ANEMIAS:
Causes: Priary: unknown
Secondary:
acute: infections
-mycoplasma pneumonia
-infectious mononucleosis
chronic:
lymphoproliferative diseases
Waldenström’s macroglobulinemia
Autoimmune diseases
Pathomechanism:
-Primary cold autoimmune hemolysis:
Attacks of painful acrocyanosis
Cause:
in cold (30 oC) RBC
agglutination is caused by
IgM in peripheral circulation
IgM Ab titer is less than 1:1000
- Secondary cold autoimmune hemolysis:
Occur when intravascular temperature is
20-25 oC
Signs of hemolysis that is caused by
monoclonal IgM
Ab titer is higher than 1 : 1000
Signs:
acrocyanosis, Raynaud’s phenomenon
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C./ BITHERMIC IGG TYPE AIHA:
- Paroxysmal cold hemoglobinuria:
Cause:
the most common AIHA in childhood
- primary: unknown
- secondary: syphilis, mumps, mononucleosis,
Pathomechaanism:
20 oC:
IgG and RBC attachment, IgG 
complement binding capacity of RBCs
37oC:
IgG antibodies dissociate from RBCs
complement is activated
RBC hemolysis occur
Signs of AIHA:
Extravascular hemolysis:
Lyisis of RBCs that are filtered by liver and spleen,
thus (especially when chronic) hepatosplenomegaly
occur
Intravascular hemolysis:
Rare, usually after acute infection
Signs of increased bone marrow and peripheral RBC
formation
In decompensated hemolysis general signs of anemia are
seen as well
2./ Non-immune haemolytic anemias
Cause: Physical: a./ Mechanical or traumatic RBC injury
large vessels:
vessle graft, synthetic valves,
march hemoglobinuria
microcirculation:
in microangiopathy (DIC, TTP, HUS)
fibrin fibers cause RBC damage
b./Heat:
combustion
Chemical: a./ Chemicals: copper, lead, distilled water
b./ Biologic agents:
snake, spider and bee bites, malaria
Signs:
Abnromal RBC shapes: occurence of
schystocyte and
acantocyte, etc
RBC AGGLUTINATION
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PROGRESS OF HEMOLYTIC ANEMIAS:
1./ Chronic
a./ compensated hemolysis and
-  RBC formation (tenfold than normal) are seen, this
compensate increased hemolysis and thus
- there is no signs of anemia
b./ decompensated, hemolysis and
-  RBC formation (erythropoiesis) are seen but this cannot
compensate the amount of hemolysis and thus
- signs of anemia are presented as well
2./ Acute (hemolytic crisis) a./ spontaneous
b./ acute exacerbation of chronic hemolysis
SIGNS OG HEMOLYTIC ANEMIAS
GENERAL SIGNS
Signs of increased RBC lysis:
Blood: elevated Se nc indirect Bi
Se free hemoglobin
Se iron
Se transferrin saturation
Se K (released form disintegrated RBCs)
Se LDH1 isoenzyme (also released from cells)
decreased Se (free) haptoglobin level
(in iv. hemolysis)
Se hemopexin (only when Se haptoglobin level is
unmeasurable)
Se TIBC
Feces:
dark
Urine:
Ubg incerased
Hemoglobinuria, and as a result proteinuria might occur
(small Mw enables filtration via glmeruli; hemoglobinuiria
occur only when extent reach the tubular maximum)
Signs of increased RBC formation:
Blood:
reticulocytosis (sign of accelerated RBC formation)
Bone marrow: erythroid hyperplasia
CLINICAL SIGNS OF ACUTE HEMOLYTIC CRISIS
- shivering, high body tempareture, sweating
- dyspnea, tachypnea
- drop of blood pressure
- pruritus, urticaria, flush
- headache
- nausea, vomitus
- hemoglobinuria
COMPLICATIONS OF HEMOLYTIC ANEMIAS
1./ Chronic hemolytic anemias jaundice
splenomegaly
pigment gallstones
2./ Acute hemolytic anemias
shock
acute renal failure
DIC
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C./ ANEMIAS CAUSED BY/FOLLOWING BLOOD LOSS
1./Anemia following acute (recent) blood loss:
Cause:
sudden and severe blood loss
Signs:
Signs caused by hypoxia and hypovolemia:
weakness, fatigue, sweating, thirst, pallor, dyspnea,
coma and stupor
Tachycardia, hypotension and hyperventilation
Phases:
a./ Shortly after blood loss:
Hypovolemia causes catecholamine release
and thus cause
RBC mobilization form storages, thus RBC
count remains normal
b./ In some hours (approx. 3 hours):
Hypovolemia cause: RAAS activation and
ADH release
Htk decreases
Normocytic-normochromic anemia develops
c./ In 1 day:
Hypoxia  erythropoietin (EPO) synthesis
EPO cause
increased RBC formation
increased reticulocyte count
Total normalization of RBC count and Hgb level
requires 6-8 weeks
Rate of regenartion depends on:
severity of bleeding/hemorrhage and
amount of stored iron
2./ Anemia following chronic (persistent) blood loss:
Cause:
occult (slight, unnoticed but long lasting) hemorrhages:
in gastrointestinal system: ulcer, tu, hemorrhoids and salycilate
urogenital system:
menstruation
hemorrhages:
telangiectasis,
thrombocyte count and functional disorder
Signs:
Signs of iron deficiency anemia
D./ ABNORMAL DISTRIBUTION OF BLOOD
Cause:
hypersplenia syndrome
portal hypertension
myeloproliferative diseases
storage disorders
infectious diseases
Pathomechanism:
Increased RBC storage in enlarged spleen
Signs:
Pancytopenia, or only one cell line is affectd
Hyperplastic bone marrow
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Mezei_RBC_2017
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