blood2 - Study Windsor

Report
BLOOD 2
RED BLOOD CELLS
JAUNDICE
ANEMIA & POLYCYTHEMIA
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CONTENT
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RED BLOOD CELLS (RBC) COUNT, FUNCTIONS, STRUCTURE
HEMOGLOBIN (Hb): CHEMISTRY, REACTIONS, FUNCTIONS, CONCENTRATION
ERYTHROPOIESIS, CONTROL OF ERYTHROPOIESIS
DESTRUCTION OF RBC, METABOLISM OF Hb AND IRON. HEMOSIDEROSIS
JAUNDICE
ERYTHROCYTE SEDIMENTATION RATE
TYPES OF ANEMIA, SICKLE CELL DISEASE
POLYCYTHEMIA
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OBJECTIVES
Describe the functional consequence of the lack of a nucleus, ribosomes, and mitochondria for a)
protein synthesis and b) energy production within the red blood cell.
Relate the three red blood cell concentration estimates, red blood cell count, hematocrit, and
hemoglobin concentration.
Know the importance of MCV and be able to calculate the mean corpuscular volume.
Describe the structure of hemoglobin (Hb). Describe the differences between the major normal types
of Hb (adult A and A2, glucosilated, fetal). Predict the changes in Hb types present in blood when
synthesis of beta chains of globin is deficient. Describe the abnormal types of Hb (Hb S, thalassemias).
Describe the normal and abnormal Hb reactions (oxyHb, MetHb, carboxyHb). Calculate the mean
corpuscular Hb concentration and the mean corpuscular Hb.
Identify the site of erythropoietin production, the adequate stimulus for erythropoietin release, and
the target tissue for erythropoietin action. Describe the role of vitamin B12 & folic acid, and various
hormones in regulation of RBC formation. Describe the dietary requirements for RBC production.
Relate the rate of red blood cell production and the percentage of immature reticulocytes in the blood.
Describe the metabolism of iron in the body.
Describe the metabolism of Hb (pre-hepatic, hepatic, post-hepatic).
Describe the three types of jaundice (pre-hepatic, hepatic and post-hepatic). Compare and contrast the
laboratory findings and urine/stool color in the three types of jaundice.
Describe physiological jaundice of the newborn.
Discuss the normal balance of red blood cell synthesis and destruction, including how imbalances in
each lead to anemia or polycythemia. Compare and contrast the main types of anemia (nutritional,
hemolytic, aplastic, hemorrhagic). Be able to describe different types of anemia in terms of MCV and
MCHC. Describe the main effects of anemia and polycythemia on body functions.
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RBC: Functions
• Transport of O2 from the lungs to the tissues and CO2 in the opposite
direction
– Hemoglobin
– Carbonic anhydrase
• Catalyses the reaction H2O + CO2 ↔ H2CO3
• Maintenance of pH homeostasis (globin, phosphate and bicarbonate
buffers)-hemoglobin in the cells is an excellent acid-base buffer
• Contribution to the blood viscosity
• ↓ blood oncotic P (by keeping Hb-protein inside the cells)
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RBC COUNT
• Normal values
– Adult males: 4 600 000 – 6 200 000/mm3 (5.4million/mL)
– Adult females: 4 200 000 – 5 400 000/mm3 (4.8million/mL)
• Abnormally high count – polycythemia
• Abnormally low count – anemia
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STRUCTURE OF THE MATURE RBC
Small size
Excess of the plasma
membrane & specific shape
High surfaceto-volume
ratio
Deformation of the cells
without stretching the
plasma membrane
Rapid diffusion
of respiratory
gases to and
from the cell
Easy passage
through the small
capillaries
RBC - biconcave discs with
central depression on each side
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Red Blood Cells
Figure 16-5
STRUCTURE OF THE MATURE RBC (cont.)
• Membrane contains special proteins and polysaccharides that differ from
person to person – blood groups
• Lack of the nucleus and organelles
– Cannot undergo mitosis
– Generate ATP anaerobically → do not use oxygen they transport
– Can not synthesize new cellular components to replace damaged ones
Life span - 120 days
• Contain a red pigment, hemoglobin (red color of the blood)
– Occupies 1/3 of cellular volume
– 280 million Hb molecules/RBC
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MEAN CORPUSCULAR VOLUME
• Mean volume of a RBC
MCV: 82-99 fL
• Values
– Normal range 82 – 99 femtolitre (fL)
– Low volume in microcytic anemia
– High volume in macrocytic anemia
• Calculation of the MCV
Hematocrit x 10
RBC count (in millions/mL blood)
fL= 10-15 L
• Sample calculation: Htc = 40, RBC count = 5 (x 106/mL)
MCV = (40 x 10)/5 = 80 fl
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RBC Morphology
In a normal individual RBCs show
minimal anisocytosis(Excessive
variation in
the size of cells )and
poikilocytosis(irregularly shaped
erythrocytes).
Larger than average RBCs are
macrocytic (left), while those
smaller than average are
microcytic (right).
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Pale cells (central pallor >1/3 dia)
are referred to as hypochromic
(right), while cells without central
pallor are called hyperchromic
(left).
Normal peripheral blood RBCs
are normochromic
normocytic.
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HEMOGLOBIN: Chemistry
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Protein – globin
– 4 polypeptide chains
Adult Hb – HbA, Hbα2β2
• Normal adult Hb – HbA,
Hbα2β2
– A pair of α chains (141 AA)
– A pair of β chains (146 AA)
• Adult Hb – HbA2 (2.5% of Hb),
Hbα2δ2
– β chains are replaced by δ chains
• Fetal Hb – HbF, Hbα2γ2
– β chains are replaced by γ chains
(146 AA)
• Adult Hb glucosilated – HbAIc
– Has a glucose attached to each β
chain
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Nonprotein pigment bound to each of the 4
chains – hem
– Each hem ring has 1 iron ion (Fe2+) that
can combine reversibly to 1 O2 molecule
– Each Hb molecule can bind 4 O2
molecules
Hb A
2α
2β
HbA2
2α
2δ
HbF
2α
2γ
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SICKLE CELL DISEASE
Inherited disease
High prevalence in the
malaria belt
Mutation causes formation
of HbS instead of HbA
– HbS precipitates into
long crystals when
oxygen tension is low
(hypoxia) → cell
elongation (sickling) and
damage to the cell
membrane → hemolysis
→ hypoxia (vicious
cycle)
 Rigid sickled RBCs
occlude the
microvasculature
leading to vasoocclusive crisis.
HbS – HbαA2βS2
Negatively charged glutamate is substituted for
nonpolar valine at position 6 in the β chain)
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HEMOGLOBIN: Reactions
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Oxyhemoglobin: Hb + 4 O2 (O2 attaches to Fe2+ in hem)
– Is produced in the lungs (oxygen loading)
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Reduced Hb (deoxyHb)
– Is produced in tissue capillaries after dissociation of O2 (oxygen unloading)
– Combines with H+ - acts as a buffer
– Combines with CO2 → Carbaminohemoglobin: Hb + CO2 (CO2 binds to globin, not to
hem)
OxyHb
O2
carrying
function
Buffering
function
CO2
carrying
function
COOH/COO-
NH-COONH2/NH3+
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HEMOGLOBIN: Reactions (cont.)
•
Methemoglobin (MetHb):
– Hb iron is oxidized from the ferrous (Fe2+) to the ferric state (Fe3+)
– Is incapable of carrying O2 and has a bluish color → cyanosis
– Limited amount of metHb can be converted back to Hb by methemoglobin
reductase present in the RBCs
– In normal state, 1.5% of Hb is in MetHb state
– Methemoglobinemia: Met-Hb > 1.5% (results from oxidation by nitrates,
drugs like phenacetin or sulfonamides and congenital deficiency of
methemoglobin reductase).
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Carboxyhemoglobin: Hb + CO(carbon monoxide) → cherry-red color of the skin
and mucous membranes
– CO has 200-250 times the affinity to Hb as does O2 → HbCO is a very stable
molecule
– CO ↓ the functional Hb concentration
• HbCO is unavailable for O2 transport → CO
anemia
poisoning, acute onset
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HEMOGLOBIN: Concentrations
Mean corpuscular Hb concentration concentration of Hb per unit packed cell
volume
Concentration per
unit volume of whole
blood
Hb
concentration
= Hb amount
(g)/Volume of
whole blood
(dL, L)
Males –
16.0±2.0 g/dL
Females –
14.0±2.0 g/dL
MCHC = Hb amount / Volume of packed RBC
Plasma
Calculation:
MCHC = Hb concentration x 100
Htc
Sample calculation:
[Hb] = 14.5 g/dL, Htc = 45 mL/dL
MCHC = (14.5/45) x 100 = 32.2 g/dL packed
cells
RBC
Normal range:
31-37 g/dL packed cells
↓ value – hypochromia (i.e., Hb deficiency)
↑ value – hyperchromia (i.e., spherocytosis)
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Hb CONCENTRATION: Mean corpuscular Hb (MCH)
• Is the total Hb content of a RBC
• Values
– Normal range – 27-31 pg
– ↓ value – hypochromia (i.e., iron deficiency anemia)
– ↑ value – hyperchromia (i.e., vit B12 deficiency)
MCH
• Calculation
MCH = Hb in grams/100 mL blood x 10
RBC count in million/L blood
• Sample calculation: [Hb] = 12 g/dL, RBC count = 4 x 106/mL
MCH = 12/4 x 10 = 30 pg
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RBC CHARACTERISTICS: SUMMARY
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Erythropoiesis
• Concept: The
production of new
red blood cells to
replace the old and
died ones
• In the adult, all the
red cells are
produced in bone
marrow
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Erythropoiesis- Pluripotent stem cells
 in the bone marrow
 can produce any type of
blood cells.
 is capable of both selfreplication and
differentiation to
committed precursor
cells that can produce
only a specific cell line.
CFU:colonyforming unit
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Erythropoiesis-CPU-E
 the committed red cell precursor undergoes several
divisions.
 The daughter cells becomes progressively smaller,
 the cytoplasm changes color from blue to pink as
hemoglobin is synthesized,
 the nucleus becomes small and dense and then extruded.
Early Intermediate Late
Proerythroblast
Polychromatophilic
Reticulocyte
(Pronormoblast)
Normoblast
Basophilic
Orthochromatophilic Erythrocyte
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Erythropoiesis-CPU-E
 The resulting non-nucleated cells is termed a
reticulocyte since it still contains RNA.
 Within a few days of entering the circulation, the
reticulocytes lose their RNA and becomes mature red
cells
Early
Intermediate Late
Proerythroblast
Polychromatophilic
Reticulocyte
(Pronormoblast)
Normoblast
Basophilic
Orthochromatophilic Erythrocyte
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Normoblast
Normoblast
Regulation of Erythropoiesis
 A. Erythropoietin,
 a glycoprotein released predominantly from the
kidneys in response to tissue hypoxia.
 also produced by reticuloendothelial system of
the liver and spleen.
 Effect:
 a, Stimulates the proliferation and differentiation of
the committed red cell precursor
 b, Accelerates hemoglobin synthesis
 c, Shortens the period of red cell development in the
bone marrow.
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CONTROL OF ERYTHROPOIESIS: Hypoxia
Hypoxia stimulates
production of EPO by
the kidneys - the
tubular epithelial
cells and
juxtaglomerular cells
(90% of EPO) & the
liver
Tissue
oxygenation is the
most powerful
regulator of the
RBC production
(but not the RBC
count in the blood)
↑
↑
↓
Biological
effects of EPO:
1. ↑ production
of
proerythroblasts
from
hematopoietic
stem cells
2. ↑ speed of
erythropoietic
stages
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ERYTHROPOIESIS
Morpho-functional changes (proerythroblast → RBC)
Appearance of Hb
Some Hb is present in
the early erythroblasts
Late erythroblasts are
saturated with Hb
Degeneration of the nucleus
Starts in the late erythroblast
stage
Disappeared by the
reticulocyte stage
Degeneration
of the cell
organelles
Progressi
ve ↓ in the
cell size
Reticulocytes enter the blood and within 1-2 days develop into mature RBC.
Only mature RBC and reticulocytes are present in the blood
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RETICULOCYTES & ERYTHROPOIESIS RATE
• Normal reticulocytes count in the blood
– 1-4% of the circulating RBC in adults
– 2-6% in newborns
• ↑ reticulocytes count – indicator of rapid RBC
production (i.e., hypoxia, hemorrhage, stress,
effective therapy of anemia)
• ↓ reticulocytes count - ↓ erythropoiesis (↓ EPO
production, ↓ ability of red bone marrow to respond
to EPO, nutritional anemia, etc.)
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CLINICAL FOCUS: BLOOD DOPING AND EPO
• Beneficial effects of EPO
– ↑ RBC count and O2 carrying capacity of the blood → ↑ O2 delivery
to tissues, ↑ muscular performance, ↓ muscular fatigue
– Recombinant EPO (rhEPO) is used for treatment of anemias
associated with chronic renal failure, AIDS and cancer chemotherapy
• Dangers of excessive EPO
– Genetically engineered EPO (i.e., darbepoetin) has increased life time
– ↑ Htc → ↑ blood viscosity, ↑ peripheral resistance, ↑ blood
pressure, ↓ heart rate (secondary to increased blood pressure), ↑
blood clotting
– Genetically engineered EPO often cause production of antibodies
against natural EPO and destruction of the RBC
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CONTROL OF ERYTHROPOIESIS:
Vitamin B12 and folic acid
•
•
Are required for
maturation of the RBC
– ↑ Synthesis of DNA
(synthesis of
thymidine
triphosphate – DNA
building block) →
rapid proliferation of
the erythroblastic
cells
Vitamin B12
(cyanocobolamin)
– Is required for action
of folic acid on
erythropoiesis
Dietary B12
Parietal/oxyntic cells of gastric
mucosa produce intrinsic factor (IF)
B12+IF
B12 binds with the IF –
protection from digestion by GIT
secretions
Complex of Vit B12 +IF complex
binds to the mucosal receptors in
the ileum → transport across
mucosa
Release of B12 into the portal
blood freed of IF
Binding to the plasma globulins
(transcobolamin I, II and III) → red bone
marrow or storage in the liver (very large
quantities – 3-4 years reserve)
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CONTROL OF ERYTHROPOIESIS:
Other factors
• Testosterone
– Stimulates the release of EPO
• Adrenal cortical steroids and ACTH
– In physiological concentrations stimulate EPO production
– Large doses are inhibitory
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DESTRUCTION OF THE RBC
• Sites of destruction
– Circulating blood (10% of senescent RBCs)
– Macrophage system (spleen and liver)
• Senescent RBC
– ↓ metabolic rate → ↑ fragility → rupture of the membrane when
RBC pass through tight spots of the circulation (i.e., red pulp of the
spleen)
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METABOLISM OF Hb
• Prehepatic
– Takes places in the macrophages
– Results in formation of bilirubin – a bile pigment
• Hepatic
– Takes place in the liver (hepatocytes)
– Conjugation of bilirubin with glucuronic acid – bilirubin mono- or biglucuronide and secretion of conjugated bilirubin into the bile
• Posthepatic
– Takes place in the GI and kidneys
– Formation of urobilinogen and stercobilinogen and excretion
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PREHEPATIC METABOLISM OF Hb
RBC or remnant
Cell remnants
Hemoglobin
Macrophages
Hem
Conversion of
the hem
pigment into
the bile pigment
biliverdin + CO
→ bilirubin →
blood plasma
Pigment
CO
Globin
Fe++
Biliverdin
Bilirubin
Exhaled
In the plasma water
insoluble bilirubin
combines with
albumin to form
water soluble
complex → liver
Removal of the
globin from Hb
in macrophages
→ protein pool
of the body
Blood
Albumin
Bilirubin-albumin
Liver
Fe++ pool
Protein pool
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HEPATIC & POSTHEPATIC METABOLISM OF BILIRUBIN
•
•
In the liver
– Replacement of albumin with
glucuronic acid – bilirubin
mono- or bi-glucuronide (water
soluble)
– Excretion of conjugated
bilirubin into the small intestine
via the bile
In the small intestine
– Conversion of bilirubin to
urobilinogen by the intestinal
bacteria
• Conversion to
stercobilinogen →
oxidation and excretion in
the feces as stercobilin
• Absorption from the small
intestine & either reexcretion by the liver or
oxidation & excretion by
the kidneys as urobilin.
Transport of bilirubin from plasma into
the hepatocytes
Liver
Glucuronic
acid
Albumin
Bilirubin-glucuronide
Urobilinogen (in the small
intestine)
Reabsorption
Re-excretion in
bile
Stercobilinogen
Excretion as
urobilin in
urine
Excretion as
stercobilin in feces
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BILIRUBIN: Concentration in plasma
Bilirubin
Concentration in plasma,
mg/dL
Free bilirubin = unconjugated
bilirubin
0.1 – 1
Conjugated bilirubin
0 – 0.3
Total bilirubin
0.3 – 1.2
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JAUNDICE
Refers to the yellow color of the skin, conjunctivae and mucous
membranes caused by the presence of excessive bilirubin in the plasma
and body fluids (jaune (French) = yellow)
Blood bilirubin level must exceed three
times the normal values, for the
coloration to be easy visible
Types of jaundice:
Pre-hepatic – the pathology occurs prior to the liver
Hepatic – the pathology is located in the liver
Post-hepatic – the pathology occurs after the conjugation of bilirubin in the
liver
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PRE-HEPATIC JAUNDICE
Excessive hemolysis of the RBCs – hemolytic jaundice
 bilirubin
production
↑ unconjugated (indirect)
bilirubin
Normal conjugated (direct)
bilirubin
 urobilinogen formation
  urobilinogen → dark
urine
N
Capacity of the liver to
conjugate bilirubin is exceeded
(saturation of enzyme
glucuronyl transferase)
↑ stercobilinogen
→ dark feces
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HEPATIC JAUNDICE
Results from infective or toxic damage to the liver cells (hepatocellular damage)
Uptake, conjugation
and/or excretion of
bilirubin is affected
↑ urobilinogen in blood
(↓ enterohepatic
circulation and hepatic
extraction of blood
urobilinogen by
damaged hepatocytes)
↑ unconjugated bilirubin
Normal/decreased
conjugated bilirubin
↑ urobilinogen
filtration and excretion
in urine
Dark urine
Pale/N stool
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POSTHEPATIC JAUNDICE
Results from obstruction of the bile ducts by stones, tumors, etc.
Functioning of the hepatic
cells is normal
Normal unconjugated
bilirubin
N
 plasma level of
conjugated bilirubin due
to the bile entry into the
blood from ruptured
congested canaliculi and
↑ total bilirubin
 urobilinogen formation
Conjugated bilirubin
in urine (kidney can
excrete small
quantities of highly
soluble conjugated
bilirubin) → dark urine
↓ or absent
urobilin in urine
↓ stercobilin content
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in feces → pale feces
PHYSIOLOGICAL JAUNDICE OF THE NEWBORN
Hemolysis of the excess RBC when
the infant is suddenly exposed to a
high oxygen environment and
hence does not need so many RBC
as in the uterus
Immaturity of the liver (inability to
conjugate significant quantities of
bilirubin with glucuronic acid for
excretion into the bile) to handle the
excess bilirubin (especially in
premature babies)
↑ plasma total bilirubin concentration (less than 1 mg/dL → 5 mg/dL)
Mild jaundice (yellowness) of the infant’s skin and the sclerae for 1-2
weeks
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IRON METABOLISM
1.
2.
3.
4.
Dissociation of Fe from the hem
→ plasma → binding to
transferrin, transport in the
blood →
2
Detachment from transferrin &
storage in the liver, muscle cells
& macrophages attached to
ferritin or hemosiderin →
Release from the storage sites,
transport in the blood by
transferrin
Transport into the RBC precursor
cells by receptor mediated
endocytosis → Hem synthesis
1
3
4
↓ quantities of transferrin → ↓ Hb content in
the RBC – hypochromic anemia
Synthesis of transferrin increases with iron
deficiency but decreases with any type of
chronic disease.
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FORMS OF IRON IN THE BODY
• Recommended daily intake - 15 – 18 mg (250-330 μmol)
• Minimal absorption to balance iron loss
– Adult males - 35 μmol
– Adult females - 175 μmol
• Distribution of body iron in an average man
– Hb, 2100 mg
– Ferritin - water soluble protein-iron complex , 700 mg (in the liver,
spleen, marrow and plasma)
– Hemosiderin - water insoluble complex (macrophages of the liver
and bone marrow), 300 mg
– Myoglobin - local oxygen reserve, 200 mg
– Tissue (heme and nonheme) enzymes, 150 mg
– Transport-iron compartment in plasma (transferrin), 3 mg.
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HEMOCHROMATOSIS
•
Reasons
– Primary - one of the most common autosomal recessive genetic disorders characterized
by excessive absorption of dietary iron resulting in a pathological increase in total
body iron stores
• Failure to reduce iron reabsorption in response to increased iron level in the body
– Secondary – is not genetic (results from anemia, alcoholism, transfusion iron overload –
hemosiderosis, etc.)
•
Consequences
– Deposition of iron in the body tissues (liver, heart, pancreas, pituitary, joints, and skin)
initially as ferritin and than as hemosiderin
– Toxic action on organs and damage of cells due to action as a pro-oxidant (↑ formation
of free radical formation, i.e., the hydroxyl radical and the superoxide radical) → DNA
cleavage, impaired protein synthesis, and impairment of cell integrity and cell
proliferation, leading to cell injury and fibrosis.
• Cirrhosis, hyperpigmentation of skin, diabetes mellitus, impotence, joint diseases,
etc.
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ERYTHROCYTE SEDIMENTATION RATE (ESR)
•
•
•
Specific weight of the RBC is higher than that of the
plasma  in a stabilized blood, RBC slowly sink towards
the bottom of the test tube -sedimentation
Factors increasing ESR
– ↓ Htc, ↓ blood viscosity
– ↑ concentration of fibrinogen (i.e., pregnancy,
vascular diseases, heart diseases), haptoglobulin,
lipoproteins, immunoglobulins
– Macrocytic RBC
– Extreme elevation of WBC count (leukemia)
Factors decreasing ESR
– ↑ Htc
– Change in the RBC shape (i.e., sickle-cell anemia,
poikilocytosis – nonuniformity of shape)
– ↑ albumin concentration
Males – 3-6 mm/h
Females – 8-10 mm/h
ESR
Clumps of RBCs
43
ANEMIA
•
Deficiency of blood Hb due to
– ↓ RBC count (too rapid loss or/and too slow production)
– ↓ Hb quantity in the RBC
WHO's Hemoglobin thresholds used to define anemia (1 g/dL = 0.6206 mmol/L)
Age or gender group
Hb threshold
(g/dl)
Hb threshold
(mmol/l)
Children (0.5-5.0 yrs)
11,0
6,8
Children (5-12 yrs)
11,5
7,1
Children (12-15 yrs)
12,0
7,4
Women, nonpregnant (>15yrs)
12,0
7,4
Women, pregnant
11,0
6,8
Men (>15yrs)
13,0
8,1
44
ANEMIA: CONSEQUENCES
• ↓ oxygen-carrying capacity
of the blood → hypoxia →
vasodilation
• ↑ in pulse and respiratory
rates (effort to supply
sufficient oxygen to tissues)
• ↓ exercise & cold
tolerance
• Pale skin (↓ red colored
oxyHb)
• ↑ fatigue and lassitude
• ↓ blood viscosity → ↓
peripheral vascular
resistance → ↑ blood flow,
venous return, cardiac
output and work load on
the heart
45
ANEMIAS: Classifications
Classification
according to
etiological
ground
•
•
•
•
Nutritional
Aplastic
Hemorrhagic
Hemolytic
Anemia: classification according to MCV
Macrocytic anemia Normocytic anemia
(MCV>100)
(80<MCV<100)
Deficiency of vit
B12, folic acid,
or IF.
Hypothyroidism.
Alcoholism. Liver
diseases. Drugs
that inhibit DNA
replication (i.e.,
methotrexate,
zidovudine)
Acute blood
loss, chronic
diseases, bone
marrow failure,
hemolysis
Microcytic anemia
(MCV<80)
Hem synthesis
defect (i.e., iron
deficiency, chronic
diseases)
Globin synthesis
defect (i.e.,
thalassemia)
Sideroblastic defect
46
ANEMIA: Nutritional
Iron deficiency
• Is the most common type
• Reasons
– Premenopousal women: Blood loss during menses (20% of all women
of childbearing age have iron deficiency anemia, compared with only 2%
of adult men)
– Males and postmenopausal females: Excessive iron loss due to chronic
occult bleeding (peptic ulcer, tumor, etc.)
– Increased iron demands (i.e., pregnancy and lactation)
– Inadequate iron intake or absorption (i.e., vit. C deficiency)
– Parasitic infestation (hookworm, amebiasis, schistosomiasis)
– Chronic intravascular hemolysis (if the amount of iron released during
hemolysis exceeds the plasma iron-binding capacity)
47
IRON DEFICIENCY ANEMIA: CONSEQUENCES
• Low serum ferritin (serum iron) level
– Plasma ferritin concentration is an excellent indicator of the iron
stored in the body, because of a dynamic balance between intraand extracellular ferritin iron
• ↓ bone marrow iron stores (ferritin and hemosiderin)
• ↓ saturation of transferrin
• ↓ RBC count & Htc
• RBC are small and look pale - microcytic
hypochromic anemia
• Abnormal fissuring of the angular (corner)
sections of
the lips (angular stomatitis).
• Abnormal craving to eat substances
(eg, ice, dirt,
paint).
48
DEFICIENCY OF IRON UTILIZATION: SIDEROBLASTIC
ANEMIA
• Inadequate marrow utilization of iron for
Hb synthesis despite the presence of
adequate or increased amounts of iron
• Reasons: Hereditary or acquired, including
lead and ethanol toxicity, pyridoxine
deficiency
• Deficient reticulocyte production,
intramedullary death of RBCs, and bone
marrow erythroid hyperplasia (and
dysplasia)
• Presence of polychromatophilic, stippled
RBCs (siderocytes)
• Hipochromic, microcytic RBCs, variations
in RBC size
Ring sideroblasts are erythroid
precursors whose mitochondria
(located around the nucleus) are
loaded with nonheme iron.
49
ANEMIA: Nutritional (cont.)
Deficiency of vitamin B12 and/or folic acid
•
•
Reasons
– Inadequate intake (a strict vegetarian diet excluding all meat, fish, dairy products, and eggs;
chronic alcoholism)
– Inadequate GI absorption
• Lack of IF - pernicious anemia
– Autoimmune destruction of parietal cells (atrophic gastric mucosa) or AB against IF
– Removal of the functional portion of the stomach, such as during gastric bypass
surgery
• Crohn's disease intestinal malabsorption disorders
• Resection (or inflammation) of the ileum (site of B12 reabsorption)
Consequences
– Maturation failure
• Failure of DNA synthesis with preserved RNA synthesis,
which result in
restricted cell division of the progenitor cells.
• Production of large precursor cells – megaloblasts and
larger
irregular oval erythrocytes – macrocytes fully
saturated with Hb –
macrocytic (megaloblastic) anemia
• ↑ fragility of the plasma membrane → ↓ life span →
anemia
– Vitamin B12 deficiency only results in peripheral neuropathy
and spinal
cord degeneration
50
ANEMIA: Hemorrhagic
• Results from abnormal blood loss (mild or severe; acute or chronic)
– Replacement of lost fluid within 1 – 3 days (much faster than
the replacement of lost RBC) → dilution of the RBC
• Is normocytic
• Prolonged but mild loss of the blood causes microcytic
hypochromic anemia (iron deficiency)
51
ANEMIA: Aplastic
• Results from suppression or destruction of the bone marrow (i.e.,
overexposure to ionizing radiation, adverse drug reaction, toxic
chemicals, severe infections)
• Is usually normocytic
• Panhypoplasia of the marrow is associated with leukopenia and
thrombocytopenia
52
ANEMIA: Hemolytic
•
Is caused by an abnormally high rate of the RBCs destruction
(hemolysis) due to:
– Structural abnormalities of the RBC (more fragile cells)
• Hereditary spherocytosis – cells are spherical and can
not be compressed
• Sickle cell anemia – cells have sickle shape →
hemolysis
– Bacterial toxins, parasitic infections (i.e., malaria)
– Adverse drug reactions
– Autoimmune reactions
• The bone marrow is unable to compensate for premature
destruction of RBC by increasing their production.
Thalassemias (α, β)
• Hereditary hemolytic anemia
• Abnormal or nonfunctional genes → globin chains are normal in
structure but are produced in reduced amounts
• Cells are microcytic and hypochromic
Spherocytosis
53
ANEMIA OF CHRONIC DISEASE
• Occurs as part of a chronic disorder (i.e., infection, inflammatory disease,
or cancer)
• Pathophysiologic mechanisms
– Shortened RBC survival
– ↓ EPO production and marrow responsiveness to EPO
– Impaired intracellular iron metabolism
• Is microcytic or marginal normocytic
54
POLYCYTHEMIA
•
↑ RBC count, Htc and Hb concentration
•
Reasons
– Hypoxic erythropoietic drive (i.e., high altitudes, chronic
pulmonary or cardiac disease)
– Hemoconcentration - dehydration (i.e., heavy sweating,
vomiting or diarrhea)
– Polycythemia vera or erythremia – uncontrolled RBC
production (i.e., neoplastic disease condition of
hemocytoblastic cells)
•
Results in
– ↑ blood viscosity
– ↑ peripheral resistance → ↓ venous return to the heart
– ↑ blood volume tends to ↑ venous return
– ↑ arterial BP
– Ruddy skin and mucosa membranes with cyanotic tint
(sluggish blood flow → ↑ blood deoxygenation in the skin
circulation)
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CLINICAL CASE
A 14-year-old girl complained of fatigue and loss of stamina. Her appetite was marginal,
as she was very conscious of maintaining her body weight at 96 pounds. Her monthly
menstrual flow was always heavy and long from its onset at twelve years of age.
Relevant laboratory findings included the following:
– Hematocrit (Hct) - 28%
– Hemoglobin (Hgb) - 9 g/dL
– Iron 16 µg/dL
– Bone marrow iron - absent
– Erythrocytes - small and pale
Suggested treatment included ferrous sulfate or ferrous gluconate for six months orally
between meals, since food may reduce absorption. A well-balanced diet was also
suggested, as well as a gynecological examination.
Questions.
1. What is the primary disorder of this individual?
2. What does the ferrous sulfate or ferrous gluconate provide? Why is it necessary?
3. What dietary inclusions would you suggest?
4. Why is the gynecological examination important?
5. Why is bone marrow iron an important clinical indicator in this individual?
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PAST EXAMS QUESTION
A 51-year old male complains of generalized weakness and weight loss
over the past 6 months. His blood pressure and pulse rate are
elevated. Laboratory values revealed a hematocrit of 35% and
hemoglobin level of 10.9 g/dL. A blood smear shows hypochromic and
microcytic cells. A stool test for occult blood is positive. Which of the
following would be the most likely cause of the findings?
a. Acute blood loss
b. Iron deficiency
c. Spherocytosis
d. Folic acid deficiency
e. Autoimmune reactions
B.
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