Transcript Introduction to clinical medicine(ICM).

Introduction to clinical
medicine(ICM).
HEMATOLOGY AND BLOOD
DYSCRASIAS.
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 surface-tovolume 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.)
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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)
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
Males –
16.0±2.0 g/dL
Females –
14.0±2.0 g/dL
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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A 65-year-old previously well man presents to the clinic with
complaints of fatigue of 3-months' duration. Questioning reveals
diffuse weakness and feeling winded when walking uphill or climbing
more than one flight of stairs. All of the symptoms have slowly
worsened over time. There are no other complaints, and the review
of systems is otherwise negative. The patient has no significant
medical history, social history, or family history. On physical
examination, he appears somewhat pale, with normal vital signs. The
physical examination is unremarkable except for his rectal
examination, which reveals brown, guaiac-positive stool (suggests the
presence of blood in the stool). A blood test reveals anemia.
A. What is the most likely form of anemia in this man? What is the probable
underlying cause?
B. What is the mechanism by which this disorder results in anemia?
C. What might one expect to see in the peripheral blood smear?
D. What is the pathophysiologic mechanism of this patient's fatigue, weakness, and
shortness of breath? Why is he pale?
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
(Pronormoblast)
Polychromatophilic
Reticulocyte
Normoblast
Basophilic
Orthochromatophilic Erythrocyte 23
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
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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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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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CONTROL OF ERYTHROPOIESIS:
Vitamin B12 and folic acid
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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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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 easily 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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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 jaundice
– Takes places in the macrophages
– Results in formation of bilirubin – a bile pigment
• Hepatic jaundice
– 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 jaundice
– Takes place in the GI and kidneys
– Formation of urobilinogen and stercobilinogen and excretion
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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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PREHEPATIC METABOLISM OF Hb
RBC or remnant
Cell remnants
Hemoglobin
Hem
Conversion of the
hem pigment into
the bile pigment
biliverdin + CO →
bilirubin → blood
plasma
Globin
Pigment
CO
Macrophages
Fe++
Biliverdin
Removal of the
globin from Hb in
macrophages →
protein pool of
the body
Bilirubin
Exhaled
In the plasma water
insoluble bilirubin
combines with
albumin to form water
soluble complex →
liver
Blood
Albumin
Bilirubin-albumin
Liver
Fe++ pool
Protein pool
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HEPATIC & POSTHEPATIC METABOLISM OF BILIRUBIN
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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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HEPATIC JAUNDICE
Results from infective or toxic damage to the liver cells (hepatocellular damage)
Uptake, conjugation and/or
excretion of bilirubin is
affected
↑ unconjugated bilirubin
Normal/decreased
conjugated bilirubin
↑ urobilinogen in blood (↓
enterohepatic circulation
and hepatic extraction of
blood urobilinogen by
damaged hepatocytes)
↑ urobilinogen filtration
and excretion in urine
Dark urine
Pale/N stool
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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
↑ unconjugated bilirubin
Normal/decreased
conjugated bilirubin
↑ urobilinogen in blood (↓
enterohepatic circulation
and hepatic extraction of
blood urobilinogen by
damaged hepatocytes)
↑ 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
N
normal
Normal unconjugated
bilirubin
 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 in
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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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ANEMIA
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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
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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
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ANEMIAS: Classifications
Classification
according to
etiological
ground
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Nutritional
Aplastic
Hemorrhagic
Hemolytic
Anemia: classification according to MCV
Macrocytic anemia
(MCV>100)
Deficiency of vit
B12, folic acid, or
IF. Hypothyroidism.
Alcoholism. Liver
diseases. Drugs that
inhibit DNA
replication (i.e.,
methotrexate,
zidovudine)
Normocytic anemia
(80<MCV<100)
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
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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)
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A 4 –day-old infant weighing 7lb,6oz is brought to the
emergency room by his parents. The examining
emergency room physician notes that his skin and
sclera are icteric. A blood test indicates elevated
uncojugated bilirubin in the serum. The elevated
bilirubin levels in this patient are most likely the result
of which of the following?
(a)Deficiency of enzymes regulating bilirubin solubility
(b)Hepatocellular proliferation
(c)Decreased destruction of red blood cells
(d)Dilation of the common bile duct
(e)Increased hepatocyte uptake of bilirubin
Structure of bone marrow:
-stroma : is the support tissue
-parenchyma: hemopoietic tissue
Stroma:
1. Formed of reticular fibers and reticulocytes
2. Reticular cells have branching cytoplasm to form a meshwork
1 & 2 form a meshwork in the interstices of which are present blood forming
cells
3. Cells over the years become accumulated with lipid and become adipocytesbasis for the formation of yellow bone marrow
4. Also are found collagen fibers with matrix containing adhesion molecules like
laminin, fibronectin to bind the cells, growth factors etc.
Red bone marrow
Granulopoiesis:
A 6-year-old boy presents to the pediatric emergency department. His mother states
that he has had 3 days of general malaise and fevers to 38.5C. He has no other localizing
symptoms. Medical history is remarkable for multiple febrile illnesses. His mother says,
It seems like he gets sick every month.; Physical examination is notable for cervical
lymphadenopathy and oral ulcers. Blood tests reveal a neutrophil count of 200/μL. The
patient is admitted to the hospital. Blood, urine, and cerebrospinal fluid cultures are
negative, and over 48 hours, his neutrophil counts return to normal. He is then
discharged.
A. What is the likely pathogenesis of cyclic neutropenia? What evidence supports
this theory?
B. What aspects of this case presentation support the diagnosis of cyclic
neutropenia? What is the expected clinical course?
C. Assuming that the diagnosis of cyclic neutropenia is correct, what would one
expect the peripheral blood smear to look like? What would the bone marrow
examination results be at this second admission? What would they be in 2 weeks?
3 days – mitotic ; 4
days maturation
Is a buffer
system – 4
days
1- 4 days
CLINICAL ANATOMY:
-The appearance of large number of immature neutrophil (band cell) in the blood is called a
shift to the left and is clinically significant, usually indicating bacterial infection.
Changes in the no of neutrophils in the peripheral circulation must be evaluated by taken all
the compartments into consideration.
Thus neutrophilia, an increase in the no of neutrophils in the circulation ,does not necessarily
imply an increase in neutrophil production.
Intense muscular activity or the administration of epinephrine causes neutrophils in the
marginating compartment to move into the circulating compartment,causing an apparent
neutrophilia even though neutrophil production has not increased.
Neutrophilia may also result from liberation of greater numbers of neutrophils from the
medullary storage compartment, this type of neutrophilia is transitory and is followed by a
recovery period during which no neutrophils are released.
The neutrophila that occurs during the course of infection is due to an increase in production
of neutrophils at a shorter duration of these cells in the medullary storage compartment.
In such cases, immature forms such as band cells, neutrophil metamyelocyte, and even
myelocytes may appear in the blood stream. The neutrophilia that occurs during infection is
of longer duration than that which occurs as a result of intense muscular activity.