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‫תאי מח עצם יצירה והתמיינות‬

F
CFU- G-CS
Granulocytes
GM
IL-3, GM-CSF, SCF
IL-6
M-CSF
Monocytes
CFU-MEG
SCF TPO
CFU- IL-3, GM-
GEMM CSF Platelets
BFU-E CFU-E
Epo EPO
SCF Erythropoietin

IL-3 Erythrocyte
Pluripotent
CFU-Eo s
Stem Cell
IL-3, GM-
Lymphoid CSF
Progenitor
Eosinophils
Lymphopoiesis
BONE MARROW BIOPSY
BONE MARROW ASPIRATE
Major steps of erythropoiesis and
erythropoietin dependence
Hematopoietic stem cell

†BFU-E

‡CFU-E Erythropoietin
dependence

Erythroblasts

Reticulocytes
† BFU-
BFU-E = burst-
burst-forming unit–
unit–erythroid; ‡ CFU-
CFU-E = colony-
colony-forming unit–
unit–erythroid
Bron, Seville 2000
Physiology of Erythropoietin

Recombinant
erythropoietin
‫הבשלת אריטרוציטים מתבצעת בלשד העצם עד שלב הרטיקולוציט‪.‬‬

‫יום ‪.‬‬ ‫אורך חיי הכדורית בדם היקפי ‪120‬‬


ERYTHROPOIETIN

carbohydrate

protein

protein + carbohydrate = glycoprotein


Amino Acid Sequence *
of Erythropoietin
1 10 20
30
S S
S 160
S
40

150 60
140
50
130 70
80

90 N-linked (3)
120 glycosylation
100 O-linked (1)
110 glycosylation

Amino acid
Erslev (1991); Mulcahy (2001)
*
Erythropoietin
• 165 - amino acid Glycoprotein hormone of 34 kDa.

• Produced in kidney and liver; trace amounts in brain

• Promotes survival,proliferation and differentiation of


erythroid progenitors.

Lacombe (1998, 1999); Krantz (1991); Bernaudin (2000)


Erythropoietin Receptor
Activation

Erythropoietin Bivalent Disulfide Erythropoietin mimetic


antibody bond peptides
Mulcahy (2001)
Normal Erythropoiesis

Iron Erythroid Erythropoietin


marrow

RE
cells

Red blood cells O2 delivery

RE = reticuloendothelial
Hillman (1998)
The physiological role of
erythropoietin in the healthy adult
Decreased oxygen delivery to the kidneys

Peritubular interstitial cells detect


low oxygen levels in the blood

Pro-erythroblasts in red
bone marrow mature more
Peritubular interstitial cells quickly into reticulocytes
secrete erythropoietin (EPO)
EPO into the blood

More reticulocytes
enter circulating blood
Increased oxygen delivery to tissues
Larger number of red blood cells (RBC)
Return to homeostasis when response brings in circulation
oxygen delivery to kidneys back to normal
Biological effects of EPO

Erythropoiesis
• Controls RBC production
• Promotes survival, proliferation, and
differentiation of erythroid progenitors
• Exerts effects on late erythroid
progenitors

Mulcahy, Seville 2000


Erythroid marrow function
BFU-E sTfR
CFU-E ETU
(progenitors) (total erythropoiesis) SeFe Ferritin
Tf satur (iron stores)
(marrow iron supply)
Erythroid RES
marrow (macrophages)

Reticulocyte index
(effective erythropoiesis)

Hypochromic RBC
(functional iron deficiency)

Hb – Hct - RBC
Normal values

Men Woman

Hematocrit (%) 47 ± 7 42 ± 5

Hemoglobin (gm %) 16 ± 2 14 ± 2

Red cell count (106/µl) 5.4 ± 0.8 4.8 ± 0.6


Normal hemoglobin in adult blood

HbA HbF HbA2

Structure α2β2 α2γ2 α2δ2

Normal (%) 96-98 0.5-0.8 1.5-3.2


GENE CLUSTER & HB SWITCH
Normal Values
• MCV = hematocrit x 10
= 90 ± 8µ3
red cell count x 106

• MCH = hemoglobin x 10
= 30 ± 4µg
red cell count x 106

• MCHC = MCH hgb.


= 33 ± 2gr/100ml
MCV hct (red cells)
Normal adult red cell values
Male Female
Hemoglobin (g/dl) 13.5-17.5 11.5-15.5

Hematocrit (PCV) (%) 40-52 36-48

Red cell count (x1012+/l) 4.5-6.5 3.9-5.6

Mean cell hemoglobin (pg) 27-34

Mean cell volume (fl) 80-95

Mean cell hemoglobin 30-35


concentration (g/dl)
Reticulocyte count (x109/l) 25-125
Anemia
• Definition : Decreased RBC mass and HB
concentration
• Anemia is a result of imbalance between
between RBC production and destruction
• Hypo-regenerative anemia is due to
decreased RBC production secondary to
Defining Anemia
Hb level (g/dL)

National Cancer World Health


Grade Institute (NCI) Organization (WHO)
0 Normal limits* >11
1 10–normal 9.5–10.9
2 8–10 8–9.4
3 6.5–7.9 6.5–7.9
4 <6.5 <6.5

*14–18 g/dL for men and 12–16 g/dL for women


Groopman (1999)
Mechanisms of Anemia

Production Disorders:
◗ Factor Deficiency (RBC Size)
-Iron, Vit. B12, Folate
◗ Hematopoietic Cell Damage
Survival Disorders:
◗ Blood Loss
◗ Red Blood Cell Destruction (Shape)
-Hemolytic Anemias
Signs and symptoms of anaemia

Immune system
CNS
 Impaired T cell and
 Debilitating fatigue
macrophage function
 Dizziness, vertigo
 Depression Cardiorespiratory system
 Exertional dyspnoea
 Impaired cognitive function
 Tachycardia, palpitations
 Cardiac enlargement, hypertrophy
Gastro-intestinal system  Increased pulse pressure,
 Anorexia systolic ejection murmur
 Nausea  Risk of life-threatening cardiac
failure

Vascular system
 Low skin temperature Genital tract
 Menstrual problems
 Pallor of skin, mucous
 Loss of libido
membranes and conjunctivae

Adapted from Ludwig H, Fritz E. Semin Oncol 1998;25(Suppl. 7):2–6


Iron deficiency anemia

The most common cause of anemia


worldwide

Pathogenesis : Imbalance between


iron body requirement and reduced
iron supply/increased lost
Microcytic Hypochromic
Anemia
Characterized by reduced RBC indices :
MCV, MCH , MCHC
Peripheral blood smear : small (microcytic)
and pale (hypochromic) RBC
Differential Diagnosis :
Iron deficiency
Thalassaemia
Sideroblastic
anemia Anemia
of Chronic disease
Iron stores and transport
• Ferritin : main iron storage protein in the
RES. Consists of 22 units of apoferritin
and iron core. Each subunit binds ≈ 4500
atoms of iron
• Hemosiderin : Insoluble iron- protein
complex derived from ferritin
• Transferin : Main iron transport protein in
the blood. Normally 1/3 of iron binding
sites are saturated
Iron absorption

• Average western diet contains 10–15 mg


iron/day.
• 5-10% of dietary iron normally absorbed
(1-1.5mg)
• Dietary iron is in the form of :
∗ organic iron (heam or protein bound).
∗ inorganic iron .
• Iron absorption occurs in the duodenum
PALLOR ‫חוורון‬
Glositis

Angular cheilosis

Koilonychia
(spoon nails)
Iron deficiency- clinical
features
Symptoms: Fatigue, weakness, palpitations,
shortness of breath, headaches, decreased
performance status ,aggravation of angina
pectoris

Rare symptoms: Dysphagia, PICA syndrome

Signs: pallor of mucous membranes,


tachycardia, orthostatic hypotension,
functional systolic murmur, glossitis,
angular stomatitis, koilonychia
Iron-Deficiency Anemia
Laboratory workup

• CBC: MCV fl = HCT/RBC X 10


Low HB
80-93fl
MCV < 80fl
• Peripheral blood smear:
microcytosis,hypochromia
• Body iron status:
Serum iron 50-150µg/dl
Transferrin 300-360 µg/dl
Ferritin 50-150 µg/dl M ,15-50 µ
g/dl F
Cause of iron deficiency
anemia
Iron deficient diet (elderly, institutionalized,
developing countries)
Increased iron demands ( pregnancy,growth)
Increased Iron loss (GIT, uterine)
Malabsorption (post gastrectomy, celiac )
Stages of iron deficiency:
Iron store depletion
Iron deficient
erythropoiesis
Iron deficiency anemia
Treatment of Iron
deficiency
• Treatment according to severity of anemia
and etiology.
• In adults : GIT workup mandatory.
• In case of iron loss → treat the cause.
• Oral iron: Ferrous sulfate 325mg x 1-3/d
for 3-6 month
• Parenteral treatment : for patients with
malabsorption / oral iron intolerance
Megaloblastic Anemia