P.

07 ANEMIA o First morphologically recognizable erythroid

Dr. Buliyat | September 3, 2018 precursor in the bone marrow
o Undergoes 4 cell divisions  16- 32
Reticulocytes
OUTLINE
I. Define anemia
 Erythrocytes
II. Hematopoeisis and physiologic regulation of
o Replaced daily at a rate of 0.8-1% of all
erythropoiesis
circulating RBCs
III. Clinical manifestation of anemia
o Average life span: 100- 120 days
A. Acute anemia
B. Chronic or progressive anemia
ERYTHROPOIETIN (EPO)
IV. Approach to the patient with anemia
V. Treatment of anemia  primary regulatory hormone for erythropoiesis
A. Kinetic approach  Absence leads to the apoptosis of committed erythroid
B. Morphological approach precursor cells
VI. Classification of anemia o Produced and released by peritubular capillary
VII. Sample cases lining cells within the kidney
 Primary stimulus for production is the availability of O2
(oxygen tension) for tissue metabolic needs
I. DEFINITION OF ANEMIA
 WHO: Hemoglobin level <130g/L (13g/dL) in men and Hypoxia- inducible factor- 1α (HIF-1α)
<120g/L (12g/dL) in women  key to EPO gene regulation
 Reduction in hemoglobin, hematocrit concentration or RBC  HIF gene is normally suppressed in the blood since the
count blood is not normally hypoxic
 Generally, anemia is recognized in the laboratory when the
patient’s hemoglobin or hematocrit falls below the
expected value or normal range. The likelihood and
severity of anemia are defined based on the deviation of
the patient’s Hgb or Hct from values expected for age and
sex- matched normal subjects

II. HEMATOPOEISIS AND PHYSIOLOGIC REGULATION OF

ERYTHROPOIESIS
The process by which formed elements of blood are produced.
The process is regulated through a series of steps and the organ
responsible for this process is called the ERYTHRON.

ERYTHRON
 Dynamic organ responsible for red cell production
 Rapidly proliferating pool of marrow erythroid precursor
cells and a large mass of circulating RBCs
o Balance between production and destruction of
RBCs
HEMATOPOIETIC STEM CELLS
 Capable of producing red cells, all classes of
granulocytes, monocytes, platelets, and the cells of the
immune system
ERYTHROID CELL PRODUCTION
 Common erythroid/ megakaryocyte progenitor cells
o Needs the expression of GATA-1 and FOG-1
transcription factors
 GATA-1 and FOG-1 dictates transformation of progenitor
cells to become precursor cells.
 Without the transcription factor, the progenitor cells
undergo apoptosis.
 Pronormoblast:
This is an illustration of the physiologic regulation of
hematopoiesis. It begins with the level of Oxygen in the blood.
When there is impaired Oxygen delivery to the kidney due to
various reasons like decreased red cell mass or anemia;
hypoxemia maybe due to a lung disease or impaired Oxygen
loading of the hemoglobin (maybe an effect of cigarette
smoking); impaired hemodynamics maybe from heart failure or
rarely from impaired blood flow to the kidneys like that in renal
artery stenosis, there is a proportionate increase in the
production of EPO granted that the kidneys are functioning well.
EPO then stimulate the bone marrow to increase its production of
red cells granted that there is sufficient stores of substrates
needed like iron, folate and vit B12. The bone marrow replaces
the deficient red cell mass until it normalizes which can be
detected by the kidneys through a normal Oxygen level in the
blood.

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Substrates for RBC production
a. Iron – heme production (hemoglobin)
b. Vit B12- maturation
c. Folate - maturation
 How important is EPO in the presence of anemia?
o Plasma EPO levels increase in proportion to the
severity of anemia when Hgb falls below 100-
120g/L.
o Binds to specific receptors on marrow erythroid
precursors inducing them to proliferate and
mature
 RBC production can increase 4- 5 fold within a 1- 2-
week period but only in the presence of adequate
nutrients especially Iron.
Exogenous EPO administration among athletes is
banned since it causes induced polycythemia to increase oxygen
supply to the muscles therefore increasing an athlete’s
endurance and strength (Lance Armstrong)
III. CLINICAL PRESENTATION OF ANEMIA
A. ACUTE ANEMIA:
 Due to BLOOD LOSS OR HEMOLYSIS
 Hypovolemia dominates the picture in acute blood loss
o Hgb and Hct values DO NOT reflect the volume of
blood loss.
o Hemodymanic compromise and decreased organ
perfusion problems rather than anemia.
 Acute blood loss (Extravascular)
o 10-15%: signs of vascular instability (500cc)
 Tachycardia and tachypnea
o >30%: failure of compensatory mechanism (1.5L)
 Postural hypotension
o >40%: hypovolemic shock (2L)
 Hypovolemic shock, Encephalopathic
due to decrease oxygen supply to the
brain.
 Commonly happens in Trauma – exsanguination,
extravascular bleeding
 Concern yourself about the circulating volume since
compensatory mechanisms won’t work in acute blood
loss
 Acute Hemolysis (Intravascular bleeding)
o Renal failure due to sudden release of massive
amount of free hemoglobin
o The problem is acute iron overload in the blood
which leads to acute renal failure
B. CHRONIC OR PROGRESSIVE ANEMIA:
 May be asymptomatic
 Moderate anemia <100g/ L
o Fatigue, loss of stamina, headache, breathlessness,
palpitations, bounding pulses and tachycardia.
 Compensatory Mechanisms to Chronic Anemia
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o Increase in 2,3- bisphosphoglycerate intracellular
levels  shifts the dissociation curve to the right
 facilitates O2 unloading
o Maintains O2 delivery when Hgb deficit is at 20-30
g/L only
o Changes in cardiac output (increase CO,
tachycardia) and regional blood flow (vasodilation)
 Shunting of blood away from organs relatively rich in
blood supply particularly the kidney, gut (stress ulcer)
and skin (pallor)
IV. APPROACH TO THE PATIENT WITH ANEMIA
ALWAYS KEEP IN MIND THE PHYSIOLOGY OF ERYTHROPOIESIS
“The functional capacity of the ERYTHRON requires
normal renal production of EPO, a functioning erythroid
MARROW, and an adequate supply of substrates for
HEMOGLOBIN synthesis” KEEP THIS IN MIND!!!
“The size of the red cell mass reflects the balance of
RBC production and destruction”
If there is sudden RBC destruction but the body does
not increase RBC production, there is a problem in SYNTHESIS
If the synthesis is intact but there is still blood loss, then
check on the peripheral circulation.
CLINICAL EVALUATION:
1. Nutritional history
 Drugs and alcohol intake – aspirin, immune
suppressants, alcohol – vit b12 deficiency
 Dietary restrictions
o Self-imposed – Vegan, Vegetarians
o Religion – Hinduism and Judaism
o Best source of iron – Red Meat
2. Family history
3. Geographic backgrounds and Ethnicity
 Middle eastern or African origin: high frequency of G6PD
deficiency
 Asians are more affected by abnormal globin synthesis
like thalassemias
4. Exposure to toxic agents or drugs – radioactive substances
5. Co- morbid conditions
 Chronic Kidney disease
 Chronic inflammatory diseases (Connective Tissue
Disease)
 Malignancy and Lymphoproliferative diseases
 Chronic Liver Disease
 Renal Artery Stenosis
6. Symptoms
 Fatigue; malaise; bleeding; fever; night sweats; weight
loss; and other systemic symptoms
7. Physical Examination
 Infection; blood in the stool; lymphadenopathy;
splenomegaly; and petechiae
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  Pallor (at Hgb <80-100g/L); forcefull heartbeat; strong  Serum Ferritin: used to evaluate total body Iron stores
peripheral pulses, and a systolic “flow” murmur b. TOTAL IRON BINDING CAPACITY (TIBC)
 iron carrying capacity of the blood
c. PERCENT TRANSFERRIN SATURATION
LABORATORY EVALUATION  Transferrin is a glycoprotein the carries iron in the
blood.
1. COMPLETE BLOOD COUNT (CBC) – used to establish anemia
Iron Defficiency Anemia
 Hemoglobin
 Hematocrit  Low Iron level
 Red Cell Indices – rate of synthesis and maturation of  High TIBC
erythropoiesis  Low Ferritin
o Mean Cell Volume (MCV)  Most common type of anemia
o Mean Cell Hemoglobin (MCH)
o Mean Concentration of Hemoglobin per volume of 4. BONE MARROW EXAMINATION
Red Cells (MCHC)  Hypoproliferative anemia especially with normal Iron
 Microcytosis: MCV <80 stores
 Macrocytosis: MCV> 100  Aplastic anemia
 MCHC and MCH: reflect defects in  Myelofribrosis
Hgb synthesis (hypochromia)  Infiltrative Bone Marrow disorders – something colonizes
 Reticulocyte Count the BM, destroying the native cells
o Reticulocyte Index  Malignancy
 “Key to the initial classification of anemia”  Lymphoproliferative disorders
o Reticulocytes: newly formed immature, RBCs  Evaluate iron stores
released from the bone marrow and have a life span o Ferritin
of 24- 36 hrs o Hemosiderin
o (+) Anemia/ Hgb <100g/L  RBC production is
V TREATMENT
increased 2-3x in 10 days
“An overriding principle in the treatment of mild to
o Reticulocyte count is increased 2-3x
o Correct fort the degree of anemia moderate anemia is to treat only when a specific
o Correct for prematurely released reticulocytes diagnosis is made”
 WBC Count Multiple treatment options depending on the cause:
o Pancytopenia  Aplastic Anemia or MDS  Blood component therapy
 Platelet Count  Specific nutritional replacement
o Bicytopenia: Megakaryocytic Leukemia  Recombinant EPO
 Cell Morphology  Patients on hemodialysis
 Targeted Genetic Therapy
2. PERIPHERAL BLOOD SMEAR Inherited disorders of globin synthesis (i.e., sickle cell disease)
 Complimentary to red cell indices
 Variations in cell size (Anisocytosis) TWO TYPES OF APPROACH
 Correlates with increases in the range of cell sizes
 Variations in cell shapes (Poikylocytosis)
 Correlates with maturation of red cell precursors of A. KINETIC APPROACH (movement)
fragmentation of circulating red cells  Targets the production and destruction of RBCs
 Polychromasia  Decreased RBC production
 Prematurely released reticulocytes o Lack of nutrients
o Bone marrow disorder
o Bone marrow suppression
Complimentry to the red cell indices is the peripheral blood
 Increased RBC production
smear because it provides important information about defects in o Increased RBC destruction
the red cell production. For instance, anicocystosis reveals o Inherited or acquired hemolytic anemia
variation in cell sizes which correlate well to increase in the RDW o Hemoglobinopathies
and Poikilocyctosis suggests defects in maturation. It may also o Blood Loss
reveal polychromasia which reflects the level of prematurely
released reticulocytes usually in response to EPO stimulation or B. MORPHOLOGICAL APPROACH (appearance)
 Microcytic
bone marrow infiltration resulting in their disorderly release.
o Reduced iron availability
o Reduced Heme synthesis
3. IRON SUPPLY STUDIES o Reduced globin synthesis
 Used to reflect the availability of Iron for Hemoglobin o Normocytic
synthesis  Macrocytic
o Liver disease
a. SERUM IRON o B12 or Folate defficiency

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 20- year- old- female, Filipino, sought consult due to a 3-month-
VI. CLASSIFICATION OF ANEMIA history of dyspnea. She also has weight loss, intermittent fever
and night sweats. On examination, she has pallor and enlarged
multifocal lymphadenopathy (cervical, supraclavicular and
axillary; and traube’s space is obliterated

 CBC
o Hgb: 72 g/L
o Hct: 20%
o WBC: 23 x 103/uL
o Neut: 32%
o Lympo: 69
o Plt: 95,000
o MCV 68
o MCH 32
o MCHC 28
o Microcytic, normochromic

- Reticulocyte index? Low, d/t infiltrative disease

- Confirmatory test for diagnosis? Bone marrow
examination
- Problem: Bone Marrow
CASE 3

45-year- old- female, known ESRD on hemodialysis 3x a week

with good compliance on consult due to decreased exercise
tolerance. On exam, BP 145/90; HR 120bpm; RR 24/min; she
has pale palpebral conjunctivae, normal JVP, distinct S 1 and S2,
no S3 nor S4 gallop; clear breath sounds; grade 1 pitting bipedal
edema
PLEASE MEMORIZE!!!  CBC
o Hgb 90 g/L
VII. SAMPLE CASES o Hct 27%
o WBC 5.8
CASE 1 o Neut 78%
o Lympo 20%
55- year- old-male, filipino with pallor. He has a 6-month- history o Platelet 200,000
of weight loss, abdominal discomfort and altered bowel habits. o MCV 68
o MCH 26
 CBC
o MCHC 30
 Hgb: 68g/L
o Hypochromic, microcytic
 Hct: 20%
 WBC 7.6cumm
- Where is the problem? Kidneys decreased EPO
 Neut: 72%
production
 Lymphocyte: 26%
- How can it be corrected? Give Exogenous EPO
 Platelet count 550,000
 MCH: 70
 MCH: 32
 Microcytic, normochromic

 PBS:
 (+) anisocytosis
 (+) poikylocytosis
 Reticulocyte Index: 2.8
ANSWER: patient has colon cancer and the anemia is due to a
bleeding tumor and anemia of chronic disease

CASE 2

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 CHECKPOINT
Idetification
1. If the patient has thalassemia, his/her CBC, reticulocyte
index would be?
2. In hemolysis or hemorrhage, patient’s index is?
3. This is the primary regulatory hormone for erythropoiesis.
4. This is responsible for the process by which formed
elements of blood are produced.
5. Blood loss or hemolysis would lead to?
6. Key to the initial classification of anemia.
7. An increase in this substance intracellularly would shift the
dissociation curve to the right which facilitates O2 unloading.
8. EPO is produced and released by?
9. Reflect defects in Hgb synthesis (hypochromia).
10. Common erythroid/ megakaryocyte progenitor cells would
need the expression of these two transcription factors.

ANSWERS: 1. Less than 2.5, 2. Greater than or equal to 2.5, 3.

Erythropoietin, 4. Erythron, 5. Acute Anemia, 6. Reticulocyte index, 7. 2,3-
bisphosphoglycerate, 8. Peritubular capillary cells lining the kidney, 9. MCHC
and MCH, 10. GATA-1 and FOG-1

END

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