Last edited: 4/19/2022

CBC | APPROACH TO ANEMIA

CBC | Aproach to Anemia Medical Editor: Jan Santico, Aldrich Christiandy

OUTLINE
I) RED BLOOD CELLS (RBC) II) ANEMIA III) RETICULOCYTE INDEX < 2% IV) APPENDIX
(A) STIMULI (A) CAUSES OF ANEMIA (A) MICROCYTIC ANEMIAS V) REVIEW
(B) LIFE CYCLE (B) CLASSIFICATION OF ANEMIA (B) NORMOCYTIC ANEMIA QUESTIONS
(C) RETICULOCYTES (C) DIAGNOSTIC (C) MACROCYTIC ANEMIA VI) REFRENCES\
PARAMETERS/TESTS

I) RED BLOOD CELLS (RBC)

Red blood cells are also known as erythrocytes
Red blood cell production occurs in the red bone marrow
Myeloid Stem Cell
o Progenitor for red blood cells, platelets, and granulocytes (e.g. neutrophil, basophil, eosinophil)
o Receives stimuli which direct it to form red blood cells

(A) STIMULI (B) LIFE CYCLE

Erythropoiesis refers to the process of red blood cell RBC Development
production o Myeloid Stem Cell
There are different factors which influence production:
o Hormones – stimulates production
o Nutrients – stimulates production
o Drug/Toxins – inhibits production
o Intrinsic Bone Marrow Function (C) RETICULOCYTES
Reticulocytes are immature/developing red blood cells
(1) Hormones It takes 1-2 days for a reticulocyte to develop into an
Thyroid Hormones (T3 and T4) RBC
Erythropoietin
o Produced by the liver and kidney
o Stimulates the bone marrow to produce RBCs
(2) Nutrients
Iron
Vitamin B12 / Cobalamin
Vitamin B9 / Folate
(3) Drugs/Toxins
Suppress RBC production in the bone marrow
Example: Alcohol

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 II) ANEMIA
Anemia refers to a decreased red blood cell mass, Anemia can be due to either:
manifested as: o External stimuli
o Decrease in Hemoglobin (Hgb) o Poor bone marrow function
o Decrease in Hematocrit (Hct) o Bleeding / Increased blood loss
o Decrease in RBCs o Increased destruction of RBCs

(A) CAUSES OF ANEMIA

(B) CLASSIFICATION OF ANEMIA
To determine the cause of anemia, a comprehensive
history and laboratory tests (e.g., complete blood
count, iron studies, peripheral blood smear, etc) are
needed.
(1) External Stimuli
There are different stimuli/factors which influence red
blood cell mass
o Hormones
o Nutrients
o Drugs/Toxins
Reticulocyte index is low (less than 2%)
(2) Poor Bone Marrow Function
Bone marrow function is affected when:
o Exposure to chemoradiation destroys the structure
of the bone marrow
o There is a neoplasm/cancer of the bone marrow
Reticulocyte index is low (less than 2%)
(3) Bleeding / Increased Blood Loss
When there is active bleeding or increased blood loss, the
RBC count may decrease
Since bone marrow function is normal, the decreased
RBC count triggers a compensatory mechanism which
increases erythropoiesis and subsequently increases the
reticulocyte index
Examples: Figure 1. Physiologic Classification of Anemia [Harrison’s Principles of
o GI bleed Internal Medicine 20th Edition]

o Frequent blood withdrawals (e.g. in the ICU) Anemia may be classified based on the reticulocyte
o Surgery index
Reticulocyte index will increase as a compensatory The reticulocyte index (RI) is a good indicator of bone
mechanism marrow function
o RI <2 % - decreased RBC production (due to
(4) Increased Destruction of RBCs / Hemolysis decreased stimuli or bone marrow dysfunction)
RBCs may be destroyed or lysed within the vasculature o RI >2% - increased destruction or loss of RBC; bone
or the spleen marrow is functioning
o Intravascular Hemolysis – destroyed within the
vasculature
o Extravascular Hemolysis – destroyed within the o The reticulocyte count shown in the diagnostic
splenic macrophages of the spleen results is NOT the reticulocyte index
Reticulocyte index will increase as a compensatory This value should be inputted in a reticulocyte index calculator
mechanism

Diagnostic tests are often necessary – on top of a

comprehensive history and physical examination – to
determine the cause of anemia
The following are the most common diagnostic tests
ordered for anemia:
o RDW – measures the variation in size of RBCs
o RBC count
o Menser’s Index (MI)
 Computed as MVC / RBC
o Iron Studies
 Fe++
 Ferritin – protein which binds to irons inside the
cells; reflects iron reserves
 Total Iron Binding Capacity (TIBC)
 Transferrin Saturation %
• Computed as Fe/TIBC
o Peripheral Blood Smear (PBS)

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 III) RETICULOCYTE INDEX < 2%
Disorders with a reticulocyte index < 2% may be further The types of anemia based on MCV value are:
classified based on the RBC morphology o Microcytic Anemia: < 80 fl
The mean corpuscular volume (MCV) determines the o Normocytic Anemia: 80 – 100 fl
size of the red blood cells o Macrocytic Anemia: > 100 fl
o Normal Value: 80 – 100 femtoliters (fl)

(A) MICROCYTIC ANEMIAS

MCV: < 80 fl
Differentials
o Iron Deficiency Anemia
o Anemia of Chronic Disease
o Thalassemia
o Sideroblastic Anemia
Diagnostic Tests
o RDW
o RBC
o MI
o Iron Studies
o Peripheral Blood Smear (PBS)
(1) Iron Deficiency Anemia (3) Thalassemia
↑ RDW ↔ or ↑ RDW
↓ RBC ↔ RBC
MI > 13% MI < 13%
↓ Ferritin o ↓↓↓ MCV / RBC
↓ Transferrin Sat %
Iron studies are not helpful
PBS is not helpful
PBS: may show basophilic stippling
(2) Anemia of Chronic Disease o Correlate with history findings (e.g. family history of
thalassemia, Mediterranean ancestry)
History is the most important factor; look for symptoms
and signs of chronic disease Hemoglobin Electrophoresis
↔ RDW o Will clinch the diagnosis of thalassemia
↓ RBC
(4) Sideroblastic Anemia
MI is not helpful
↑↑ Ferritin History: Look for exposure to lead, alcohol use,
o Ferritin is an acute phase reactant; it may be elevated medication use
when there is an active inflammatory process such as Causes: lead poisoning, toxins
in chronic diseases ↑ RDW
↓ RBCs
Transferrin Sat % is variable
Iron studies are not helpful
PBS
o Shows basophilic stippling
 Check lead (Pb) levels
o Shows sideroblasts
 Get a bone marrow biopsy to confirm

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 (B) NORMOCYTIC ANEMIA
MCV: 80-100 fl
Differentials
o Early Iron Deficiency Anemia
o Early B12 deficiency
o Early Folate deficiency
o Thyroid Disease
o Liver Disease
o Kidney Disease
o Hemolysis
Diagnostics
o Iron Studies
o B12 Levels
o Folate Levels
o Thyroid Function Tests
o Liver Function Tests
o BMP (kidney function)
o Hemolytic Labs
o Bone Marrow Biopsy
(1) Early Iron Deficiency Anemia (6) Chronic Kidney Disease
↓ Ferritin / ↑ BUN
↓ Transferrin Sat % ↑ Creatinine
(2) Anemia of Chronic Disease ↓ Erythropoietin (EPO)
o The kidney fails to produce EPO
↑↑ Ferritin
(7) Intrinsic Bone Marrow Problem
(3) B12 and Folate Deficiency
↓↓↓ Reticulocyte Index (0.1%)
↓ B12 levels Pancytopenia
↓ Folate levels o ↓ RBC
If the levels are borderline, measure the methylmalonic o ↓ WBC
acid (MMA) and homocysteine (HC) levels o ↓ Platelets
o B12 Deficiency = ↑ MMA, ↑ HC
Bone Marrow Biopsy
o Folate Deficiency = ↔ MMA, ↑ HC
o Aplastic Anemia – low proliferative bone marrow
(4) Hypothyroidism biopsy
o Myelodysplastic Syndrome (MDS)
↓ T3, T4
 hyperproliferative bone marrow due to
(5) Liver Failure overproduction of blast cells
o Pure Red Cell Aplasia (PRCA)
↑ AST, ALT (liver enzymes)
 low erythroblasts
↓ Albumin
 no pancytopenia because only the red blood cell
↑ INR
line is affected

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 (C) MACROCYTIC ANEMIA
MCV: > 100 fl
Differentials
o B12 Deficiency
o Folate Deficiency
o Hypothyroidism
o Drug-induced
o Alcohol Abuse
o Myelodysplastic Disorder (MDS)
Diagnostics
o B12 / Folate levels
o Thyroid Function Tests
o Liver Function Tests
o Look at medication use
o Blood Alcohol Concentration
o Peripheral Blood Smear
o Bone Marrow Biopsy
(1) B12 and Folate Deficiency (4) Drug-induced
↓ B12 levels Drugs which can cause macrocytic anemia include:
↓ Folate levels o Chemotherapeutic agents
If the levels are borderline, measure the methylmalonic  Methotrexate
acid (MMA) and homocysteine (HC) levels  Fluorouracil (5FU)
o B12 Deficiency = ↑ MMA, ↑ HC  Hydroxyurea
o Folate Deficiency = ↔ MMA, ↑ HC o HIV Medications
Peripheral Blood Smear: megaloblastic anemia  Zidovudine
o Shows megaloblasts (neutrophils with >5 o Antibiotics
lobes/segments)  Trimethoprim Sulfamethoxazole (TMP-SMX)
o Anti-seizure Medications
(2) Hypothyroidism  Phenytoin
History: hypothyroid symptoms  Valproic Acid
↓ T3, T4 Peripheral Blood Smear: megaloblastic anemia
(3) Liver Failure o Shows megaloblasts (neutrophils with >5
lobes/segments)
History: cirrhosis, alcohol abuse
↑ AST, ALT (liver enzymes) (5) Alcohol
↓ Albumin History: heavy alcohol use
↑ INR ↑ Blood alcohol concentration
Peripheral Blood Smear: megaloblastic anemia
o Shows megaloblasts (neutrophils with >5
lobes/segments)
(6) Myelodysplastic Disorder
Peripheral Blood Smear: non-megaloblastic anemia
o No megaloblasts / hyper-segmented neutrophils
o Suggestive of a thyroid, liver, or bone marrow issue
Bone Marrow Biopsy
o Consider in patients with pancytopenia
o Shows hyperproliferative bone marrow

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 IV) APPENDIX

V) REVIEW QUESTIONS 6) What clinical result that is always present and

unique to microangiopathic hemolytic anemia?
1) Which of the following parameters reflects bone
a) High platelet count
marrow function?
b) Low platelet count
a) Mean Corpuscular Volume
c) Warm AIHA
b) Reticulocyte Index
d) Cold AIHA
c) Total Iron Binding Capacity
d) INR 7) Osmotic fragility test is commonly used to diagnose
which type of anemia?
2) If the reticulocyte index is 0.9%, which of the
a) Hereditary spherocytosis
following is the LEAST LIKELY differential?
b) Paroxysmal nocturnal hemoglobinuria
a) B12 Deficiency
c) Thalassemia
b) Myelodysplastic Syndrome
d) G6PDH deficiency
c) G6PD Deficiency
d) Hypothyroidism VI) REFRENCES
3) A 31-year-old female patient’s CBC results showed
the following: ● Harrison, T. R., & Kasper, D. L. (2015). Harrison's principles of
Internal Medicine. McGraw-Hill Medical Publ. Division.
Hgb 10.3 g/dL
Hct 30.3 %
MCV 121
a) Iron Deficiency
b) Folate Deficiency

d) Thalassemia
4) Which of the following is CORRECTLY paired?
a) MCV < 80 : Normocytic Anemia
b) MI < 13% : Iron Deficiency Anemia
c) ↔ MMA, ↑ HC : Folate Deficiency Anemia
d) RI < 0.8% : Hemolytic Anemia
5) Reticulocyte index > 2% in anemia cases indicates
a) Functional bone marrow → compensates for blood
loss
b) Aplastic anemia → unable to compensate for blood
loss
c) Anemia caused by nutrient deficiencies
d) Anemia induced by drugs with bone marrow
suppression effect

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