Module 2.1 Fatigue
Recalls (10 points)
HEMATOPOIESIS AND PHYSIOLOGIC ● Hematopoiesis is the process of blood cell formation, involving hematopoietic stem cells, which give rise to
BASIS OF RBC PRODUCTION red cells, granulocytes, monocytes, platelets, and immune cells.
● Lineage commitment of hematopoietic stem cells, such as the erythroid/megakaryocyte progenitor, is
regulated by transcription factors GATA-1 and FOG-1.
● Erythropoiesis is the specific process of red blood cell (RBC) production and is primarily regulated by the
hormone erythropoietin (EPO). EPO prevents apoptosis in committed erythroid progenitor cells.
● In the bone marrow, the first identifiable erythroid precursor is the pronormoblast, which undergoes four to
five cell divisions, resulting in 16–32 mature RBCs.
● Increased EPO levels, either naturally or through drug administration, amplify early progenitor cell numbers,
leading to increased RBC production.
● EPO production is linked to tissue oxygenation. When tissue oxygen levels are low (hypoxia), the
production of EPO increases through the regulation of hypoxia-inducible factor (HIF)-1α.
● Under normal oxygen levels, HIF-1α is hydroxylated and degraded. When oxygen is limited, HIF-1α avoids
degradation, enters the nucleus, and upregulates the EPO gene.
● Kidney function is critical for EPO production, with small amounts also produced by the liver. Impaired
oxygen delivery to the kidney (due to anemia, hypoxemia, or renal artery stenosis) triggers increased EPO
production.
● EPO hormone levels are measurable in plasma, with normal levels ranging from 10–25 U/L. When
hemoglobin drops below 100–120 g/L (10–12 g/dL), EPO levels rise in proportion to the severity of anemia.
● EPO acts on marrow erythroid precursors, inducing them to proliferate and mature. Red cell production
can increase four- to fivefold in 1–2 weeks with adequate iron and nutrients.
● The erythron is the dynamic organ responsible for RBC production, comprising proliferating marrow
erythroid precursors and circulating mature RBCs. RBC production balances RBC destruction, reflecting
overall red cell mass.
● Normal RBC lifespan is 100–120 days, with daily replacement of 0.8–1% of RBCs.
● Anemia occurs when there is a defect in EPO production, bone marrow function, or nutrient availability. It is
defined when hemoglobin/hematocrit levels fall below normal ranges.
● The World Health Organization (WHO) defines anemia as hemoglobin <13 g/dL (130 g/L) in men and <12
g/dL (120 g/L) in women.
● Hemoglobin concentration is a better marker than hematocrit for diagnosing anemia, with normal adult male
values being 13.5–17.5 g/dL (135–175 g/L) and female values 12–15 g/dL (120–150 g/L).
● Key elements of erythropoiesis—EPO production, iron availability, bone marrow proliferation, and
maturation of red cell precursors—are used for the initial classification of anemia.
ANEMIA
(Harrison’s Principles of Internal Medicine 21E, Chapter 63, p. 432)
APPROACH TO PATIENT ● History and physical examination are critical in evaluating patients with anemia. Key components include:
○ Nutritional history, including alcohol and drug intake.
○ Family history of anemia or inherited blood disorders.
, ○ Geographic and ethnic background, which may suggest a predisposition to inherited disorders like
Glucose-6-phosphate dehydrogenase (G6PD) deficiency or hemoglobinopathies (common in
individuals of Middle Eastern or African origin).
● G6PD deficiency and certain hemoglobinopathies are more frequent in people of African and Middle
Eastern descent, including African Americans.
● Toxic exposure or drug use and symptoms related to associated disorders should also be assessed.
Common anemia-associated symptoms include:
○ Bleeding,
○ Fatigue,
○ Malaise,
○ Fever,
○ Weight loss,
○ Night sweats.
● Physical examination findings may provide clues to the underlying cause of anemia:
○ Infection,
○ Blood in stool,
○ Lymphadenopathy or splenomegaly, which suggest lymphoproliferative diseases.
○ Petechiae, which may indicate platelet dysfunction.
● Cardiovascular signs:
○ An anemic patient may exhibit a forceful heartbeat, strong peripheral pulses, and a systolic
"flow" murmur.
● Skin and mucous membranes may appear pale, especially when hemoglobin levels drop below 8–10 g/dL
(80–100 g/L).
○ Pallor is best assessed in areas where blood vessels are close to the surface, such as the mucous
membranes, nail beds, and palmar creases.
○ If the palmar creases are lighter than surrounding skin when the hand is extended, it often indicates
hemoglobin levels below 8 g/dL (80 g/L).
● Past laboratory measurements are important for determining the onset and progression of anemia.
DIAGNOSTIC TESTS Diagnostic Tests for Anemia
1. Complete Blood Count (CBC):
○ Essential for anemia evaluation, includes:
■ Hemoglobin, hematocrit, and red cell indices:
■ Mean cell volume (MCV) in femtoliters (fL).
■ Mean cell hemoglobin (MCH) in picograms per cell.
■ Mean concentration of hemoglobin per volume of red cells (MCHC) in grams per
liter (g/L).
■ MCH is the least useful index since it tends to track with the MCV.
○ Physiologic factors affecting CBC:
■ Age, sex, pregnancy, smoking, altitude.
■ High-normal hemoglobin in smokers and individuals at high altitudes (due to compensation
for oxygen displacement by carbon monoxide).
○ Red cell indices reflect the type of anemia:
, ■ Microcytosis (MCV < 80 fL).
■ Macrocytosis (MCV > 100 fL).
■ Hypochromia (low MCHC) indicates defects in hemoglobin synthesis.
■ Red cell distribution width (RDW) shows variation in red cell size (insensitive to small
populations of macrocytic or microcytic cells).
2. Peripheral Blood Smear:
○ Provides visual assessment of:
■ Anisocytosis (variation in cell size).
■ Poikilocytosis (variation in cell shape).
■ Polychromasia: premature reticulocytes appear larger and gray-blue due to residual RNA.
○ Other features such as:
■ Nucleated red cells, Howell-Jolly bodies, target cells, or sickle cells help diagnose
specific disorders.
■ Can reveal fragmentation or defects in red cell production or maturation.
3. Reticulocyte Count:
○ Measures recent red cell production.
○ Normal range: 1–2% of red cells.
○ Indicates bone marrow response to anemia. In moderate anemia, reticulocyte production should
increase 2–3 times normal within 10 days.
○ Corrections for reticulocyte count:
■ First correction adjusts for reduced red cells in circulation.
■ Second correction for prematurely released reticulocytes ("shift" cells), doubling the count if
polychromasia is observed.
○ A reticulocyte production index of <2 suggests impaired marrow response or erythroid maturation
defects.
4. Tests of Iron Supply and Storage:
○ Key measurements include:
■ Serum iron: Normal range is 9–27 μmol/L (50–150 μg/dL).
■ Total iron-binding capacity (TIBC): Normal range is 54–64 μmol/L (300–360 μg/dL).
■ Percent transferrin saturation: Normal range is 25–50%, calculated by dividing serum iron
by TIBC.
○ Serum ferritin reflects total body iron stores:
■ Normal levels:
■ Males: ∼100 μg/L (corresponding to ∼1 g iron stores).
■ Premenopausal females: ∼30 μg/L (reflecting ∼300 mg iron stores).
■ Low ferritin (<15 μg/L) suggests iron depletion, though ferritin can be elevated in
inflammation (acute-phase reactant).
5. Bone Marrow Examination:
○ Indicated in cases of hypoproliferative anemia or unexplained anemia.
○ Can diagnose:
■ Primary marrow disorders (e.g., myelofibrosis).
■ Infiltrative diseases (e.g., malignant infiltration).
■ Red cell maturation defects.
, ○Myeloid/Erythroid (M/E) ratio provides insight into marrow activity:
■ Normal ratio: 2–3:1 in hypoproliferative anemia.
■ Ratio shifts (e.g., 1:1) in hemolytic anemia with high marrow production.
○ Staining can detect iron stores in bone marrow, where ferritin or hemosiderin granules are seen in
developing erythroblasts.
Summary of Anemia Evaluation:
● The CBC and peripheral smear provide crucial insights into anemia type and severity.
● Reticulocyte count is central in assessing bone marrow function and response.
● Iron studies help in diagnosing iron deficiency or overload.
● Bone marrow examination is critical when other tests are inconclusive or suggest marrow pathology.
CLASSIFICATION OF ANEMIA Classification of Anemia
Anemia can be broadly classified into three functional categories:
1. Marrow Production Defects (Hypoproliferation):
○ Characterized by inadequate production of red blood cells (RBCs) in the bone marrow.
○ Anemia typically appears as normocytic, normochromic (normal size and color).
○ Low reticulocyte production index (RPI).
○ Common causes: iron deficiency, inflammation, bone marrow damage, decreased erythropoietin
(EPO) stimulation due to renal failure or hypothyroidism.
○ Represents 75% of all anemia cases.
○ Marrow fails to proliferate in response to anemia.
○ Common causes:
■ Iron deficiency: Leads to inadequate hemoglobin synthesis.
■ Inflammation: Suppresses erythropoiesis via cytokines like interleukin-1.
■ Renal failure: Decreased EPO production.
■ Hypothyroidism: Reduces tissue oxygen needs.
○ Lab findings:
Recalls (10 points)
HEMATOPOIESIS AND PHYSIOLOGIC ● Hematopoiesis is the process of blood cell formation, involving hematopoietic stem cells, which give rise to
BASIS OF RBC PRODUCTION red cells, granulocytes, monocytes, platelets, and immune cells.
● Lineage commitment of hematopoietic stem cells, such as the erythroid/megakaryocyte progenitor, is
regulated by transcription factors GATA-1 and FOG-1.
● Erythropoiesis is the specific process of red blood cell (RBC) production and is primarily regulated by the
hormone erythropoietin (EPO). EPO prevents apoptosis in committed erythroid progenitor cells.
● In the bone marrow, the first identifiable erythroid precursor is the pronormoblast, which undergoes four to
five cell divisions, resulting in 16–32 mature RBCs.
● Increased EPO levels, either naturally or through drug administration, amplify early progenitor cell numbers,
leading to increased RBC production.
● EPO production is linked to tissue oxygenation. When tissue oxygen levels are low (hypoxia), the
production of EPO increases through the regulation of hypoxia-inducible factor (HIF)-1α.
● Under normal oxygen levels, HIF-1α is hydroxylated and degraded. When oxygen is limited, HIF-1α avoids
degradation, enters the nucleus, and upregulates the EPO gene.
● Kidney function is critical for EPO production, with small amounts also produced by the liver. Impaired
oxygen delivery to the kidney (due to anemia, hypoxemia, or renal artery stenosis) triggers increased EPO
production.
● EPO hormone levels are measurable in plasma, with normal levels ranging from 10–25 U/L. When
hemoglobin drops below 100–120 g/L (10–12 g/dL), EPO levels rise in proportion to the severity of anemia.
● EPO acts on marrow erythroid precursors, inducing them to proliferate and mature. Red cell production
can increase four- to fivefold in 1–2 weeks with adequate iron and nutrients.
● The erythron is the dynamic organ responsible for RBC production, comprising proliferating marrow
erythroid precursors and circulating mature RBCs. RBC production balances RBC destruction, reflecting
overall red cell mass.
● Normal RBC lifespan is 100–120 days, with daily replacement of 0.8–1% of RBCs.
● Anemia occurs when there is a defect in EPO production, bone marrow function, or nutrient availability. It is
defined when hemoglobin/hematocrit levels fall below normal ranges.
● The World Health Organization (WHO) defines anemia as hemoglobin <13 g/dL (130 g/L) in men and <12
g/dL (120 g/L) in women.
● Hemoglobin concentration is a better marker than hematocrit for diagnosing anemia, with normal adult male
values being 13.5–17.5 g/dL (135–175 g/L) and female values 12–15 g/dL (120–150 g/L).
● Key elements of erythropoiesis—EPO production, iron availability, bone marrow proliferation, and
maturation of red cell precursors—are used for the initial classification of anemia.
ANEMIA
(Harrison’s Principles of Internal Medicine 21E, Chapter 63, p. 432)
APPROACH TO PATIENT ● History and physical examination are critical in evaluating patients with anemia. Key components include:
○ Nutritional history, including alcohol and drug intake.
○ Family history of anemia or inherited blood disorders.
, ○ Geographic and ethnic background, which may suggest a predisposition to inherited disorders like
Glucose-6-phosphate dehydrogenase (G6PD) deficiency or hemoglobinopathies (common in
individuals of Middle Eastern or African origin).
● G6PD deficiency and certain hemoglobinopathies are more frequent in people of African and Middle
Eastern descent, including African Americans.
● Toxic exposure or drug use and symptoms related to associated disorders should also be assessed.
Common anemia-associated symptoms include:
○ Bleeding,
○ Fatigue,
○ Malaise,
○ Fever,
○ Weight loss,
○ Night sweats.
● Physical examination findings may provide clues to the underlying cause of anemia:
○ Infection,
○ Blood in stool,
○ Lymphadenopathy or splenomegaly, which suggest lymphoproliferative diseases.
○ Petechiae, which may indicate platelet dysfunction.
● Cardiovascular signs:
○ An anemic patient may exhibit a forceful heartbeat, strong peripheral pulses, and a systolic
"flow" murmur.
● Skin and mucous membranes may appear pale, especially when hemoglobin levels drop below 8–10 g/dL
(80–100 g/L).
○ Pallor is best assessed in areas where blood vessels are close to the surface, such as the mucous
membranes, nail beds, and palmar creases.
○ If the palmar creases are lighter than surrounding skin when the hand is extended, it often indicates
hemoglobin levels below 8 g/dL (80 g/L).
● Past laboratory measurements are important for determining the onset and progression of anemia.
DIAGNOSTIC TESTS Diagnostic Tests for Anemia
1. Complete Blood Count (CBC):
○ Essential for anemia evaluation, includes:
■ Hemoglobin, hematocrit, and red cell indices:
■ Mean cell volume (MCV) in femtoliters (fL).
■ Mean cell hemoglobin (MCH) in picograms per cell.
■ Mean concentration of hemoglobin per volume of red cells (MCHC) in grams per
liter (g/L).
■ MCH is the least useful index since it tends to track with the MCV.
○ Physiologic factors affecting CBC:
■ Age, sex, pregnancy, smoking, altitude.
■ High-normal hemoglobin in smokers and individuals at high altitudes (due to compensation
for oxygen displacement by carbon monoxide).
○ Red cell indices reflect the type of anemia:
, ■ Microcytosis (MCV < 80 fL).
■ Macrocytosis (MCV > 100 fL).
■ Hypochromia (low MCHC) indicates defects in hemoglobin synthesis.
■ Red cell distribution width (RDW) shows variation in red cell size (insensitive to small
populations of macrocytic or microcytic cells).
2. Peripheral Blood Smear:
○ Provides visual assessment of:
■ Anisocytosis (variation in cell size).
■ Poikilocytosis (variation in cell shape).
■ Polychromasia: premature reticulocytes appear larger and gray-blue due to residual RNA.
○ Other features such as:
■ Nucleated red cells, Howell-Jolly bodies, target cells, or sickle cells help diagnose
specific disorders.
■ Can reveal fragmentation or defects in red cell production or maturation.
3. Reticulocyte Count:
○ Measures recent red cell production.
○ Normal range: 1–2% of red cells.
○ Indicates bone marrow response to anemia. In moderate anemia, reticulocyte production should
increase 2–3 times normal within 10 days.
○ Corrections for reticulocyte count:
■ First correction adjusts for reduced red cells in circulation.
■ Second correction for prematurely released reticulocytes ("shift" cells), doubling the count if
polychromasia is observed.
○ A reticulocyte production index of <2 suggests impaired marrow response or erythroid maturation
defects.
4. Tests of Iron Supply and Storage:
○ Key measurements include:
■ Serum iron: Normal range is 9–27 μmol/L (50–150 μg/dL).
■ Total iron-binding capacity (TIBC): Normal range is 54–64 μmol/L (300–360 μg/dL).
■ Percent transferrin saturation: Normal range is 25–50%, calculated by dividing serum iron
by TIBC.
○ Serum ferritin reflects total body iron stores:
■ Normal levels:
■ Males: ∼100 μg/L (corresponding to ∼1 g iron stores).
■ Premenopausal females: ∼30 μg/L (reflecting ∼300 mg iron stores).
■ Low ferritin (<15 μg/L) suggests iron depletion, though ferritin can be elevated in
inflammation (acute-phase reactant).
5. Bone Marrow Examination:
○ Indicated in cases of hypoproliferative anemia or unexplained anemia.
○ Can diagnose:
■ Primary marrow disorders (e.g., myelofibrosis).
■ Infiltrative diseases (e.g., malignant infiltration).
■ Red cell maturation defects.
, ○Myeloid/Erythroid (M/E) ratio provides insight into marrow activity:
■ Normal ratio: 2–3:1 in hypoproliferative anemia.
■ Ratio shifts (e.g., 1:1) in hemolytic anemia with high marrow production.
○ Staining can detect iron stores in bone marrow, where ferritin or hemosiderin granules are seen in
developing erythroblasts.
Summary of Anemia Evaluation:
● The CBC and peripheral smear provide crucial insights into anemia type and severity.
● Reticulocyte count is central in assessing bone marrow function and response.
● Iron studies help in diagnosing iron deficiency or overload.
● Bone marrow examination is critical when other tests are inconclusive or suggest marrow pathology.
CLASSIFICATION OF ANEMIA Classification of Anemia
Anemia can be broadly classified into three functional categories:
1. Marrow Production Defects (Hypoproliferation):
○ Characterized by inadequate production of red blood cells (RBCs) in the bone marrow.
○ Anemia typically appears as normocytic, normochromic (normal size and color).
○ Low reticulocyte production index (RPI).
○ Common causes: iron deficiency, inflammation, bone marrow damage, decreased erythropoietin
(EPO) stimulation due to renal failure or hypothyroidism.
○ Represents 75% of all anemia cases.
○ Marrow fails to proliferate in response to anemia.
○ Common causes:
■ Iron deficiency: Leads to inadequate hemoglobin synthesis.
■ Inflammation: Suppresses erythropoiesis via cytokines like interleukin-1.
■ Renal failure: Decreased EPO production.
■ Hypothyroidism: Reduces tissue oxygen needs.
○ Lab findings:
