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Anemia and Polycythemia

Chapter 66 | Part 2 – Cardinal Manifestations & Presentation · Part 2 – Cardinal Manifestations & Presentation · Chapter 66

Key Clinical Points

  1. Anemia is defined as blood counts below normal for a given population; it affects ~2 billion people worldwide.
  2. Erythropoietin (EPO) is the primary regulator of red cell production, produced primarily by peritubular capillary cells in the kidney.
  3. HIF-1α is the key transcription factor for EPO gene regulation; it is degraded in the presence of oxygen but stabilizes under hypoxia to upregulate EPO.
  4. Reticulocyte count is a critical indicator of bone marrow response: high counts suggest destruction/loss, while low counts suggest production failure.
  5. Corrected Reticulocyte Count = Measured % Reticulocytes imes (Patient Hematocrit / 45%).
  6. Serum ferritin >200 μg/L indicates iron stores are present even in inflammatory states; <30 μg/L suggests depletion.
  7. Morphological clues: Howell-Jolly bodies (asplenia), Target cells (thalassemia/liver disease), Spur cells (severe liver disease or McLeod blood group).
  8. Anemia of inflammation is characterized by low EPO levels for the degree of anemia and elevated hepcidin.
  9. Transfusion indications include hypotension or signs of cardiac compromise (angina, heart failure).
  10. RDW is high in iron deficiency (anisocytosis) but low in thalassemia (homogeneous cell volume).
  11. Macrocytosis can be caused by B12/folate deficiency (oval macrocytes) or membrane defects (round macrocytes).
  12. Bone marrow examination is indicated for severe pancytopenia, circulating blasts, or unexplained severe anemia.

DEFINITION & OVERVIEW

• Anemia: Defined as blood counts below normal for a given population.

• Erythropoiesis: The process by which the formed elements of blood are produced. ◦ Regulated through a series of steps beginning with the hematopoietic stem cell. ◦ Stem cells produce red cells, all classes of granulocytes, monocytes, platelets, and immune system cells. ◦ Erythroid cells require GATA-1 and FOG-1 (friend of GATA-1) transcription factors for development.

• Erythron: The organ responsible for red cell production. ◦ Dynamic organ consisting of a rapidly proliferating pool of marrow erythroid precursor cells and a large mass of mature circulating red cells.

• Red Cell Characteristics: ◦ Average lifespan: 100–120 days. ◦ Size: 8 μm diameter; anucleate, discoid shape, highly pliable to traverse microcirculation. ◦ Function: Biconcave disk maximizes surface area for oxygen delivery.

• White Blood Cell Types: ◦ Neutrophils: Most abundant (10–14 μm); lobulated nucleus (2–5 lobes). ◦ Bands: Immature neutrophils with U-shaped nuclei; indicate a left shift. ◦ Vacuolated Neutrophils: May signal bacterial sepsis. ◦ Döhle bodies: 1–2 μm blue cytoplasmic inclusions; seen in infection, burns, or inflammation. ◦ Toxic granulations: Large, dark blue granules; suggest systemic inflammation. ◦ Basophils: Rare; large dark blue granules; may increase in chronic myeloid leukemia. ◦ Lymphocytes: Small (normal) or larger with abundant cytoplasm (reactive, seen in viral infections). ◦ Monocytes: Largest white blood cells (15–22 μm diameter); nucleus often appears folded.

• Morphological Indicators: ◦ Howell-Jolly bodies: Nuclear remnants; indicate asplenia or hyposplenism. ◦ Target cells: Bull's-eye appearance; seen in thalassemia or liver disease. ◦ Spur cells (Acanthocytes): Distorted red cells with thorn-like projections; seen in severe liver disease or McLeod blood group. ◦ Burr cells (Echinocytes): Regularly spaced, small, spiny projections; characteristic of uremia. ◦ Schistocytes: Fragments of red cells; indicate mechanical damage (e.g., TTP, HUS, DIC). ◦ Macro-ovalocytes: Larger, oval-shaped red cells; caused by DNA synthesis defects (B12/folate deficiency). ◦ Polychromasia: Reticulocytes with residual RNA; appear grayish blue on Wright-Giemsa stain.

Red Cell Indices

Table 1 provides the standard measurements for red cell size and hemoglobin content: • MCV (Mean Corpuscular Volume): Hct/RBC count imes 10 (85–95 fL) → indicates RBC size. • MCH (Mean Corpuscular Hemoglobin): Hgb/RBC count imes 10 (28.5–32.3 pg) → varies linearly with MCV; limited additional value. • MCHC (Mean Corpuscular Hemoglobin Concentration): Hgb/Hct imes 100 (33.8–34.2 g/dL) → changes little in most cases of anemia; limited value.

EPIDEMIOLOGY

• Prevalence: Anemia is one of the most common medical problems globally. ◦ Affects ~2 billion people. ◦ Significant source of morbidity and reduced quality of life.

• Geriatric Impact: ◦ Common in patients >65 years. ◦ 11% of community-dwelling; up to 40% of nursing home residents are anemic. ◦ Associated with increased risk of death, hospitalization, and frailty.

• Demographics: ◦ High prevalence in premenopausal women due to menstrual losses. ◦ Iron deficiency is the most common nutritional deficiency worldwide.

Table 2 details normal values by age/sex: • At birth: Hb 17 g/dL, Hct 52%. • Childhood: Hb 12 g/dL. • Adolescence: Hb 13 g/dL, Hct 40%. • Adult man: Hb 16 (±2) g/dL, Hct 47 (±6) %. • Adult woman (menstruating): Hb 13 (±2) g/dL, Hct 40 (±6) %. • Adult woman (postmenopausal): Hb 14 (±2) g/dL, Hct 42 (±6) %. • During pregnancy: Hb 12 (±2) g/dL, Hct 37 (±6) %.

ETIOLOGY & PATHOPHYSIOLOGY

• Compensatory Mechanisms: The body adapts to anemia through three primary pathways: 1. Increased Cardiac Output: → occurs within minutes; higher risk for patients with limited cardiac reserve. 2. Increased 2,3-DPG: → reduces oxygen affinity of hemoglobin; takes hours to days. 3. Increased Plasma Volume: → maintains blood pressure and lowers viscosity; takes weeks; can lead to heart failure/edema if excessive.

• Erythropoietin (EPO) Regulation: Primary regulator of red cell production. ◦ Produced by peritubular capillary cells in the kidney. ◦ Mechanism: HIF-1α is the key transcription factor. → In presence of O2: HIF-1α is hydroxylated → ubiquitinated → degraded. → In absence of O2 (Hypoxia): HIF-1α remains stable → enters nucleus → upregulates EPO gene. ◦ Clinical Note: Serum EPO levels are 10–25 U/L; they rise logarithmically when Hb falls below 120 g/L (12 g/dL).

• Inflammation & Renal Impact: ◦ Inflammation: → decreases EPO production + increases hepcidin → blocks iron absorption/release. ◦ Renal Disease: Often associated with anemia due to lack of EPO; typically present when GFR <30 mL/min/1.73 m².

• Nutritional Deficiencies: ◦ Iron: Required for heme synthesis (4 atoms per Hb molecule). ◦ Vitamin B12 & Folate: Required for DNA synthesis; deficiency leads to macrocytosis and hypersegmented neutrophils. ◦ Copper: Deficiency associated with neurologic disease and neutropenia. ◦ Vitamin C: Deficiency linked to scurvy and severe anemia.

• Marrow Pathology: ◦ Myelophthisis: Marrow replaced by infection (TB, histoplasmosis) or neoplasm (multiple myeloma, prostate cancer). ◦ Aplastic Anemia: Hypocellular marrow; caused by autoimmune, drugs, or toxins. ◦ Pure Red Cell Aplasia: Only red cell precursors reduced; associated with parvovirus B19 or autoimmune processes.

CLINICAL FEATURES

• General Symptoms: Symptoms are often unreliable for predicting exact hematocrit. ◦ Hypoxia-related: Tiredness, shortness of breath. ◦ Physical Exam: Paleness of mucosa/conjunctiva, resting tachycardia.

• Specific Conditions: ◦ Atherosclerosis: May present with angina or TIA/stroke. ◦ Iron Deficiency: May present with pica. ◦ B12 Deficiency: May present with neuropathy.

• Diagnostic Clues from Morphology: Blood smear review is crucial for identifying specific causes. ◦ Spleen involvement: Splenomegaly or blood in stool. ◦ Reticulocyte count: Assesses bone marrow's functional response to anemia.

DIFFERENTIAL DIAGNOSIS

• Microcytic Anemia (Small Cells): Indicates defects in hemoglobin production. ◦ Thalassemia (protein synthesis defect). ◦ Iron deficiency (heme synthesis failure). ◦ Sideroblastic anemia. ◦ Anemia of chronic disease (iron delivery issue).

• Macrocytic Anemia (Large Cells): Often indicates DNA synthesis defects or membrane issues. ◦ Oval Macrocytes: B12/folate deficiency, certain drugs, bone marrow disorders. ◦ Round Macrocytes: Alcohol use, liver disease, drug effects, etc.

• Normocytic Anemia (Normal Size): Broad differential; requires further investigation of reticulocytes and marrow. ◦ Aplastic anemia. ◦ Renal disease. ◦ Marrow infiltration (myeloma, leukemia). ◦ Pure red cell aplasia.

• Polycythemia Differentiation: Based on Figure 66-18/Flowchart 1 logic: 1. Assess Oxygen Saturation: → If <93% at rest or exercise → Likely related to hypoxia (e.g., high altitude, chronic lung disease). 2. Evaluate Persistence: → If no prior elevation and asymptomatic → Re-test in 1 month. 3. Assess Serum EPO Levels: → If Elevated → Renal disease, Tumors, Chuvashov polycythemia (VHL), EPAS1 (HF ext{-}2alpha) mutation, or High O_2 affinity hemoglobin. → If Normal or Low → Proceed to Mutation Assay (JAK2, LMNA). → If Positive (VAF geq 5%) → Polycythemia vera. → If Negative or VAF < 5% → Polycythemia vera, Renal disease, Tumors, Erythropoietin receptor mutation, or High O_2 affinity hemoglobin.

DIAGNOSTIC APPROACH

  1. Initial Laboratory Workup: → CBC and Reticulocyte count. → Determine if reticulocytes are high (destruction/loss) or low (production failure).
  2. Morphological Analysis: → Evaluate blood smear for size (MCV), shape (poikilocytosis), and specific features (Howell-Jolly, Target cells, Schistocytes).
  3. Iron Metabolism Assessment: → Serum Iron (9–27 μmol/L), TIBC (54–64 μmol/L), Transferrin Saturation (25–50%). → Serum Ferritin: → >200 μg/L indicates iron stores are present even in inflammation.
  4. Specialized Testing: → EPO levels (Normal 10 ext{--}25 U/L) to differentiate renal disease or inflammation. → Bone marrow examination: Indicated for severe pancytopenia, circulating blasts, or unexplained severe anemia.

MANAGEMENT & TREATMENT

  1. Transfusion Therapy: → Indicated for patients with hypotension. → Indicated for signs of cardiac compromise (angina, heart failure).
  2. Nutritional Therapy: → Iron supplementation for iron deficiency. → Vitamin B12 and Folate for megaloblastic anemia.
  3. Advanced Therapies: → Specific treatments based on underlying cause (e.g., treatment of primary neoplasm or renal failure).

KEY PEARLS & HIGH-YIELD POINTS

• Reticulocyte Interpretation: A high percentage of reticulocytes can be misleading in severe anemia; always use absolute counts (Figure 66-13). • Iron vs. Inflammation: Ferritin >200 μg/L is a key threshold to rule out absolute iron deficiency in the presence of inflammation. • Morphology as Diagnosis: → Howell-Jolly = Asplenia. → Schistocytes = Microangiopathic hemolysis (TTP, HUS, DIC). → Target cells = Thalassemia or Liver disease. → Burr cells = Uremia. → Spur cells = Severe liver disease or McLeod blood group. • EPO Dynamics: EPO rises logarithmically when Hb falls below 12 g/dL; low EPO in the setting of anemia suggests renal failure or inflammation.

Reference Tables

TABLE 66-1 Red Cell Indices INDEX Mean corpuscular volume (MCV) Mean corpuscular hemoglobin concentration Mean…

Harrison's 22e, p.445

INDEX FORMULA NORMAL
VALUES		 COMMENT
Mean corpuscular
volume (MCV)		 Hct/RBC
count × 10		 85–95 fL RBC size
Hgb/Hct × 100 33.8–34.2 g/dL
Mean corpuscular
hemoglobin (MCH)		 Hgb/RBC
count × 10		 28.5–32.3 pg Varies linearly with MCV;
therefore, of limited
additional value

TABLE 66-2 Changes in Normal Hemoglobin/Hematocrit Values with Age, Sex, and Pregnancy AGE/SEX At birth Childhood…

Harrison's 22e, p.445

AGE/SEX HEMOGLOBIN, g/dL HEMATOCRIT, %
At birth 17 52
12
Adolescence 13 40
16 (±2)
Adult woman
(menstruating)		 13 (±2) 40 (±6)
14 (±2)
During pregnancy 12 (±2) 37 (±6)

TABLE 66-3 Red Cell Morphology Macro-ovalocytes

Harrison's 22e, p.447

PATHOPHYSIOLOGY DISEASE STATES
Macro-ovalocytes Hemoglobin excess
(nuclear-cytoplasmic
dyssynchrony)		 B and/or folate deficiencies
12
Myelodysplasia
Loss of membrane
Hypochromia Hemoglobin deficiency
(corresponds to low
mean corpuscular
hemoglobin
concentration)		 Iron deficiency
Thalassemia
Sideroblastic anemia
Anemia of chronic disease
Red blood cell
fragmentation
Sickle cell Hemoglobin
polymerization		 Sickle cell disease
Relative membrane
excess
Polychromatophilia Persistence of
polyribosomes
(corresponds to high
reticulocyte count)		 Hemolytic anemia
Pathologic precipitation
of polyribosomes

TABLE 66-4 Classification of Anemia By Size of Red Cell Microcytic Anemia of inflammation Iron deficiency Sideroblastic…

Harrison's 22e, p.449

  • By Size of Red Cell
  • Microcytic
  • Anemia of inflammation
  • Iron deficiency
  • Sideroblastic
  • Thalassemia
  • Macrocytic
  • Oval Macrocytes
  • Vitamin B deficiency
    12
  • Folate deficiency
  • Medications (chemotherapy, some antiseizure medications)
  • Myelodysplasia
  • Round Macrocytes
  • Alcohol use
  • Dysproteinemia
  • Hypothyroidism
  • Hypoxia
  • Liver disease
  • Reticulocytosis
  • Smoking
  • Normocytic
  • Aplastic anemia
  • Endocrinopathies
  • Marrow invasion
  • Myeloma
  • Pure red cell aplasia
  • Renal disease
  • By Mechanism
  • Hyperproduction
  • Bleeding
  • Hemolysis
  • Acquired
  • Autoimmune
  • Mechanical
  • Congenital
  • Hemibrain defect
  • Hemoglobinopathies
  • Enzyme defects
  • Underproduction
  • Nutritional Deficiency
  • Vitamin B
    12
  • Copper
  • Folate
  • Iron
  • Vitamin C
  • Absence of Red Cell Precursors
  • Aplastic anemia
  • Pure red cell aplasia
  • Lack of Erythropoietin
  • Anemia of inflammation
  • Renal disease
  • Anemia of aging
  • Marrow Replacement
  • Granulomatous disease
  • Infection
  • Neoplasm
  • Stem Cell Defects
  • Acute leukemia
  • Chronic leukemia
  • Myelodysplasia