Chapter 16:Anemia: Definition, Symptoms, and Diagnosis

• Anemia is functionally defined as a decrease in the oxygen-carrying capacity of the blood.
• Operationally, anemia is defined as a reduction in the hemoglobin content of the blood.

Clinical Findings in Anemia

• Decreased oxygen delivery to tissues reduces energy for daily activities, leading to fatigue.
• Other symptoms include pica, pallor, jaundice, and shortness of breath.
• Moderate anemia (hemoglobin 7-10 g/dL) may cause pallor of conjunctivae and nail beds, but might not show other symptoms if onset is slow.
• Severe anemia (hemoglobin <7 g/dL) typically results in pallor, dyspnea, vertigo, and headache.

Importance of History and Physical Examination

• Key historical elements include dietary habits (iron, vitamin B12, folate intake).
• Also important are gastrointestinal symptoms, menstrual history, chronic diseases, and medication use.
• Consider toxin exposure (lead, benzene) and family history (sickle cell disease, thalassemia).
• Physical examination can offer important diagnostic clues.

Body's Adaptation to Anemia

• In severe blood loss, blood volume decreases, causing hypotension and reduced blood supply to the brain and heart.
• Sympathetic overdrive increases heart rate, respiratory rate, and cardiac output.
• Short-term anemia redirects blood to vital organs like the brain, muscle, and heart.
• Oxygen is preferentially supplied to vital organs, even with reduced oxygen-carrying capacity.
• Tissue hypoxia increases RBC 2,3-bisphosphoglycerate, shifting the oxygen dissociation curve to the right and increasing oxygen delivery.
• Long-term adaptations to slowly developing anemia increase the oxygen-carrying capacity of a reduced amount of hemoglobin.
• This improves oxygen delivery but strains the heart, potentially leading to cardiac failure.
• Increased erythropoietin stimulates the bone marrow to produce more RBCs.
• Fluid levels increase to compensate for decreased blood volume to maintain blood pressure and osmotic balance.
• This results in a decreased hematocrit (lower ratio of cells to fluid).

Decreased RBC Survival

• Decreased lifespan can occur through increases in hemolytic processes (intravascular, extravascular).
• Blood loss is a unique subset, which can be acute or chronic.
• Chronic blood loss often leads to iron deficiency.

Types of Erythropoiesis

• Effective erythropoiesis involves normal production of functional RBCs, like in anemia due to acute blood loss.
• Ineffective erythropoiesis is the production of defective erythroid precursor cells, leading to premature destruction in the bone marrow (e.g., megaloblastic anemia, thalassemia major), and is hypercellular.
• Insufficient erythropoiesis is a decreased number of erythroid precursors in the bone marrow, leading to decreased RBC production due to inadequate erythropoietic stimulus or marrow failure (e.g., aplastic anemia, chronic kidney disease), and is hypocellular.

Initial Laboratory Procedures for Diagnosing Anemia

• A complete Blood Count (CBC) evaluates hemoglobin, hematocrit, and RBC indices (MCV, MCH, MCHC, RDW).
• Mean cell volume (MCV) and red cell distribution width (RDW) are important.
• Reticulocyte Count assesses marrow production of erythroids.
• Peripheral Blood Smear identifies RBC morphology and abnormalities.
• Bone Marrow Examination is done if marrow failure, myelodysplasia, or infiltrative disease is suspected.
• Iron studies (serum Fe, serum ferritin, TIBC, transferrin saturation)
• Serum haptoglobin, lactate dehydrogenase, and unconjugated bilirubin (to detect excessive hemolysis).
• Renal and hepatic function tests.
• Homogeneous cell population (low RDW) is often associated with genetic or longstanding disorders.
• Heterogeneous cell population (high RDW) is more likely caused by acquired or progressing disorders.

Importance of Reticulocyte Count

• Reticulocyte count helps determine if anemia is due to an RBC production defect or premature hemolysis/shortened survival.
• Corrected reticulocyte count involves multiplying the reticulocyte percentage by the patient’s hematocrit and dividing by 45.
• If reticulocytes are released prematurely and remain in circulation for 2-3 days, the corrected reticulocyte count must be divided by maturation time to determine the reticulocyte production index.
• The adult reference interval for the reticulocyte count is 0.5% to 2.5% of total RBCs.
• The newborn reference interval is 1.5% to 6.0%, which changes to adult levels within a few weeks.

Peripheral Blood Film Examination

• Spherocytes indicate hereditary spherocytosis or autoimmune hemolytic anemia.
• Schistocytes indicate microangiopathic hemolytic anemia (MAHA), DIC, or TTP.
• Target cells indicate liver disease or thalassemia.
• Bite cells indicate G6PD deficiency.
• Howell-Jolly bodies indicate post-splenectomy.
• Basophilic stippling indicates lead poisoning or thalassemia.
• Rouleaux formation indicates multiple myeloma.

Variations in Red Blood Cell Morphology

• Inclusions include Howell-Jolly bodies (nuclear remnants), Pappenheimer bodies (iron deposits), and Heinz bodies (denatured hemoglobin in G6PD deficiency).
• Color Changes include hypochromia (iron deficiency) and polychromasia (reticulocytosis).
• Volume Changes include microcytosis (iron deficiency, thalassemia) and macrocytosis (megaloblastic anemia, alcoholism).
• Variations in Arrangement include rouleaux formation (multiple myeloma) and agglutination (cold agglutinin disease).

Anemia Classification based on RBC Production

Microcytosis with hypochromia

• Examples include Iron deficiency and thalassemia

Normocytic/Normochronic Anemias

• MCV of 80 – 100 fL
• MCHC of 32 – 36 g/dL
• Small subset of spherocytic disorders (MCHC >36 g/dL)
• Widely varied group of disorders è more difficult to identify/diagnose
• Hemolytic anemias (most causes of)
• Membrane defects
• Hemoglobinopathies (most types)
• Immune/autoimmune causes
• Enzymopathies
• Malaria/Babesia infection
• BM failure (aplastic anemias)*

Macrocytosis

• Examples include Vitamin B12/folate deficiency and liver disease.
• MCV greater than 100 fL
• MCHC within reference range (32 –36 g/dL)
• RBCs appear macrocytic
• May be megaloblastic or non- megaloblastic
• Refers to the characteristic abnormality seen in the developing cells in the bone marrow

Algorithm Incorporating Mean Cell Volume (MCV)

Measure MCV:

• MCV is calculated in femtoliters (fL) and determines the average volume of a red blood cell.
• Reference range typically: 80−100 100 fL):
• Common Causes:
• Vitamin B12 Deficiency: Often due to malabsorption or dietary deficiency.
• Folate Deficiency: Can be dietary or due to increased requirements.
• Liver Disease: Affects RBC membrane lipids.
• Hypothyroidism: Slow metabolic processes affect RBC maturation.
• Alcoholism: Can interfere with folate metabolism.
• Myelodysplastic Syndromes: Disorders caused by poorly formed blood cells.

Next Steps:

• Microcytic: Check serum ferritin, serum iron, TIBC, and hemoglobin electrophoresis.
• Normocytic: Consider reticulocyte count to differentiate between production issues and increased destruction. Investigate renal function, inflammatory markers, or bone marrow biopsy if needed.
• Macrocytic: Assess for vitamin B12 and folate levels. Evaluate liver function tests, thyroid function, and a peripheral blood smear.