• Pernicious anemia is a specific form of megaloblastic anemia caused by a deficiency in vitamin B12 due to a lack of intrinsic factor.

• The deficiency impairs DNA synthesis, which disrupts the normal maturation and division of red blood cell precursors in the bone marrow.

• This results in the production of larger-than-normal red blood cells, described as macrocytic (increased MCV) and often oval-shaped (macro-ovalocytes).

Why the other options are incorrect:

• a) Microcytic: This is characteristic of anemias with defective hemoglobin synthesis, such as iron deficiency or thalassemia.

• b) Spherocytic: This is the hallmark of hereditary spherocytosis and is seen in autoimmune hemolytic anemia.

• c) Hypochromic: This describes pale red cells with low hemoglobin content and is a key feature of iron deficiency anemia and thalassemia.

• Pernicious anemia = autoimmune destruction of gastric parietal cells → intrinsic factor deficiency → vitamin B12 deficiency.

• B12 deficiency impairs DNA synthesis, leading to megaloblastic anemia.

Peripheral smear findings:

• Macrocytosis (large RBCs, ↑ MCV).

• Oval macrocytes.

• Hypersegmented neutrophils.

• In severe cases → pancytopenia (↓ RBCs, WBCs, and platelets) due to impaired DNA synthesis across all hematopoietic lines.

Why the other options are incorrect:

• b) Leukocytosis and elliptocytosis: Leukocytosis (high white count) is not present; leukopenia is. Elliptocytosis is a feature of hereditary elliptocytosis, not pernicious anemia.

• c) Leukocytosis and ovalocytosis: Leukocytosis is incorrect. While ovalocytes (macro-ovalocytes) are characteristic, they occur in the setting of pancytopenia, not leukocytosis.

• d) Pancytopenia and microcytosis: While pancytopenia can occur, the red cells are macrocytic, not microcytic. Microcytosis is the hallmark of iron deficiency or thalassemia.

• Macrocytosis (enlarged red blood cells) is the hallmark of megaloblastic anemia caused by Vitamin B12 (or folate) deficiency. The deficiency impairs DNA synthesis, leading to larger, immature red blood cells.

• Pancytopenia (a reduction in all blood cell lines—red cells, white cells, and platelets) occurs because Vitamin B12 deficiency affects all rapidly dividing cells in the bone marrow, not just the red blood cell precursors.

• G6PD deficiency → X-linked enzyme defect in red blood cells → reduced ability to handle oxidative stress.

• Triggers of hemolysis include:

  • Fava beans (favism)

  • Certain drugs (e.g., sulfa drugs, antimalarials)

  • Infections

• Clinical features during hemolytic episode:

  • Sudden fatigue/lethargy

  • Abdominal or back pain

  • Hemoglobinuria (dark urine due to intravascular hemolysis)

Other options:

• a) Dehydration  → May worsen general health but does not trigger hemolysis.

• b) Excess iron → Not a trigger; iron overload is unrelated.

• d) Increased glucose → Actually beneficial; glucose helps NADPH production via pentose phosphate pathway.

• LDH is an enzyme found inside red blood cells. When red blood cells are destroyed (lysed) prematurely, as in hemolytic anemia, LDH is released into the bloodstream, causing an elevated serum LDH level. It is a direct marker of cell damage and hemolysis.

Why the other options are incorrect:

• a) Haptoglobin: This is low or absent in hemolytic anemia. Haptoglobin binds to free hemoglobin released from lysed red cells, and the complex is rapidly cleared from the blood, depleting haptoglobin levels.

• c) Serum folate: Folate levels can become depleted in chronic hemolytic anemia due to increased red cell production (erythropoiesis) consuming folate, but it is not a direct marker of hemolysis and is not consistently elevated.

• d) Serum ferritin: This measures iron stores. It is not a marker for hemolysis. In chronic hemolytic states, ferritin can be elevated due to repeated blood transfusions, but this is an indirect effect.

• Aplastic anemia is defined by bone marrow failure. The central problem is that the bone marrow becomes hypocellular or acellular, meaning it is empty and contains mostly fat, with very few blood-forming (hematopoietic) cells.

• This failure to produce cells leads to pancytopenia (a reduction in all blood cell lines: red blood cells, white blood cells, and platelets) in the peripheral blood.

Why the other options are incorrect:

• a) Increased bone marrow cellularity: This is the opposite of what is found in aplastic anemia. Increased cellularity is seen in conditions like leukemia or myeloproliferative neoplasms.

• c) Increased reticulocytes: Reticulocytes are young red blood cells. Because the bone marrow is failing, it cannot produce new red blood cells effectively. Therefore, the reticulocyte count is typically very low (inappropriately low for the degree of anemia).

• d) Increased serum iron: While this can be a consequence of aplastic anemia (because the bone marrow isn’t using iron to make new red blood cells), it is not the defining feature. The hallmark pathological finding is the decreased bone marrow cellularity.

Here’s why this is the correct answer and the others are not:

• Macrocytic anemia: This means the red blood cells are larger than normal (high MCV). This is a hallmark of megaloblastic anemia.

• Hypersegmented neutrophils: This is a classic, specific finding in megaloblastic anemia caused by a deficiency in vitamin B12 or folate, where the DNA synthesis of white blood cells is also impaired.

• Glossitis: This is inflammation of the tongue, which is a common symptom of both vitamin B12 and folate deficiencies.

Why the other options are incorrect:

• a) Iron deficiency anemia: This causes microcytic (small) red blood cells, not macrocytic.

• c) Thalassemia minor: This also causes microcytic red blood cells, and it does not cause hypersegmented neutrophils or glossitis.

• d) Anemia of chronic disease: This is typically a normocytic (normal-sized) anemia, not macrocytic.

• produces more transferrin in an attempt to scavenge and bind any available iron. This increased capacity to bind iron results in an elevated TIBC.

• Storage Iron: Decreased
  This is the fundamental issue. Iron stores in the bone marrow (as ferritin and hemosiderin) are depleted or absent before a full-blown anemia develops. In a severe case, they are markedly decreased.

This combination of low serum iron, high TIBC, and low storage iron is the hallmark laboratory triad for uncomplicated iron deficiency anemia.

Why the other options are incorrect:

• a) Serum Iron: Decreased, TIBC: Decreased, Storage Iron: Decreased: A decreased TIBC is typical of anemia of chronic disease, not iron deficiency.

• c) Serum Iron: Increased, TIBC: Decreased, Storage Iron: Increased: This pattern is seen in conditions like hemochromatosis or iron overload, where iron levels are high.

• d) Serum Iron: Increased, TIBC: Normal, Storage Iron: Decreased: This is not a typical pattern for any common anemia. Increased serum iron with low storage iron is a contradiction.

• Sideroblastic anemia is characterized by a failure to incorporate iron into the heme molecule within the mitochondria of developing red blood cells.

• This is due to defective enzymes in the heme synthesis pathway (often involving aminolevulinic acid synthase (ALAS) or other enzymes in the porphyrin pathway).

• Because iron cannot be used properly, it accumulates in the mitochondria of erythroid precursors, forming a ring of iron-laden mitochondria around the nucleus. These are the ringed sideroblasts, which are the hallmark of this anemia.

• Supravital stains (such as crystal violet or methylene blue) are applied to living cells or unfixed blood smears.

• Heinz bodies are denatured hemoglobin and are not visible on a standard Wright-stained smear.

• The supravital stain specifically precipitates and stains these denatured hemoglobin inclusions, making them appear as small, round, purple-blue granules attached to the inner red cell membrane.

Why the other options are incorrect:

• a) Wright stain: This is the standard stain used for routine blood smears. It does not reliably demonstrate Heinz bodies.

• b) Prussian blue stain: This stain detects iron (specifically ferric iron) and is used to identify hemosiderin in bone marrow macrophages, confirming iron stores.

• d) PAS stain (Periodic Acid-Schiff): This stain detects carbohydrates (glycogen, glycoproteins). It is used in hematology to identify abnormal cells in conditions like acute lymphoblastic leukemia (ALL) or erythroleukemia (M6), not Heinz bodies.

• HbS stands for Hemoglobin S.

• It is caused by a specific point mutation in the beta-globin gene, where valine is substituted for glutamic acid at the sixth position.

• This structural change causes the hemoglobin to polymerize and form long, rigid fibers under conditions of low oxygen, which distorts the red blood cell into the characteristic sickle shape.

Why the other options are incorrect:

• a) HbC: This is a different hemoglobin variant that can cause mild hemolytic anemia but does not cause sickling.

• c) HbA2: This is a normal, minor adult hemoglobin. Its levels are elevated in conditions like beta-thalassemia, but it is not the cause of sickle cell disease.

• d) HbE: This is another common hemoglobin variant, especially in Southeast Asia, that is associated with a mild microcytic anemia but not sickling.

• Megaloblastic anemia (B12 or folate deficiency): defective DNA synthesis → nuclear maturation lags behind cytoplasm.

• This leads to nuclear remnants inside RBCs that appear as Howell–Jolly bodies (single, round, purple inclusions).

• They are also seen in asplenia/hyposplenism (since spleen normally removes them).

Why the other options are incorrect:

• b) Heinz bodies: These are denatured hemoglobin and are associated with G6PD deficiency and other oxidative hemolytic anemias. They are not visible on a standard Wright stain and require a supravital stain.

• c) Basophilic stippling: This is the aggregation of ribosomes and is classically associated with lead poisoning and thalassemia.

• d) Pappenheimer bodies: These are small iron-containing granules (aggregates of ferritin) and are associated with sideroblastic anemias and post-splenectomy. They are visible with a Prussian blue iron stain.

Here’s why the other options are incorrect:

• a) High serum ferritin: This is the opposite of what is found. Ferritin is a measure of iron stores. In iron deficiency, ferritin is low. A high ferritin can be seen in anemia of chronic disease.

• c) Increased MCV: MCV (Mean Corpuscular Volume) measures the average size of red blood cells. In iron deficiency anemia, the MCV is typically low (microcytic anemia), not high. An increased MCV is seen in anemias like B12 or folate deficiency.

• d) Elevated reticulocyte count: Reticulocytes are young red blood cells. An elevated count indicates the bone marrow is actively producing new cells. In iron deficiency, the bone marrow is unable to produce adequate red blood cells due to the lack of iron, so the reticulocyte count is typically low or inappropriately normal.

• Sickle cell anemia patients normally have chronic hemolytic anemia, often with baseline hemoglobin ~8 g/dL and elevated reticulocyte count (compensatory).

• Presentation: sudden drop in hemoglobin to 4 g/dL + reticulocytopenia (0.1%) indicates the bone marrow is not producing RBCs.

• Most common cause: infection with parvovirus B19, which temporarily suppresses erythropoiesis → aplastic crisis.

Why the other options are incorrect:

• a) Increased hemolysis due to hypersplenism: While increased hemolysis can cause a drop in hemoglobin, it would be accompanied by a high reticulocyte count as the bone marrow tries to compensate. The low reticulocyte count here rules this out.

• c) Thrombotic crisis (Vaso-occlusive crisis): This causes severe pain from tissue ischemia but does not typically cause a dramatic fall in hemoglobin or suppress the reticulocyte count.

• d) Occult blood loss: Blood loss would also trigger a compensatory increase in reticulocytes as the bone marrow responds. The low reticulocyte count is inconsistent with blood loss.

• The Schilling test was a specialized medical procedure used to determine whether a patient could absorb vitamin B12. It specifically helped distinguish the cause of a B12 deficiency.

• The test involved administering radioactive vitamin B12 orally and then measuring its excretion in the urine. Poor absorption indicated a problem in the gut.

• The test was then repeated with the addition of oral intrinsic factor. If absorption normalized with intrinsic factor, it confirmed that the deficiency was due to a lack of intrinsic factor, which is the defining cause of pernicious anemia.

Why the other options are incorrect:

• a) Iron deficiency anemia: Diagnosed with tests like serum ferritin, iron, and TIBC.

• c) Hemolytic anemia: Diagnosed with tests like LDH, bilirubin, haptoglobin, and a direct Coombs test.

• d) Thalassemia: Diagnosed with hemoglobin electrophoresis and genetic testing.

• Haptoglobin is a protein that binds free hemoglobin released from destroyed red blood cells.

• In hemolytic anemia, the rate of red cell destruction exceeds the liver’s ability to produce haptoglobin, leading to a low serum haptoglobin level. This makes it a very sensitive and direct marker for intravascular hemolysis.

Role of the other tests:

• a) Serum ferritin: This measures the body’s iron stores. It is used to diagnose iron deficiency, not hemolysis.

• b) Reticulocyte count: This is an excellent measure of the bone marrow’s response to anemia. In hemolytic anemia, the count is high, but it is an indirect sign of destruction, not a direct measure of it.

• d) Serum folate: This measures folate levels and is used to diagnose folate deficiency, which can cause megaloblastic anemia.

• Basophilic stippling = presence of aggregated ribosomal RNA in RBCs.

• Classically seen in lead poisoning, which inhibits enzymes (δ-ALA dehydratase and ferrochelatase) in heme synthesis → defective hemoglobin production.

• Also seen in thalassemia and sideroblastic anemia, but the classic exam answer is lead poisoning.

Why the other options are incorrect:

• a) Iron deficiency anemia: The hallmark findings are microcytosis and hypochromia, not basophilic stippling.

• c) Pernicious anemia: This is a megaloblastic anemia, characterized by macro-ovalocytes and hypersegmented neutrophils, not basophilic stippling.

• d) Hemolytic anemia: While basophilic stippling can be seen in some hemolytic anemias like beta-thalassemia (due to unbalanced globin chain synthesis), it is not a general feature of all hemolytic anemias. Lead poisoning is the more specific and classic association for prominent basophilic stippling.

• Paroxysmal cold hemoglobinuria (PCH): a rare autoimmune hemolytic anemia, often post-viral in children.

• Caused by Donath-Landsteiner antibody, which is:

  • IgG type

  • Biphasic hemolysin → binds RBCs at cold temperatures (periphery) and activates complement → causes intravascular hemolysis when warmed (central circulation).

Why the other options are incorrect:

• a) IgM cold agglutinin: This describes the antibody in Cold Agglutinin Disease. The DL antibody is IgG, not IgM.

• b) Biphasic IgM hemolysin: This is incorrect on two counts. The DL antibody is IgG, not IgM, and classic IgM cold agglutinins are not typically described as “biphasic hemolysins” in this manner.

• d) IgG warm agglutinin: This describes the antibodies found in Warm Autoimmune Hemolytic Anemia. These antibodies react best at 37°C and typically cause agglutination, not the biphasic hemolysis characteristic of PCH.

• Spherocytes are small, spherical, and densely staining red blood cells that have lost their normal biconcave shape.

• They are the hallmark finding in hereditary spherocytosis. This condition is caused by a genetic defect in the red blood cell membrane skeleton (often spectrin, ankyrin, or band 3), which makes the membrane unstable and causes the cell to lose surface area and become spherical.

Why the other options are incorrect:

• b) Iron deficiency anemia: This typically causes microcytic, hypochromic cells, not spherocytes.

• c) Megaloblastic anemia: This causes macrocytic (large) ovalocytes, not spherocytes.

• d) Beta-thalassemia trait: This causes microcytic, hypochromic cells, often with target cells, not spherocytes.

• Heinz bodies are denatured, insoluble clumps of hemoglobin that form within red blood cells.

• They occur when the red cell is exposed to oxidative stress.

• In G6PD deficiency, the pentose phosphate pathway is impaired, leading to a shortage of NADPH. This reduces the cell’s ability to maintain protective levels of glutathione, making it highly susceptible to oxidative damage. This damage causes hemoglobin to denature and form Heinz bodies.

• The spleen normally “pits” these Heinz bodies out of the cells, leading to “bite cells.”

Why the other options are incorrect:

• b) Iron deficiency anemia: The primary issue is a lack of hemoglobin production, not oxidative damage leading to denatured hemoglobin.

• c) Aplastic anemia: The problem is bone marrow failure and a lack of production of all blood cell lines, not an intrinsic red cell defect.

• d) Sickle cell anemia: The pathology is due to the polymerization of a mutant hemoglobin (HbS) under low oxygen conditions, not the oxidative denaturation of normal hemoglobin. While sickle cells can be damaged, Heinz bodies are not a characteristic feature.

• MCV directly measures the average size of the red blood cells. A low MCV (typically defined as <80 fL) is the definitive characteristic of a microcytic anemia.

Why the other options are incorrect:

• b) MCHC (Mean Corpuscular Hemoglobin Concentration): This measures the concentration of hemoglobin within red cells. While it can be low in iron deficiency and thalassemia, it is less sensitive and specific than the MCV for initially classifying the anemia as microcytic.

• c) RDW (Red Cell Distribution Width): This measures the variation in red cell size (anisocytosis). It is very useful in determining the cause of a microcytic anemia (e.g., high in iron deficiency, normal in thalassemia), but it doesn’t tell you if the cells are microcytic on average.

• d) Reticulocyte Count: This measures bone marrow response and is crucial for determining if the anemia is due to underproduction or increased destruction, but it does not provide information about red cell size.

• Normal individuals have 4 functional alpha-globin genes (two on each chromosome 16).

• The severity of alpha-thalassemia depends on how many of these genes are missing or non-functional.

Let’s break down the genotypes:

• a) 1 of 4 alpha-globin genes missing: This is the “silent carrier” state. It is asymptomatic with no hematologic abnormalities.

• b) 2 of 4 alpha-globin genes missing: This is alpha-thalassemia trait (or minor). It causes mild microcytic anemia.

• c) 3 of 4 alpha-globin genes missing: This is Hemoglobin H (HbH) disease. With only one functional gene, there is a significant shortage of alpha-globin chains. The excess beta-globin chains form tetramers called Hemoglobin H (β₄), which are unstable and precipitate, causing hemolytic anemia.

• d) All 4 alpha-globin genes missing: This is Hb Bart’s hydrops fetalis, which is fatal in utero or shortly after birth. The excess gamma-globin chains form tetramers called Hemoglobin Bart’s (γ₄).

Paroxysmal nocturnal hemoglobinuria (PNH):

• Caused by an acquired mutation in the PIGA gene in hematopoietic stem cells.

• This leads to loss of GPI-anchored proteins (like CD55 = decay accelerating factor, and CD59 = MAC-inhibitory protein) from the RBC membrane.

• Without these protective proteins, RBCs become abnormally sensitive to complement-mediated lysis → intravascular hemolysis.

Why the other options are incorrect:

• a) Temperature-dependent antibodies: This describes the mechanism in Cold Agglutinin Disease, not PNH.

• c) Antibody-mediated complement activation: This describes the mechanism in Autoimmune Hemolytic Anemia, where an external antibody binds to the RBC and activates complement. In PNH, the problem is the lack of protection on the cell itself; no external antibody is required.

• d) A complement-independent mechanism: This is incorrect. The hemolysis in PNH is profoundly complement-dependent.

• Beta-thalassemia major = defective β-globin synthesis → ↓ HbA → severe anemia.

• RBC morphology:

  • Microcytosis (small cells, low MCV)

  • Target cells (excess membrane relative to reduced Hb content)

  • Also, anisopoikilocytosis (variation in size and shape).

Why the other options are incorrect:

• a) Macrocytosis: This is seen in megaloblastic anemias (B12/folate deficiency), not thalassemia.

• c) Howell-Jolly bodies: These nuclear remnants are seen in patients with a non-functioning or absent spleen. While thalassemia major patients often require splenectomy, the bodies are a consequence of the treatment, not a primary feature of the disease itself.

• d) Spherocytes: These are the hallmark of hereditary spherocytosis and are seen in autoimmune hemolytic anemia.

This is a specific point mutation in the gene that codes for the beta-globin chain of hemoglobin. The substitution of the amino acid valine for glutamic acid causes the hemoglobin to polymerize under low oxygen conditions, distorting the red blood cell into the characteristic sickle shape. This abnormal hemoglobin is called Hemoglobin S (HbS).

Why the other options are incorrect:

• b) Lysine replaces glutamic acid at position 6 of beta chain: This specific substitution creates a different abnormal hemoglobin called Hemoglobin C (HbC), which causes a milder hemolytic anemia.

• c) Deletion of alpha globin gene: This is the genetic cause of alpha-thalassemia, not sickle cell disease.

• d) Insertion mutation in beta globin gene: Sickle cell disease is caused by a point mutation (a single nucleotide change), not an insertion or deletion.

• Aplastic anemia = failure of bone marrow → ↓ RBCs, WBCs, platelets (pancytopenia).

• The anemia is normocytic, normochromic, but the marrow cannot respond → low reticulocyte count.

• Microcytic: The red blood cells are smaller than normal (low MCV). This occurs because iron is a crucial component of heme, and a deficiency limits hemoglobin production. The cell divides more times before filling with hemoglobin, resulting in a smaller final size.

• Hypochromic: The red blood cells have less color (low MCHC) because they contain less hemoglobin, the pigment that gives them their red color. This appears as a large area of central pallor on a blood smear.

Why the other options are incorrect:

• b) Macrocytic, hyperchromic RBCs: This is seen in megaloblastic anemias (e.g., B12 or folate deficiency). “Hyperchromic” is also a misnomer, as cells are typically normochromic but appear overly colored because they are larger.

• c) Sickle-shaped RBCs: This is the hallmark of sickle cell disease.

• d) Bite cells: These are associated with oxidative hemolysis, as seen in G6PD deficiency.

• Renal cell carcinoma (RCC) can produce ectopic erythropoietin → stimulates red blood cell production → secondary polycythemia/erythrocytosis.

• Other tumors that may rarely cause erythrocytosis via EPO production: hepatocellular carcinoma, cerebellar hemangioblastoma.

Other options:

• a) Sarcoma → Not typically associated with EPO production.

• c) Basal cell carcinoma  → Local skin cancer, not linked to erythrocytosis.

• d) Squamous cell carcinoma of the lung  → Not associated with EPO-mediated polycythemia.

• MCHC (Mean Corpuscular Hemoglobin Concentration) measures the average concentration of hemoglobin within red blood cells.

• In hereditary spherocytosis, the loss of membrane surface area (without a proportional loss of hemoglobin) causes the red cell to become more spherical and densely packed.

• This results in a consistently elevated MCHC (typically >36 g/dL), which is one of the most characteristic and reliable screening clues for this condition.

Why the other options are less consistent:

• a) RBC count, c) Hemoglobin: These values are decreased (showing anemia), but the degree of anemia can vary significantly among individuals with HS, from being very mild to severe.

• b) MCV (Mean Corpuscular Volume): The MCV is usually normal or slightly low. It is not a standout finding like the elevated MCHC.

• Autoimmune gastritis → autoimmune destruction of gastric parietal cells → loss of intrinsic factor.

• Intrinsic factor is required for Vitamin B12 absorption in the ileum.

• Result = Vitamin B12 deficiency → megaloblastic anemia → pernicious anemia.

Why the other options are incorrect:

• a) Sideroblastic anemia: This is caused by a defect in heme synthesis within the mitochondria, leading to ringed sideroblasts in the bone marrow. It is not related to autoimmune gastritis.

• b) Aplastic anemia: This is a bone marrow failure syndrome, often idiopathic or caused by toxins, drugs, or viruses, not specifically by autoimmune gastritis.

• d) Hemolytic anemia: This is characterized by the premature destruction of red blood cells and has many causes (e.g., autoimmune, mechanical, enzymatic defects), but it is not the direct result of autoimmune gastritis.

• The Direct Antiglobulin Test (DAT / Coombs test) detects antibodies or complement bound to the surface of red blood cells.

• Positive DAT → suggests immune-mediated hemolysis (e.g., autoimmune hemolytic anemia, drug-induced hemolysis, hemolytic disease of the newborn).

• Negative DAT → favors inherited RBC membrane disorders, such as hereditary spherocytosis.

Other options:

• a) Intravascular vs extravascular hemolysis  → DAT does not distinguish this; labs like haptoglobin, LDH, bilirubin help.

• b) Heterozygous vs homozygous thalassemia  → Diagnosed by Hb electrophoresis, not DAT.

• d) Sickle cell trait vs disease → Distinguished by Hb electrophoresis, not DAT.

• In beta-thalassemia minor, there is a reduced synthesis of the beta-globin chains of hemoglobin.

• This causes a compensatory increase in the production of other, non-beta chains.

• HbA2 (alpha-2/delta-2) is consistently elevated above 3.5%, which is a key diagnostic feature.

• HbF (alpha-2/gamma-2) is also frequently elevated.

Why the other options are incorrect:

• a) Sickle cell trait: Hemoglobin electrophoresis shows mostly normal HbA with a significant amount of HbS (typically around 40%). HbA2 and HbF levels are not characteristically elevated.

• b) Iron deficiency anemia: This can actually cause a decrease in the HbA2 level, which can potentially mask the diagnosis of co-existing beta-thalassemia trait.

• d) Alpha-thalassemia trait: Hemoglobin electrophoresis is typically normal because the genetic defect leads to a decreased production of alpha chains, but there is no compensatory hemoglobin like HbA2 or HbF that can form without alpha chains. The diagnosis is often one of exclusion.

Anemia of chronic inflammation (ACI / anemia of chronic disease) occurs in chronic infections, autoimmune diseases, or malignancy.

• Microcytic or normocytic anemia

• Low serum iron → iron is sequestered in macrophages

• Low TIBC → liver decreases transferrin synthesis

• Normal or high ferritin → iron stores are adequate but unavailable for erythropoiesis

Why other options are incorrect:

• a) Iron deficiency anemia  → TIBC is high and ferritin is low.

• c) Hemochromatosis → Serum iron and ferritin are high, not low.

• d) Acute blood loss → Usually normocytic anemia, iron studies are initially normal.

• Paroxysmal nocturnal hemoglobinuria (PNH) is caused by a PIGA gene mutation in hematopoietic stem cells.

• This leads to a deficiency of GPI-anchored proteins (CD55 = decay-accelerating factor, CD59 = MAC inhibitory protein).

• Without these protective proteins, RBCs become abnormally sensitive to complement-mediated lysis, especially at night → hemoglobinuria in the morning.

Other options:

• a) Vitamin B12 deficiency → Causes megaloblastic anemia, not PNH.

• c) Iron deficiency  → Microcytic anemia, not due to complement.

• d) Malaria infection  → Can cause hemolysis, but mechanism is parasitic destruction, not complement sensitivity.

• Hereditary spherocytosis (HS) is caused by genetic mutations in proteins of the red blood cell’s membrane skeleton, such as ankyrin, band 3, spectrin, or protein 4.2.

• A deficiency in any of these proteins (with band 3 and ankyrin being the most common) leads to a loss of membrane surface area and the formation of spherical, fragile red blood cells (spherocytes).

• Therefore, a decreased level of one of these membrane proteins (like band 3) is the underlying molecular defect.

• Hemoglobin electrophoresis directly identifies and quantifies the different types of hemoglobin present in the blood (HbA, HbA2, HbF, and abnormal variants like HbS).

• This is the key to diagnosing thalassemia:

  • In beta-thalassemia trait, it shows an elevated HbA2 (>3.5%).

  • In more severe beta-thalassemia, it shows elevated HbF.

  • It helps distinguish thalassemia from other microcytic anemias and can also identify structural hemoglobin variants.

Why the other options are incorrect:

• b) Serum ferritin: This is the best test for iron deficiency. It is crucial to rule out iron deficiency as a cause of microcytosis, but it does not diagnose thalassemia.

• c) Reticulocyte count: This measures bone marrow response. It may be elevated in thalassemia due to ineffective erythropoiesis, but it is not specific and does not confirm the diagnosis.

• d) Coombs test: This is used to diagnose autoimmune hemolytic anemia, not thalassemia.

• In chronic hemolytic anemia, there is ongoing breakdown of RBCs → ↑ unconjugated bilirubin.

• Excess bilirubin precipitates in the gallbladder → formation of pigment gallstones (black stones).

Why the other options are incorrect:

• a) Kidney stones: While not a classic direct association, some hemolytic conditions like sickle cell disease can cause renal damage and a specific type of kidney stone, but it is not the most universal risk.

• c) Peptic ulcers: This is not a direct complication of hemolysis.

• d) Lung fibrosis: This is not a typical complication of chronic hemolytic anemia.

• Bite cells are the classic morphologic finding on a Wright-Giemsa stained peripheral blood smear during an acute hemolytic episode in G6PD deficiency. They are formed when splenic macrophages “bite out” and remove oxidized, denatured hemoglobin (Heinz bodies) from the red blood cell.

Let’s review why the other options are incorrect:

• a) Cabot rings: These are rare, thread-like inclusions seen in red blood cells in severe anemias like megaloblastic anemia or lead poisoning, not specifically in G6PD deficiency.

• b) Microcytosis: This refers to small red blood cells and is the hallmark of iron deficiency anemia and thalassemias, not hemolytic anemias like G6PD deficiency.

• d) Heinz bodies: These are the primary intracellular abnormality, consisting of denatured hemoglobin. However, they are not visible on a standard Wright-Giemsa stain. They require special supravital staining (e.g., with crystal violet). The bite cell is the visible effect of the Heinz body being removed.

While dietary deficiency is a significant cause, especially in certain populations, chronic blood loss from sources like gastrointestinal bleeding (often due to hookworm infection, ulcers, or other GI conditions) and, in women of reproductive age, menstrual blood loss, is the most frequent global cause.

• Idiopathic (now called Hereditary) Hemochromatosis is a genetic disorder (most commonly an HFE gene mutation) that causes increased absorption of dietary iron from the intestines.

• The central pathology is the progressive accumulation of excess iron, which is stored in organs and tissues throughout the body. This iron overload is the defining feature of the disease and leads to damage in the liver, pancreas, heart, and joints.

Why the other options are incorrect:

• a) Target cells: These are associated with liver disease, hemoglobinopathies (like thalassemia), and post-splenectomy, not specifically with hemochromatosis.

• c) Cabot rings: These are rare, ring-shaped RBC inclusions seen in severe anemias, particularly megaloblastic anemia, and are not a feature of hemochromatosis.

• d) Ringed sideroblasts: These are the hallmark of sideroblastic anemia, a disorder of ineffective heme synthesis within the bone marrow. While iron accumulates in the mitochondria of erythroid precursors in that disease, the systemic iron overload in hemochromatosis is a different process.

• Lead poisoning inhibits enzymes in heme synthesis (δ-ALA dehydratase and ferrochelatase).

• This causes accumulation of ribosomal RNA fragments in RBCs → visible as basophilic stippling on peripheral smear.

• Clinically: anemia, abdominal pain, neurologic symptoms (esp. in children).

Why the other options are incorrect:

• a) Macrocytosis: This is seen in megaloblastic anemias (e.g., B12 or folate deficiency), not lead poisoning. Lead poisoning can sometimes cause a mild microcytosis.

• b) Target cells (codocytes): These are associated with hemoglobinopathies (like thalassemia), liver disease, and post-spelenectomy.

• d) Rouleaux formation: This occurs due to high levels of plasma proteins (e.g., in multiple myeloma or inflammation) and is not a feature of lead poisoning.

• Megaloblastic anemia (from vitamin B12 or folate deficiency) is caused by defective DNA synthesis.

• In the bone marrow, this leads to asynchronous development:

  • Nucleus matures slowly (because DNA synthesis is impaired).

  • Cytoplasm matures normally (RNA/protein synthesis unaffected).

Why the other options are incorrect:

• a) Proliferation of erythrocyte precursors: While the bone marrow is hypercellular in megaloblastic anemia due to ineffective erythropoiesis, the key problem is not proliferation but defective maturation due to impaired DNA synthesis.

• c) Inadequate production of erythropoietin: This is the cause of anemia in chronic kidney disease, not megaloblastic anemia.

• d) A deficiency of G6PD: This causes a hemolytic anemia due to oxidative damage, not a maturation defect in the bone marrow.

• Thalassemias are inherited disorders caused by reduced or absent synthesis of one of the globin chains of hemoglobin.

  • α-thalassemia → ↓ or absent alpha-globin chains.

  • β-thalassemia → ↓ or absent beta-globin chains.

• This leads to imbalance in α:β chain ratio, ineffective erythropoiesis, and hemolysis.

• RBC morphology: microcytosis, hypochromia, target cells, basophilic stippling.

Why the other options are incorrect:

• a) Structural abnormality in the hemoglobin molecule: This describes hemoglobinopathies like sickle cell disease (HbS) or hemoglobin C disease (HbC), where the amino acid sequence of the globin chain is altered.

• b) Absence of iron in hemoglobin: This is the problem in iron deficiency anemia. Heme synthesis itself is normal in thalassemia, but it is inefficient due to the lack of globin chains.

• c) Decreased rate of heme synthesis: This is the primary issue in sideroblastic anemias, where the mitochondria are unable to incorporate iron into protoporphyrin to form heme.

• G6PD Deficiency is the most common enzyme deficiency worldwide that leads to hemolytic anemia.

• It is triggered by exposure to certain drugs (like antimalarials, sulfa drugs), infections, or fava beans, which cause oxidative stress.

• This oxidative damage denatures hemoglobin, which then forms insoluble precipitates attached to the red cell membrane called Heinz bodies. These are the “red cell inclusions formed by denatured hemoglobin.”

Why the other options are incorrect:

• a) Pyruvate kinase: Deficiency causes a chronic hemolytic anemia, but it is not typically drug-induced and is not characterized by Heinz bodies.

• b) Lactate dehydrogenase (LDH): This is a marker found in the blood when hemolysis occurs; it is not an enzyme whose deficiency causes anemia.

• c) Hexokinase: Deficiency is extremely rare and causes a hemolytic anemia, but it is not the common drug-induced condition described.

• The osmotic fragility test measures the ability of red blood cells to swell in a hypotonic (dilute) saline solution without bursting.

• Spherocytes (the hallmark of hereditary spherocytosis) have a decreased surface-area-to-volume ratio because they are already nearly spherical.

• As a result, they cannot swell as much as normal, biconcave red blood cells and will lyse (burst) more easily in a hypotonic solution. This is reflected as increased osmotic fragility.

• In chronic kidney disease (CKD), the damaged kidneys cannot produce enough erythropoietin (EPO).

• EPO is the hormone that stimulates bone marrow to produce RBCs.

• Result → normocytic, normochromic anemia.

Other options:

• a) Iron malabsorption  → Seen in GI disorders, not the primary mechanism in CKD.

• c) Folate deficiency  → Causes macrocytic anemia, not typical of CKD.

• d) Hemolysis  → Not the main cause in CKD.

• The Direct Antiglobulin Test (DAT or Direct Coombs Test) is the definitive diagnostic test for Autoimmune Hemolytic Anemia (AIHA).

• It detects the presence of antibodies (IgG) or complement components (C3d) bound to the surface of the patient’s red blood cells in vivo.

• A positive DAT confirms the autoimmune mechanism of the hemolysis, which is the core defining feature of AIHA.

Why the other options are incorrect.

• a) Increased reticulocyte count: This is a common response to hemolysis seen in many hemolytic anemias (like hereditary spherocytosis or G6PD deficiency), but it is not specific to the autoimmune cause.

• b) Leukopenia and thrombocytopenia: This combination is more characteristic of conditions like aplastic anemia or certain leukemias. In isolated AIHA, the white blood cell and platelet counts are usually normal or elevated.

• c) Peripheral spherocytosis: Spherocytes are commonly seen on the blood smear in AIHA because macrophages in the spleen partially ingest antibody-coated red cells, removing membrane. However, spherocytes are also the hallmark of hereditary spherocytosis, so their presence alone is not diagnostic of an autoimmune cause. The positive DAT is what distinguishes AIHA from hereditary spherocytosis.

• Polycythemia vera = myeloproliferative neoplasm with ↑ RBC mass.

• Standard treatment = repeated phlebotomy to reduce hematocrit and prevent thrombosis.

• Frequent blood removal → gradual depletion of iron stores → iron deficiency.

• This limits erythropoiesis, which actually helps control the high hematocrit.

Why the other options are incorrect:

• a) Vitamin B12: While B12 levels can be low in some PV patients, this is not a direct result of phlebotomy treatment.

• b) Folic acid: Phlebotomy does not directly cause folate deficiency. Folate is water-soluble and not stored in significant amounts in red blood cells in a way that phlebotomy would deplete.

• d) Erythropoietin: In PV, erythropoietin levels are typically low because the red cell production is autonomous and not driven by EPO. Phlebotomy does not cause a “deficiency” of this hormone; the low level is part of the disease’s diagnostic profile.

Megaloblastic anemia, caused by vitamin B12 or folate deficiency, affects all cell lines in the bone marrow due to impaired DNA synthesis. This results in ineffective hematopoiesis for all blood cells, leading to:

• Anemia (from defective red blood cell production)

• Neutropenia (low neutrophil count)

• Thrombocytopenia (low platelet count)

Why the other options are incorrect:

• b) Decreased LD activity: Lactate dehydrogenase (LD) is markedly increased in megaloblastic anemia due to the destruction of the defective red blood cell precursors within the bone marrow (ineffective erythropoiesis).

• c) Increased erythrocyte folate levels: This is the opposite of the finding. In folate deficiency anemia, erythrocyte folate levels are decreased. In B12 deficiency, folate levels can be variable but are not diagnostically increased.

• d) Decreased plasma bilirubin levels: Unconjugated (indirect) bilirubin is often elevated due to the breakdown of the fragile, abnormal red blood cell precursors in the marrow (intramedullary hemolysis).

• In G6PD deficiency, oxidative stress (from drugs, fava beans, infections) causes denaturation of hemoglobin → forms Heinz bodies inside RBCs.

• Splenic macrophages “bite out” these Heinz body inclusions → producing bite cells (degmacytes).

Why the other options are incorrect:

• a) Target cells: These are associated with liver disease, obstructive jaundice, hemoglobinopathies (like thalassemia), and post-spelenectomy, not specifically with G6PD deficiency.

• c) Spherocytes: These are the hallmark of hereditary spherocytosis and are also seen in autoimmune hemolytic anemia. While some spherocytes may be present in G6PD deficiency due to membrane loss, bite cells are the more specific finding.

• d) Howell-Jolly bodies: These are nuclear remnants seen in the red blood cells of patients with a non-functioning or absent spleen, not in G6PD deficiency.

• Ring sideroblasts are the defining pathological feature of sideroblastic anemia. They are erythroid precursor cells (normoblasts) in the bone marrow where iron-laden mitochondria form a ring or collar around the nucleus. This is visible with a special Prussian blue stain that highlights iron.

• This finding indicates a failure to properly incorporate iron into heme, despite adequate or even increased iron stores.

Why the other options are incorrect:

• a) Iron deficiency anemia: The bone marrow in this condition shows an absence of stainable iron, not ringed sideroblasts.

• c) Aplastic anemia: The bone marrow is hypocellular and empty, lacking the erythroid precursors necessary to form ring sideroblasts.

• d) Pernicious anemia: This is a type of megaloblastic anemia due to B12 deficiency. The bone marrow shows large, immature erythroid precursors (megaloblasts), not ring sideroblasts.

• olic acid is essential for DNA synthesis.

• A deficiency causes megaloblastic anemia, where the development of the red blood cell’s nucleus is impaired, but its cytoplasm matures normally.

• This results in the production of larger-than-normal red blood cells, described as macrocytic cells (high MCV). These cells are often specifically oval-shaped (macro-ovalocytes).

Why the other options are incorrect:

• a) Target cells: These are associated with hemoglobinopathies (like thalassemia), liver disease, and post-spelenectomy, not folic acid deficiency.

• c) Basophilic stippling: This is the aggregation of ribosomes and is classically associated with lead poisoning and thalassemia.

• d) Rouleaux formation: This occurs when red blood cells stack like coins due to elevated plasma proteins and is seen in conditions like multiple myeloma and inflammatory states, not folic acid deficiency.

• Reticulocytes are immature red blood cells released from the bone marrow.

• Reticulocytosis indicates that the bone marrow is actively increasing its production of red blood cells.

• In hemolytic anemia, the premature destruction of red blood cells in the periphery triggers a compensatory response from the bone marrow to produce and release more cells. This leads to a high reticulocyte count.

Why the other options are incorrect:

• a) Aplastic anemia: This is a condition of bone marrow failure, resulting in a low reticulocyte count (the marrow cannot produce new cells).

• c) Megaloblastic anemia: In deficiencies of Vitamin B12 or folate, DNA synthesis is impaired, leading to ineffective erythropoiesis and the destruction of red cell precursors within the marrow. Despite the anemia, the reticulocyte count is low.

• d) Iron deficiency anemia: The lack of iron, a key building block for hemoglobin, impairs the bone marrow’s ability to produce new red blood cells effectively, resulting in an inappropriately low or normal reticulocyte count.

• Pernicious anemia is a specific type of megaloblastic anemia caused by an autoimmune destruction of the parietal cells in the stomach.

• These parietal cells produce intrinsic factor, which is essential for the absorption of vitamin B12 in the small intestine.

• Without intrinsic factor, vitamin B12 cannot be absorbed, leading to a deficiency.

Why the other options are incorrect:

• a) Folic acid: A deficiency causes megaloblastic anemia, but it is not called pernicious anemia.

• b) Vitamin C: A deficiency causes scurvy, not pernicious anemia.

• d) Vitamin D: A deficiency causes issues with bone metabolism (rickets, osteomalacia), not anemia.

The key pathophysiologic feature is iron sequestration. The body’s inflammatory response, mediated by cytokines like hepcidin, traps iron within storage cells (macrophages) of the reticuloendothelial system, making it less available for red blood cell production.

This leads to a classic triad of iron study results:

• Decreased serum iron

• Decreased total iron-binding capacity (TIBC)

• Normal or increased ferritin (reflecting adequate iron stores that are trapped and not accessible)

Why the other options are incorrect:

• a) Decreased iron stores in the reticuloendothelial system: This is the hallmark of iron deficiency anemia. In ACD, iron stores are normal or increased, but the iron is sequestered and not released.

• b) Increased serum iron binding capacity (TIBC): This is characteristic of iron deficiency anemia. In ACD, the TIBC is decreased because inflammation suppresses the production of transferrin, the iron-transport protein measured by TIBC.

• d) Macrocytic erythrocytes: ACD is typically a normocytic, normochromic anemia. Macrocytic erythrocytes are seen in megaloblastic anemias (e.g., B12 or folate deficiency).

• Anemia of chronic inflammation (ACI / anemia of chronic disease) is the most common anemia in hospitalized patients.

• Causes include: chronic infections, autoimmune diseases, malignancies, and critical illness.

• Mechanisms:

  • Hepcidin-mediated iron sequestration → iron trapped in macrophages

  • Suppressed erythropoietin production → decreased RBC production

  • Shortened RBC lifespan

Laboratory features:

• Normocytic or mildly microcytic anemia

• Low serum iron

• Low TIBC

• Normal or high ferritin

Why other options are incorrect:

• a) Inadequate iron intake  → Rare in hospitalized patients, more common in dietary deficiency populations.

• b) Hemolytic anemia → Relatively uncommon.

• c) Inadequate folate intake → Can cause megaloblastic anemia but less common in acute hospital settings.

• Low Serum Iron: The body sequesters iron within storage cells (like macrophages in the liver and spleen) as part of the immune response and inflammatory process. This makes it less available in the bloodstream for red blood cell production.

• Low Total Iron-Binding Capacity (TIBC): TIBC is an indirect measure of transferrin, the protein that transports iron. Inflammation suppresses the liver’s production of transferrin, leading to a low TIBC.

In hemolytic anemia, red blood cells are destroyed prematurely → leading to:

• ↑ LDH → released from lysed RBCs.

• ↑ Unconjugated bilirubin → from increased heme breakdown.

• ↓ Haptoglobin → consumed as it binds free hemoglobin.

• ↑ Reticulocyte count → bone marrow compensatory response.

• Possible hemoglobinuria/hemosiderinuria in intravascular hemolysis.

Why others are wrong:

• a) Decreased bilirubin; normal reticulocyte count → Bilirubin is increased and reticulocytes are elevated in hemolysis.

• b) Decreased LDH; normal catabolism of heme  → LDH is increased due to cell lysis.

• d) Increased haptoglobin; marked hemoglobinuria → Haptoglobin is decreased, not increased, in hemolysis.

• HbC disease is characterized by the formation of intracellular hemoglobin C crystals. These appear as dense, rod-shaped crystals within the red blood cells, often with blunt ends. They are a key diagnostic feature visible on a peripheral blood smear.

Let’s review why the other options are incorrect:

• a) HbS (Sickle Cell Anemia): HbS polymerizes under low oxygen conditions, forming long, flexible tactoids that cause the red blood cell to sickle into a crescent shape, not rod-shaped crystals.

• c) HbSC disease: This is a compound heterozygote state. The blood smear can show a combination of features, including both folded target cells (from HbC) and a few sickle cells (from HbS). While occasional crystals may be seen, the predominant abnormal morphology is not specifically rod-shaped crystals.

• d) HbD: This variant does not cause crystallization or sickling. It is typically asymptomatic and does not have a characteristic crystal formation.

• Hemoglobin C disease results from a point mutation in the β-globin chain (glutamic acid → lysine at position 6).

• RBCs show:

  • Target cells (due to excess membrane relative to Hb content).

  • Intracellular HbC crystals may also be seen.

Why the other options are incorrect:

• a) Macrocytosis: This is seen in megaloblastic anemias (B12/folate deficiency), not hemoglobin C disease.

• b) Spherocytosis: This is the hallmark of hereditary spherocytosis and autoimmune hemolytic anemia.

• c) Rouleaux formation: This is associated with high levels of plasma proteins, such as in multiple myeloma or inflammation, not hemoglobin C disease.