Haem Cram

6. OVERVIEW OF ANAEMIA

Definition

Anaemia is a decrease in total red cell mass, usually detected as low haemoglobin concentration, hematocrit (PCV), or RBC count for age and sex.

Pathophysiologic classification

Core idea: anaemia results from decreased production, increased destruction, or blood loss.

  1. Decreased RBC production

    • Nutritional: iron, vitamin B12, folate deficiencies.

    • Bone marrow failure: aplastic anaemia, myelophthisis, pure red cell aplasia.

    • Chronic disease: anaemia of chronic inflammation.

    • Primary marrow disorders: myelodysplastic syndromes.

  2. Increased RBC destruction (haemolytic)

    • Intrinsic RBC defects: membrane (hereditary spherocytosis), enzymes (G6PD, pyruvate kinase), hemoglobinopathies (sickle cell, thalassemia).

    • Extrinsic: immune-mediated, microangiopathic, infections, toxins, hypersplenism.

  3. Blood loss

    • Acute: trauma, surgery, GI bleed.

    • Chronic: GI malignancy, hookworm, menorrhagia, causing iron deficiency.

Morphological classification (MCV‑based)

  • Microcytic (low MCV): iron deficiency, thalassemia, sideroblastic anaemia, anaemia of chronic disease (sometimes).

  • Normocytic (normal MCV): acute blood loss, early anaemia of chronic disease, hemolytic anaemias, aplastic anaemia.

  • Macrocytic (high MCV): megaloblastic (B12, folate deficiency) vs non‑megaloblastic (liver disease, alcoholism, hypothyroidism, reticulocytosis).

Clinical presentation

Fatigue, pallor, dyspnea, palpitations, tachycardia, bounding pulse; severe anaemia may cause high-output heart failure; specific causes give additional signs (e.g., koilonychia in iron deficiency, neurologic signs in B12 deficiency).

Diagnosis

CBC with RBC indices (Hb, MCV, MCH, MCHC), reticulocyte count, peripheral smear.

Iron studies, B12, folate levels, renal/liver function, LDH, haptoglobin, Coombs test, etc., depending on suspected cause.

Treatment

Directed at cause: iron, B12, folate replacement; treat chronic disease; immunosuppression for autoimmune hemolysis; transfusion, ESAs, disease-specific therapy.

Review questions – Overview of Anaemia

  1. What are the three broad mechanistic categories explaining all causes of anaemia?

  2. List the major causes of microcytic anaemia.

  3. How does reticulocyte count help distinguish between decreased production and increased destruction/ loss?

  4. Which anaemia type is most commonly associated with neurologic deficits, and which nutrient deficiency is responsible?

7. MECHANISMS OF RED CELL DESTRUCTION

Definition

Red cell destruction (hemolysis) is premature breakdown of RBCs before their normal lifespan of about 120 days.

Core mechanisms

The key concept: hemolysis is either intravascular (within circulation) or extravascular (mainly spleen/liver).

  1. Extravascular hemolysis

    • Occurs mainly in spleen and liver, where macrophages remove damaged or antibody‑coated RBCs.

    • Causes: hereditary spherocytosis, sickle cell disease, most warm autoimmune hemolytic anaemia, some hemoglobinopathies.

    • Features: splenomegaly, unconjugated hyperbilirubinemia, jaundice, pigment gallstones, elevated LDH, normal-to-slightly low haptoglobin; spherocytes or other abnormal forms in smear.

  2. Intravascular hemolysis

    • RBCs lyse directly in circulation.

    • Causes: mechanical trauma (prosthetic valves, microangiopathic hemolytic anaemia), complement-mediated lysis (paroxysmal nocturnal hemoglobinuria, mismatched transfusion), severe infections, toxins.

    • Features: hemoglobinemia, hemoglobinuria, hemosiderinuria, marked LDH elevation, low haptoglobin; schistocytes on smear.

Laboratory patterns

  • Both types: elevated LDH, increased unconjugated bilirubin, reticulocytosis.

  • Coombs (direct antiglobulin) test positive in immune-mediated hemolytic anaemia.

Review questions – Mechanisms of Red Cell Destruction

  1. What are the main differences in site and typical lab features between intravascular and extravascular hemolysis?

  2. Name two conditions that cause primarily extravascular hemolysis.

  3. Name two causes of intravascular hemolysis.

  4. Which test detects antibody or complement on RBC surfaces in immune hemolytic anaemia?

8. PATHOLOGY OF THE SPLEEN

Definition

Splenic pathology includes conditions that alter splenic size, architecture, or function, impacting hematologic and immune homeostasis.

Major categories

  1. Splenomegaly

    • Congestive: portal hypertension (cirrhosis), splenic vein thrombosis → enlarged, firm spleen with congested red pulp.

    • Infective: acute (septicemia, infectious mononucleosis) vs chronic (malaria, kala‑azar).

    • Hematologic: hemolytic anaemias (hereditary spherocytosis, thalassemia), myeloproliferative neoplasms (CML, myelofibrosis) → massive splenomegaly.

  2. Hypersplenism

    • Triad: splenomegaly, cytopenias (especially anemia, leukopenia, thrombocytopenia), and marrow hyperplasia.

    • Due to increased sequestration and destruction of blood cells.

  3. Infarction

    • Due to embolic events (endocarditis, atrial fibrillation) or sickle cell disease.

    • Wedge-shaped pale areas; in sickle cell, repeated infarctions can lead to autosplenectomy.

  4. Rupture

    • Blunt trauma, especially with pre-existing splenomegaly; can cause life‑threatening intraperitoneal hemorrhage.

  5. Functional Asplenia / Hyposplenism

    • Seen in sickle cell disease (autosplenectomy) or post-splenectomy.

    • Leads to increased risk of severe infections by encapsulated organisms and presence of Howell–Jolly bodies on smear.

Review questions – Pathology of the Spleen

  1. What clinical triad characterizes hypersplenism, and what is its pathophysiologic basis?

  2. Name three common causes of splenomegaly.

  3. How does sickle cell disease lead to functional asplenia, and what smear finding reflects this?

  4. Why are asplenic patients predisposed to severe infections with encapsulated organisms?

9. INTRODUCTION TO HAEMOLYTIC ANAEMIA

Definition

Haemolytic anaemia is anaemia caused by increased rate of RBC destruction exceeding bone marrow compensatory capacity.

Key framework

The core idea: classify by site of hemolysis (intra vs extravascular) and by whether the defect is intrinsic to the RBC or extrinsic.

  1. Intrinsic (intracorpuscular) causes

    • Membrane defects: hereditary spherocytosis, hereditary elliptocytosis.

    • Enzyme defects: G6PD deficiency, pyruvate kinase deficiency.

    • Hemoglobinopathies: sickle cell disease, thalassemia.
      These are often hereditary and cause primarily extravascular hemolysis.

  2. Extrinsic (extracorpuscular) causes

    • Immune: autoimmune hemolytic anaemia (warm IgG, cold IgM), alloimmune (hemolytic disease of newborn, transfusion reactions).

    • Mechanical: prosthetic heart valves, microangiopathic (DIC, TTP, HUS, malignant hypertension).

    • Infectious and toxic: malaria, Clostridial sepsis, severe burns, venom.

Clinical features

Jaundice, dark urine (hemoglobinuria or urobilinogen), splenomegaly (in extravascular forms), gallstones, pallor, fatigue; in intravascular forms, acute back pain, hemoglobinuria, and very low haptoglobin.

Diagnostic approach

CBC with reticulocyte count (usually elevated).

Peripheral smear (spherocytes, schistocytes, bite cells, sickle cells).

LDH, bilirubin, haptoglobin levels.

Direct Coombs test (for immune causes).

Specific tests for hereditary conditions (osmotic fragility for hereditary spherocytosis, electrophoresis for hemoglobinopathies, enzyme assays for G6PD).

Review questions – Introduction to Haemolytic Anaemia

  1. What is the basic definition of haemolytic anaemia in terms of RBC lifespan and marrow response?

  2. Give two examples each of intrinsic and extrinsic causes of haemolytic anaemia.

  3. Which lab findings are typical of hemolysis (regardless of cause)?

  4. What is the role of the direct antiglobulin (Coombs) test in evaluating haemolytic anaemia?

  5. 5. RED CELL METABOLISM

    Definition

    Red cell metabolism refers to the biochemical pathways that allow anucleate RBCs (no mitochondria) to generate ATP, maintain membrane integrity, and keep iron in the reduced state for oxygen binding.

    Core pathways

    The core idea: RBCs depend on glycolysis for ATP, the HMP shunt for NADPH, and specific shunts for 2,3‑BPG and antioxidant defense.

    1. Anaerobic glycolysis (Embden–Meyerhof pathway)

      • Main source of ATP (since RBCs lack mitochondria).

      • Pyruvate kinase and hexokinase are key enzymes; deficiencies cause hemolytic anaemia due to decreased ATP, membrane fragility, and shortened RBC survival.

    2. Hexose monophosphate (HMP) shunt / pentose phosphate pathway

      • Generates NADPH via glucose‑6‑phosphate dehydrogenase (G6PD).

      • NADPH keeps glutathione reduced, protecting against oxidative damage.

      • G6PD deficiency → episodic hemolysis with oxidative stress (drugs, infections, fava beans) and Heinz bodies.

    3. Rapoport–Luebering shunt

      • Produces 2,3‑bisphosphoglycerate (2,3‑BPG), which shifts the oxyhemoglobin dissociation curve to the right, facilitating oxygen unloading in tissues.

      • Alterations in 2,3‑BPG affect tissue oxygen delivery.

    Clinical relevance

    Enzyme deficiencies (G6PD, pyruvate kinase) cause hereditary non‑spherocytic hemolytic anaemia.

    Disturbed RBC metabolism leads to increased susceptibility to oxidative damage, hemolysis, and altered oxygen delivery.

    Review questions – Red Cell Metabolism

    1. Why do RBCs rely exclusively on anaerobic glycolysis for ATP production?

    2. What is the main function of the HMP shunt in RBCs, and which enzyme deficiency is classic?

    3. How does 2,3‑BPG affect haemoglobin function?

    4. Which enzyme deficiency causes chronic hemolytic anaemia due to low ATP and membrane fragility?


    3. ANATOMY OF THE SPLEEN

    Definition / Location

    The spleen is a highly vascular lymphoid organ located in the left upper quadrant, intraperitoneal, between the 9th–11th ribs, along the axis of the 10th rib.

    Gross Anatomy

    It has a diaphragmatic surface (smooth, convex) and a visceral surface bearing hilum (for vessels and nerves).

    It is connected to the stomach via the gastrosplenic ligament and to the left kidney by the splenorenal ligament, which transmit short gastric vessels and the splenic vessels, respectively.

    The splenic artery (branch of the celiac trunk) supplies it; splenic vein drains into the portal vein.

    Microscopic Anatomy

    Core concept: red pulp filters blood; white pulp is immune tissue.

    • White pulp: periarteriolar lymphoid sheaths (PALS, T‑cell zones) around central arteries and lymphoid follicles (B‑cell areas).

    • Red pulp: splenic cords and sinusoids that filter and remove old or damaged RBCs and platelets; major site of extravascular hemolysis.
      Marginal zone at the interface of red and white pulp where antigen-presenting cells capture antigens.

    Functions

    Immune surveillance and response to blood-borne antigens.

    Removal of senescent RBCs, imperfect platelets, and inclusion bodies (Howell–Jolly bodies normally removed by spleen).

    Storage of platelets and some RBCs.

    Clinical significance

    Splenomegaly occurs in many hematologic diseases (e.g., hemolytic anaemia, portal hypertension, myeloproliferative disorders).

    Splenectomy predisposes to sepsis with encapsulated organisms; peripheral smear shows Howell–Jolly bodies and target cells.

    Review questions – Anatomy of the Spleen

    1. What are the two main functional regions of the spleen and their primary roles?

    2. Which ligament carries the splenic artery and vein to the spleen?

    3. What blood-borne elements are primarily removed and “culled” by the red pulp?

    4. What peripheral smear findings are seen after splenectomy?