Doctors Revision

Doctors Revision

Blood : Related Physiologies

Physiology of Red Blood Cells

I. Erythropoiesis: The Journey of a Red Blood Cell

Erythropoiesis is the highly regulated process of red blood cell (RBC) production, primarily occurring in the bone marrow in adults. It's a continuous, dynamic process designed to maintain a stable red blood cell mass and oxygen-carrying capacity in the blood.

A. Sites of Erythropoiesis

Embryonic/Fetal Life

  • Yolk Sac (0-3 mo): Initial primitive site.
  • Liver (3-7 mo): Primary peak activity.
  • Spleen (3-6 mo): Contributes lesser extent.
  • Bone Marrow (5 mo+): Gradually takes over.

Adult Life

  • Red Bone Marrow: Exclusive site (Vertebrae, sternum, ribs, pelvis, proximal long bones).
  • Extramedullary: Reversion to Liver/Spleen in severe pathology (e.g., myelofibrosis).

B. Stages of Erythropoiesis

Progresses from Stem Cell to Mature RBC through distinct morphological changes.

1. Pluripotent Hematopoietic Stem Cell (HSC)

"Master cells" capable of self-renewal. Differentiate into Common Myeloid Progenitors (CMPs).

2. Erythroid Progenitors (BFU-E & CFU-E)
  • BFU-E: Primitive, EPO-sensitive but not dependent.
  • CFU-E: Mature, highly sensitive and dependent on EPO for survival.
3. Pronormoblast (Proerythroblast)

First recognizable precursor. Large (20-25 µm), basophilic cytoplasm (ribosomes), prominent nucleoli. Begins globin synthesis.

4. Basophilic Normoblast

Smaller, intensely basophilic cytoplasm. Active hemoglobin synthesis begins.

5. Polychromatophilic Normoblast

Grayish-blue cytoplasm (mix of ribosomes + Hb). Most active stage of Hb synthesis.

6. Orthochromatophilic Normoblast

Smallest nucleated precursor. Dense, pyknotic nucleus. Pink cytoplasm (massive Hb). Nucleus is extruded at this stage.

7. Reticulocyte (Polychromatophilic Erythrocyte)
  • Anucleated, contains residual RNA network (reticulum).
  • Released from marrow to blood.
  • Constitutes 0.5-2.5% of circulating RBCs.
  • Reticulocytosis: Indicates increased production (e.g., response to anemia).
8. Mature Erythrocyte
  • Biconcave disc, anucleated, no organelles.
  • Packed with Hemoglobin for O2 transport.
  • Lifespan: ~120 days.

C. Regulation of Erythropoiesis

1. Erythropoietin (EPO) - The Key Hormone

  • Source: Kidneys (90%), Liver (10%).
  • Stimulus: Renal Hypoxia (Low O2) due to anemia, altitude, lung disease.
  • Action: Binds receptors on progenitors (CFU-E) → Promotes proliferation, survival, Hb synthesis, and early release.

2. Nutritional Requirements

  • Iron: Essential for Heme. Deficiency = Anemia.
  • B12 & Folate: DNA synthesis cofactors. Deficiency = Macrocytic Anemia.
  • Protein/Vitamins: Globin synthesis, C, B6, Copper, Zinc.

3. Hormonal Influences

  • Androgens (Testosterone): Stimulate EPO + direct marrow effect (Higher RBCs in males).
  • Thyroid/Growth Hormone: Stimulatory effects. Hypothyroidism can cause mild anemia.

II. Hemoglobin Synthesis

Hemoglobin (Hb) is the primary protein within red blood cells, responsible for oxygen transport from the lungs to the tissues and carbon dioxide transport from the tissues back to the lungs. It is a complex molecule, and its synthesis is a highly coordinated process.

A. Structure of Hemoglobin

A mature hemoglobin molecule is a tetramer (four subunits). Each subunit has two parts:

1. Heme (Non-Protein)

  • Porphyrin ring structure with a central Iron (Fe2+) atom.
  • Function: Site where oxygen binds reversibly.
  • Capacity: 4 Heme groups per Hb molecule = 4 O2 molecules.

2. Globin (Protein)

  • Four polypeptide chains (typically 2 pairs).
  • Adult Hb: Two alpha (α) + Two beta (β) chains.
  • Each globin chain enfolds a heme group.
  • Specific combination determines Hb type.

B. The Synthesis Process

Occurs primarily in the cytoplasm of developing RBCs (pronormoblasts through reticulocytes).

1. Globin Chain Synthesis

Occurs on ribosomes in the cytoplasm.

  • Alpha (α) chains: Encoded on Chromosome 16.
  • Beta (β), Gamma (γ), Delta (δ), Epsilon (ε): Encoded on Chromosome 11.

2. Heme Synthesis

Multi-step enzymatic pathway occurring in Mitochondria and Cytoplasm.

  • Start: Succinyl CoA + Glycine.
  • Rate-Limiting Step: Formation of delta-aminolevulinic acid (ALA) by ALA synthase.
  • Intermediates: Porphobilinogen → Uroporphyrinogen → Coproporphyrinogen → Protoporphyrin.
  • Final Step: Insertion of Ferrous Iron (Fe2+) into Protoporphyrin IX ring by Ferrochelatase (Heme synthase).

Iron Delivery: Transported by Transferrin, taken up via Transferrin Receptors.

3. Assembly

Heme + Globin rapidly combine.

  • 1 Globin + 1 Heme = Globin-Heme Monomer.
  • 4 Monomers assemble = Final Hemoglobin Tetramer.

C. Types of Normal Hemoglobin & Developmental Changes

Globin chain production changes to adapt to oxygen environments.

1. Embryonic Hemoglobins (First 8-10 weeks)
  • Gower 1 (ζ2ε2): Zeta + Epsilon.
  • Gower 2 (α2ε2): Alpha + Epsilon.
  • Hb Portland (ζ2γ2): Zeta + Gamma.

Very high O2 affinity for extraction from maternal blood.

2. Fetal Hemoglobin (HbF - α2γ2)

Predominant from 10 weeks to birth.

  • Composition: 2 Alpha (α) + 2 Gamma (γ).
  • Function: Higher O2 affinity than adult Hb (HbA). Crucial for O2 transfer across placenta.
  • Post-Birth: Constitutes 60-90% at birth; gradually declines and is replaced by HbA.
3. Adult Hemoglobins
Hemoglobin A (HbA - α2β2):
  • 95-97% of adult Hb.
  • 2 Alpha (α) + 2 Beta (β).
  • Affinity regulated by 2,3-BPG for efficient tissue release.
Hemoglobin A2 (HbA2 - α2δ2):
  • 1.5-3.5% (Minor).
  • 2 Alpha (α) + 2 Delta (δ).
  • Elevated in Beta-thalassemia trait.

D. Regulation of Hemoglobin Synthesis

  • Iron Availability: Most critical. Deficiency impairs heme synthesis → reduced Hb.
  • Globin Chain Balance: Synthesis of alpha/non-alpha chains is tightly balanced. Imbalance (Thalassemias) causes unstable chains/ineffective erythropoiesis.
  • Erythropoietin (EPO): Indirectly stimulates synthesis by promoting precursor proliferation/maturation.

III. Red Blood Cell Metabolism

Unlike most cells in the body, mature red blood cells (erythrocytes) are anucleated and lack mitochondria, endoplasmic reticulum, and other organelles. This means they cannot synthesize proteins or carry out oxidative phosphorylation. Their metabolism is highly specialized and focuses on two main goals:

  • Generating energy (ATP): To maintain membrane integrity, ion gradients (Na+/K+ pump), and cell shape.
  • Protecting hemoglobin from oxidative damage: Hemoglobin is susceptible to oxidation, which impairs function and damages the cell.

A. Energy Production (ATP Generation)

RBCs rely almost exclusively on Anaerobic Glycolysis (Embden-Meyerhof pathway).

1. Embden-Meyerhof Pathway

Converts Glucose → Pyruvate → Lactate.

Yield: Net 2 ATP per glucose.

Key Functions of ATP:
  • Ion Gradients: Powers Na+/K+ ATPase pump (prevents osmotic lysis).
  • Cell Shape: Phosphorylation of cytoskeletal proteins maintains deformability.

2. Rapoport-Luebering Shunt

Offshoot pathway producing 2,3-Bisphosphoglycerate (2,3-BPG).

Significance:
  • Binds deoxyhemoglobin, stabilizing T-state → Promotes O2 release.
  • High BPG: Decreased affinity (Right shift) → Increased delivery.
  • Low BPG: Increased affinity (Left shift) → Decreased delivery.

Cost: Consumes 1 ATP otherwise generated by glycolysis.

B. Protection Against Oxidative Damage

RBCs have antioxidant systems to neutralize Reactive Oxygen Species (ROS) that cause Methemoglobin (Fe3+) or Heinz bodies (denatured Hb).

1. Hexose Monophosphate (HMP) Shunt

Most important pathway.

  • Reduces NADP+ to NADPH.
  • NADPH is the primary reductant required by Glutathione Reductase.
G6PD Deficiency: Lack of Glucose-6-Phosphate Dehydrogenase (rate-limiting enzyme) → Low NADPH → Impaired defense → Hemolytic Anemia under stress.

2. Glutathione System

  • Glutathione Reductase: Uses NADPH to reduce Oxidized Glutathione (GSSG) → Reduced Glutathione (GSH).
  • Glutathione Peroxidase: Uses GSH to neutralize H2O2 into Water.

3. Methemoglobin Reductase Pathway

Uses NADH (from glycolysis) to reduce Methemoglobin (Fe3+) back to functional Hemoglobin (Fe2+).

Vital to maintain O2 capacity.

4. Catalase: Converts H2O2 into water and oxygen.

C. Maintenance of Cell Membrane Integrity

Flexible lipid bilayer supported by cytoskeleton (Spectrin, Ankyrin, Band 3, Band 4.1).

ATP Requirement: Maintains phosphorylation of proteins and ion pumps → Preserves biconcave shape/deformability for capillary navigation.

D. Red Blood Cell Lifespan and Destruction

Lifespan: ~120 days.

1. Senescence (Aging)

  • Decreased ATP (Loss of shape/ion balance).
  • Decreased Antioxidant capacity (Oxidative damage).
  • Increased Membrane Rigidity.
  • Exposure of "eat me" signals.

2. Destruction (Extravascular Hemolysis)

Primary method. Macrophages in Spleen ("Graveyard"), Liver, Bone Marrow remove aged cells.

Breakdown Products

Globin Chains:

Recycled into amino acids.

Heme:
  • Iron (Fe2+): Salvaged. Bound to Transferrin → Marrow (reuse) or Ferritin (storage).
  • Porphyrin Ring: Catabolized to Biliverdin → Unconjugated Bilirubin.
Bilirubin Pathway:
  1. Unconjugated: Insoluble. Binds Albumin → Liver.
  2. Liver: Conjugated with glucuronic acid (UGT1A1) → Soluble. Excreted in Bile.
  3. Intestine: Bacteria convert to Urobilinogen → Stercobilin (Brown Feces) or Urobilin (Yellow Urine).

3. Intravascular Hemolysis

Less common/pathological (e.g., trauma, complement). Releases free Hb into plasma. Binds Haptoglobin.
Note: If Haptoglobin saturated, free Hb filtered by kidneys → Hemoglobinuria.

Classification and Differentiation of Anemia

Anemia is characterized by a decrease in RBC count, hemoglobin, or oxygen-carrying capacity. It is not a diagnosis in itself, but a sign of an underlying condition.

I. Defining Anemia

Definitions

  • Clinical: Reduced O2 capacity → Tissue hypoxia.
  • Laboratory: Decrease in Hb, Hct, or RBC count.

Reference Ranges

  • Men: Hb < 13.5 g/dL; Hct < 40%.
  • Women: Hb < 12.0 g/dL; Hct < 36%.
  • Children: Age-dependent.

II. Clinical Manifestations

Related to reduced oxygen delivery. Depends on severity and rate of onset.

General/Non-Specific:

Fatigue, weakness, pallor (skin/conjunctiva), dyspnea on exertion, dizziness, headache, palpitations/tachycardia.

Severe/Chronic Compensation:

Angina (chest pain), Congestive Heart Failure, Intermittent claudication.

Specific Signs:
  • Jaundice: Hemolytic anemias (bilirubin).
  • Glossitis/Cheilitis: Iron or B12 deficiency.
  • Pica: Iron deficiency (craving ice/dirt).
  • Neurological (Paresthesias): B12 deficiency.
  • Bone Pain: Marrow expansion (severe hemolysis).

III. Classification of Anemia

A. Morphological Classification (Based on MCV)

Initial classification determined by Mean Corpuscular Volume (MCV).

MCV < 80 fL

1. Microcytic Anemia

Pathophysiology: Small cells due to defects in Hb synthesis (heme or globin). Extra divisions to normalize concentration.

Key Causes (T.I.C.S.):
  • Thalassemia: Defective globin.
  • Iron Deficiency (IDA): Most common. Insufficient heme.
  • Chronic Disease (ACD): Iron sequestration.
  • Sideroblastic Anemia: Defective heme (iron in mitochondria).
  • Lead Poisoning: Inhibits heme enzymes.
MCV 80-100 fL

2. Normocytic Anemia

Pathophysiology: Normal size, reduced number. Acute loss, decreased production, or destruction.

Key Causes:
  • Acute Blood Loss.
  • Chronic Disease (ACD) / Renal Disease (Low EPO).
  • Underproduction (Aplastic Anemia, Leukemia).
  • Hemolysis (G6PD, AIHA).
  • Early Iron Deficiency.
  • Pregnancy (Dilutional).
MCV > 100 fL

3. Macrocytic Anemia

Pathophysiology: Large cells due to DNA synthesis defects (impaired division) OR release of large immature reticulocytes.

Key Causes:
  • Megaloblastic (DNA defect): B12 or Folate Deficiency.
  • Non-Megaloblastic: Alcoholism, Liver Disease, Hypothyroidism.
  • Reticulocytosis: Marrow response to hemorrhage/hemolysis.
  • MDS: Myelodysplastic Syndromes.

B. Pathophysiological Classification (Based on Mechanism)

1. Decreased RBC Production

  • Nutritional: Iron, B12, Folate.
  • Marrow Failure: Aplastic Anemia (pancytopenia), Pure Red Cell Aplasia, MDS.
  • Infiltration: Leukemia, Lymphoma, Metastasis.
  • Decreased EPO: Chronic Kidney Disease, Chronic Inflammation (ACD).

2. Increased Destruction (Hemolytic Anemias)

Lifespan < 120 days. Marrow compensates (Reticulocytosis).

Intrinsic (Defect in RBC):
  • Membrane: Spherocytosis.
  • Enzyme: G6PD, Pyruvate Kinase.
  • Hb: Sickle Cell, Thalassemia.
Extrinsic (Outside Factor):
  • Immune: AIHA, Transfusion reaction.
  • Mechanical: MAHA (TTP/HUS/DIC), Valves.
  • Infection/Toxic: Malaria, Drugs.

3. Blood Loss

  • Acute: Trauma, GI bleed. Rapid drop, normal MCV initially. Reticulocytosis follows.
  • Chronic: Ulcers, Menorrhagia. Leads to Iron Deficiency (Microcytic/Hypochromic) over time.

In clinical settings, initial CBC with MCV guides investigation (Iron studies, B12/Folate, Reticulocyte count, etc.).

Common Anemic Conditions: Iron Deficiency Anemia

Iron Deficiency Anemia (IDA) is the most prevalent form of anemia worldwide. It results from insufficient iron to support normal erythropoiesis, leading to microcytic, hypochromic RBCs.

A. Pathophysiology

The body maintains iron balance through regulated absorption (duodenum), transport (transferrin), and storage (ferritin). IDA disrupts this balance via four main mechanisms:

1. Increased Iron Loss (Most Common in Adults)

  • Chronic Blood Loss: GI bleeding (ulcers, cancer, hemorrhoids), Menorrhagia (heavy periods), frequent blood donation.
  • Urinary Tract: Hematuria.
  • Pulmonary: Idiopathic pulmonary hemosiderosis.

2. Inadequate Dietary Intake

Vegetarian/vegan diets without supplementation, poverty, malnourishment.

3. Decreased Absorption

  • Gastrectomy/Bariatric Surgery: Reduced acid (Fe3+ → Fe2+ conversion) and surface area.
  • Celiac Disease: Villi damage.
  • IBD / H. pylori.
  • Drugs: Antacids, PPIs (reduce acidity).

4. Increased Requirements

Pregnancy (fetal growth) and Rapid Growth (infancy/adolescence).

B. Clinical Features

In addition to general anemia symptoms (fatigue, pallor, dyspnea):

Pica

Craving non-nutritive substances (ice, dirt, clay).

Koilonychia

Spoon-shaped concave nails.

Angular Cheilitis

Fissures at corners of mouth.

Glossitis

Smooth, red, painful tongue.

Plummer-Vinson

Dysphagia due to esophageal web (rare).

Restless Legs Syndrome

C. Diagnosis

1. Complete Blood Count (CBC)

  • Low Hb & Hct.
  • Microcytic (MCV < 80 fL) & Hypochromic (MCH < 27 pg).
  • High RDW: Anisocytosis (variation in size) - often elevated early.
  • Platelets: Normal or Reactive Thrombocytosis.

2. Iron Studies (Confirmatory)

Parameter Result in IDA Notes
Serum Ferritin ↓ Decreased Most sensitive/specific for stores. Can be falsely normal in inflammation.
Serum Iron ↓ Decreased Bound to transferrin.
TIBC ↑ Increased Reflects empty transferrin trying to find iron.
Transferrin Sat. ↓ Decreased <15-20%.

3. Other Findings

  • Smear: Microcytic, hypochromic, anisocytosis, poikilocytosis.
  • Reticulocyte Count: Low/Normal (Inadequate response).
  • Erythrocyte Protoporphyrin: Increased.

D. Management

Primary Step: Identify Cause

Paramount. Ignoring cause (e.g., GI bleed) can mask cancer or serious conditions. Mandatory investigation in men/post-menopausal women.

1. Oral Iron
  • Agents: Ferrous sulfate, gluconate, fumarate.
  • Dose: 150-200 mg elemental/day.
  • Duration: 3-6 months post-normalization to fill stores.
  • Tips: Empty stomach with Vit C (OJ). Avoid tea/dairy/antacids.
  • Side Effects: GI upset (nausea, constipation, dark stools).
2. IV Iron

For malabsorption, intolerance, severe loss, or need for rapid increase. Newer forms allow safer single doses.

3. Transfusion

Reserved for severe symptoms, hemodynamic instability, or active bleeding.

Common Anemic Conditions: Megaloblastic Anemias

Megaloblastic anemias are characterized by defective DNA synthesis, leading to impaired cell division (nuclear maturation defect) but continued cytoplasmic growth. This results in abnormally large (macrocytic) RBC precursors and circulating macro-ovalocytes. Primary causes are B12 or Folate deficiency.

A. Vitamin B12 (Cobalamin) Deficiency

1. Pathophysiology

B12 is a coenzyme for two crucial reactions:

  1. Methylmalonyl-CoA → Succinyl-CoA: Vital for myelin synthesis.
    Deficiency = Neurological symptoms.
  2. Homocysteine → Methionine: Regenerates THF from methyl-THF. Essential for DNA synthesis.
    Deficiency = "Folate Trap" (impairs DNA synthesis).
Causes:
  • Pernicious Anemia: Autoimmune destruction of parietal cells (Lack of Intrinsic Factor). Most common in adults.
  • Malabsorption: Gastrectomy (no IF), Pancreatic insufficiency, Crohn's/Resection (no absorption site), Bacterial overgrowth, Fish tapeworm.
  • Dietary: Strict vegans.
  • Drugs: PPIs/H2 Blockers (reduce acid needed to release B12).

2. Clinical Features

General anemia symptoms plus:

Neurological (Unique to B12)

Can occur without anemia.

  • Subacute Combined Degeneration: Loss of vibration/position sense, ataxia, spasticity.
  • Paresthesias (tingling/numbness).
  • Cognitive impairment, depression.
  • Peripheral neuropathy.
Gastrointestinal
  • Glossitis: Beefy red, sore tongue.
  • Anorexia, weight loss, diarrhea.

3. Diagnosis

  • CBC: Macrocytic (MCV > 100-120 fL), High RDW, possible Pancytopenia.
  • Smear: Macro-ovalocytes and Hypersegmented Neutrophils (>5 lobes).
  • Serum B12: Low (< 200 pg/mL).
  • Metabolites (Specific):
    • MMA (Methylmalonic Acid): ↑ Elevated (Specific for B12).
    • Homocysteine: ↑ Elevated.
  • Antibodies: Intrinsic Factor / Parietal Cell Abs (Positive in Pernicious Anemia).

4. Management

  • Parenteral B12 (IM): For Pernicious Anemia/Severe malabsorption. 1000 µg daily (loading) → monthly (life).
  • Oral B12: High doses for dietary deficiency/mild cases.
  • Response: Reticulocyte crisis in 5-7 days. Neuro symptoms may improve but can be permanent.

B. Folate (Folic Acid) Deficiency

1. Pathophysiology

Folate is essential for purine/pyrimidine synthesis (DNA). Crucial for converting deoxyuridylate to deoxythymidylate.

Causes:
  • Inadequate Intake (Most Common): Lack of leafy greens, alcoholism, poverty, cooking (destroys folate).
  • Increased Requirements: Pregnancy (neural tube defects), Hemolysis, Malignancy.
  • Malabsorption: Celiac, Sprue.
  • Drugs: Methotrexate, Trimethoprim, Anticonvulsants.
  • Loss: Dialysis.

2. Clinical Features

  • Similar to B12 (Anemia + GI symptoms).
  • NO Neurological Symptoms. (Key differentiator).

3. Diagnosis

  • CBC/Smear: Identical to B12 (Macrocytic, Hypersegmented Neutrophils).
  • Serum Folate: Low (< 3 ng/mL).
  • RBC Folate: Low (Better indicator of tissue stores).
  • Metabolites (Differentiation):
    • Homocysteine: ↑ Elevated.
    • MMA: Normal (Critical to distinguish from B12).

4. Management

  • Folic Acid: 1 mg/day oral (higher for pregnancy history).
  • Diet: Increase leafy greens.
Critical Warning

Always rule out B12 deficiency before treating with Folate. Giving folate to a B12 deficient patient will fix the anemia ("masks" the problem) but allow irreversible neurological damage to progress.

Common Anemic Conditions: Thalassemia

A. Pathophysiology

Thalassemia results from inherited defects in genes producing alpha (α) or beta (β) globin chains. This imbalance causes:

  • Reduced Hb Production: Anemia.
  • Precipitation: Unpaired excess chains are unstable and precipitate in RBC precursors.
  • Ineffective Erythropoiesis: Precipitates damage precursors in marrow → premature destruction.
  • Hemolysis: Circulating RBCs damaged and destroyed in spleen.
  • Iron Overload: Due to increased absorption and transfusions.
Genetic Basis:
  • Alpha (α) Genes: Chromosome 16. Total of 4 genes (2 per chromosome).
  • Beta (β) Genes: Chromosome 11. Total of 2 genes (1 per chromosome).

B. Types of Thalassemia

1. Alpha (α) Thalassemia

Caused by deletions. Severity depends on number of genes deleted (out of 4).

1 Gene Deletion (α-/αα): Silent Carrier

Asymptomatic. Normal CBC. Detected by genetic testing.

2 Genes Deletion (α-/α- or --/αα): Alpha Thalassemia Trait

Mild microcytic, hypochromic anemia. Asymptomatic. Common in Asian/African populations.

3 Genes Deletion (--/α-): Hemoglobin H Disease

Significant hemolytic anemia. Excess beta chains form Hb H (β4) tetramers. Splenomegaly, bone changes. Transfusions during crises.

4 Genes Deletion (--/--): Hydrops Fetalis

Lethal. No alpha chains. Excess gamma chains form Hb Barts (γ4) (High affinity, no O2 release). Severe fetal edema/heart failure.

2. Beta (β) Thalassemia

Caused by mutations. Severity depends on 2 genes. (β+ = reduced, β0 = absent).

Beta Thalassemia Minor (Trait)

1 Gene Mutation.

  • Asymptomatic or mild microcytic anemia.
  • Confused with IDA (but normal iron).
  • Hallmark: Elevated Hb A2 (> 3.5%).
Beta Thalassemia Intermedia

2 Gene Mutations (often β+/β+).

Symptoms between Minor and Major. May not need regular transfusions but suffers from iron overload/complications.

Beta Thalassemia Major (Cooley's Anemia)

2 Gene Mutations (β0/β0 or β+/β0).

  • Severe, life-threatening hemolytic anemia. Onset in infancy.
  • Transfusion Dependent: Lifelong.
  • Clinical Features: Hepatosplenomegaly, "Chipmunk facies" / "Hair-on-end" skull (marrow expansion), Iron overload (hemochromatosis), Jaundice.
  • Electrophoresis: Markedly elevated Hb F, absent/low Hb A.

C. Clinical Features (Summary)

  • Microcytic, Hypochromic Anemia: Characteristic.
  • Jaundice/Gallstones: Chronic hemolysis.
  • Splenomegaly: RBC destruction/Extramedullary hematopoiesis.
  • Bone Deformities: Marrow expansion.
  • Iron Overload: Major complication.

D. Diagnosis

  • CBC: Microcytic, hypochromic; Elevated RBC count (disproportionate to Hb), Low MCV, Normal RDW.
  • Smear: Target cells, tear drops, basophilic stippling, nucleated RBCs.
  • Iron Studies: Normal/Elevated (Diff. from IDA).
  • Hb Electrophoresis (Key):
    • Alpha: Hb H or Hb Barts bands.
    • Beta: Elevated Hb A2 / Hb F.
  • Genetics: Confirmation/Prenatal.

E. Management

Beta Thalassemia Major
  • Transfusions: Regular.
  • Chelation: (Deferoxamine) Essential to manage iron overload.
  • Splenectomy: For hypersplenism.
  • Stem Cell Transplant (HSCT): Only potential cure.
  • Folic acid supplementation.
Hb H Disease

Occasional transfusions (crises). Folic acid. Avoid Iron.

Traits (Minor)

Genetic counseling. Avoid unnecessary iron.

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