Hemoglobinopathies and Sickle Cell Disease Quiz

Diagnosis of Erythrocyte Production and Destruction

• Erythropoiesis, granulocytopoiesis, and thrombocytopoiesis are all ensured by hematopoietic bone marrow at birth.
• Erythrokinetics encompasses the production, circulation, and destruction of erythrocytes.
• Impaired or inefficient erythropoiesis leads to fewer peripheral erythrocytes.
• Damaged or destroyed erythrocytes impact the balance between efficient and inefficient erythropoiesis.

Methods for Evaluating Erythrokinetics

• Direct methods include:

  • Peripheral blood cell counts (hemoglobin, hematocrit) and nucleated elements in bone marrow.
  • Morphological examination of peripheral blood (blood smear) and bone marrow.
  • Lifespan of erythrocytes using radioactive labeling with 51Cr or 32P.
  • Plasma iron turnover (dosage of sideremia).
  • Urine bilirubin excretion (UBG).

• Indirect methods include determination of blood volume and erythrocyte mass. Isotopic dilution methods are used for these. Results depend on factors like body weight, age, and sex.

Normal Aspects of the Blood Smear

• Size (anisocytosis): Red blood cell (RBC) sizes vary normally across different ages, reflecting developmental patterns according to the Prince-Jones curve.
• Microcytosis: RBC size less than 7.2 μm, commonly linked to anemia.
• Macrocytosis: RBC size greater than 12 μm, associated with megaloblastic anemia, cirrhosis, and CO intoxications.

Tinctoriality

• Hypochromia: Reduced hemoglobin concentration, often associated with microcytosis. Annular cells often present.
• Hyperchromia: Changes in RBC thickness, usually seen in macrocytes and spherocytes.

Other Erythrocyte Abnormalities

• Anisochromia: Normal and hypochromic erythrocytes
• Acromocytosis: Degenerated erythrocytes with crescent appearance
• Target cells: (Mexican hat) hemoglobin centrally and on edges of RBC
• Basophilic erythrocytes: Erythroblasts (young RBCs) that lose their nucleus.
• Polychromatophilic erythrocytes: Large immature RBCs, often violet colored.
• Basophilic punctations: Blue spots in RBCs, a sign of nuclear remnants.
• Jolly bodies: Round, purple stained red blood cell remnants
• Cabot rings: Erythrocyte ring-like remnant of nuclear substance
• Azurophilic granules/chromatin powder: Chromatin remnants appearing in purple stain or in rare cases red/purplish
• Poikilocytosis: Non-normal shapes.
• Spherocytes: Uniform colored ring (Ø= 4μm), often in congenital hemolytic jaundice, sickle cells & S hemoglobinosis
• Ovalocytes: Oval morphology.
• Sickle cells: Characteristic shape, in sickle cell anemia and S hemoglobinosis
• Schizocytes: Irregular fragments of erythrocytes, indicative of hemolytic anemias.

The Myelogram

• Myelogram - a method to assess erythroid activity in bone marrow.
• Evaluation of cellularity density
• Ratio between granulocytic to the number of erythroblasts

Maturation Stage (Criterion for evaluating Marrow Production)

• Maturity of erythroblasts (immature precursors) expressed as a percentage
• Normal values for pro-, basophilic, polychromatophilic, and oxyphilic erythroblasts are provided.
• Ratio of polychromatophilic erythroblasts and oxyphilic erythroblasts reflects normal marrow production.

Reticulocytes

• Reticulocytes are the last stage of erythroblast maturation.
• They are an important marker of the efficiency of erythropoiesis.
• Reticulocyte counts are a proxy to assess the body's ability to produce RBCs via erythropoiesis, and in cases of hyperhemolysis.
• Hemolysis accounts for the production of increased reticulocytes.
• Normal values (0.5-1.5%) of reticulocytes are provided as an index for erythropoiesis.

Life Span of Erythrocytes

• Normal life span of erythrocyte is around 120 days.
• Destruction processes include:
  • Splenic destruction.
  • Occult hemorrhages (small internal bleeds).
• The balance (isocythemia) between production and consumption of erythrocytes is achieved through effective erythropoiesis.

Plasma Iron Turnover

• Includes sideroblasts (iron-containing erythroblasts)
• Hemosiderin (iron-storage substance in tissue)
• Total transferrin iron binding capacity (CT): 15 γ % ml serum
• Latent Fe binding capacity of transferrin (CL): 215 γ % ml serum
• Saturation coefficient (SC): 0.3

Fecal UBG Excretion

• Allows evaluation of erythrocyte catabolism and phagocytosis of erythroblasts.
• Helpful for assessing erythropoietic activity.

Erythrocyte Constants and Indices

• The number of erythrocytes per microliter of blood
• Hemoglobin concentration in grams per deciliter (g/dL)
• Hematocrit expressed as a percentage in blood

Mean Corpuscular Values

• Mean corpuscular volume (MCV)
• Mean corpuscular hemoglobin (MCH)
• Mean corpuscular hemoglobin concentration (MCHC)

Erythrocyte Destruction/Hemolysis

• Hemolysis is the physiological process of removing senescent erythrocytes.
• Senescent erythrocytes lose their functions (especially O2 transport).
• Changes in membrane composition occur that trigger an immunological response, resulting in the removal by macrophages.
• The limited lifespan of erythrocytes (120 days) causes structural and metabolic changes.
• Hemolysis, if excessive, can lead to anemia despite the compensatory capacity of the bone marrow to increase its production by 7x.

Diagnosis of Hemolysis

• Anamnesis (history or background)
• Clinical examination (pallor, skeletal changes, jaundice).
• Laboratory tests (blood and biochemical examinations that evaluate markers of hemolysis)
  • Hematologic examinations
  • Biochemical examinations

Intravascular vs. Extravascular Hemolysis

• Most hemolysis is extravascular, occurring in the spleen.
• Intravascular hemolysis involves breakdown of RBCs within the blood vessels.
• Both mechanisms can contribute to hemolytic anemia depending on primary cause.

Degradation of Hemoglobin (Formation of Bilirubin)

• Normal erythrocyte lifespan and breakdown.
• Reticuloendothelial system plays a role.
• Bilirubin is formed through a series of steps, including the breakdown of hemoglobin, isomerization to biliverdin, and reduction to different forms of conjugated bilirubin until its excretion in bile and urine (or stool).

Anemia

• ↓hemoglobin, ↓ hematocrit,↓ in the number of erythrocytes over 10% compared with standard values for age and sex

Classification of Anemia

• Normocytic normochromic
• Microcytic hypochromic (thalassemia, iron deficiency)
• Macrocytic normochromic (megaloblastic)

Hypo/Hyperchromic Anemia

• Hypochromia is low hemoglobin concentration and is frequently associated with anemia
• Hyperchromia is caused by increased hemoglobin concentration.

Classification of Hemolytic Anemia

• Intrinsic (intracorpuscular) deficits

• Extrinsic (extravascular) deficits

• Membrane abnormalities

• Enzyme deficiencies (G6PD defects)

• Hemoglobinopathies

• Paroxysmal nocturnal hemoglobinuria (PNH)

Hereditary Spherocytosis

• Hereditary spherocytosis is a genetic disorder resulting from abnormalities in RBC membrane proteins, causing spherically shaped RBCs.
• Clinical findings include jaundice, splenomegaly, and hemolytic anemia.
• Osmotic fragility test
• Autohemolysis test

Hereditary Elliptocytosis

• Hereditary Elliptocytosis is a genetic disorder resulting in oval-shaped RBCs.
• Clinical symptoms and laboratory findings are similar to other hemolytic anemias.

Hereditary Pyropoikilocytosis (PPK)

• Hereditary Pyropoikilocytosis (PPK) is a rare hemolytic anemia with severe RBC membrane abnormalities.
• PPK results in fragile and easily damaged erythrocytes.

• No definitive treatment.

Enzyme Deficiencies

• Dysfunction of erythrocyte enzymes causes intravascular/extravascular hemolysis, reducing erythrocyte oxygen transport.

G6PD Deficiency

• G6PD deficiency → increased susceptibility to oxidative stress.
• Heinz bodies
• Disorders of G6PD function
• Affected individuals present with episodic hemolytic crises triggered by stressors (like infections and certain medications)

PK Deficiency

• PK deficiency = Non-spherocytic chronic hemolytic anemia.
• Results in abnormally shaped erythrocytes.

• Leads to hemolysis, particularly intrasplenic hemolysis.
• Autohemolysis test.

Hemoglobinopathies

• Defects in the hemoglobin molecule's structure or synthesis.
• Example is sickle cell anemia
• Results in decreased or unstable Hb function and abnormal erythrocyte morphology.

• Causes chronic hemolytic anemia

Thalassemia

• imbalances between amounts of α- and non-α chains of the hemoglobin.
• Qualitative and quantitative defects in the synthesis of normal hemoglobin.
• Results in different forms.
• Severe forms are life-threatening.

Megaloblastic Anemias

• General cellular suffering due to inadequate DNA synthesis.
• Deficiencies of vitamin B12 or folic acid.
• Clinical features include macrocytic, megaloblastic cells and characteristic laboratory findings.
• The development of appropriate treatment requires an understanding of the deficient substrates and the related intracellular pathways (methylation).

Causes of Hemolysis and Iron Deficiency Anemia

• Hemolysis occurs due to a multitude of causes that stem from structural defects to intrinsic/extracorpuscular defects.
• Iron deficiency stems from reduced or inappropriate intake or absorption leading to dietary depletion to deficiency of Fe.

Test your knowledge on sickle cell disease and related hemoglobinopathies with this quiz. It covers key mechanisms, symptoms, diagnostic mutations, and laboratory examinations vital for understanding these conditions. Perfect for students studying hematology or pathophysiology.