Hematology and Blood Components Practice Flashcards

Functions and Composition of Red Blood Cells (RBCs)

• Oxygen Transport: Hemoglobin (Hb) serves to increase the maximum solubility of oxygen within the blood.

• Carbonic Anhydrase Activity: RBCs contain carbonic anhydrase, which facilitates the reaction between carbon dioxide ($CO_2$) and water ($H_2O$) to form carbonic acid/bicarbonate ions ($HCO_3^-$). This is essential for gas transport.

• Acid-Base Balance: Both Hemoglobin and bicarbonate ions function as powerful pH buffers for the blood, maintaining homeostasis.

• Blood Composition:     * Hematocrit: This refers to the cellular component of the blood, which typically constitutes around $40-45\%$.     * Components include Red Blood Cells (RBCs) and leukocytes (White Blood Cells).

Morphology and Characteristics of Red Blood Cells

• Shape: Described as a biconcave disc (resembling a donut without a hole).

• Dimensions:     * Diameter: $7.8\,\mu m$     * Thickness: $2.5\,\mu m$

• Structural Optimization: The biconcave shape is optimized for:     * Maximum elasticity and resistance to deformation when passing through tight spaces.     * Maximum surface area-to-volume ratio to facilitate efficient gas exchange.

• Concentration in Blood:     * Men: Average of $5.2 \times 10^6\,\text{cells}/mm^3$ (5.2 million).     * Women: Average of $4.7 \times 10^6\,\text{cells}/mm^3$ (4.7 million).

• Organelles: Mature RBCs lack a nucleus and other organelles.

• Division: Mature RBCs are unable to divide.

Origin and Life Cycle of RBCs

• Origin (Erythropoiesis): Erythrocytes are generated from Hematopoietic Stem Cells (HSPC).

• Developmental Timeline:     * First few weeks of gestation: Produced in the yolk sac.     * Rest of gestation: Primarily produced in the liver.     * After birth: Produced in the bone marrow.

• Average Lifespan: RBCs circulate for approximately $120\,\text{days}$ in a healthy person.

• Fate of Senescent RBCs:     * Cells break down while passing through narrow capillaries, particularly in the spleen.     * They are captured and digested by macrophages.     * Heme Degradation: Iron is either released for reuse or stored. The porphyrin ring is secreted as bilirubin.

Regulation of Erythropoiesis

• Expansion Inducers: Growth inducers such as Interleukin-3 ($IL-3$) promote the expansion of stem cells.

• Commitment Inducers: Differentiating inducers like Erythropoietin (EPO) promote commitment to a specific cell lineage.

• Erythropoietin (EPO):     * Structure: A circulating $34\,kDa$ hormone.     * Source: Mainly produced in the kidneys.     * Trigger: Produced in response to low oxygen conditions (hypoxia) caused by high altitude, hemorrhage, or ischemia.     * Mechanism: Acts on EPO receptors located on Colony-Forming Unit-Erythrocyte (CFU-E) cells to drive differentiation.

Hemoglobin Synthesis and Assembly

• Heme Biosynthesis Pathway:     * $2\,\text{Succinyl-CoA} + 2\,\text{Glycine} \rightarrow \delta\text{-aminolevulinic acid (ALA)}$.     * $2\,\text{ALA} \rightarrow 1\,\text{Porphobilinogen (PBG)}$.     * $4\,\text{PBG} \rightarrow \text{Protoporphyrin IX}$.     * $\text{Protoporphyrin IX} + Fe^{3+} \rightarrow \text{Heme}$.

• Regulation: A negative feedback loop exists where high concentrations of Heme inhibit the synthesis of ALA.

• Hemoglobin Assembly:     * Hemoglobin is an iron-containing globular metalloprotein.     * Peptides called globins bind to heme to form a hemoglobin chain.     * Chains: There are $\alpha$-chains and $\beta$-chains.     * Quaternary Structure: A complete hemoglobin molecule is a tetramer composed of $2\,\alpha\text{-chains}$ and $2\,\beta\text{-chains}$.     * Capacity: Each complete hemoglobin molecule can carry $4\,\text{atoms}$ of oxygen or carbon dioxide.

RBC Maturation and Nutritional Requirements

• Requirements for DNA Replication: High levels of hematopoietic cell proliferation require a steady dietary supply of:     * Vitamin B12     * Folic Acid (Vitamin B9)

• Deficiency Effects: A lack of these nutrients leads to maturation failure and the production of large, abnormal RBCs called macrocytes.

• Iron Requirement: Heme production demands a steady supply of iron; low iron results in anemia.

Iron Metabolism

• Body Reserves: Total iron in the human body averages $4-5\,g$.

• Distribution:     * $65\,\%$ is in Hemoglobin (RBCs).     * $15-30\,\%$ is in Ferritin (stored in the liver).     * $4\,\%$ is in Myoglobin (found in muscles and the heart).     * $\approx 1\,\%$ is in Transferrin (circulating in plasma).

• Absorption and Transport:     * Dietary iron binds to apotransferrin to form transferrin, which moves through the epithelium into the plasma.     * In tissues, $Fe^{3+}\text{-bound}$ transferrin is internalized into cells where it releases free iron.

• Storage: Excess iron is stored as ferritin in the liver and, to a lesser extent, in the reticuloendothelial cells of the bone marrow.

• Excretion: Iron is mostly excreted through feces, bound to bilirubin.

Pathophysiology: Types of Anemias

• Blood Loss Anemia: Due to hemorrhage or donation. Plasma volume is restored in $1-3\,\text{days}$, and RBC concentration returns to normal in $3-6\,\text{weeks}$. Usually requires no treatment.

• Aplastic Anemia: Caused by defective or absent RBC production in the bone marrow. Triggers include high-dose radiation, pesticides, toxic chemicals, or autoimmune diseases like Lupus. Primary treatment is blood transfusion.

• Pernicious Anemia:     * Vitamin B12 must bind to Intrinsic Factor (secreted by gastric parietal cells) for absorption.     * Loss of the ability to secrete intrinsic factor leads to lower RBC levels.

• Folic Acid Deficiency:     * Folic acid is found in fruit, vegetables, and organ meat, but is degraded by cooking.     * GI absorption disorders, such as sprue, can lead to RBC maturation failure.

• Hemolytic Anemia (Sickle Cell Disease):     * Mutation in the Gene encoding the hemoglobin subunit $\beta$ (HBB).     * The $\beta^S$ allele results in a single amino acid substitution: Glutamate to Valine (Glu/Val).     * Under low oxygen, the subunits polymerize, causing the RBC to take a sickle shape, making it fragile and less effective.

Polycythemia

• Definition: An increased number of RBCs (the opposite of anemia).

• Physiological Polycythemia: Adaptation to chronic low oxygen conditions; common in individuals living at high altitudes.

• Polycythemia Vera:     * Caused by a Janus kinase-2 (JAK2) mutation.     * Leads to neoplastic proliferation of hematopoietic progenitor cells.     * Complications include increased blood viscosity and thromboses.     * Treatment involves periodic removal of blood.

Leukocytes (White Blood Cells) and Platelets

• Function: Protection against infections.

• Counts:     * Approximately $7000\,\text{WBCs}/\mu L$ (compared to 5 million RBCs).     * Platelets: Cell fragments numbering approximately $300,000/\mu L$. They are replaced every $10\,\text{days}$.

• Origins:     * Myelocytes: Generated in the bone marrow (Neutrophils, Basophils, Eosinophils, Monocytes).     * Lymphocytes: Generated in the lymphatic system.

• Lifespan:     * Granulocytes: $4-8\,\text{hours}$ in circulation; $4-5\,\text{days}$ in tissue.     * Monocytes: $10-20\,\text{hours}$ in circulation; months in tissue.     * Lymphocytes: Weeks or months in circulation.

Morphology and Roles of Specific Leukocyte Types

• Basophils / Mast Cells:     * Primary role in allergic reactions.     * Morphology: Bi- or poly-lobed nucleus often obscured by deep dark purple granules.     * Resident version in tissue is the Mast Cell (often at capillary beds).     * Mechanism: Possess $IgE\text{-antibody}$ complexes that release histamine, bradykinin, serotonin, heparin, and lysosomal substances.

• Eosinophils:     * Account for $2\,\%$ of all leukocytes.     * Morphology: Polynucleated acid-containing granules (intense red/pink on Wright staining).     * Specialize in multicellular parasites; release Larvicidal Polypeptide (Major Basic Protein) and oxidizing agents.

• Neutrophils:     * Part of the polymorphonuclear (PMN) family.     * Very short-lived and highly motile.     * Engulf bacteria via pseudopodia (phagocytosis).     * Utilize Neutrophil Extracellular Traps (NETs) made of DNA, histones, and antimicrobial proteins.

• Monocytes / Macrophages:     * Morphology: Clear cytoplasm with a large horseshoe-shaped nucleus.     * Differentiate into tissue macrophages, which are powerful phagocytes containing hydrolytic enzymes and oxidizing agents.

Macrophage Response and Chemotaxis

• Resident Macrophages: First line of defense. Derived from the yolk sac and fetal liver; colonized tissues during development and stay for years as specialized sentinels.

• Recruited Macrophages: Derived from circulating bone marrow monocytes during infection/injury. They are short-lived.

• Chemotaxis: Leukocytes follow chemical gradients to reach infection sites.     * PAMPs: Pathogen Associated Molecular Patterns (e.g., bacterial/viral toxins).     * DAMPs: Damage Associated Molecular Patterns (from injured tissue).     * Detection occurs via specialized receptors like Toll-like receptors (TLRs) or cytokine/chemokine receptors.

• Neutrophilia: An exponential increase in neutrophil numbers within hours of infection.

Multi-Line Defense and Phagocytosis

• Phagocytosis Comparison:     * Neutrophils: Start immediately upon entering tissue; die after becoming exhausted.     * Macrophages: Slower response (due to differentiation) but longer-lasting; can engulf larger cells and act as Antigen Presenting Cells (APCs).

• Progressive Immune Response:     * First Line: Resident macrophages.     * Second Line: Neutrophil invasion.     * Third Line: Monocyte wave (takes up to $8\,\text{hours}$ to recruit).     * Fifth Line: Bone marrow increases production of progenitors resulting in WBC levels $20-50\,\text{times}$ higher than normal.

• Pus: Formed from dead neutrophils and macrophages that have engulfed pathogens.

Leukocyte Disorders

• Leukopenia:     * Characterized by very low WBC counts, leaving the body unprotected.     * Symptoms: Ulcers, severe respiratory infections, potential death.     * Causes: Irradiation (X-rays, gamma rays), exposure to benzene or anthracene nuclei, chloramphenicol, or thiouracil.

• Leukemia:     * Increased WBC count due to cancerous mutation.     * Lymphocytic: Cancerous production in lymph nodes.     * Myelogenous: Cancerous production of young myelogenous cells in the bone marrow.     * Results: Frequent infections, anemia, increased bone fractures, and nutrient starvation due to excessive cell division.