Introduction to Blood and Hemopoiesis

Functions and Physiological Role of Blood

• Transportion:

  • Blood acts as a transporter for nutrients, gases, waste products, and hormones throughout the body.
  • It is the primary medium that gets essential materials to where they need to go, such as delivering energy substrates to working tissues.

• Regulation and Homeostasis:

  • Blood plays a critical role in regulating various physiological processes.
  • Buffering Capacity: It provides an important buffering capacity for pH to maintain acid-base balance.
  • Osmotic Pressure: Blood regulates fluid distribution via osmotic pressure, which is primarily influenced by sodium levels and the presence of proteins (like albumin).
  • Temperature Regulation: Blood helps maintain body temperature by distributing metabolic heat. It can be involved in shunting blood flow from the body's core to the skin to dissipate heat.

Physical Properties and Constants of Blood

• pH Levels:

  • The normal pH range of blood is between $7.35$ and $7.45$.
  • Its homeostatic set point is approximately $7.4$.
  • Despite the small range (0.1 units), the pH scale is logarithmic, meaning this range represents a significant physiological dynamic range.

• Osmolarity:

  • Blood osmolarity is maintained within a specific range of $280$ to $296\,mOsm$.
  • In clinical and mathematical contexts, this is often rounded to $300\,mOsm$ for ease of calculation.
  • Isotonic Equivalency: This osmolarity is equivalent to a $0.9\%\,NaCl$ (sodium chloride) solution. Consequently, hospital IV saline is typically $0.9\%\,saline$ to remain iso-osmotic with the blood.

• Viscosity:

  • Viscosity is defined as a liquid's resistance to flow, resulting from particle cohesion.
  • Blood is significantly more viscous than water due to the presence of red blood cells and plasma proteins.
  • Whole Blood: It is $4.5$ to $5.5$ times more viscous than water.
  • Plasma (cells removed): It is approximately $2$ times more viscous than water.
  • Roughly $50\%$ of viscosity is attributed to cells and $50\%$ to protein content.

• Temperature:

  • The temperature of blood is approximately $38^{\circ}C$.
  • This is exactly one degree higher than the normal core body temperature, which is $37^{\circ}C$ ($98.6^{\circ}F$).

• Volume and Proportions:

  • Blood volume accounts for approximately $8\%$ of total body mass.
  • This equates to roughly $80$ to $85\,ml/kg$ of body weight.
  • Genetic Males: Typically contain $5$ to $6\,L$ of blood.
  • Genetic Females: Typically contain $4$ to $5\,L$ of blood.
  • Volume is proportional to size; a $150\,lb$ ($68\,kg$) male has about $5.4\,L$, while an $180\,lb$ male may have $6.5$ to $6.9\,L$.
  • Weight Gain Impact: For every extra pound of fat, approximately $200$ miles of additional capillaries are added, requiring extra blood volume to fill.

Blood Composition: Formed vs. Non-Formed Elements

• Formed Elements (Cells and Cell Fragments):

  • Erythrocytes: Also known as Red Blood Cells (RBCs).
  • Leukocytes: Also known as White Blood Cells (WBCs).
  • Platelets: Also known as thwombocytes; these are cell fragments rather than whole cells.

• Non-Formed Elements (Plasma):

  • This is the liquid extracellular matrix (ECM) of the blood.
  • It consists of water, ions, dissolved gases (Oxygen and Carbon Dioxide), nutrients, wastes, and proteins.

• Hematocrit:

  • Hematocrit is the percentage of whole blood that is composed of packed cells, determined by spinning blood in a centrifuge.
  • Packed Red Blood Cells: Approximately $45\%\pm$ (varies by sex).
  • Buffy Coat: A thin layer containing leukocytes and platelets, making up less than $1\%$ of volume.
  • Plasma: Makes up approximately $55\%$ of the volume, consistent with the definition of connective tissue having a large ECM.

Detailed Components of Plasma

• Water Content: Plasma is approximately $91\%\pm$ water.
• Electrolytes:
  • $90\%$ of plasma cations are Sodium ($Na^+$).
  • As an extracellular fluid, it maintains high sodium and low potassium ($K^+$) concentrations.
• Organic Molecules and Nutrients:
  • Glucose: Normal range is approximately $70$ to $100\,mg/dL$.
  • Lipids and Amino Acids.
  • Nitrogenous wastes.
• Plasma Proteins:
  • Albumin ($60\%$): Synthesized by the liver; acts as a carrier protein for hormones (carries $25\%$ of corticoid hormones) and is majorly responsible for osmolarity and capillary function.
  • Globulins ($36\%$): Categorized into alpha ($\alpha$), beta ($\beta$), and gamma ($\gamma$) globulins. Gamma globulins include many antibodies.
  • Fibrinogen ($4\%$): A fibrous precursor protein (an \"-ogen\") that converts into fibrin to facilitate blood clotting.
• Enzymes in Plasma:
  • Carbonic Anhydrase: Catalyzes the reaction: $CO_2 + H_2O \rightleftharpoons H_2CO_3 \rightleftharpoons HCO_3^- + H^+$. Important for buffering in blood and bone.
  • Plasmin: Involved in blood clotting.
  • Renin and Angiotensin Converting Enzyme (ACE): Involved in hormonal signaling.
• Trace Pigments: Includes Bilirubin, a breakdown product of hemoglobin.

Erythrocyte (RBC) Structure and Hemoglobin

• Morphology:

  • RBCs are biconcave discs, thicker on the outer edge ($2.0\,\mu m$) and thinner in the middle ($1.0\,\mu m$ or less).
  • Average diameter is $7.5\,\mu m$.
  • This shape provides a massive surface area for gas exchange and allows for flexibility to squeeze through capillaries ($5$ to $10\,\mu m$ diameter).

• Internal Composition:

  • Mature RBCs lack a nucleus, endoplasmic reticulum, Golgi apparatus, ribosomes, and mitochondria.
  • They consist of a cytoskeleton and are packed with hemoglobin.
  • Energy is produced via glycolysis and fermentation (anaerobic) because they lack mitochondria.

• Hemoglobin ($Hb$) Details:

  • There are approximately $270,000,000$ hemoglobin molecules per RBC.
  • Quaternary Structure: Composed of four polypeptide subunits. In adults, this includes two alpha ($\alpha$) and two beta ($\beta$) chains.
  • Heme Group: Each subunit contains a heme group, an organic molecule with nitrogen atoms surrounding a central Iron ($Fe$) atom.
  • Oxygen Binding: One hemoglobin molecule can bind up to four oxygen molecules (reversibly).
  • Oxyhemoglobin: Bright red, fully saturated with oxygen.
  • Deoxyhemoglobin: Dark red, occurs when oxygen is released (even if $3$ out of $4$ sites are bound).
  • Isoforms: Fetal hemoglobin has a higher affinity for oxygen. In adults, high blood glucose can lead to glycosylation of the alpha subunit, measured by the A1c test to monitor diabetes.

• Hemoglobin Concentrations:

  • Genetic Males: $13$ to $18\,g/dL$ (grams per deciliter, where $1\,dL = 100\,ml$).
  • Genetic Females: $12$ to $16\,g/dL$.

Hemopoiesis: The Production of Blood Cells

• Definitions:

  • Hemopoiesis: The general process of making all blood cells from stem cells.
  • Poiesis: Greek suffix meaning \"to make.\"
  • Erythropoiesis: The specific formation of red blood cells.

• The Hemopoietic Stem Cell:

  • Starts with a multipotent stem cell (hemocytoblast) in the red bone marrow.
  • Myeloid Progenitor (Myeloid Hemopoiesis): Occurs in the medullary cavity of bones; produces RBCs, platelets, and most WBCs (granulocytes and monocytes).
  • Lymphoid Progenitor: Produces natural killer (NK) cells, T lymphocytes, and B lymphocytes (which can become plasma cells).

• Erythropoiesis Process:

  • Takes approximately $3$ to $5$ days.
  • Mature RBCs live about $120$ days before removal.
  • Transformation Steps:
    1. Hemocytoblast $\rightarrow$ Myeloid progenitor $\rightarrow$ Pro-urethroblast (dedicated stage).
    2. Ribosome synthesis to facilitate massive protein production.
    3. Hemoglobin accumulation ($33\%$ of cell protein).
    4. Nucleus and organelle ejection.
    5. Reticulocyte: The penultimate stage before becoming a mature erythrocyte.

• Location of Red Bone Marrow (Adults):

  • Cranial bones.
  • Pelvic bones (Os coxa, especially the ileum).
  • Vertebrae (bodies).
  • Sternum.
  • Proximal epiphyses of the humerus and femur.
  • Note: Other bones are filled with yellow bone marrow (fat).

Regulation and Hormonal Control of RBCs

• Erythropoietin (EPO):

  • A glycoprotein hormone secreted primarily by granular cells in the kidney (renal juxtaglomerular organ) and some liver cells.
  • Stimulates erythrocyte colony-stimulating units to differentiate into urethroblasts.

• Stimuli for EPO Secretion:

  • Testosterone: Explains higher hematocrit and hemoglobin in genetic males.
  • Hypoxemia: Low blood oxygen sensed by kidneys and liver.
  • Altitude and Exercise: Increased demand for oxygen delivery.
  • Blood Loss/Anemia: Indirectly triggers EPO through hypoxemia.

• Iron ($Fe$) Metabolism:

  • Required for hemoglobin synthesis.
  • Dietary iron ($Fe^{3+}$ and $Fe^{2+}$) is processed in the stomach; acid converts $Fe^{3+}$ to $Fe^{2+}$ (ferrous).
  • Gastroferritin: Binds iron in the stomach for transport to the intestine.
  • Transferrin: Plasma protein that carries iron to the liver or bone marrow.
  • Ferritin: Storage form of iron in the liver. When iron is not bound, the protein is called apoferritin.
  • Ferroptosis: Potential cell death caused by unsequestered (excess) iron damaging mitochondria.

RBC Recycling and Breakdown

• The Role of the Spleen:
  • Old RBCs undergo wear and tear; fragments are recognized and phagocytosed by macrophages in the spleen.
• Molecular Breakdown:
  • Globin: Broken down into amino acids for energy or protein synthesis.
  • Iron: Removed from heme and recycled via transferrin.
  • Heme $\rightarrow$ Biliverdin $\rightarrow$ Bilirubin:
    • Bilirubin is sent to the liver and incorporated into bile.
    • In the intestine, bacteria convert it into pigments that color feces brown.
    • Some is processed by kidneys, giving urine its yellow color.

Blood Pathologies

• Anemia (Low Oxygen-Carrying Capacity):

  • Causes: Kidney failure (low EPO), iron deficiency, B12 deficiency (affects cell division), hemorrhage, or hemolytic diseases (destruction of RBCs).
  • Symptoms: Lethargy, pallor (pale skin), edema (swelling due to low osmolarity), heart failure, and dyspnea (trouble breathing).
  • Pernicious Anemia: Lack of B12 or intrinsic factor (required to absorb B12 in the gut).

• Polycythemia (Excessive RBCs):

  • Primary Polycythemia: Cancer of the erythropoietic line (unregulated producer of urethroblasts).
  • Secondary Polycythemia: Caused by dehydration (relative concentration), persistent hypoxemia (lung disease, smoking, high altitude), or blood doping (EPO injections).
  • Risks: High viscosity, high blood pressure, and increased stroke risk.

• Sickle Cell Anemia:

  • Recessive mutation of the hemoglobin beta subunit.
  • At low oxygen levels, hemoglobin polymerizes into a gel, causing the cell to adopt a rigid sickle shape.
  • Agglutination: Sickled cells clump, blocking capillaries and causing intense pain.
  • Malaria Resistance: Heterozygous carriers are protected against malaria (pleiotropy).

• Thalassemia (Mediterranean Anemia):

  • Deficiency or absence of alpha or beta chains due to a mutation in the non-coding/regulatory regions of the gene.
  • Signs include enlarged spleen (handling abnormal cells), jaundice (liver strain), and dark urine.

Questions & Discussion

• Question: In the transition from a pro-urethroblast to a reticulocyte, what happens? (a) Ribosomes are synthesized, (b) Hemoglobin is accumulated, (c) Organelles are ejected, (d) All of the above.
• Response: (d) All of the above.
• Dietary Iron sources: Red meat, fish, poultry (heme sources), egg yolks, dark leafy greens, dried fruits, strawberries, watermelon, legumes, maple syrup, and molasses.