Erythrocytes, Blood Typing, and Hemostasis

Erythrocytes

  • Definition: Erythrocytes are red blood cells.
  • Appearance: Biconcave shape, collapsed in the middle with a thick rim.

Principal Functions

  • Carry oxygen from the lungs to the tissues.
  • Pick up carbon dioxide from the tissues and transport it to the lungs.
  • Significance: Lack of red blood cells can lead to death in minutes due to oxygen deprivation.

Characteristics

  • Biconcave discs with a thick rim where most of the color is concentrated.
  • Very flexible and able to change shape.
  • Absence of Nucleus and Organelles: No nucleus or organelles, only some enzymes and hemoglobin.

Significance of No DNA or Mitochondria

  • No DNA: Means no cellular repair, limiting lifespan to about 120 days.
  • No Mitochondria: Only anaerobic fermentation for ATP production; prevents consumption of carried oxygen.

Structure and Composition

  • Thick rim with concentrated hemoglobin.
  • Very little cytoplasm, mainly in the rim.
  • No organelles.
  • Cell Membrane Components: Glycoproteins and glycolipids determine blood type.
  • Cytoskeletal Proteins: Provide durability for bending through capillaries.

Function of Red Blood Cells

  • Major function is transport.
  • Hemoglobin (Hb): Approximately 280 million molecules per red blood cell.
    • Transports oxygen from lungs to tissues.
    • Transports carbon dioxide from tissues to lungs.
  • Carbonic Anhydrase: An enzyme that makes carbonic acid from carbon dioxide and water, important for gas transport and pH balance.
  • CO2 + H2O \rightleftharpoons H2CO3

Hemoglobin Structure

  • Four protein chains (globin):
    • Adults: two alpha and two beta chains.
    • Fetus: two alpha and two gamma chains.
  • Fetal Hemoglobin: Gamma chains bind oxygen more strongly, allowing the fetus to draw oxygen from the mother's blood at the placenta.
  • Globin binds to carbon dioxide.
  • Four heme groups (non-protein moiety) with iron at the center; this is where the color comes from.

Oxygen Loading and Unloading

  • Oxyhemoglobin: Hemoglobin loaded with oxygen in the lungs, bright/ruby red.
  • Deoxyhemoglobin (Reduced Hemoglobin): Oxygen unloaded in tissues, dark red.
  • Carbaminohemoglobin: Carbon dioxide bound to globin in tissues; does not compete with oxygen and does not change blood color.

Blood Analysis

  • Red blood cell counts and hemoglobin concentration indicate blood's oxygen capacity.
    • Hematocrit: Percentage of red blood cells in whole blood.
    • Hemoglobin Concentration: Amount of hemoglobin in whole blood.
    • Red Blood Cell Count: Number of red blood cells.

Factors Affecting Red Blood Cell Values

  • Values are generally lower in women.
    • Androgens (e.g., Testosterone): Stimulate red blood cell production, higher in men.
    • Menstrual Losses: Periodic blood loss in women.
    • Body Fat: Hematocrit is inversely proportional to body fat; women have more body fat.

Erythropoiesis (Red Blood Cell Production)

  • About one million red blood cells produced per second.
  • Average lifespan is about 120 days.
  • Development takes three to five days.
  • Process includes cell size reduction, mitosis, hemoglobin production, and removal of the nucleus and organelles.

Steps of Erythropoiesis

  • Hemopoietic Stem Cell: Common origin for red blood cells, white blood cells, and platelets.
  • Colony Forming Units: First committed cells with receptors for erythropoietin (EPO).
  • Erythropoietin (EPO): Hormone from kidneys, released when low oxygen is detected.
    • Stimulates erythroblasts to multiply and synthesize hemoglobin.
  • Reticulocytes: Immature red blood cells released into circulation with some endoplasmic reticulum.
    • Mature in one to two days.

Reticulocyte Count

  • Normal range: 0.5% to 1.5% of red blood cells.
  • Indicates the rate of red blood cell production.

Nutritional Requirements

  • Iron: Key nutritional requirement.
    • Lost through urine, feces, and bleeding.
    • Men need less than women.
    • Low absorption rate.
  • Iron Absorption: Converted to absorbable form, binds with gastroferritin, transported to blood, and picked up by transferrin.
  • Iron Storage: Stored in the liver or red bone marrow.
  • Toxicity of Free Iron: Number one fatal poisoning of children is multivitamins with iron.
  • Conversion and Transport: Dietary iron converted in the stomach, picked up by a protein, and transported. In the blood, it binds to transferrin.
  • Vitamin B12: Deficiency leads to pernicious anemia with misshapen red blood cells.
  • Folic Acid, Vitamin C, and Copper: Needed for hemoglobin synthesis; vitamin C and copper act as coenzymes.

Homeostasis of Red Blood Cells

  • Negative feedback control.
  • Hypoxemia: Low oxygen levels detected by kidneys.
  • Erythropoietin (EPO) Release: Kidneys release EPO.
  • Red Bone Marrow Stimulation: EPO stimulates red bone marrow, increasing red blood cell count.

Stimuli for Erythropoiesis

  • Low oxygen levels in blood.
  • High altitude (lower partial pressure of oxygen).
  • Increased exercise.
  • Emphysema (lung damage impairs oxygenation).

Negative Feedback Loop

  • Low oxygen sensed by kidneys/liver, leading to erythropoietin secretion.
  • Erythropoietin stimulates red bone marrow to produce more red blood cells.
  • Increased red blood cells typically lead to more oxygen transport.

Red Blood Cell Destruction

  • One million red blood cells destroyed per second, balanced with production.
  • Rupture occurs in the spleen or liver.
  • Hemolysis: Rupture in the bloodstream is dangerous, releases hemoglobin, causes renal failure.
  • Macrophages: In spleen and liver break down hemoglobin.

Hemoglobin Breakdown

  • Globin: Hydrolyzed into amino acids and recycled.
  • Heme:
    • Iron is pulled off and recycled.
    • Pigment is excreted.
  • Heme Pigment Conversion: Converted to biliverdin (green) then to bilirubin (yellow).
  • Bilirubin Disposal:
    • Spleen sends bilirubin to the liver, which secretes it in bile.
    • Bile released into the small intestine.
    • Bacteria in the large intestine convert pigments into urobilogens.
    • Urobilogens converted to stercobilin (brown color of feces).
    • Some urobilogens reabsorbed, converted to urochrome, and removed by kidneys (yellow urine).

Life and Death of Erythrocytes

  • Small intestine absorbs nutrients, sent to red bone marrow.
  • Red blood cells produced for 120 days.
  • Spleen and liver break down worn out red blood cells.
  • Hemoglobin broken down by macrophages.
    • Globin to free amino acids (recycled).
    • Heme: iron is reused; pigment converted to biliverdin then to bilirubin, excreted in feces.

Erythrocyte Disorders and Blood Typing

Polycythemia

  • Excess of red blood cells.
  • Primary Polycythemia (Polycythemia Vera): Cancer of the erythropoietic cell in red bone marrow, hematocrit up to 80%.
  • Secondary Polycythemia: Caused by another disorder (e.g., dehydration, emphysema, high altitude, physical conditioning).
  • Dangers: Increased blood volume and viscosity, leading to high blood pressure; can cause embolism, stroke, or heart failure.

Anemia

  • Causes fall into three categories:
    • Inadequate erythropoiesis or hemoglobin production.
    • Hemorrhagic anemias (bleeding).
    • Hemolytic anemia (red blood cell destruction).

Inadequate Erythropoiesis

  • Kidney Failure: Lack of erythropoietin production.
  • Iron Deficiency Anemia: Insufficient iron to produce hemoglobin.
  • Pernicious Anemia: Lack of vitamin B12, impairing hemoglobin production.

Hemorrhagic Anemias

  • Bleeding leads to loss of red blood cells.
  • Acute or chronic (e.g., stomach ulcer).

Hemolytic Anemia

  • Red blood cells are destroyed.

Consequences of Anemia

  • Hypoxia and Necrosis: Low oxygen levels lead to tissue death.
  • Reduced Osmolarity: Less reabsorption, producing tissue edema; blood pressure may also decrease.
  • Low Blood Viscosity: Blood pressure drops, heart races to compensate, can cause cardiac failure.

Sickle Cell Disease

  • Hereditary defect mostly in people of African descent.
  • Recessive allele modifies hemoglobin structure.
  • Effect: Hemoglobin does not bind well with oxygen, red blood cells become rigid, sticky, and clump together, blocking small blood vessels.
  • Consequences: Kidney or heart failure, stroke, extreme joint pain, and paralysis.

Blood Types

Antigens and Antibodies

  • Based on interactions between antigens and antibodies.
  • Antigen: Complex molecule on cell surface that activates an immune response (antibody generating).
  • Antibodies: Proteins (gamma globulins) secreted by plasma cells (from B lymphocytes) in response to foreign matter.
  • Agglutination: Antibodies bind to antigens, causing cells to clump together.

Human Blood Groups

  • Over 500 different antigens and at least 100 different blood groupings.
  • ABO and Rh groupings are most important clinically due to severe transfusion reactions.
  • Mismatched blood causes antibodies to agglutinate red blood cells, leading to hemolysis, hemoglobin release, and potential renal failure.

ABO Group

  • Determined by presence or absence of A and B antigens.
    • Type A: A antigens.
    • Type B: B antigens.
    • Type AB: Both A and B antigens.
    • Type O: Neither A nor B antigens.
  • Most common is type O, rarest is type AB.
  • Antibodies are anti-A (agglutinate A antigens) and anti-B (agglutinate B antigens).
  • Antibodies appear 2-8 months after birth and reach maximum concentration by 8-10 years of age.
  • Antibodies are in body fluids like plasma.

ABO Group Review

  • Type A: A antigens, anti-B antibodies (cannot receive blood with B antigens).
  • Type B: B antigens, anti-A antibodies (cannot receive blood with A antigens).
  • Type AB: Both A and B antigens, no antibodies (universal recipient).
  • Type O: No A or B antigens, both anti-A and anti-B antibodies (can only receive type O blood).

Testing Blood Type

  • Purified antibodies are added to blood samples.
    • Type A will clump with anti-A antibodies, but not anti-B antibodies.
    • Type B will clump with anti-B antibodies, but not anti-A antibodies.
    • Type AB will clump with both anti-A and anti-B antibodies.
    • Type O will not clump with either anti-A or anti-B antibodies.

Agglutination

  • Each antibody can attach to several antigens on red blood cells simultaneously, causing clumping.
  • Clumped red blood cells block small blood vessels, leading to hemolysis.
  • Released hemoglobin blocks kidney tubules, causing acute renal failure.

Universal Donor and Recipient

  • Type O is the universal donor type, lacking A and B antigens.
  • Type AB is the universal recipient type, lacking plasma antibodies.

Rh Group

  • Includes C, D, and E antigens, discovered in rhesus monkeys.
  • D antigen is most reactive; positive if D antigen is present, negative if absent.
  • Anti-D antibodies are not naturally present; develop only after exposure to positive blood.

Hemolytic Disease of the Newborn

  • Occurs if an Rh-negative mother has formed anti-D antibodies and is pregnant with an Rh-positive child.
  • Maternal anti-D antibodies cross the placenta and attack the fetal red blood cells.
  • Prevention: RhoGAM (anti-D antibodies) can be given to the mother to bind fetal D antigens and prevent her from forming anti-D antibodies.
  • First pregnancy with a positive child usually has no issues, but subsequent pregnancies are at risk.

Leukocytes Overview

  • Least abundant formed elements (5,000 to 10,000 per microliter).
  • Protect against infectious microorganisms and pathogens.
  • Typically spend a few hours in the bloodstream before migrating to connective tissue, lymph nodes, and spleen.
  • Retain organelles and nucleus.

Granulocytes

  • Possess specific granules containing enzymes and chemicals used against pathogens.

Neutrophils

  • Most abundant white blood cell, also known as polymorphonuclear leukocytes (PMNs).
  • Nucleus is multi-lobed.
  • Very antibacterial; important in the immune system.

Eosinophils

  • 2-4% of white blood cells.
  • Numbers increase during parasitic infections and allergic reactions.
  • Release enzymes to destroy large parasites.

Basophils

  • Less than 1% of white blood cells.
  • Secrete histamine (vasodilator) to increase blood flow to injured areas.
  • Produce heparin (anticoagulant) to prevent clot formation.

Agranulocytes

  • Lack specific granules.

Lymphocytes

  • T cells (T lymphocytes): Key component of the third line of defense in the immune system.
  • B cells (B lymphocytes): Transform into plasma cells that produce antibodies.
  • Natural killer (NK) cells.

Monocytes

  • Numbers increase during viral infections and inflammation.
  • Transform into macrophages when they leave the bloodstream.

Leukopoiesis

  • Production of white blood cells.
  • Originates from hemopoietic stem cells in the red bone marrow.
  • Differentiates into colony forming units, which develop into specific types of white blood cells.
  • Circulating white blood cells migrate to connective tissue.

Leukocyte Disorders

Leukopenia

  • Low white blood cell count (below 5,000).
  • Causes include radiation, poisons, and infectious diseases.
  • Effects: Increased susceptibility to infection.

Leukocytosis

  • High white blood cell count.
  • Indicates ongoing infection, allergic reaction, or disease.

Leukemia

  • Cancer of hemopoietic tissue.
  • Characterized by high numbers of abnormal circulating leukocytes.

Complete Blood Count (CBC)

  • Includes several values:
    • Hematocrit: Percentage of red blood cells (indicating polycythemia or anemia).
    • Hemoglobin Concentration: Oxygen carrying capacity.
    • Total Count for Red Blood Cells.
    • Reticulocyte Count: Immature red blood cells, indicating rate of production.
    • Differential White Blood Cell Count: Percentages of different types of white blood cells (lymphocytes, monocytes, neutrophils).
  • Red Blood Cell Size and Hemoglobin Concentration: Helpful in diagnosing certain anemias, e.g., pernicious anemia (oversized, misshapen, pale red blood cells).

Hemostasis

  • Stopping bleeding to prevent death.
  • Hemorrhaging is excessive bleeding.
  • Three mechanisms work together: Vascular spasm, platelet plug formation, and coagulation (blood clotting).

Platelets

  • Small cell fragments of megakaryocytes.
  • Normal count: 130,000 to 400,000 per microliter.

Platelet Functions

  • Secrete vasoconstrictors for vascular spasm, reducing blood loss.
  • Stick together to form a platelet plug, sealing small breaks.
  • Secrete procoagulants or clotting factors to promote clotting.
  • Initiate clot-dissolving enzyme formation.
  • Chemically attract neutrophils and monocytes to inflammation sites.
  • Internalize and destroy bacteria.
  • Produce growth factors that stimulate mitosis and vessel repair.

Thrombopoiesis

  • Platelet production.
  • Stem cells develop receptors for thrombopoietin hormone and become megakaryocytes.
  • Megakaryocytes live in the bone marrow next to blood sinusoids.
  • Cytoplasm fragments split off to form platelets.
  • Platelets circulate for 5-6 days.
  • 40% are stored in the spleen.

Mechanisms of hemostasis

  • First one is vascular spasm.
  • Second one is a platelet plug formation.
    • Last one is coagulation the blood clot.

Vascular Spasm

  • Vasoconstriction of broken vessel cuts off blood supply, providing immediate protection against blood loss.
  • Pain receptors, injury to smooth muscle, and serotonin release by platelets can cause vascular spasm.

Platelet Plug Formation

  • Intact vessels have smooth endothelium coated with prostacyclin (platelet repellent).
  • Broken vessels expose collagen fibers.
  • Platelets stick to collagen and then to each other, forming pseudopods and contracting to create a plug.
  • Platelet degranulation releases chemicals that attract more platelets, creating a positive feedback cycle until the break is sealed.

Coagulation

  • Effective defense against bleeding.
  • Converts soluble fibrinogen into insoluble fibrin threads.
  • Clotting factors in plasma; one factor activates another in a reaction cascade (domino effect).
  • Fibrinogen and clotting factors produced by the liver; liver damage impairs clotting.

Coagulation Pathways

  • Extrinsic pathway: Factors released by damaged tissue start coagulation quickly.
  • Intrinsic pathway: Slower, started by platelets.
  • Injured tissue activates both pathways simultaneously for fast coagulation.
  • Calcium and vitamin K are essential for both pathways.

Last Steps of Clotting Cascade

  • Extrinsic or intrinsic pathway leads to prothrombin activator.
  • Prothrombin activator converts prothrombin to thrombin.
  • Thrombin converts fibrinogen to fibrin monomers which polymerize.
  • Prothrombin \xrightarrow{Prothrombin \, Activator} Thrombin
  • Fibrinogen \xrightarrow{Thrombin} Fibrin

Events Following Blood Clot Formation

  • Platelets and endothelial cells secrete platelet-derived growth factor to stimulate vessel repair.
  • Fibrinolysis: Breaking down the blood clot by producing plasmin enzyme.

Preventing Inappropriate Clotting

  • Prostacyclin coating of blood vessels repels platelets.
  • Thrombin is diluted and washed away by flowing blood.
  • Natural anticoagulants: Heparin from basophils and mast cells; antithrombin from the liver.

Clotting Disorders

Hemophilia

  • Deficiency of one or more clotting factors.

Thrombosis

  • Abnormal clotting in an unbroken vessel.
  • Embolus: Anything that travels in the blood and blocks the blood vessels, causing tissue death and infarction.
    • Stroke (brain).
    • Myocardial infarction (MI, heart attack).
    • Pulmonary embolism (lungs).

Clinical Management of Blood Clotting

  • Vitamin K antagonists (e.g., warfarin) tie up vitamin K to prevent formation of clotting factors.
  • Aspirin suppresses one of the clotting factors.
  • Other anticoagulants: Medicinal leeches and snake venom.