Chapter 18 Lecture Notes - Circulatory System

Functions of Blood

• Transportation:
  • Oxygen from the lungs and nutrients from the digestive tract.
  • Metabolic wastes from cells to the lungs and kidneys for elimination.
  • Hormones from endocrine glands to target organs.
• Regulatory:
  • Maintain appropriate body temperature by absorbing and distributing heat.
  • Maintain normal pH in body tissues using buffer systems.
• Protection:
  • Prevents blood loss by platelet activation and clot formation.
  • Prevents infection by WBCs, antibodies, and cytokines.

Properties and Volume of Blood

• Color varies from bright red (oxygenated) to dark red (deoxygenated).
• pH of blood is 7.35–7.45 (slightly basic, but considered neutral for humans).
• Temperature is 38°C.
• Blood accounts for approximately 8% of body weight.
• Average volume:
  • 5–6 L (1.5 gallons) for males.
  • 4–5 L for females.

Blood as a Connective Tissue

• Blood is a liquid connective tissue.
• Composed of liquid plasma (extracellular matrix) and formed elements.
• Formed elements include:
  • Erythrocytes (red blood cells or RBCs).
  • Leukocytes (white blood cells or WBCs).
  • Platelets.
• Hematocrit: The percentage of RBCs out of the total blood volume (normally 42/47 +/- 5%).

Blood Plasma Composition

• About 90% water, but contains over 100 solutes, including:
  • Proteins:
  • Albumin (most abundant).
  • Globulins.
  • Clotting proteins (fibrinogen).
  • Gamma globulins (antibodies made by plasma cells).
  • Lactic acid, urea, creatinine.
  • Organic nutrients:
  • Glucose.
  • Carbohydrates.
  • Amino acids.
  • Electrolytes:
  • Sodium.
  • Potassium.
  • Calcium.
  • Chloride.
  • Bicarbonate.
  • Respiratory gases:
  • Oxygen.
  • Carbon dioxide.

Blood Viscosity and Osmolarity

• Viscosity: Resistance of a fluid to flow, resulting from the cohesion of its particles.
  • Whole blood is 4.5 to 5.5 times as viscous as water.
  • Plasma is 2.0 times as viscous as water (albumin).
  • Important in circulatory function.
  • Increase in viscosity leads to increase in blood pressure.
• Osmolarity of blood: The total concentration of dissolved particles that cannot pass through a blood vessel wall.
  • If osmolarity is too high, blood pressure increases.
  • If osmolarity is too low, blood pressure decreases, leading to edema.

Formed Elements

• Erythrocytes, leukocytes, and platelets.
  • Only WBCs are complete cells.
  • RBCs have no nuclei or organelles, and platelets are cell fragments.
• Most formed elements survive in the bloodstream for short time spans.
• Most blood cells do not divide but are renewed by cells in bone marrow, where stem cells give rise to new cells.

Hematopoiesis

• Hematopoiesis = creating formed elements.
  • Yolk sac in embryo.
  • Liver, spleen, thymus, and lymph nodes in fetus.
  • Red bone marrow from 3 months before birth and afterwards.
  • Occurs in axial skeleton and proximal epiphyses of humerus and femur.

Hematopoietic Stem Cells

• Includes various progenitor cells for different blood cell lineages, such as:
  • Erythroid progenitor (EPO) -> Erythrocytes
  • Megakaryocyte progenitor (IL-11, TPO) -> Platelets
  • Granulocyte macrophage progenitor -> Basophil/Mast cells, Eosinophil, Neutrophil, Monocytes -> Macrophages
  • Common Lymphoid Progenitor -> T-Lymphocyte, B-Lymphocyte, Natural Killer Cells

Erythrocytes

• Two principal functions:
  • Carry oxygen from lungs to cell tissues.
  • Pick up carbon dioxide from tissues and bring to lungs.
• Insufficient RBCs can cause death in minutes due to lack of oxygen to tissues.
• Biconcave Discs with thick rim:
  • Flexible; can change shape.
  • No nucleus or organelles.
  • Significance of no DNA or mitochondria: cannot divide or perform aerobic respiration; all energy obtained via glycolysis.

The Structure of Erythrocytes

• Diameter: 7.5 \, \mu m
• Thickness: 2.0 \, \mu m

Erythrocytes: Form and Function

• Gas transport is the major function.
• 33% of cytoplasm is hemoglobin (Hb).
• 280 million hemoglobin molecules on one RBC.
• Oxygen delivery to tissue and carbon dioxide transport to lungs.
• Hemoglobin molecules carry both oxygen (O2) and carbon dioxide (CO2).

Hemoglobin Structure

• Each Hb molecule consists of:
  • Four protein chains—globins:
  • Hb has two alpha and two beta chains.
  • Globins bind carbon dioxide (5% of CO_2 in blood).
  • Four heme groups:
  • Heme groups bind oxygen to iron (Fe) at its center.
  • Each Hb molecule can transport four molecules of oxygen.
  • Each RBC contains about 250 million Hb molecules, so each can carry ~1 billion molecules of oxygen.

Erythrocyte Production

• Erythropoiesis—RBC production.
• Approximately 1 million RBCs are produced per second.
• Average lifespan of about 120 days.
• Development takes 3 to 5 days:
  • Reduction in cell size, increase in cell number, synthesis of hemoglobin, and loss of nucleus.

Erythrocyte Production

• First committed cell—erythrocyte colony-forming unit.
  • Has receptors for erythropoietin (EPO) from kidneys.
• Erythroblasts (normoblast) multiply and synthesize hemoglobin.
• Nucleus discarded to form a reticulocyte.
  • Named for fine network of endoplasmic reticulum.
  • 0.5% to 1.5% of circulating RBCs are reticulocytes.
  • A reticulocyte count indicates the rate of RBC production.

Role of Iron in RBC Production

1. Mixture of ferrous (Fe^{2+}) and ferric (Fe^{3+}) is ingested.
2. Stomach acid converts (Fe^{3+}) to (Fe^{2+}).
3. (Fe^{2+}) binds to gastroferritin.
4. Gastroferritin transports (Fe^{2+}) to small intestine and releases it for absorption.
5. In blood plasma, (Fe^{2+}) binds to transferrin.
6. In liver, some transferrin releases (Fe^{2+}) for storage.
7. (Fe^{2+}) binds to apoferritin to be stored as ferritin.
8. Remaining transferrin is distributed to other organs where (Fe^{2+}) is used to make hemoglobin, myoglobin, etc.

Notes:

• Unbound iron is toxic.
• Ferric (Fe^{3+}) and ferrous (Fe^{2+}) are dietary forms of iron.

Erythrocyte Homeostasis

• Negative feedback control:
  • Drop in RBC count causes hypoxemia detected by kidney.
  • Kidney and liver production of erythropoietin stimulates bone marrow.
  • RBC count increases in 3 to 4 days.
• Stimuli for increasing erythropoiesis:
  • Low levels of oxygen (hypoxemia).
  • High altitude.
  • Increase in exercise.
  • Loss of lung tissue in emphysema.

Correction of Hypoxemia by Negative Feedback

• Hypoxemia (inadequate O_2 transport) sensed by liver and kidneys.
• Secretion of erythropoietin.
• Stimulation of red bone marrow.
• Increased RBC count.
• Increased O_2 transport.
• Accelerated erythropoiesis.

The Life and Death of Erythrocytes

• Vitamin B12 and folic acid are required for DNA synthesis.
• Vitamin C and copper are cofactors in hemoglobin production.

Erythrocyte Disorders

• Polycythemia—an excess of RBCs:
  • Primary polycythemia (polycythemia vera):
  • Cancer of erythropoietic cell line in red bone marrow.
  • Secondary polycythemia:
  • From dehydration, emphysema, high altitude, or physical conditioning.
  • Dangers of polycythemia:
  • Increased blood volume, pressure, and viscosity.
  • Can lead to embolism, stroke, or heart failure.

Anemia

• Anemia: decreased oxygen carrying capacity.
  • Causes of anemia fall into three categories:
  • Inadequate erythropoiesis or hemoglobin synthesis:
    • Kidney failure: how would this cause anemia? Reduced EPO production.
    • Iron-deficiency anemia.
    • Pernicious anemia: Deficiency of vitamin B12.
    • Hypoplastic and aplastic anemia.
  • Hemorrhagic anemias from bleeding.
  • Hemolytic anemias from RBC destruction.

Sickle-Cell Disease (Anemia)

• Hereditary defects that occur mostly among people of African descent.
• Caused by recessive allele that modifies structure of Hb (makes HbS):
  • Differs only on the sixth amino acid of the beta chain.
  • HbS does not bind oxygen well.
  • RBCs become rigid, sticky, pointed at ends.
  • Clump together and block small blood vessels.
  • Can lead to kidney or heart failure, stroke, joint pain, or paralysis.

Consequences of Anemia

• Anemia has three potential consequences:
  • Tissue hypoxia and necrosis:
  • Patient is lethargic; shortness of breath; necrosis of brain, heart, or kidney.
  • Blood osmolarity is reduced, producing tissue edema.
  • Blood viscosity is low:
  • Pressure drops and heart races.
  • Cardiac failure may ensue.

Leukocytes

• Least abundant formed element: 5,000 to 10,000 WBCs/μL.
• Protect against infectious microorganisms/pathogens.
• Spend only a few hours in the bloodstream before migrating to connective tissue.
• Retain their organelles and nucleus.
• Granules:
  • All WBCs have lysosomes called nonspecific granules.
  • Granulocytes (some WBCs) have specific granules that contain enzymes and other chemicals employed in defense against pathogens.

Leukocytes (White Blood Cells or WBCs)

• Are less numerous than RBCs.
• Make up 1% of the total blood volume.
• Can leave capillaries via diapedesis.
• Move through tissue spaces.

Leukocytes: Granulocytes

• Granulocytes: neutrophils, eosinophils, and basophils.
  • Cytoplasmic granules stain specifically with Wright’s stain.
  • Larger and shorter-lived than RBCs.
  • Lobed nuclei.
  • Phagocytic.
  • Neutrophil:
    • Most numerous WBC
    • multilobed nucleus
    • Bacteria slayers
  • Eosinophil:
    • bilobed nucleus
    • Digest parasitic worms too large to be phagocytized
  • Basophil:
    • Rarest WBC
    • bilobed nucleus
    • Release histamine to attract other WBC

Leukocytes: Agranulocytes

• Lymphocyte
  • Large circular nucleus
  • Crucial to immunity (B and T cells)
• Monocyte
  • Largest WBC
  • U or kidney-shaped nuclei
  • Enter tissues as macrophages -> phagocytosis of viruses, intracellular bacterial parasites

Leukocyte Disorders

• Leukopenia: low WBC count: below 5,000 WBCs/μL.
  • Causes: radiation, poisons, infectious disease.
  • Effects: elevated risk of infection.
• Leukocytosis: high WBC count: above 10,000 WBCs/μL.
  • Causes: infection, allergy, disease.

Blood Types

• Blood types are based on interactions between antigens and antibodies.
• Antigens
  • Molecules on surface of cell membrane that activate an immune response
  • “Antibody generating”
  • Antigens on the surface of the RBC are the basis for blood typing

Blood Types

• Antibodies
  • Proteins (gamma globulins) secreted by plasma cells
  • Part of immune response to foreign matter
  • Forms antigen–antibody complexes
  • Macrophages phagocytose cells bound by antibody
• Agglutination (cell clumping)
  • Antibody molecule binding to antigens causes clumping of red blood cells

The ABO Group

• Agglutination (cell clumping)
  • Antibody molecule binding to antigens causes clumping of red blood cells
• Responsible for mismatched transfusion reaction
  • Agglutinated RBCs block small blood vessels, hemolyze, and release their hemoglobin over the next few hours or days
  • Hb blocks kidney tubules and causes acute renal failure

Human Blood Groups

• Have over 500 different antigens on RBC membranes
• At least 100 different blood groupings
• Typically use the ABO blood grouping and the Rh blood grouping
  • These cause the most severe transfusion reactions.
  • Agglutination + hemolysis (RBC destruction by macrophages)

The ABO Group

• Your ABO blood type is determined by presence or absence of antigens (agglutinogens) on RBCs
  • Blood type A person has A antigens on RBCs
  • Blood type B person has B antigens on RBCs
  • Blood type AB has both A and B antigens on RBCs
  • Blood type O person has neither antigen on RBCs

The ABO Group

• Antibodies (agglutinins); anti-A and anti-B
  • Appear 2 to 8 months after birth; maximum concentration by 8-10 years of age
  • Where do you find your antibodies? In the plasma
  • You do not form antibodies against your antigens!

The Rh Group

• Rh (C, D, E) agglutinogens discovered in rhesus monkey in 1940
  • Rh D is the most reactive and a patient is considered blood type Rh+ if having D antigen (agglutinogens) on RBCs

The Rh Group

• Anti-D antibodies not normally present
  • Rh− individuals must be exposed to Rh+ blood
• Hemolytic disease of the newborn (HDN) can occur if Rh− mother has formed antibodies and is pregnant with second Rh+ child
  • Anti-D antibodies can cross placenta
• Prevention: RhoGAM given to pregnant Rh− women
  • Binds fetal antigens in her blood so she will not form anti-D antibodies

Platelets and Hemostasis—The Control of Bleeding

• Hemostasis—the cessation of bleeding
  • Stopping potentially fatal leaks
  • Hemorrhage: excessive bleeding
• Three hemostatic mechanisms
  • Vascular spasm
  • Platelet plug formation
  • Blood clotting (coagulation)
• Platelets (fragments of megakaryocytes) play an important role in all three

Platelet Production

• Megakaryocytes—live in bone marrow adjacent to blood sinusoids
  • Long tendrils of cytoplasm (proplatelets) protrude into the blood sinusoids and splits off
• Platelets (fragments of megakaryocytes) circulate freely for 5-6 days
  • 40% are stored in spleen

Vascular Spasm

• Vasoconstriction of a broken vessel.
• Most immediate protection against blood loss.
• Causes:
  • Pain receptors.
  • Smooth muscle injury.
  • Platelets release serotonin (vasoconstrictor).

Platelet Plug Formation

• Intact vessels have a smooth endothelium coated with prostacyclin (platelet repellant).
• Broken vessel exposes collagen.
• Platelet pseudopods stick to the collagen and to each other.
• Pseudopods contract - draw together a platelet plug.
• Platelets degranulate releasing chemicals that attracts more platelets.
• Positive feedback cycle until break is sealed.

Coagulation

• Coagulation (clotting)—last and most effective defense against bleeding
  • Conversion of fibrinogen into insoluble fibrin threads (framework of clot)
  • Procoagulants (clotting factors) in plasma
  • Activate one factor and it will activate the next to form a reaction cascade
  • Fibrinogen and most clotting factors are produced by Liver

Coagulation

• Extrinsic pathway
  • Factors released by damaged tissues
  • Faster
• Intrinsic pathway
  • Initiated by platelets
  • Slower
• Calcium required for either pathway
• Liver and Platelets required for making the clotting factors

Fibrinolysis: Blood Clot Dissolution

• Factor XII converts Prekallikrein to Kallikrein
• Kallikrein Converts Plasminogen to plasmin
• Plasmin dissolves the fibrin polymer
• Positive feedback loop

Prevention of Inappropriate Clotting

• Prostacyclin-coated endothelium repels platelets
• Thrombin diluted and washed away by flowing blood
  • Heart slowing in shock can result in clot formation
• Natural anticoagulants
  • Heparin (from basophils and mast cells blocks prothrombin activator)
  • Antithrombin (from liver)

Clotting Disorders

• Hemophilia—family of hereditary diseases characterized by deficiencies of one factor or another
• Thrombus—abnormal clotting in unbroken vessel
• Embolus – anything that can travel in the blood and block blood vessels
  • Infarction (tissue death) may occur
  • MI or stroke
  • Pulmonary embolism: 650,000 Americans die annually of thromboembolism