Discuss the consequences of the failure of a formed clot to dissolve.

Chapter 19 LECTURE NOTES

Blood

I. The Cardiovascular System: An Introduction

  1. The cardiovascular system is basically a circulating transport system. It includes a pump (the heart) a conducting system (the blood vessels) and a fluid medium (the blood).
  2. The cardiovascular system transports materials such as oxygen, carbon dioxide, nutrients, waste products, hormones and immune system components to and from the cells.

II. The Nature of Blood

  1. Blood is a specialized fluid connective tissue that contains cells suspended in a fluid matrix.
  2. Blood has 5 basic functions;
    1. The transport of dissolved gases, nutrients, hormones and metabolic wastes.
    2. The regulation of the pH and ion composition of interstitial fluids.
    3. The restriction of fluid losses at injury sites.
    4. Defense against toxins and pathogens.
    5. The stabilization of body temperature.
  3. Whole blood is composed of 2 basic subunits:
    • plasma, which is the fluid part
    • formed elements, which include all the cells and solid parts
  4. Plasma contains water, dissolved plasma proteins and other solutes. It is similar to, and exchanges fluids with, interstitial fluid.
  5. There are 3 types of formed elements suspended in the plasma:
    • red blood cells (RBCs or erythrocytes) transport oxygen
    • white blood cells (WBCs or leukocytes) are part of the immune system
    • platelets are cell fragments involved in clotting
  6. Formed elements are produced by myeloid and lymphoid stem cells in the process of hemopoiesis.
  7. Blood has 3 general physical characteristics:
    • A normal temperature of 38 degrees C (100.4 degrees F)
    • A high viscosity
    • A slightly alkaline pH (7.35 – 7.45)
  8. An individual’s blood volume (in liters) is about 7% of their body weight in kilograms. An adult male has about 5 – 6 liters of blood.

III. Plasma

  1. Plasma makes up about 50 to 60 percent of blood volume, and more than 90 percent of plasma is water.
  2. Like interstitial fluid, plasma is an extracellular fluid. Water, ions, and small solutes are continually exchanged between the plasma and interstitial fluid across the walls of capillaries.
  3. The differences between plasma and interstitial fluids are:
    1. different levels of oxygen and carbon dioxide
    2. different amounts and types of dissolved proteins (plasma proteins do not pass through capillary walls)

Plasma Proteins

  1. There are 3 main classes of plasma proteins:
    1. albumins (60%)
    2. globulins (35%)
    3. fibrinogen (4%)
  2. Albumins transport substances such as fatty acids, thyroid hormones and steroid hormones.
  3. Globulins include:
    1. antibodies (immunoglobulins)
    2. transport globulins (for small molecules and compounds):
      1. hormone-binding proteins
      2. metalloproteins
      3. apolipoproteins (lipoproteins)
      4. steroid-binding proteins
  4. Fibrinogen molecules form clots by producing long, insoluble strands of fibrin. Without anti-clotting treatment, the dissolved fibrinogen in a blood sample will convert to solid fibrin, leaving a liquid called serum.
  5. Origins of plasma proteins:
    1. 90% of plasma proteins are made in the liver
    2. antibodies are made by plasma cells
    3. peptide hormones are made by endocrine organs

IV. Red Blood Cells

RBCs make up 99.9% of the blood’s formed elements.

Abundance of RBCs

  1. Red blood cells can be measured in 2 ways:
    1. A red blood cell count is the number of RBCs in a microliter (cubic millimeter) of whole blood.
    2. The hematocrit is the percentage of packed (centrifuged) red blood cells in a whole blood sample (also called packed cell volume,PVC).
  2. In the adult male, normal red blood cell count is 4.5 to 6.3 million per microliter, and normal hematocrit is 40-52. Values for females are slightly lower.

Structure of RBCs

  1. A red blood cell is a small, highly specialized disc — thin in the middle and thicker around the edges (biconcave). The shape and size of a red blood cell are extremely important because:
  2. It gives each RBC a high surface-to-volume ratio, to quickly absorb and release oxygen.
  3. It enables RBCs to form stacks, which smooths the flow through narrow blood vessels.
  4. It enables RBCs to bend and flex when entering small capillaries and branches. (A 7.8 micrometer diameter RBC can pass through a 4 micrometer capillary.)
  5. Because RBCs have no nuclei, mitochondria or ribosomes, they live only about 120 days.

Hemoglobin

  1. Hemoglobin (Hb) is the protein molecule responsible for transporting respiratory gases. The normal hemoglobin value for adult males is 14-18 grams per deciliter of whole blood.
  2. Hemoglobin has a complex quaternary structure. Each of the 4 globular protein subunits contains a single molecule of heme. Each heme molecule contains a single iron ion which associates with oxygen to form oxyhemoglobin (a bright red pigment). Oxygen easily dissociates from the iron ion to become deoxyhemoglobin (a darker red pigment).
  3. Embryos contain a stronger form of hemoglobin called fetal hemoglobin, which can take oxygen from the mother’s hemoglobin.
  4. Each RBC can carry more than a billion molecules of oxygen bound to hemoglobin. When plasma levels of oxygen are low (in peripheral capillaries), the hemoglobin releases oxygen and binds carbon dioxide, forming carbaminohemoglobin, which is carried to the lungs.
  5. Several conditions may cause hematocrit or hemoglobin levels to fall below normal, producing anemia.

RBC Formation and Turnover

  1. About 1% of circulating RBCs wear out and are replaced every day — about 3 million RBCs per second.
  2. Macrophages of the liver, spleen and bone marrow monitor the condition of RBCs and try to engulf them before they rupture (hemolyze). If too much hemolysis occurs in the blood stream, the hemoglobin breaks down and is eliminated in the urine, causing hemoglobinuria. Kidney damage can cause whole red blood cells to appear in the urine (hematuria).
  3. Phagocytes break hemoglobin molecules down into their components, which are recycled:
    • the globular proteins are reduced to amino acids
    • the heme units lose their iron and become biliverdin (green) which is converted to bilirubin (yellow) (Bilirubin is excreted by the liver in bile. If bilirubin builds up, jaundice occurs.)
    • bacteria in the intestine convert bilirubin to compounds which (on exposure to oxygen) become urobilins and stercobilins, which color urine and feces
    • the iron is bound to proteins such as the plasma protein transferrin; excess iron is stored as feritin or hemosiderin
  4. In adults, red blood cell production (erythropoiesis) occurs only in red bone marrow (myeloid tissue). The cell must pass through several stages of maturation to become a RBC:
    • hemocytoblasts (stem cells) in bone marrow divide to produce myeloid stem cells (which become RBCs) and lymphoid stem cells (which become lymphocytes)
    • myeloid stem cells differentiate into proerythroblasts
    • proerythroblasts mature in several stages, losing organelles and reducing in size to become a reticulocyte
    • reticulocytes are released into the blood steam and complete maturation

Blood Types

  1. The body’s immune system identifies cells in the body as normal or foreign by substances on the surface of the cell called surface antigens. Normal cells are ignored, foreign cells are attacked.
  2. Your blood type is determined (genetically) by the presence or absence of specific surface antigens on the membrane of the RBC. The most important RBC surface antigens are A, B and Rh.
  3. The 4 basic blood types are:
    • A, which has only surface antigen A
    • B, which has only surface antigen B
    • AB, which has both antigens A and B
    • O, which has neither antigen

Type O blood is the universal donor. Type AB blood is the universal recipient

  1. Whichever antigens (also called agglutinogens) are on the surface of your RBCs, your immune system will identify as normal. However, your plasma carries antibodies that will attack (agglutinate) any blood cells with a different blood antigen. (i.e. Type A blood has Type B antibodies in the plasma; Type B blood has Type A antibodies; Type O blood has both A and B antibodies.)
  2. In addition, the blood can be either Rh positive (Rh+) or Rh negative (Rh-) depending on the presence or absence of the Rh antigen (also called the D antigen). Unlike the ABO system, type Rh- blood does not normally carry anti-Rh antibodies, unless the individual has been sensitized by previous exposure. The most common blood type is O+.
  3. Before a blood transfusion can be administered, it is important to determine if the blood types of the donor and recipient are compatible. If plasma antibodies meet their specific antigens, the blood will agglutinate and hemolyze in a cross-reaction or transfusion reaction
  4. Whichever antigens (also called agglutinogens) are on the surface of your RBCs, your immune system will identify as normal. However, your plasma carries antibodies that will attack (agglutinate) any blood cells with a different blood antigen. (i.e. Type A blood has Type B antibodies in the plasma; Type B blood has Type A antibodies; Type O blood has both A and B antibodies.)
  5. In addition, the blood can be either Rh positive (Rh+) or Rh negative (Rh-) depending on the presence or absence of the Rh antigen (also called the D antigen). Unlike the ABO system, type Rh- blood does not normally carry anti-Rh antibodies, unless the individual has been sensitized by previous exposure. The most common blood type is O+.
  6. Before a blood transfusion can be administered, it is important to determine if the blood types of the donor and recipient are compatible. If plasma antibodies meet their specific antigens, the blood will agglutinate and hemolyze in a cross-reaction.
  7. A blood-type test is performed to determine blood type and compatibility. Clumping occurs when the sample contains the specified surface antigens. In an emergency in which there is no time to cross-match for blood type, type O- blood may be administered, since it has neither Type A, Type B or Rh surface antigens.
  8. If time allows, a cross-match test is performed on the donor and recipient blood to confirm compatibility.

V. White Blood Cells

  1. A blood-type test is performed to determine blood type and compatibility. Clumping occurs when the sample contains the specified surface antigens. In an emergency in which there is no time to cross-match for blood type, type O- blood may be administered, since it has neither Type A, Type B or Rh surface antigens.
  2. If time allows, a cross-match test is performed on the donor and recipient blood to confirm compatibility.

WBC Circulation and Movement

  1. Circulating WBCs have 4 characteristics:
    • All can migrate out of the bloodstream.
    • All are capable of amoeboid movement.
    • All are attracted to specific chemical stimuli (positive chemotaxis).
    • Some are capable of phagocytosis (neutrophils, eosinophils, and monocytes)

Types of WBCs

  1. There are 5 major types of WBCs:
    • neutrophils
    • eosinophils
    • basophils
    • monocytes
    • lymphocytes
  2. Neutrophils (polymorphonuclear leukocytes) make up 50 to 70 % of all circulating WBCs. Their cytoplasm is packed with pale granules containing lysosomal enzymes and bacteria-killing compounds (hydrogen peroxide and superoxide anions). Neutrophils are very active and are generally the first to attack bacteria at the site of an injury.
  3. While digesting pathogens, neutrophils release prostaglandins that affect local capillaries, and leukotrienes that attract other phagocytes. The breakdown of used neutrophils in an infected wound forms pus.
  4. Eosinophils (acidophils) make up about 2-4 percent of circulating WBCs. Their main mode of attack is to excrete toxic compounds such as nitric oxide and cytotoxic enzymes, which are effective against parasites that are too large to engulf.
  5. Eosinophils are also sensitive to allergens and increase during allergic reactions. They control the spread of inflammation by releasing enzymes that counteract the inflammatory effects of neutrophils and mast cells.
  6. Basophils are small and make up less than 1% of circulating WBCs. They accumulate in damaged tissue and release histamine, which dilates blood vessels, and heparin, which prevents blood clotting.
  7. Monocytes are large, spherical cells that make up 2 to 8% of circulating WBCs. Monocytes enter peripheral tissues to become tissue macrophages which can engulf large particles and pathogens. They secrete substances that attract other immune system cells and fibroblasts to the injured area.
  8. Lymphocytes, slightly larger than RBCs, make up 20 to 30% of circulating WBCs. They migrate in and out of the blood, and spend most of their time in the body’s connective tissues and lymphatic organs. Lymphocytes are part of the body’s specific defense system. They are the primary defense against viruses.
  9. There are 3 functional classes of lymphocytes:
    • T cells (cell-mediated immunity) attack foreign cells directly
    • B cells (humoral immunity) differentiate into plasma cells which synthesize antibodies
    • Natural killer (NK) cells detect and destroy abnormal tissue cells such as cancers and virus infected cells

The Differential Count and Changes in WBC Profiles

  1. A differential count of circulating WBCs can detect characteristic changes in the WBC population that indicate pathogenic infections, inflammation and allergic reactions.
    • leukopenia is an abnormally low number of circulating WBCs
    • leukocytosis is an abnormally high number of circulating WBCs
    • extreme leukocytosis may indicate leukemia

WBC Production

  1. All blood cells originate from hemocytoblasts, which produce myeloid stem cells and lymphoid stem cells. Myeloid stem cells differentiate into progenitor cells, which produce all of the WBCs except lymphocytes (which are produced by the lymphoid stem cells).
  2. All WBCs except monocytes develop fully in the bone marrow. (Monocytes develop into macrophages in peripheral tissues.) Some lymphoid stem cells migrate to peripheral lymphoid tissues (thymus, spleen and lymph nodes) which also produce lymphocytes (the process of lymphopoiesis).
  3. Chemical communication between lymphocytes and other WBCs coordinate the immune response.

IV. Platelets

  1. In humans, platelets are cell fragments involved in the clotting system — along with plasma proteins and cells of the vascular system.
  2. Platelets circulate for 9-12 days before being removed by the spleen. About 1/3 of the body’s platelets are circulating, the rest are held in reserve for bleeding emergencies.
  3. Normal platelet concentration is 150,000 to 500,000 platelets per microliter.
    • thrombocytopenia is an abnormally low platelet count
    • thrombocytosis is an abnormally high platelet count
  4. The 3 main functions of platelets are:
    • The release of chemicals important to the clotting process.
    • The formation of a temporary patch in the walls of damaged blood vessels.
    • Active tissue contraction after clot formation has occurred.
  5. Platelet production (thrombocytopoiesis) occurs in bone marrow. Giant cells called megakaryocytes manufacture platelets by shedding cytoplasm packets until they are used up.

VII. Hemostasis

  1. Hemostasis (the cessation of bleeding) consists of 3 phases:
    1. the vascular phase
    2. the platelet phase
    3. the coagulation phase

The Vascular Phase

  1. Cutting the wall of a blood vessel triggers a vascular spasm which contracts the diameter of the blood vessel at the site of the injury for about 30 minutes (the vascular phase).
  2. During the vascular phase:
    • The endothelial cells contract and expose the underlying basal lamina to the bloodstream.
    • The endothelial cells begin releasing chemical factors and local hormones that stimulate smooth muscle contraction and cell division.
    • The endothelial cell membranes become “sticky,” sealing off blood flow.

The Platelet Phase

  1. In the platelet phase (within 15 seconds after injury) platelets attach to sticky endothelial surfaces, basal laminae and exposed collagen fibers (platelet adhesion). Many platelets stick together (platelet aggregation) to form a platelet plug that closes small breaks.
  2. Platelets arriving at an injury site become activated, releasing several compounds including: Especially calcium ions required for clotting

The Coagulation Phase

  1. The coagulation phase does not begin until 30 seconds or more after the injury.Blood clotting (coagulation) involves a series of steps leading to the conversion of circulating fibrinogen into the insoluble protein fibrin. The fibrin network covers the platelet plug and traps blood cells, forming a blood clot that seals off the area.
  2. Normal blood clotting depends on the presence of clotting factors (procoagulants) in the plasma.
  3. During the coagulation phase, enzymes and proenzymes react in chains or cascades that form 3 pathways:
    • the extrinsic pathway, which begins in the vessel wall, outside the blood stream
    • the intrinsic pathway, which begins with a circulating proenzyme within the bloodstream
    • the common pathway, where intrinsic and extrinsic pathways converge
  4. The extrinsic pathway begins with the release of Factor III or Tissue Factor (TF) by damaged cells. TF combines with a series of other compounds which activate Factor X, the first step in the common pathway.
  5. The intrinsic pathway begins with the activation of enzymes exposed to collagen at the injury site. Platelets release several factors (including PF-3) involved in a series of reactions that lead to the activation of Factor X.
  6. The common pathway begins with the activation of Factor X, forming the enzyme prothrombinase which converts the protein prothrombin to the enzyme thrombin
  7. Thrombin converts soluble fibrinogen to insoluble fibrin.
  8. Thrombin stimulates blood clotting by: (1) stimulating the formation of tissue factor, and (2) stimulating the release of PF-3, which forms a positive feedback loop with the intrinsic and extrinsic pathways, accelerating clotting.
  9. A small puncture wound usually stops bleeding in 1-4 minutes (bleeding time).
  10. The body produces several substances that restrict clotting to the wound area, including:
    • anticoagulant plasma proteins (e.g. antithrombin-III, alpha-2-macroglobulin)
    • heparin
    • protein C (activated by thrombomodulin)
    • prostacyclin
  11. Other factors essential to the clotting process are calcium ions and vitamin K.

Fibrinolysis

  1. Fibrinolysis is the process in which the clot slowly dissolves:
    • The proenzyme plasminogen is activated by the enzymes thrombin and tissue plasminogen activator (t-PA).
    • Plasminogen produces the enzyme plasmin, which digests the fibrin strands.

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