Chapter 14 The Cardiovascular System: Blood Copyright 2010, John Wiley & Sons, Inc.

Copyright 2010, John Wiley & Sons, Inc. Functions Transportation: water, gases, nutrients, hormones, enzymes, electrolytes, wastes, heat Regulation: pH, temperature, water balance Protection: blood clotting, defense: phagocytic cells, interferons, complement Copyright 2010, John Wiley & Sons, Inc.

Copyright 2010, John Wiley & Sons, Inc. Composition A connective tissue with components readily seen when blood is centrifuged: Plasma(~55%): soluble materials (mostly water); lighter so at top of tube Formed elements (~45%): cells (heavier so at bottom of tube) Mostly red blood cells (RBCs) Percent of blood occupied by RBCs = hematocrit (Hct) Normal hematocrit value: 42-47% Females: 38 to 46%; males: 40 to 54% Buffy coat: site of white blood cells (WBCs), platelets Copyright 2010, John Wiley & Sons, Inc.

Copyright 2010, John Wiley & Sons, Inc. Composition Copyright 2010, John Wiley & Sons, Inc.

Copyright 2010, John Wiley & Sons, Inc. Composition Copyright 2010, John Wiley & Sons, Inc.

Plasma: Liquid Portion of Blood Water: 91.5% Plasma proteins: 7% Albumin (54%): function in osmosis; carriers Globulins (38%): serve as antibodies Fibrinogen (7%): important in clotting Other: 1.5% Electrolytes, nutrients, gases, hormones, vitamins, waste products Copyright 2010, John Wiley & Sons, Inc.

Copyright 2010, John Wiley & Sons, Inc. Formed Elements I. Red Blood Cells (RBCs) II. White blood cells (WBCs) Granular leukocytes Neutrophils Eosinophils Basophils Agranular leukocytes Lymphocytes and natural killer (NK) cells Monocytes III Platelets Copyright 2010, John Wiley & Sons, Inc.

Formation of Blood Cells Called hemopoiesis or hematopoiesis Occurs throughout life In response to specific hormones, stem cells undergo a series of changes to form blood cells Pluripotent stem cells in red marrow Lymphoid stem cells  lymphocytes (in lymphatic tissues) Myeloid stem cells  all other WBCs, all RBCs, and platelets (in red bone marrow) Copyright 2010, John Wiley & Sons, Inc.

Formation of Blood Cells Copyright 2010, John Wiley & Sons, Inc.

Formation of Blood Cells Copyright 2010, John Wiley & Sons, Inc.

Copyright 2010, John Wiley & Sons, Inc. Erythrocytes (RBCs) Hemoglobin (red pigment) Carries 98.5% of O2 and 23% of CO2 RBC count: about 5 million/µl Male: 5.4 million cells/µl; female: 4.8 million/µl Structure of mature RBC No nucleus/DNA so RBCs live only 3 to 4 months Lack of nucleus causes biconcave disc shape with extensive plasma membrane Provides for maximal gas exchange Is flexible for passing through capillaries Copyright 2010, John Wiley & Sons, Inc.

Copyright 2010, John Wiley & Sons, Inc. RBC Recycling Cleared by macrophages (liver and spleen) Recycled components Globin  amino acids recycled to form proteins Heme broken down into: Fe Carried in blood by transferrin (“protein escort” of Fe) Recycled in bone marrow for forming synthesis of new hemoglobin; proteins and vitamin B12 required also Non-Fe portion of heme biliverdin  bilirubin Bilirubin to liver  bile  helps absorb fats Intestinal bacteria convert bilirubin into other chemicals that exit in feces (stercobilin) or urine (urobilin) Copyright 2010, John Wiley & Sons, Inc.

Copyright 2010, John Wiley & Sons, Inc. Formation and Destruction of RBC’s Amino acids Reused for protein synthesis Globin Circulation for about 120 days Bilirubin Red blood cell death and phagocytosis Transferrin Fe3+ Liver + Vitamin B12 Erythopoietin Key: in blood in bile Erythropoiesis in red bone marrow Macrophage in spleen, liver, or Ferritin Heme Biliverdin 10 9 8 7 6 5 4 3 2 1 Amino acids Reused for protein synthesis Globin Circulation for about 120 days Red blood cell death and phagocytosis Transferrin Fe3+ Liver + Vitamin B12 Erythopoietin Key: in blood in bile Erythropoiesis in red bone marrow Macrophage in spleen, liver, or Ferritin Heme Biliverdin Bilirubin 9 8 7 6 5 4 3 2 1 Amino acids Reused for protein synthesis Globin Stercobilin Bilirubin Urobilinogen Feces Small intestine Circulation for about 120 days Bacteria Red blood cell death and phagocytosis Transferrin Fe3+ Liver + Vitamin B12 Erythopoietin Key: in blood in bile Erythropoiesis in red bone marrow Macrophage in spleen, liver, or Ferritin Heme Biliverdin 12 11 10 9 8 7 6 5 4 3 2 1 Amino acids Reused for protein synthesis Globin Urine Stercobilin Bilirubin Urobilinogen Feces Small intestine Circulation for about 120 days Bacteria Red blood cell death and phagocytosis Transferrin Fe3+ Liver + Vitamin B12 Erythopoietin Key: in blood in bile Erythropoiesis in red bone marrow Kidney Macrophage in spleen, liver, or Ferritin Urobilin Heme Biliverdin 13 12 11 10 9 8 7 6 5 4 3 2 1 Amino acids Reused for protein synthesis Globin Urine Stercobilin Bilirubin Urobilinogen Feces Large intestine Small Circulation for about 120 days Bacteria Red blood cell death and phagocytosis Transferrin Fe3+ Liver + Vitamin B12 Erythopoietin Key: in blood in bile Erythropoiesis in red bone marrow Kidney Macrophage in spleen, liver, or Ferritin Urobilin Heme Biliverdin 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Amino acids Reused for protein synthesis Globin Circulation for about 120 days Red blood cell death and phagocytosis Transferrin Fe3+ Liver + Vitamin B12 Erythopoietin Key: in blood in bile Erythropoiesis in red bone marrow Macrophage in spleen, liver, or Ferritin Heme 8 7 6 5 4 3 2 1 Amino acids Reused for protein synthesis Globin Red blood cell death and phagocytosis Transferrin Fe3+ Liver + Vitamin B12 Erythopoietin Key: in blood in bile Macrophage in spleen, liver, or red bone marrow Ferritin Heme 7 6 5 4 3 2 1 Globin Red blood cell death and phagocytosis Key: in blood in bile Macrophage in spleen, liver, or red bone marrow Heme 2 1 Red blood cell death and phagocytosis Key: in blood in bile Macrophage in spleen, liver, or red bone marrow 1 Amino acids Reused for protein synthesis Globin Red blood cell death and phagocytosis Key: in blood in bile Macrophage in spleen, liver, or red bone marrow Heme 3 2 1 Amino acids Reused for protein synthesis Globin Red blood cell death and phagocytosis Transferrin Fe3+ Key: in blood in bile Macrophage in spleen, liver, or red bone marrow Heme 4 3 2 1 Amino acids Reused for protein synthesis Globin Red blood cell death and phagocytosis Transferrin Fe3+ Liver Key: in blood in bile Macrophage in spleen, liver, or red bone marrow Ferritin Heme 6 5 4 3 2 1 Amino acids Reused for protein synthesis Globin Red blood cell death and phagocytosis Transferrin Fe3+ Liver Key: in blood in bile Macrophage in spleen, liver, or red bone marrow Ferritin Heme 5 4 3 2 1 Copyright 2010, John Wiley & Sons, Inc.

RBC Synthesis: Erythropoiesis Develop from myeloid stem cells in red marrow Cells lose nucleus; are then released into bloodstream as reticulocytes These almost-mature RBCs develop into erythrocytes after 1-2 days in bloodstream High reticulocyte count (> normal range of 0.5% to 1.5% as more of these circulate in bloodstream) indicates high rate of RBC formation Copyright 2010, John Wiley & Sons, Inc.

RBC Synthesis: Erythropoiesis Production and destruction: normally balanced Stimulus for erythropoiesis is low O2 delivery (hypoxia) in blood passing to kidneys  Kidneys release erythropoietin release (EPO)  Stimulates erythropoiesis in red marrow  increased O2 delivery in blood (negative feedback mechanism) Copyright 2010, John Wiley & Sons, Inc.

RBC Synthesis: Erythropoiesis Signs of lower-than-normal RBC count  changes in skin, mucous membranes, and finger nail beds Cyanosis: bluish color Anemia: pale color Copyright 2010, John Wiley & Sons, Inc.

Regulation of Erythropoiesis Copyright 2010, John Wiley & Sons, Inc.

Characteristics & functions of blood cells

White Blood Cells (WBCs or Leukocytes) Appear white because lack hemoglobin Normal WBC count: 5,000-10,000/µl WBC count usually increases in infection Two major classes based on presence or absence of granules (vesicles) in them] Granular: neutrophils, eosinophils, basophils Neutrophils usually make up 2/3 of all WBCs Agranular: lymphocytes, monocytes Major function: defense against Infection and inflammation Antigen-antibody (allergic) reactions Copyright 2010, John Wiley & Sons, Inc.

White Blood Cell Functions Neutrophils: first responders to infection Phagocytosis Release bacteria-destroying enzyme lysozyme Monocytes  macrophages (“big eaters”) Known as wandering macrophages Eosinophils Phagocytose antibody-antigen complexes Help suppress inflammation of allergic reactions Respond to parasitic infections Copyright 2010, John Wiley & Sons, Inc.

White Blood Cell Functions Basophils Intensify inflammatory responses and allergic reactions, e.g. after contact with poison oak. Release chemicals that strongly dilate blood vessels, such as histamine and serotonin; also release heparin (anticoagulant) Poison ivy reaction Copyright 2010, John Wiley & Sons, Inc.

White Blood Cell Functions Lymphocytes Three types of lymphocytes T cells B cells Natural killer (NK) cells Play major roles in immune responses B lymphocytes respond to foreign substances called antigens and differentiate into plasma cells that produce antibodies. Antibodies attach to and inactivate the antigens. T lymphocytes directly attack microbes. Copyright 2010, John Wiley & Sons, Inc.

White Blood Cell Functions Major histocompatibility (MHC) antigens Proteins protruding from plasma membrane of WBCs (and most other body cells) Called “self-identity markers” Unique for each person (except for identical twins) An incompatible tissue or organ transplant is rejected due to difference in donor and recipient MHC antigens MHC antigens are used to “type tissues” to check for compatibility and reduce risk of rejection Copyright 2010, John Wiley & Sons, Inc.

Copyright 2010, John Wiley & Sons, Inc. WBC Life Span WBCs: 5000-10,000 WBCs/µl blood RBCs outnumber WBCs about 700:1 Life span: typically a few hours to days Abnormal WBC counts Leukocytosis: high WBC count in response to infection, exercise, surgery Leukopenia: low WBC count Differential WBC count: measures % of WBCs made up of each of the 5 types Copyright 2010, John Wiley & Sons, Inc.

Copyright 2010, John Wiley & Sons, Inc. Platelets Myeloid stem cells  megakaryocytes  2000–3000 fragments = platelets Normal count: 150,000-400,000/µl blood Functions Plug damaged blood vessels Promote blood clotting Life span 5–9 days Copyright 2010, John Wiley & Sons, Inc.

Hemostasis: “Blood Standing Still” Sequence of events to avoid hemorrhage Vascular spasm Response to damage Quick reduction of blood loss Platelet plug formation Platelets become sticky when contact damaged vessel wall Blood clotting (coagulation) Series of chemical reactions involving clotting factors    Copyright 2010, John Wiley & Sons, Inc.

Blood Clotting (Coagulation) Extrinsic pathway Tissue factor(TF) from damaged cells 1  2  3 Intrinsic Pathway Materials “intrinsic” to blood  1  2  3 Common pathway: 3 major steps Prothrombinase  Prothrombin  thrombin Fibrinogen  fibrin  clot Ca++ plays important role in many steps Copyright 2010, John Wiley & Sons, Inc.

Copyright 2010, John Wiley & Sons, Inc. Tissue trauma Tissue factor (TF) Blood trauma Damaged endothelial cells expose collagen fibers (a) Extrinsic pathway (b) Intrinsic pathway Activated XII Ca2+ platelets Platelet phospholipids Activated X Activated PROTHROMBINASE V Prothrombin (II) THROMBIN Loose fibrin threads STRENGTHENED FIBRIN THREADS Activated XIII Fibrinogen (I) XIII (c) Common pathway 1 2 3 + Tissue trauma Tissue factor (TF) Blood trauma Damaged endothelial cells expose collagen fibers (a) Extrinsic pathway (b) Intrinsic pathway Activated XII Ca2+ platelets Platelet phospholipids Activated X Activated PROTHROMBINASE V Prothrombin (II) THROMBIN (c) Common pathway 1 2 + Tissue trauma Tissue factor (TF) Blood trauma Damaged endothelial cells expose collagen fibers (a) Extrinsic pathway (b) Intrinsic pathway Activated XII Ca2+ platelets Platelet phospholipids Activated X Activated PROTHROMBINASE V 1 Stages of Clotting Copyright 2010, John Wiley & Sons, Inc.

Triggering of blood coagulation

Clot Retraction and Vessel Repair Clot plugs ruptured area Gradually contracts (retraction) Pulls sides of wound together Repair Fibroblasts replace connective tissue Epithelial cells repair lining Copyright 2010, John Wiley & Sons, Inc.

Hemostatic Control Mechanisms Fibrinolysis: breakdown of clots by plasmin Inactivated plasminogen  Activated (by tPA)  plasmin Inappropriate (unneeded) clots Clots can be triggered by roughness or micro-lesions on vessel wall = can cause thrombosis Loose (on-the-move) clot = embolism Anticoagulants: decrease clot formation Heparin Warfarin (Coumadin) Copyright 2010, John Wiley & Sons, Inc.

Anti-blood coagulation drugs  1. Aspirin (low doses, 80mg "Baby pill")  - inhibits vasoconstriction and platelet aggregation in low concentrations  - blocks formation of vaso-regulatory prostaglandins due to inhibition of the cyclooxygenase enzyme  - synthetic anti-coagulant (acetyl-salicylic acid) - side effects includes he danger of internal bleedings ("hemorrhages") especially in individuals with pre- existing ulcers;      2. Heparin (natural (physiological) anti-coagulant)   - inhibits the conversion of prothrombin into thrombin (Factor IIa) by interferingwith coagulation factors   - produced by mast cells and basophils 

3. Hirudin - traditional medicinal anti-coagulant derived from the saliva of leeches (Hiruda medicinalis)   4. natural or recombinant tissue plasminogen activator (r-tPA; "Actilyse") -  blood clot dissolving body- produced protease enzyme which converts plasminogen into plasmin  - released by endothelial cells  - often used to treat acute stroke or heart attack patients

5. Warfarin ("Coumarin-derivative") - plant-derived antagonist of vitamin K which blocks the synthesis of 4 coagulation factors 6. Streptokinase - thrombolytic protein produced by streptococcal bacteria - first thrombolytic agent approved in 1982 to dissolving blood clots in the   heart arteries of heart attack patients   7. ACD or CPD - calcium ion-chelating, citrate- containing solution routinely used to prevent spontaneous clotting of donated blood in blood banks and laboratories

Blood Groups and Blood Types RBCs have antigens (agglutinogens) on their surfaces Each blood group consists of two or more different blood types There are > 24 blood groups Two examples: ABO group has types A, B, AB, O Rh group has type Rh positive (Rh+), Rh negative (Rh–) Blood types in each person are determined by genetics Copyright 2010, John Wiley & Sons, Inc.

Copyright 2010, John Wiley & Sons, Inc. ABO Group Two types of antigens on RBCs: A or B Type A has only A antigen Type B has only B antigen Type AB has both A and B antigens Type O has neither A nor B antigen Most common types in US: type O and A Typically blood has antibodies in plasma These can react with antigens Two types: anti-A antibody or anti-B antibody Blood lacks antibodies against own antigens Type A blood has anti-B antibodies (not anti-A) Type AB blood has neither anti-A nor anti-B antibodies Copyright 2010, John Wiley & Sons, Inc.

Copyright 2010, John Wiley & Sons, Inc. ABO Group Copyright 2010, John Wiley & Sons, Inc.

Blood type distribution

Copyright 2010, John Wiley & Sons, Inc. Rh Blood Group Name Rh: antigen found in rhesus monkey Rh blood types If RBCs have Rh antigen: Rh+ If RBCs lack Rh antigen: Rh– Rh+ blood type in 85-100% of U.S. population Normally neither Rh+ nor Rh– has anti-Rh antibodies Antibodies develop in Rh- persons after first exposure to Rh+ blood in transfusion (or pregnancy  “hemolytic disease of newborn” Copyright 2010, John Wiley & Sons, Inc.

Copyright 2010, John Wiley & Sons, Inc. Transfusions If mismatched blood (“wrong blood type”) given, antibodies bind to antigens on RBCs  hemolyze RBCs Type AB called “universal recipients” because have no anti-A or anti-B antibodies so can receive any ABO type blood Type O called “universal donors” because have neither A nor B antigen on RBCs so can donate to any ABO type Misleading because of many other blood groups that must be matched Copyright 2010, John Wiley & Sons, Inc.

Complement & Immune system

Blood & Health There is a connection of life style habits and healthy blood function as well as cardiovascular health: Following factors are critical: 1. Watch cholesterol (& LDL) levels 2. Quit smoking (Free radicals & mutagens) 3. Exercise regularly & moderately 4. Watch blood pressure 4. Cope effectively with psychological and physical stress 5. Eat a heart-healthy diet rich in anti- oxidants, fibers, and flavonoids  

Hematocrit A simple measure for the percentage of red blood cells (RBCs) in the blood (= blood cell count method). A normal hematocrit of 40 means that 40% of the volume of blood is composed of RBCs; - hematocrit 40:                normal - hematocrit 35:                mild anemia - hematocrit 15:                severe anemia - hematocrit > 40:            often the case in extreme athletes or                                          in humans living in high altitudes           

Induced polycythemia Abnormal increase of the RBC count in blood over an hematocrit of 55% due to "EPO doping“, the injection of the RBC-differentiating hormone erythropoietin (EPO), usually in its recombinant form ("Epoetin alpha”). Leads to a vastly increased risk for heart attacks and strokes.

Hemophilia X-chromosome-inherited human genetic disorder. Affected humans. mostly of male gender, show a deficiency or absence of normal blood clotting which leads to continuous bleeding which may occur spontaneously or after traumatic injury. Caused by mutations of the genes of critical coagulation factors (CF), e.g. the gene for CV VIII. Disorder is characterized by spontaneous or traumatic subcutaneous and intramuscular hemorrhaging, nosebleeds, blood in the urine, and hemorrhages in the joints that generate pain and tissue damage. Treatment: transfusions of fresh plasma or of the deficient coagulation factor, e.g. in form of recombinant (= bio-technologically produced) CF versions.