Cardiovascular System: Blood Overview (BIOL2220) PDF

The Cardiovascular System Part III: Blood Anatomy & Physiology II BIOL2220 Version 03 1 The Cardiovascular System Overview – Basic Functions & Components Functions: 1. Distributes The Following To All Cells In T...

The Cardiovascular System Part III: Blood Anatomy & Physiology II BIOL2220 Version 03 1 The Cardiovascular System Overview – Basic Functions & Components Functions: 1. Distributes The Following To All Cells In The Body: Nutrients. Oxygen. Hormones. 2. Carries-Away Metabolic Waste Products. Veins Arteries Components: 1. Blood. 2. Heart. Capillaries 3. Arteries (Arterioles). 4. Veins (Venuoles). CO2 - Nutrients – Waste O2 5. Capillaries. 2 The Cardiovascular System General Overview – Blood Blood: 1. Males 5 – 6 Liters & Females 4 – 5 Liters. 2. Two (2) Fractions: Plasma. Formed Elements. 3. Plasma: 55% Total Blood Volume. 92% H2O. Electrolytes. Proteins. 4. Formed Elements: Blood Cells. Platelets. 5. Blood Cells: Red Blood Cells (Erythrocytes, RBCs, Etc.): No Nucleus. Bi-Concaval. 99.9% Of All Blood Cells. 95% Is Hemoglobin (Hb). Hb Can Reversibly Bind 4O2 & 4CO2. 280 million Molecules Of Hb In Each RBC. White Blood Cells: 0.1% Of All Blood Cells. Five Types. 6.Platelets: Have A Nucleus. Thrombocytes. Engulf & Destroy Pathogens. Involved In Blood Clotting. Induce Inflammation. Fight Parasitic Infections. 3 Produce Antibodies & Provide Immunity. The Cardiovascular System Plasma Overview – Blood Hematocrit Normal Hematocrits of male (a) and female (b). Blood is Plasma is a pale yellow fluid that consists of separated into plasma, about 92% water and 8% other substances, erythrocytes, and a small such as proteins, ions, nutrients, gases, and amount of leukocytes and waste products. It is a colloidal solution, platelets, which rest on the which is a liquid containing suspended erythrocytes. The Hematocrit substances that do not settle out of solution. Measurement includes only Most of the suspended substances are the erythrocytes and does not plasma proteins, which include albumins, measure the leukocytes and globulins, and fibrinogen. platelets. Plasma Volume remains relatively constant. Normally, water intake through the digestive tract closely matches water loss through the 4 kidneys, lungs, digestive tract, and skin. The Cardiovascular System Formed Elements & Hematopoiesis Overview – Blood Erythrocyte Production In response to decreased blood oxygen (hypoxemia), the kidneys release the hormone erythropoietin. Erythropoietin stimulates erythrocyte production in the red bone marrow. This process increases blood oxygen levels. 5 The Cardiovascular System Erythrocytes - RBCs Overview – Blood Erythrocytes or red blood cells are the Most Numerous type of cell in the blood. They function in the transportation of the respiratory gases O2 and CO2. They are about 700 times more numerous than Leukocytes and 17 times more numerous than Platelets. Males have about 5.4 million Erythrocytes per cubic millimeter of blood (range: 4.6 - 6.2 million), whereas females have about 4.8 million Erythrocytes per cubic millimeter of blood (range: 4.2 - 5.4 million). Therefore, males have approximately 10% more Erythrocytes then females. Normal Erythrocytes are biconcave disks about 7.5 micrometers in diameter with edges that are thicker than the center of the cell. Compared with a flat disk of the same size, the biconcave shape increases the surface area of the erythrocyte. The greater surface area makes the movement of gases (because they are responsible for the Transport Of Oxygen And Carbon Dioxide) into and out of the Erythrocyte more rapid. In addition, the Erythrocyte can bend or fold around its thin center, decreasing its size and enabling it to pass more easily through small blood vessels. RBC Factoids: Women average about 4.8 million of these cells per cubic millimeter (mm3; which is the same as a microliter [µl]) of blood. Men average about 5.4 x 106 per µl. These values can vary over quite a range depending on such factors as health and altitude. Peruvians living at 18,000 feet may have as many as 8.3 x 106 RBCs per µl. RBC precursors mature in the bone marrow closely attached to a macrophage. They manufacture hemoglobin until it accounts for some 90% of the dry weight of the cell. The Nucleus Is Squeezed Out Of The Cell and is ingested by the Macrophage. No- longer-needed Proteins are expelled from the cell in vesicles called Exosomes. RBCs are Terminally Differentiated; that is, They Can Never Divide. They live about 120 days and then are ingested by Phagocytic Cells In The Liver and Spleen. Most of the Iron In Their Hemoglobin Is Reclaimed For Reuse. The remainder of the Heme portion of the molecule is degraded into Bile Pigments and secreted by the Liver. Some 3 million RBCs die and are scavenged by the liver each second. 6  The Cardiovascular System Hemoglobin & The Bohr Effect Overview – Blood Oxygen Transport pH, Temp, [O2] Carbaminohemoglobin Oxyhemoglobin Bohr/Haldane Effect In adult humans the Hemoglobin (Hb) Molecule: pH, Temp, [O2] Consists of four (4) polypeptides: Two (2) Alpha (α) Chains of 141 amino Carbon Dioxide Transport acids. Carbon dioxide (CO2) combines with water forming Carbonic Two (2) Beta (β) Chains of 146 amino Acid, which dissociates into a Hydrogen Ion (H+) and a Bi- acids. Carbonate Ions: CO2 + H2O ↔ H2CO3 ↔ H+ + HCO3− Each of these is attached the Prosthetic Group ~95% of the CO2 generated in the tissues is carried in the red Heme. blood cells: It probably enters (and leaves) the cell by Diffusing There is one atom of Iron at the center of each Through Transmembrane Channels in the Plasma Heme. Membrane. (One of the proteins that forms the channel is the D Antigen that is the most important factor in the Rh One molecule of Oxygen can bind to each System of blood groups.) Heme. Once inside, about one-half of the CO2 is directly bound to Hemoglobin (at a site different from the one that binds The reaction is reversible: Oxygen). The rest is converted — following the equation above — Under the conditions of lower temperature, by the Enzyme Carbonic Anhydrase into: higher pH, and increased oxygen pressure in Bi-Carbonate ions that diffuse back out into the the capillaries of the lungs, the reaction Plasma. proceeds to the right. The purple-red Hydrogen ions (H+) that bind to the protein portion deoxygenated hemoglobin of the venous blood of the hemoglobin (thus having no effect on pH). becomes the bright-red oxyhemoglobin of the Only about 5% of the CO2 generated in the tissues dissolves arterial blood. directly in the plasma. (A good thing, too: if all the CO2 we make were carried this way, the pH of the blood would drop from its Under the conditions of higher temperature, normal 7.4 to an instantly-fatal 4.5!). lower pH, and lower oxygen pressure in the When the red cells reach the lungs, these reactions are tissues, the reverse reaction is promoted and reversed and CO2 is released to the air of the alveoli. 7 oxyhemoglobin gives up its oxygen. The Cardiovascular System Review Bohr Effect “Bind to Oxygen” “Release Oxygen” Hemoglobin pH pH Temp Temp [O2] [O2] Oxyhemoglobin Carbaminohemoglobin 8 The Cardiovascular System Review Haldane Effect “Bind to Carbon Dioxide” Hemoglobin “Release Carbon Dioxide” pH pH Temp Temp [CO2] [CO2] Carbaminohemoglobin Oxyhemoglobin 9 The Cardiovascular System CO2 is an Acid, Man Review The Problem of CO2… CO2 + H2O ↔ H2CO3 ↔ H+ + HCO3− 10 The Cardiovascular System Hemoglobin: CO2 Transport & Buffering Overview – Blood The Answer to the Problem! Hb % 50 CO2 is temporarily 9 5% RBC bound to (buffered by) hemoglobin Kreb’s 50 Cycle CO2 % H2CO3 H+ + HCO3- 5% PLASMA Bound Transported out of the (buffered) cell & into by the the general amino circulation. H2CO3 acids of Used as a globin circulating buffer. H+ HCO3- 11  The Cardiovascular System Leukocytes Overview – Blood White Blood Cells: Are much less numerous than red (the ratio is around 1:700). Have nuclei. Participate in protecting the body from infection. Consist of Lymphocytes and Monocytes with relatively clear cytoplasm, and three (3) types of Granulocytes, whose cytoplasm is filled with granules. Lymphocytes: There are several kinds of Lymphocytes (although they all look alike under the microscope), each with different functions to perform. The most common types of Lymphocytes are : The B - Lymphocytes ("B Cells"). These are responsible for making antibodies. The T - Lymphocytes ("T Cells"). There are several subsets of these: The Inflammatory T-Cells that recruit macrophages and neutrophils to the site of infection or other tissue damage. The Cytotoxic T-Lymphocytes (CTLs) that kill virus-infected and, perhaps, tumor cells. The Helper T-Cells that enhance the production of antibodies by B cells. Although bone marrow is the ultimate source of Lymphocytes, the Lymphocytes that will become T-Cells migrate from the bone marrow to the Thymus where they mature. Both B-Cells and T-Cells also take up residence in lymph nodes, the Spleen and other tissues where they encounter Antigens, continue to divide by mitosis, and mature into fully functional 12 cells. The Cardiovascular System Leukocytes Overview – Blood Monocytes Monocytes leave the blood and become Macrophages. This scanning electron micrograph shows a single Macrophage surrounded by several Lymphocytes. Macrophages are large, Phagocytic Cells that engulf foreign material (Antigens) that enter the body of dead and dying cells of the body. Neutrophils The most abundant of the WBCs. This photomicrograph shows a single Neutrophil surrounded by RBCs. Neutrophils squeeze through the capillary walls and into infected tissue where they kill the invaders (e.g., bacteria) and then engulf the remnants by Phagocytosis. This is a never-ending task, even in healthy people: Our throat, nasal passages, and colon harbor vast numbers of bacteria. Most of these are Commensuls, and do us no harm. But that is because Neutrophils keep them in check. However, heavy doses of radiation chemotherapy and many other forms of stress can reduce the numbers of Neutrophils so that formerly harmless bacteria begin to proliferate. The resulting opportunistic infection can be life- threatening. 13 The Cardiovascular System Leukocytes Overview – Blood Eosinophils The number of Eosinophils in the blood is normally quite low (0– 450/µl). However, their numbers increase sharply in certain diseases, especially infections by parasitic worms. Eosinophils are Cytotoxic, releasing the contents of their granules on the invader. Basophils The number of Basophils also increases during infection. Basophils leave the blood and accumulate at the site of infection or other inflammation. There they discharge the contents of their granules, releasing a variety of mediators such as: Histamine. Serotonin. Prostaglandines & Leukotrienes. These increase the blood flow to the area and in other ways add to the inflammatory process. The mediators released by Basophils also play an important part in some allergic responses such as hay fever and an Anaphylactic Response to insect stings. 14 The Cardiovascular System Platelets Overview – Blood Platelets Collagen Receptor Platelets are Cell Fragments produced from Megakaryocytes. Blood normally contains 150,000–350,000 per microliter (µl) or cubic millimeter (mm3). This number is normally Platelet maintained by a homeostatic (negative-feedback) mechanism. If this value should drop much below 50,000/µl, there is a danger of uncontrolled bleeding because of the essential role that platelets have in Blood Clotting. Thrombin Receptor Many different causes: Biologic Triggers such as Collagen, , and Inactive Activated Thrombin Certain drugs and herbal remedies Autoimmunity (Factor V Leiden) When blood vessels are cut or damaged, the loss of blood from the system must be stopped before shock and possible death occur. This is accomplished by solidification of the blood, a process formally called Coagulation (Clotting). Fibrin Clot A Blood Clot consists of a Plug Of Platelets enmeshed in a Network Of Insoluble Fibrin Molecules. Platelets 15 Blood Clotting Hemostasis - Overview Coagulation Of Blood Is A Complex Process Primary Hemostasis During Which Blood Forms Solid Clots. The Process Of Coagulation Starts When A Platelets Collagen Vessels Endothelium Is Damaged. Fibers Body’s Response Is Quick – Within Seconds! Form 1 Coagulation Is Initiated By Collagen (Which Is Plug Outside The Blood Vessel In Local Tissue). Primary Hemostasis Involves Platelets Hemostatic Plug Forming A Platelet Plug At The Site Of Damage. Fibrin Strands Secondary Hemostatis Involves Clotting Factors (In An Enzyme/Protein Cascade) Which Form Fibrin Strands Which Strengthen The Platelet Plug. Fibrin is the water- Make 2 insoluble protein that holds the clot together. Plug Strong Blood Clotting Mechanisms, Though Absolutely Vital To Tissue Repair, Must Be Clotting Managed. Too Much Or Too Little (e.g. ITP, Factors DIC, Hemophilia, Etc.) Secondary Hemostasis 16 Blood Clotting Primary Hemostasis Review 1 Damage To Endothelium Blood Platelets Collagen 22 Collagen Vascular Receptor Initial Fibers Endothelium Glycoprotein Adhesion Mediated By vWF Platelets Platelet 3 Collagen Secondary Receptor Fibers Hemostasis Glycoprotein Activated Platelet Releases: Thromboxane, Tissue 4 Factor, and Serotonin Platelets Granules Activate Other Thrombin Activates Activated 5 6 Platelets & TFP Platelets By Collagen Fibrin Links Platelets (Also) Blood Plasma Platelet 17 Plug  Secondary Hemostasis Blood Clotting With Positive Feedback Review Endothelium XII XIIA Damage TF VII 1 2 XI XIA TF/VIIA Ca++ VIIIA VIII & vWF IX IXA Ca++ X XA X + + V VA Platelet + Activation Prothrombin Aka Factor II Thrombin 1 Contact Activation-starts with collagen, XIIIA HMWK, and prekallikrein 2 Tissue Factor-starts with tissue Fibrinogen CLOT Factor on damaged tissue Aka Factor I Fibrin I 18  Secondary Hemostasis Blood Clotting With Positive Feedback Review vWF/8 + + 8 13 Ca++ Ca++ 12 11 9 10 Thrombin Fibrin 5 + TF/7 What About The Missing Factor #’s? Factor 3=Tissue Factor Factor 4=Ca++ Factor 6=Activated Factor 5 Blood Clotting General Points Hemostasis - Overview A blood clot consists of: Typical Initiation of the Clotting Cascade a plug of platelets enmeshed in network Damaged cells display a surface protein called of insoluble fibrin molecules. tissue factor (TF) Tissue factor binds to Factor VII. Platelet aggregation and fibrin formation both The TF-VII complex is a protease that works on require the proteolytic enzyme Thrombin two substrates: (Factor II). Factor X Factor IX The Clotting Cascade also requires: Follow Factor X: Calcium ions (Ca2+)(which is why blood Factor X binds and activates Factor V. This banks use a chelating agent to bind the heterodimer is called prothrombinase because calcium in donated blood so the blood it is a protease that converts prothrombin (also will not clot in the bag). known as Factor II) to thrombin. Thrombin has several different activities: About a dozen other protein clotting Accelerates the clumping of platelets factors. Most of these circulate in the Positive feedback activation of Factors V, blood as inactive precursors. They are VIII, and XI. activated by proteolytic cleavage Proteolytic cleavage of fibrinogen (aka becoming, in turn, active proteases for "Factor I") to form soluble molecules of other factors in the system. By tradition, fibrin these factors are designated by Roman Activation of Factor XIII which forms numerals. covalent bonds between the soluble fibrin molecules converting them into an insoluble meshwork: aka, the clot. FYI: (Thrombin and activated Factors IX, X and XI are all known as “serine proteases”.) 20 Blood Clotting General Points Hemostasis - Overview Amplifying the Clotting Process A Follow Up Note About Platelet Activity The clotting process also has several positive When blood vessels are damaged, fibrils of feedback loops which quickly magnify a tiny collagen in the extracellular matrix (ECM) are initial event into what may well be a lifesaving exposed. Platelets then begin to adhere to the plug to stop bleeding. collagen through the action of specific receptors for collagen present on their plasma The TF-VII complex (which started the membrane, and von Willebrand factor which process) also activates Factor IX. links the platelets to the collagen. Factor IX binds to Factor VIII, a protein that These actions cause a plug of platelets to circulates in the blood stabilized by yet form at the site. another protein, the von Willebrand Factor (vWF). The bound platelets release: This complex activates more Factor X. Thromboxane A2, which recruits and As thrombin is generated, it activates more: activate still more platelets circulating in Factor V the blood. (This role of thromboxane Factor VIII accounts for the beneficial effect of low Factor XI (all shown with red arrows). doses of aspirin — a cyclooxygenase inhibitor — in avoiding heart attacks.) Factor XI amplifies the production of activated Factor IX. Tissue factor, which activates Factor VII Thus what may have begun as a tiny, localized Serotonin, which also enhances their event rapidly expands into a cascade of clumping and promotes constriction of activity. the blood vessel. 21 Blood Clotting General Points Hemostasis - Overview As Has Been Noted, The Secondary The Key for all of this is Thrombin: Hemostatic Coagulation Cascade Consists Of 2 Pathways: 1. Primary Role Is Conversion Of Fibrinogen To Fibrin. 1. Contact Activation Pathway. 2. It Activates Platelets. 2. Tissue Factor Pathway. 3. Activates FV, FVIII, FXI 4. Activates FXIII The Dominant Pathway Is The Tissue Factor (TF) Pathway. Three Mechanisms Keep The Clotting Process Tissue Factor Pathway: In Check: 1. Main Role Is to Generate A “Thrombin 1. Protein C Is A Key Co-Factor Inhibitor. Burst”. 2. Anti-Thrombin Is A Serine Protease 2. The Most Important Component Of The Inhibitor – Increased By Presence Of Cascade Is Thrombin. Heparin. (Remember: Thrombin and activated Factors IX, X and XI are serine 3. Factor FVIIA Is Circulating At Higher proteases...So, Heparin inhibits them,) Levels Than Any Other Coagulation 3. Tissue Factor Pathway Inhibitor (TFPI) Factor. Inhibits FVIIA , and therefore activation 4. The FVIIA + TF Complex Is What of FIX & FX. Activates FIXA & FXA. Contact Activation Pathway: Minor Role. Clotting Can Occur Without It. 22 Blood Clotting Control & Diagnostic Testing Hemostasis - Overview Co-Factors: Other Screening Tests: 1. Calcium & Phospholipids 1. Bleeding Time. 2. Vitamin K Is An Essential Factor In The 2. Platelet Count. Hepatic Production Of FII, FVII, FIX & FX. 3. D-Dimer. Testing Of Coagulation: Bleeding Time Test: 1. Activated Partial Thromboplastin Time 1. Normal Range 6 – 8 Min. (aPTT) Test. 2. Causes Of Abnormal Test: 2. International Normalized Ratio Thrombocytopenia. (Prothrombin Time) Test – INR (PT). Von Willebrand’s Disease. Drugs. INR – PT / Tissue Factor Test: Uremia 1. Detects Defects In Tissue Factor & Platelet Count: Common Pathway e.g. I, II, V, VII & X. 1. Normal Range Is 150K – 450K / µl. 2. Causes Of Abnormal Test: 2. Causes Of Abnormal Test: Liver Disease. Traumatic Bleeding. Vitamin K Deficiency. Spontaneous Bleeding. Warfarin (Coumadin). D-Dimer Test: 1. Detects Overactivation Of Fibrinolytic aPTT / Contact Factor Test: System. 1. Detects Defects In Contact Activation & 2. Causes Of Abnormal Test: Common Pathway e.g. I, II, V, VIII, IX, X, DIC – Disseminated Intravascular XI & XII. Coagulation (Clotting Everywhere). 2. Causes Of Abnormal Test: Surgery. Hemophilia A & B. DVT – Deep Vein Thrombosis Von Willebrand Disease. (Leading To Pulmonary Embolism). 23 Heparin Therapy. Blood Clotting Fibrinolysis - Overview Plasmin: Comes from enzymatic conversion of FYI plasminogen. Plasmin lyses fibrin, and Antifibrinolytics: to limit fibrinolytic activity degrades factors V and VIII, inhibiting further - e-aminocaproic acid (EACA): clotting. competitively inhibits plasminogen and Plasminogen activators: plasminogen activators from binding to - Tissue-type plasminogen fibrin activator (t-PA): t-PA, a serine protease, -alpha2-antiplasmin: a serine protease adheres to fibrin molecule and absorbs inhibitor that neutralizes plasminogen and then cleaves the any free circulating plasmin. plasminogen to liberate plasmin. -Plasminogen activator inhibitor-1: a - Urokinase: activating circulating serine protease inhibitor that inhibits tissue- plasminogen to plasmin type plasminogen activator. - Streptokinase: It is an exotoxin from certain b-hemolytic streptococci. It binds noncovalently to plasminogen and confers plasmin-like proteolytic activity. Clinical Uses of Plasminogen Activators - Anistreplase: a combination of Acute myocardial infarction streptokinase with an acylated plasminogen, Life-threatening pulmonary embolism which becomes deacylated in plasma. Deep venous thrombosis Deacylated form is the same as streptokinase- Stroke/Cerebrovascular thrombosis plasminogen complex. 24 Blood Clotting Anticoagulants & Thrombocytopathics Direct-acting anticoagulants: Several… Platelet Inhibitors (Thrombocytopathics) Apixaban (Eliquis) and Rivaroxaban (Xarelto) Aspirin are both highly selective, orally bioavailable, and reversible direct inhibitors of factor X - Inhibition of Thromboxane synthesis, resulting in decreased platelet aggregation. Heparin: - 81.25 mg/day of aspirin to reduce the risk of myocardial infarction still used by many. Mechanisms of action: -it accelerates antithrombin III (a serine protease inhibitor) activity 1000 fold, which in turn: Dipyridamole -permanantly inactivates factors IX, X, and XI. - Vasodilation and increase blood flow. - the heparin-antithrombin III complex binds to and - Inhibition of phosphodiesterase, resulting in inactivates thrombin…so, without thrombin, no reduced platelet aggregation. fibrin is made. - All available forms of heparin must be administered parenterally, since they are highly charged and rapidly hydrolyzed in the GI tract. - Heparin antagoinst: protamine sulfate. Indirect-acting anticoagulants: Main one used is Dicumarol or Warfarin sodium. Mechanism of action: - It inhibits Vitamin K, which serves as a cofactor in the production of clotting factors II, VII, IX, and X. -Can be administered orally. 25 The most toxic drug side-effect: hemorrhage