Basic Medical Science 1 - PDF

Heme/Onc/ID Basic Medical Science I Cathleen J. Ciesielski, Ph.D.  Objectives BMS 1.6 The student will describe the epidemiology, pathogenesis and pathophysiology and relate the genetic and molecular mechanisms of disease to hematopoieti...

Heme/Onc/ID Basic Medical Science I Cathleen J. Ciesielski, Ph.D.  Objectives BMS 1.6 The student will describe the epidemiology, pathogenesis and pathophysiology and relate the genetic and molecular mechanisms of disease to hematopoietic and lymph tissue changes and classify the following types of hematopoietic disorders: Cytopenias o Anemias ▪ Blood loss ▪ Hemolytic ▪ Hypoproliferative Proliferative disorders o Secondary erythrocytosis BMS 1.7 The student will explain maturation sequence and function of: neutrophilic granulocytes, eosinophilic granulocytes, basophilic granulocytes, and tissue mast cells. BMS 1.8 The student will explain the effects of over-production and under-production of leukocytes. BMS 1.9 The student will describe the epidemiology, pathogenesis and pathophysiology and relate the genetic and molecular mechanisms of disease to hematopoietic and lymph tissue changes and classify the following types of hematopoietic disorders: Cytopenias o Leukopenias ▪ Neutropenia ▪ Lymphocytopenia Proliferative disorders o Reactive leukocytosis ▪ Neutrophilia ▪ Lymphocytosis ▪ Monocytosis ▪ Eosinophilia BMS 1.10 The student will explain activation sequence and function of thrombocytes.  Objectives BMS 1.13 The student will explain conditions as a result of asplenia. BMS 1.14 The student will describe the epidemiology, pathogenesis and pathophysiology and relate the genetic and molecular mechanisms involved to the development of the following bleeding diathesis categories: Vessel wall abnormalities Platelet related disorders o Reactive thrombocytosis o Thrombocytopenia o Thrombotic microangiopathies o Defective platelet function Coagulopathies Disseminated intravascular coagulation (DIC) BMS 1.15 The student will differentiate the epidemiology, pathogenesis, pathophysiology and genetic/molecular basis for each of the following categories of hypercoagulable states: Primary (genetic) thrombophilia o Factor V Leiden o Increased levels of factors I, VIII, IX, and XI o Protein deficiencies: AT-III, Protein C, Protein S Secondary (acquired) thrombophilia o Multifactorial o Heparin-induced thrombocytopenia (HIT) syndrome o Antiphospholipid antibody syndrome BMS 1.16 The student will describe the pathophysiology and infer the clinical consequences of the following types of thrombotic and embolic disorders: Deep venous thrombosis (DVT) Arterial (and cardiac) thrombosis Pulmonary embolism  Objectives BMS 1.18 The student will describe phagocytosis and its roles during monocyte-macrophage cell system and acute vs. chronic inflammation and micro/macrovascular inflammation. BMS 1.19 The student will explain activation sequence and function of helper T-cells, cytotoxic T-cells and suppressor T-cells. BMS 1.20 The student will explain B cell activation and antibody processing (such as complement). BMS 1.21 The student will define the thermoregulatory set point and chart the negative feedback control of body core temperature, including the role of the hypothalamic set point and how it relates to the pathophysiology of fever. BMS 1.22 The student will explain hypersensitivity response. BMS 1.23 The student will describe the epidemiology, pathogenesis and pathophysiology and relate the genetic and molecular mechanisms of disease to hematopoietic and lymph tissue changes and classify the following types of hematopoietic disorders: Neoplastic disorders o Acute and chronic lymphocytic leukemia o Acute and chronic myelogenous leukemia o Lymphoma: Hodgkin’s and Non-Hodgkin’s o Polycythemia rubra vera o Essential thrombocythemia Three Types of Formed Elements 1. Red blood cells (RBCs) or erythrocytes: ▪ transport oxygen 2. White blood cells (WBCs) or leukocytes: ▪ part of the immune system 3. Platelets or thrombocytes: ▪ cell fragments involved in clotting BMS 1.1 Three Types of Formed Elements 1. Red blood cells (RBCs) or erythrocytes: ▪ transport oxygen 2. White blood cells (WBCs) or leukocytes: ▪ part of the immune system 3. Platelets or thrombocytes: ▪ cell fragments involved in clotting BMS 1.1 Erythrocytes Erythrocytes or red blood cells (RBCs) make up 99.9% of bloods formed elements Production of RBCs requires amino acids iron vitamins B6, B12 and folic acid BMS 1.1  RBC Structure Small and highly specialized disc (~8µm) Thin in middle and thicker at edge Lacks nuclei, mitochondria & ribosomes Lifespan: ~120 days adult ~ 80 days newborn Junqueira BMS 1.1 Importance of RBC Shape & Size 1. High surface-to-volume ratio: quickly absorbs and releases oxygen & carbon dioxide 2. Disc-shape helps RBCs to form stacks (called rouleaux formation): smooth flow through narrow blood vessels 3. Discs bend and flex entering small capillaries: 7.8µm RBC passes through 4-8µm capillary BMS 1.1  Normal Human Erythrocytes Junqueira BMS 1.1  Hemoglobin (Hb) Protein molecule, transports respiratory gases Complex, quaternary protein & iron (heme) structure Enables RBCs to transport 100X more oxygen than plasma could by itself Normal hemoglobin: ~14–18g/dl whole blood in adult male BMS 1.1 Formation of Hemoglobin Four hemoglobin chains/subunits Alpha Beta Gamma Delta Hemoglobin A (adult) Two alpha chains Two beta chains Problem: Sickle cell anemia Hemoglobin A loosely binds oxygen Less severe with Hemoglobin F BMS 1.1  Hemoglobin A Structure 4 globular protein subunits (two alpha subunits & 2 beta subunits: each with 1 molecule of heme each heme contains 1 iron ion one oxygen binds per heme = 4 oxygen per hemoglobin Site on globulin (protein/amino acids) carbon dioxide binds to carbaminohemoglobin BMS 1.1  Fetal Hemoglobin Hemoglobin F Composed of two alpha subunits & two gamma subunits Strong form of hemoglobin found in fetus RBCs during gestation up to 6 months postnatal. Transport oxygen from mother’s hemoglobin to fetal tissue Hemoglobin F has a very high affinity for oxygen, giving it the ability to more readily bind material oxygen BMS 1.1 Measuring RBCs ▪ Red blood cell count: reports the number of RBCs in 1 microliter whole blood Hemoglobin (g/dL) measures the hemoglobin content of the blood ▪ Hematocrit (Ht or HCT): percentage of RBCs in centrifuged whole blood; Measures volume of red cell mass to plasma volume (%) fraction of blood composed or RBCs also known as packed cell volume (PCV) ▪ Mean Corpuscular Volume (MCV): also known as mean cell volume provides a measure of the average RBC volume BMS 1.5 Hemoglobin Structure: Review 4 oxygens can bind per hemoglobin molecule Heme (iron ions): associated with oxygen (oxyhemoglobin): bright red not combined w/oxygen (deoxyhemoglobin): purple-blue BMS 1.4 Hemoglobin A Structure: Review 4 globular protein subunits: two alpha subunits & 2 beta subunits: Site on globulin (protein/amino acids) carbon dioxide binds to carbaminohemoglobin BMS 1.4 Carbaminohemoglobin Location on the protein portion (‘globin’) of hemoglobin for carbon dioxide Binding site for carbon dioxide and carries carbon dioxide towards the lungs Carbon dioxide binds to a DIFFERENT location than oxygen (oxygen binds to the heme portion of hemoglobin) BMS 1.4  Production of Formed Elements Hematopoiesis: process of producing formed elements by myeloid and lymphoid stem cells  Hematopoiesis: Erythropoiesis ▪ Building RBCs in the myeloid tissue requires amino acids iron vitamin B12 (cobalmin) vitamin B6 (pyridoxine) Vitamin B9 (folic acid) Junqueira BMS 1.2/1.3 Erythropoietin (EPO) ▪ Mechanism of EPO stimulates stem cells to form proerythroblasts promotes release of reticulocytes from bone marrow ▪ EPO hormone is released from kidneys in response to low renal oxygenation (not necessarily # of RBCs but oxygen delivery) dysfunctional RBC low blood volume poor oxygenation (typically respiratory) poor blood flow ▪ With low renal oxygenation detected renal hypoxia triggers release of hypoxia-inducible factor (HIF-1) HIF-1 binds to a hypoxia response element on the DNA this binding triggers EPO transcription BMS 1.2  Regulation of RBC Production ▪ When  RBCs present in the blood  O2 in blood detected at the kidneys  secretion of the hormone erythropoietin by the kidneys EPO enters the blood and binds to receptors in the red bone marrow  stimulation of red bone marrow to produce RBCs RBCs (O2 carrying capacity) ▪ When  RBCs present in the blood  O2 at kidney  secretion of erythropoietin stimulation of bone marrow to produce RBCs RBCs (O2) ▪ Other factors can affect this (CO, hypoxia) BMS 1.2  Hemopoietic Stem Cell(or Hemocytoblast Cell): Origin & Differentiation of Formed Elements ▪ Stem cells in bone marrow divide to produce: myeloid stem cells: eventually become erythrocytes, thrombocytes and most leukocytes (neutrophil, eosinophil, basophil & monocyte) lymphoid stem cells: eventually become lymphocytes (T-cell, B-cell, Natural killer cell) Junqueira ANA 2.1  Progenitor Cells ▪ Progenitor cells are often called colony-forming units (CFUs): they give rise to colonies of only one cell type when cultured in vitro or injected into a spleen. ▪ There are four major types of CFUs Erythroid lineage of erythrocytes Thrombocytic lineage of megakaryocytes for platelet formation Granulocyte-monocyte lineage of all three granulocytes and monocytes Lymphoid lineage of B lymphocytes, T lymphocytes, and natural killer cell Junqueira ANA 2.1  Precursor Cells ▪ Precursor cells produce precursor cells (or –blasts). ▪ These precursor cells will mature into a functional ‘final’ cell ▪ Both progenitor and precursor cells will divide more rapidly than stem cells, producing large numbers of differentiated, mature cells Hemopoietic growth factors or colony- stimulating factors (CSF) are needed Junqueira ANA 2.1 Erythropoiesis ▪ Erythrocyte formation occurs only in red bone marrow (myeloid tissue) ▪ Myeloid stem cells mature to become RBCs ▪ Production of RBCs is under the influence of the hormone erythropoietin (EPO) EPO is produced by the kidneys Junqueira ANA 2.1 Stages of RBC Maturation ▪ Myeloid stem cell to ▪ Progenitor cell, which is influenced by EPO to become ▪ Proerythroblast ▪ Erythroblasts – several steps to get ready to expel the nucleus and fill with hemoglobin ▪ Reticulocyte – has lost its nucleus ▪ Erythrocyte: mature rbc Junqueira BMS 1.1 Red Blood Cell Production: Erythropoiesis Balance between production and destruction ~1% produced per day & ~1% destroyed per day BMS 1.1 RBC Disorders: Two Groups 1. Polycythemia: an excess of RBC’s 2. Anemia: a deficit of RBC’s In terms of the pathogenesis of anemia, think of two broad categories: Anemia due to decreased RBC production Anemia due to increased RBC destruction or blood Loss BMS 1.6  Polycythemia: Excess RBC’s ▪ Polycythemia Vera (PV): BMS 1.6  Pathophysiology of Polycythemia Vera (PV): ▪ Normal stem cells are present in the bone marrow of patients with polycythemia vera (PV). ▪ Also present are abnormal clonal stem cells. ▪ Probable etiology -unregulated neoplastic proliferation ▪ The origin of the stem cell transformation remains unknown BMS 1.6  Anemia ▪ Hematocrit or hemoglobin levels are below normal ▪ Is caused by several conditions ▪ Severity of anemia: mild, moderate, severe ▪ Physiological causes: Hypo-proliferative of RBCs or amount of hemoglobin inside of RBCs Bleeding: loss of RBCs Hemolytic: destruction of RBCs BMS 1.6  Anemia: Physiological Causes ▪ Hypo-proliferative (defective RBC/hemoglobin production) Deficiency: iron, B 12, folate (B9) Decreased EPO production Inflammation: pro-inflammatory cytokines decrease availability of iron Cancer ▪ Bleeding (loss of RBC) GI, GU, trauma ▪ Hemolytic (destruction of RBC) Altered erythropoiesis/hemoglobinopathies: sickle-cell, thalassemia, Hb variants (abnormal hemoglobins) Hemolysis Drug-induced Autoimmune BMS 1.6 Anemia: Reticulocytes ▪ Reticulocytes are slightly immature RBCs. Make up approx. 1% of RBCs. They are slightly larger and still have some cellular RNA material, unlike a mature erythrocyte. ▪ An increased production of RBCs in the bone marrow is seen in the peripheral smear as an increased reticulocyte count since new RBCs are released as reticulocytes. BMS 1.6 Summary of Variations in Color & Size of RBCs MCV 80-100um3 MCV 100um3 = increased membrane surface area BMS 1.5 Summary of Anemias ▪ Megaloblastic: large, nucleated RBC precursors with no condensed chromatin impaired DNA synthesis ▪ Non-megaloblastic: no impairment of DNA synthesis BMS 1.5  Microcytic Anemias The microcytic (likely hypochromic) anemias: decreased MCV 1) Iron deficiency anemia 2) Abnormal globin synthesis thalassemia 3) Abnormal heme synthesis micro 4) Other abnormal iron metabolism RARE: copper deficiency, zinc poisoning BMS 1.5  Iron Deficiency Anemia Iron is needed for hemoglobin synthesis Pathophysiology: ▪ Inadequate diet intake is insufficient (which type of diet more commonly affected?) ▪ Malabsorption absorption of iron is insufficient (low intestinal absorption) ▪ (Chronic) blood/iron loss o GI bleed o menorrhagia (which gender more commonly affected?) o blood donation o renal failure ▪ Excessive iron requirements o pregnancy, lactation o infancy BMS 1.6  The Thalassemias ◼ Pathophysiology: A group of inherited disorders characterized by underproduction of either the alpha-globulin or beta-globin chains of Hg molecule ◼ The hallmark of the thalassemia syndromes is decreased or absent synthesis of one or more globin chains leading to: decreased hemoglobin decreased MCV increased reticulocytes BMS 1.6  Alpha Thalassemias Thalassemia is one of the world's most common single-gene disorders (autosomal recessive disorder). ◼ Alpha Thalassemia: mutation or deletion of at least one of the alpha-globulin chain genes o impaired alpha chain production o accumulation of unpaired beta chains = less stable chain Hydrops Fetalis (HB Barts): deletions of all alpha-globulin chains o no production of Hb o massive impact of fetus Hemoglobin H disease: three mutated alpha chains o chronic hemolytic anemia (severity varies) Alpha thalassemia minor: two deletions in the alpha chains o mild anemia or without clinical significance (asymptomatic) Loss of one alpha chain: silent carrier o typically hematologically normal BMS 1.6  Beta Thalassemia ▪ Beta thalassemias: typically a point mutation have reduced production of beta-globin chains, but normal amounts of alpha produced (unpaired alpha chains) o these aggregate to form insoluble tetramers which result in RBC membrane damage, ineffective erythropoiesis, hemolytic anemia o yields a more severe disease state BMS 1.6  Beta Thalassemia ◼ Two types Heterozygous state = beta thalassemia minor (or carrier) causes mild-to-moderate microcytic anemia o typically clinically insignificant microcytic anemia Homozygous state = beta thalassemia major causes severe transfusion-dependent anemia o i.e. Cooley anemia o Why normal at birth??? BMS 1.6  Normocytic Anemia ▪ Large and complicated group of disorders! ▪ Hemolytic anemias ▪ Anemia of chronic disease/inflammation: pro-inflammatory cytokines leads to decreased availability of iron ▪ Bone marrow disorder ▪ Nutritional (early Fe, B12, folate deficiency) ▪ Renal insufficiency BMS 1.5  Macrocytic Anemias The Megaloblastic Anemias: increased MCV 1) Vitamin B12 deficiency 2) Folate Deficiency (nutritional megaloblastic anemia) 3) Inborn errors of metabolism 4) Ethanol abuse/Liver disease 5) Reticulocytosis macro Hemolytic anemia Response to blood lose 6) Abnormal DNA synthesis Chemotherapy (drug-induced) Acute myeloid leukemia (AML) BMS 1.5  Vitamin B12 Deficiency The Megaloblastic Anemias: increased MCV ◼ Vitamin B12 deficiency Decreased intake Decreased absorption Pernicious Anemia – lack of intrinsic factor make by parietal cell in stomach o Pathophysiology: Classic pernicious anemia is caused by the failure of gastric parietal cells to produce sufficient intrinsic factor to permit the absorption of adequate quantities of dietary vitamin B 12. Other disorders that interfere with the absorption and metabolism of vitamin B12 can produce cobalamin (Cbl) deficiency, with the development of a macrocytic anemia and neurological complications B12 foods: fish, meat, poultry, eggs, milk products, some legumes, NUTRITIONAL YEAST BMS 1.5  Folate Deficiency: Pathophysiology Megaloblastic anemia is caused by various DNA synthesis defects. ◼ In folate deficiency, purine biosynthesis is affected because folic acid is essential in this process. Folate foods: legumes, green vegetables ◼ The ability to repair and replicate DNA is decreased. ◼ Vitamin B12 is a cofactor for the activation of folic acid BMS 1.6  ANEMIA: Lose RBCs ▪ Anemias Secondary to RBC Destruction or Blood loss: ▪ Blood Loss - bleeding is much more common than Hemolysis ▪ Hemolytic Anemia ▪ Hemolytic Disease of the Newborn ▪ Autoimmune Hemolytic Anemia ▪ Sickle Cell Disease ▪ intrinsic ▪ G6PD Deficiency ▪ intrinsic ▪ Drug-Induced Hemolytic Anemia BMS 1.6 Anemia Secondary to Hemolysis (RBC Destruction) ◼ A normal RBC lifespan = 120 days ◼ If the RBC lifespan is shortened significantly (