Lecture 11 Structure and Function of the Hematologic System PDF

Structure and Function of the Hematologic System Dr. Naleen Mathur Lecturer Department of Pathology [email protected] 1 LEARNING OBJECTIVES Compare and contrast the disorders listed with reference to: Etiology Pathogenic mechanism Altered morphology, phys...

Structure and Function of the Hematologic System Dr. Naleen Mathur Lecturer Department of Pathology [email protected] 1 LEARNING OBJECTIVES Compare and contrast the disorders listed with reference to: Etiology Pathogenic mechanism Altered morphology, physiology Signs and symptoms and basis for signs and symptoms Genetic & environmental factors involved in the disease/disorder complications Risk factors A. Iron deficiency anemia B. Megaloblastic anemias C. Hemolytic anemias, Sickle cell anemia D. Hodgkin/Non-Hodgkin Lymphomas E. Acute and chronic myelogenous leukemia F. Multiple Myeloma G. Thrombocytopenia H. Thrombocytosis I. Qualitative platelet disorders J. Coagulation disorders-deficiency of clotting factors, DIC. 2 Functions of the Hematologic System ¡ Delivery of substances needed for cellular metabolism ¡ Removal of wastes ¡ Defense against microorganisms and injury ¡ Maintenance of acid-base balance 3  Composition of Blood ¡ 91% water and 9% solutes: 6 quarts (5.5 L) ¡ Cellular components: 45% of the blood volume ¡ Plasma: 50% to 55% of the blood volume ÷ Organic and inorganic elements Plasma proteins: ÷ Albumins ¢ Function as carriers and control the plasma oncotic pressure ÷ Globulins ¢ Carrier proteins and immunoglobulins (antibodies) ÷ Clotting factors ¢ Mainly fibrinogen 4  Composition of Blood ¡ Cellular components ÷ Erythrocytes (Red blood cells) ¢ Most abundant cells in the blood ¢ Responsible for tissue oxygenation ¢ Biconcave shape; mature erythrocyte lacks a nucleus and cytoplasmic organelles ¢ 120-day life span 5  Composition of Blood ¡ Leukocytes (white blood cells) ÷ Defend the body against infection and remove debris ÷ Granulocytes ¢ Membrane-bound granules in their cytoplasm ¢ The granules contain enzymes capable of destroying microorganisms ¢ Inflammatory and immune functions ¢ Capable of ameboid movement (diapedesis) 6  Composition of Blood — Granulocytes ¡ Neutrophils (60-70%) ÷ Polymorphonuclear neutrophil (PMN) ÷ Chief phagocytes of early inflammation ¡ Eosinophils (2-4%) ÷ Eosinophils ingest antigen-antibody complexes ÷ Induced by IgE mediated hypersensitivity ÷ Increase in parasitic infections ¡ Basophils (0.5-1%) ÷ Structurally and functionally similar to mast cells ¡ Mast cells ÷ Central cell in inflammation ÷ Found in vascularized connective tissue 7  Composition of Blood — Agranulocytes ¡ Monocytes: immature macrophages (3-8%) ¡ Macrophages: Monocytes in tissues ¡ Lymphocytes: T cells, B cells, plasma cells (20-25%) ¡ Natural killer (NK) cells Platelets ¡ Disk-shaped cytoplasmic fragments of megakaryocytes ¡ Essential for blood coagulation and control of bleeding 8  Lymphoid Organs — Primary Lymphoid organs : Thymus and Bone marrow — Secondary Lymphoid organs : — Spleen ¡ Largest secondary lymphoid organ ¡ Splenic pulp ÷ Masses of lymphoid tissue containing macrophages and lymphoid tissue ¡ Venous sinuses ÷ Phagocytosis of old, damaged, and dead blood cells ÷ Blood storage: 300ml — Lymph nodes ¡ Part of the immune and hematologic systems ÷ Facilitate maturation of lymphocytes ÷ Transport lymphatic fluid back to the circulation ÷ Cleanse the lymphatic fluid of microorganisms and foreign particles 9 Lymphoid Organs (lymph node) 10  Hematopoiesis — Hematopoiesis is the process of blood cell production — Two stages: ¡ Mitosis (proliferation) ÷ Mitosis stops before the cell enters the peripheral blood ¡ Maturation and differentiation 11  Hematopoiesis (cont’d) — Stem cell system ¡ Pluripotent stem cells ¡ Colony-stimulating factors — Bone marrow ¡ Red or active bone marrow (myeloid tissue) ¡ Yellow or inactive bone marrow ¡ In adults active bone marrow is found in ÷ Pelvic bones ÷ Vertebrae ÷ Cranium and mandible ÷ Sternum and ribs ÷ Humerus ÷ Femur 12 Hematopoiesis (cont’d) 13  Erythropoiesis — Erythrocytes are derived from erythroblasts (normoblasts) — Maturation is stimulated by erythropoietin — Erythropoietin causes an increase in red cell production and release from bone marrow — Sequence ¡ Uncommitted pluripotent stem cell, committed proerythroblast, normoblast, basophilic normoblast, polychromatophilic normoblast, orthochromic normoblast, reticulocyte (nucleus is lost), erythrocyte ¡ In each step the quantity of hemoglobin increases and the nucleus decreases in size 14 Erythropoiesis (cont’d) 15  Regulation of Erythropoiesis — Numbers of circulating red cells in healthy individuals remain constant — The peritubular cells of the kidney produce erythropoietin — Hypoxia stimulates the production and release of erythropoietin 16  Hemoglobin — Oxygen-carrying protein of the erythrocyte — A single erythrocyte contains as many as 300 hemoglobin molecules — Two pairs of polypeptide chains (globin) Two alpha chains and two beta chains — Four colorful iron-protoporphyrin complexes (heme) ÷ Each heme carries one molecule of oxygen ÷ Protoporphyrin bound to reduced ferrous iron (Fe2+) ÷ Methemoglobulin: non-reduced ferrous iron (Fe3+) cannot bind oxygen 17 Hemoglobin 18  Hemoglobin synthesis — Nutritional requirements ¡ Building blocks: ÷ Proteins ¢ Amino acids ÷ Vitamins ¢ Vitamins B12, B6, B2, E, and C; folic acid (B9); pantothenic acid; and niacin ÷ Minerals ¢ Iron and copper 19  Normal Destruction of Senescent Erythrocytes — Aged red cells are sequestered and destroyed by macrophages of the MPS (mononuclear phagocyte system), primarily in the spleen — The liver takes over if the spleen is absent — Globin chains are broken down into amino acids — Porphyrin is reduced to bilirubin, transported to the liver, and secreted in the bile 20  Development of Leukocytes — Leukocytes arise from stem cells in the bone marrow — Granulocytes mature in the bone marrow — Agranulocytes and monocytes are released into the bloodstream before they fully mature — Growth factors and colony-stimulating factors encourage production and maturation of leukocytes — Production increases in infection, presence of steroids, increased heart rate, pain, nausea/vomiting 21  Development of Platelets — Endomitosis ¡ The megakaryocyte undergoes the nuclear phase of cell division but fails to undergo cell division ¡ The megakaryocyte expands due to the doubling of the DNA and breaks up into fragments — Platelet levels are maintained by thrombopoietin and IL-11 — Platelets circulate for 10 days before losing their functional capacity — Senescent platelets sequestered and destroyed in spleen 22  Hemostasis — Hemostasis means arrest of bleeding — Requirements: ¡ Platelets ÷ Contribute to regulation of blood flow into a damaged site ÷ Initiate platelet-to-platelet interactions resulting in formation of a platelet plug ÷ Activate the coagulation (or clotting) cascade ÷ Initiate repair processes, including clot retraction and clot dissolution (fibrinolysis) ¡ Clotting factors ¡ Endothelial cells ¡ Primary hemostasis (platelet plug formation); Secondary hemostasis (Fibrin clot formation); Fibrinolysis 23  Hemostasis (cont’d) — Platelet plug formation (Primary hemostasis) ¡ Adhesion ÷ von Willebrand factor (vWF) ¡ Activation ¡ Aggregation 24  Hemostasis (cont’d) — Function of clotting factors (Secondary hemostasis) ¡ Intrinsic pathway ÷ Activated when factor XII (Hageman factor) contacts subendothelial substances exposed by vascular injury ¡ Extrinsic pathway ÷ Activated when tissue factor (TF) (tissue thromboplastin) is released by damaged endothelial cells 25 Coagulation Cascade 26 Control of Hemostatic Mechanisms — Clot retraction ¡ Fibrin strands shorten; become denser and stronger to approximate the edges of the injured vessel and site of injury ¡ Facilitated by large numbers of platelets within the clot and actin-like contractile proteins in the platelets — Lysis of blood clots ¡ Fibrinolytic system ÷ Plasminogen and plasmin ÷ Fibrin degradation products ¢ D-dimers 27 Fibrinolytic System 28  Evaluation of the Hematologic System — Tests of bone marrow function: ¡ Bone marrow aspiration ¡ Bone marrow biopsy ¡ Measurement of bone marrow iron stores — Blood tests ¡ Complete Blood Picture ¡ Iron profile ¡ Serum Vit B12 ¡ Serum Folate 29 Alterations of Hematologic Function in Children 30 Acquired Disorders of Erythrocytes — Iron deficiency anemia ¡ Most common blood disorder of infancy and childhood ¡ Lack of iron intake or blood loss ¡ Manifestations: ÷ Irritability ÷ Decreased activity tolerance ÷ Weakness ÷ Lack of interest in play 31 Acquired Disorders of Erythrocytes (cont’d) — Acquired congenital hemolytic anemia ¡ Hemolytic disease of the fetus and newborn (HDFN) (Erythroblastosis fetalis) ÷ Alloimmune disease ÷ Maternal antibody directed against fetal antigens ÷ ABO incompatibility occurs in 20% to 25% of cases ÷ Rh incompatibility occurs in less than 10% ¡ Manifestations: ÷ Anemia ÷ Hyperbilirubinemia ÷ Icterus neonatorum (neonatal jaundice) ÷ Kernicterus (bilirubin deposits in the brain) 32 Hemolytic Disease of the fetus and Newborn 33 Inherited Disorders of Erythrocytes — Sickle cell disease ¡ Disorders characterized by the presence of an abnormal hemoglobin (HbS) ÷ Mutation causes glutamic acid to be replaced by valine ¡ Deoxygenation and dehydration cause the red cells to solidify and stretch into an elongated sickle shape 34 Inherited Disorders of Erythrocytes (cont’d) — Sickle cell disease (cont’d) ¡ Sickle cell trait ÷ Child inherits HbS from one parent and HbA from another ¡ Other forms: ÷ Sickle cell-thalassemia disease ÷ Sickle cell-HbC disease ¡ Sickling is promoted by ÷ Hypoxemia; decreased pH; low temperature; Decreased plasma volume ¡ Can result in: ÷ Vaso-occlusive crisis (thrombotic crisis) ÷ Aplastic crisis ÷ Sequestration crisis ÷ Hyperhemolytic crisis 35 Sickle Cell Disease 36 Sickle Cell Disease (cont’d) 37 Inherited Disorders of Erythrocytes — Thalassemias ¡ Autosomal recessive disorders ¡ Synthesis of the globin chains of the hemoglobin molecule is slowed or defective ¡ Major: homozygous inheritance ¡ Minor: heterozygous inheritance — In alpha thalassemia, the alpha chains are affected; beta chains in beta thalassemia ¡ Beta-thalassemia minor ¡ Beta-thalassemia major (Cooley anemia) ÷ Life-threatening condition 38 Beta Thalassemia Major 39  Inherited Disorders of Erythrocytes (cont’d) ˜ Alpha trait (carrier state – Single alpha chain forming gene is defective) ˜ Alpha-thalassemia minor (Two alpha chain forming genes are defective) ˜ Hemoglobin H disease (Three alpha chain forming genes are defective) ˜ Alpha-thalassemia major (All four alpha chain forming genes are defective) Ø Fatal condition 40  Inherited Coagulation and Platelet Disorders — Hemophilias ¡ Hemophilia A (factor VIII deficiency) ¡ Hemophilia B (factor IX deficiency) ¡ Hemophilia C (factor XI deficiency) ¡ Serious bleeding disorders ¡ Involve gene deletions or point mutations ¡ First signs by age 3 to 4 years include episodes of persistent bleeding from minor injuries 41 Antibody-Mediated Hemorrhagic Disease — Idiopathic thrombocytopenic purpura (ITP) ¡ Autoimmune or primary thrombocytopenic purpura ¡ Platelet destruction rate that exceeds production ¡ 70% with antecedent viral disease ¡ Manifestations of bruising and petechial rash ¡ Prognosis excellent with 80% regaining normal platelet counts within 6 months after onset 42  Leukemia — Most common malignancy of childhood — 80% to 85% are acute lymphoblastic leukemias (ALL); remainder acute myelogenous leukemia (AML) — Result of ecogenetics — Manifestations of pallor, fatigue, purpura, and fever — Blast cell is hallmark of acute leukemia — 5-year survival rate is 80% 43  Lymphoma — Non-Hodgkin lymphoma (NHL) ¡ Nodular or diffuse (most in childhood are diffuse) ¡ Childhood NHL subdivided ÷ Small noncleaved cell (Burkitt or non-Burkitt) ÷ Diffuse Large B-cell (histiocytic) ÷ Lymphoblastic ÷ Anaplastic large cell 44  Lymphoma (cont’d) — Non-Hodgkin lymphoma (NHL) (cont’d) ¡ Etiology viral, chronic immunostimulation, congenital immunodeficiency syndromes, and genetics ¡ Manifestations specific to site involved ¡ Mediastinal mass ¡ Treatment of chemotherapy and radiation ¡ 60% to 80% cure rate 45  Lymphoma (cont’d) — Hodgkin lymphoma ¡ Rare in childhood ¡ Infectious mode of transmission ¡ Many children with Hodgkin lymphoma demonstrate a high antibody titer to Epstein-Barr virus (EBV) ¡ Manifestations : ÷ Most common: painless adenopathy with/without fever ÷ Others: anorexia, malaise, and weight loss 46