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Module 1 | Anaemia an introduction Module prepared by: Ben Woodman-Smith; Medical Student, Cardiff University Steve Allen; Professor of Paediatrics and.

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Presentation on theme: "Module 1 | Anaemia an introduction Module prepared by: Ben Woodman-Smith; Medical Student, Cardiff University Steve Allen; Professor of Paediatrics and."— Presentation transcript:

1 Module 1 | Anaemia an introduction Module prepared by: Ben Woodman-Smith; Medical Student, Cardiff University Steve Allen; Professor of Paediatrics and International Health, College of Medicine, Swansea University Ann Benton; Consultant Haematologist, ABMU Health Board, Swansea

2 Partners in Global Health Education Contents 1.0. Introduction anaemia 1.1. How to use this module 1.2. Learning outcomes The red cell life cycle 2.0. The erythrocyte: an overview 2.1. Erythropoiesis 2.2. The red cell membrane 2.3. Haematinics 2.4. Red cell metabolism 2.5. Haemoglobin and oxygen transport 2.6. Ageing and death of the red blood cell. o Quiz 1 Anaemia; an overview 3.0. Defining anaemia Prevalence of anaemia 3.2. Clinical features of anaemia o Quiz 2 Classifying Anaemia 4.0. Classification of anaemia 4.1. Red cell indices 4.2. Morphological classification 4.3. Aetiological classification of anaemia. Interpretation of Blood film 5.0. Basic interpretation of a blood film Anaemia: essential bites o Quiz 3 Glossary References Contents 1. 1Introduction 1.2 use this module 1.3 Learning outcomes 2.1. The erythrocyte 2.2. Erythropoiesis 2.3. Red cell membrane 2.4. Haematinics 2.5. Red cell metabolism 2.6. Haemoglobin 2.7. Ageing and death Quiz Defining anaemia Prevalence 3.1. Clinical features Quiz Classifying anaemia 4.1. red cell indices Morphological classification 4.3. Aetiological classification 5.0. Blood film: a basic interpretation Anaemia cards Quiz Glossary 7.0. References please click on contents to repeat a section. Please click here to move forwards or backwards through the module

3 Partners in Global Health Education | Introduction Welcome to the anaemia module! Anaemia can be defined as a reduction in the haemoglobin in the blood below normal range for age and sex. Essentially, anaemia is defined as haemoglobin (Hb) concentration: For adult males < 13.5 g/dl For adult women < 11.5 g/dl Anaemia is a global public health problem affecting both developing and developed countries. It has major consequences for human health as well as social and economic development. In 2008, iron deficiency anaemia was considered to be among the most important contributing factors to the global burden of disease. Given the importance of anaemia both globally and within the UK, it is essential that any medical student or junior doctor can understand the major causes of anaemia, recognise it’s clinical features, interpret blood results and respond with appropriate management. 1.1 Contents 1. 1Introduction 1.2 use this module 1.3 Learning outcomes 2.1. The erythrocyte 2.2. Erythropoiesis 2.3. Red cell membrane 2.4. Haematinics 2.5. Red cell metabolism 2.6. Haemoglobin 2.7. Ageing and death Quiz Defining anaemia Prevalence 3.1. Clinical features Quiz Classifying anaemia 4.1. red cell indices Morphological classification 4.3. Aetiological classification 5.0. Blood film: a basic interpretation. Quiz Glossary 7.0. References please click on contents to repeat a section. Contents 1. 1Introduction 1.2 use this module 1.3 Learning outcomes 2.1. The erythrocyte 2.2. Erythropoiesis 2.3. Red cell membrane 2.4. Haematinics 2.5. Red cell metabolism 2.6. Haemoglobin 2.7. Ageing and death Quiz Defining anaemia Prevalence 3.1. Clinical features Quiz Classifying anaemia 4.1. red cell indices Morphological classification 4.3. Aetiological classification 5.0. Blood film: a basic interpretation Anaemia cards Quiz Glossary 7.0. References please click on contents to repeat a section. Image above: scanning electron microscope image of red blood cells. Image left: Global WHO map of anaemia in preschool age children.

4 Partners in Global Health Education | how to use this module This self-directed learning (SDL) module has been designed for medical and other health care students. We suggest that you start with the learning objectives and try to keep these in mind as you go through the module slide by slide, in order and at your own pace. Complete the true/false questions as you go along to assess your learning. You should research any issues that you are unsure about. Look in your textbooks, access the on-line resources indicated at the end of the module and discuss with your peers and teachers. Finally, enjoy your learning! We hope that this module will be enjoyable to study and complement your learning about anaemia from other sources. 1.2 Contents 1. 1Introduction 1.2 use this module 1.3 Learning outcomes 2.1. The erythrocyte 2.2. Erythropoiesis 2.3. Red cell membrane 2.4. Haematinics 2.5. Red cell metabolism 2.6. Haemoglobin 2.7. Ageing and death Quiz Defining anaemia Prevalence 3.1. Clinical features Quiz Classifying anaemia 4.1. red cell indices Morphological classification 4.3. Aetiological classification 5.0. Blood film: a basic interpretation. Quiz Glossary 7.0. References please click on contents to repeat a section. Contents 1. 1Introduction 1.2 use this module 1.3 Learning outcomes 2.1. The erythrocyte 2.2. Erythropoiesis 2.3. Red cell membrane 2.4. Haematinics 2.5. Red cell metabolism 2.6. Haemoglobin 2.7. Ageing and death Quiz Defining anaemia Prevalence 3.1. Clinical features Quiz Classifying anaemia 4.1. red cell indices Morphological classification 4.3. Aetiological classification 5.0. Blood film: a basic interpretation Anaemia cards Quiz Glossary 7.0. References please click on contents to repeat a section.

5 Partners in Global Health Education | how to use this module 1.2 Information within red boxes is considered core knowledge Information within the green boxes is considered useful knowledge KEY Information within the grey boxes is considered optional to gain a broader understanding of anaemia and its causes. Key point! These are placed along the way within this module. Based on the learning objectives, these comment boxes are aimed at highlighting the important links between the structure, physiology and life cycle of the red blood cell to the pathological processes resulting in anaemia. Contents 1. 1Introduction 1.2 use this module 1.3 Learning outcomes 2.1. The erythrocyte 2.2. Erythropoiesis 2.3. Red cell membrane 2.4. Haematinics 2.5. Red cell metabolism 2.6. Haemoglobin 2.7. Ageing and death Quiz Defining anaemia Prevalence 3.1. Clinical features Quiz Classifying anaemia 4.1. red cell indices Morphological classification 4.3. Aetiological classification 5.0. Blood film: a basic interpretation. Quiz Glossary 7.0. References please click on contents to repeat a section. Contents 1. 1Introduction 1.2 use this module 1.3 Learning outcomes 2.1. The erythrocyte 2.2. Erythropoiesis 2.3. Red cell membrane 2.4. Haematinics 2.5. Red cell metabolism 2.6. Haemoglobin 2.7. Ageing and death Quiz Defining anaemia Prevalence 3.1. Clinical features Quiz Classifying anaemia 4.1. red cell indices Morphological classification 4.3. Aetiological classification 5.0. Blood film: a basic interpretation Anaemia cards Quiz Glossary 7.0. References please click on contents to repeat a section. Anaemia essential bites. These cards are designed to provide some essential information on key anaemias. These are accessible throughout the module.

6 Partners in Global Health Education | learning outcomes (L.O.) By the end of the module, you should be able to…. List the key components of erythropoiesis (red cell production) Bone marrow stroma, haemopoietic stem cells, tissue macrophages Renal system (erythropoietin) Functional DNA (globin genes) Nutrition (Iron, B12, Folate, amino acids) Link the components of red cell structure to red cell development and function components of haemoglobin molecule metabolic pathways active in red blood cells features of red cell membrane Link the classification of anaemia to the physiology of erythropoiesis and the influence of systemic pathology Interpret red cell indices reported in a full blood count and correlate with red cell morphological classification and underlying causes of anaemia Define anaemia and know the clinical symptoms and signs to look out for Recognize some key blood film abnormalities 1.3 Contents 1. 1Introduction 1.2 use this module 1.3 Learning outcomes 2.1. The erythrocyte 2.2. Erythropoiesis 2.3. Red cell membrane 2.4. Haematinics 2.5. Red cell metabolism 2.6. Haemoglobin 2.7. Ageing and death Quiz Defining anaemia Prevalence 3.1. Clinical features Quiz Classifying anaemia 4.1. red cell indices Morphological classification 4.3. Aetiological classification 5.0. Blood film: a basic interpretation. Quiz Glossary 7.0. References please click on contents to repeat a section. Contents 1. 1Introduction 1.2 use this module 1.3 Learning outcomes 2.1. The erythrocyte 2.2. Erythropoiesis 2.3. Red cell membrane 2.4. Haematinics 2.5. Red cell metabolism 2.6. Haemoglobin 2.7. Ageing and death Quiz Defining anaemia Prevalence 3.1. Clinical features Quiz Classifying anaemia 4.1. red cell indices Morphological classification 4.3. Aetiological classification 5.0. Blood film: a basic interpretation Anaemia cards Quiz Glossary 7.0. References please click on contents to repeat a section. L.O. We will place these objectives along the route to help direct your learning….

7 Partners in Global Health Education | the erythrocyte: an overview When learning about anaemia and in fact haematology in general, it is essential to go back to square one and understand the basics of cell production, function and life cycle. Within this first module we aim to tie some basic physiology of the red blood cell to the pathological manifestations of anaemia. If fully understood, it will remain as a backbone for future clinical knowledge whenever approaching an anaemic patient. With this in mind we now look in some detail at the structure, function and life cycle of the red blood cell. Please click here for next slide. Contents page 2.1. The erythrocyte: an overview. 2.1 Welcome to section one. An erythrocyte is a fully developed red blood cell!

8 Partners in Global Health Education | the erythrocyte: an overview Contents page 2.1 *L.O. Link the components of red cell structure to red cell development and function Image: scanning electron microscope of red blood cell To achieve these functions the red cell has several unique properties…. Strength : it has a strong but flexible membrane able to withstand the recurrent shear forces involved in the circulation of blood. Flexibility: the red cell is 7.8  m across and 1.7  m thick and yet it is able to fit through capillaries of only 5  m diameter. This is in-part due to the flexible membrane and shedding of the nucleus. Biconcave shape: increases surface area available for gaseous exchange. Haemoglobin content: unique to the red cell, it is this metaloprotein molecule which is pivotal in red cell development and Oxygen transport due to its affinity for O 2. Function The primary function of the erythrocyte is the carriage of oxygen from the lungs to the tissues and CO 2 from the tissues to the lungs. The red cell also plays an important role in pH buffering of the blood. Lifespan: Because the fully developed red blood cell has no nucleus the cell cannot divide or repair itself. The lifespan is therefore relatively short ( 120 days ). START HERE FINISH HERE

9 Partners in Global Health Education Kidney Bone marrow Red blood cells in circulation erythropoietin Stem cells Erythroid precursors An erythrocyte is a fully developed, mature red blood cell. The adult human makes approximately new erythrocytes every day by the process of erythropoiesis. This is a complex process that occurs within the bone marrow. Before an erythrocyte arrives fully functioning into the blood stream it must develop from a stem cell through an important number of stages. This module has simplified this process and highlights the key stages. Follow the numbered red boxes through to the end before continuing to the next slide. As with much human physiology, this system works via a feedback mechanism. 4. There is no store of EPO. The production of erythropoietin is triggered by tissue hypoxia (oxygen tension sensed within the tubules of the kidney) and stops when oxygen levels are normal. | Erythropoiesis Contents page 2.1. The erythrocyte: an overview Erythropoiesis EPO stimulates stem cells within the bone marrow which differentiate into erythroid precursors. 3. EPO continues to stimulate primitive erythroid cells (red blood cells) in the bone marrow and induce maturation. 1: Erythropoietin (EPO), a growth factor, is synthesized primarily (90%) from peritubular cells of the kidneys (renal cortex). Macrophages surround and supply iron to these erythroprogenitor cells that become erythroblastic islands. START HERE FINISH HERE List the key components of erythropoiesis (red cell production) LO

10 Partners in Global Health Education | 2.2. Erythropoiesis Contents page 2.1. The erythrocyte: an overview Erythropoiesis 2.2 Key point! In chronic states of anaemia the opposite may occur. The chronic hypoxic state increases production of EPO. This leads to an increase in the proportion of erythroblasts, expansion and eventually fatty deposition within the bone marrow. During childhood when the growth plates are still present, this expansion can lead to bone deformities such as frontal bossing. This is seen in chronic haemolysis such as thalassaemia. Key point! Chronic renal disease / bilateral nephrectomy will reduce or stop the production of EPO. It’s absence or reduction causes anaemia through reduced red cell production. Anaemia due to EPO deficiency will be normocytic in morphology; i.e. the red cell will be a normal shape and size but reduced in number. Hypoxia is the major stimulant for increased EPO production Kidney Bone marrow erythropoietin Erythroid precursors Stem cells Kidney Bone marrow erythropoietin Erythroid precursors Stem cells

11 Partners in Global Health Education |Red cell precursors and the sequence of erythropoiesis Contents page 2.1. The erythrocyte: an overview Erythropoiesis 2.2 Anaemia of chronic disease. In individuals living with a chronic disease (e.g. rheumatoid arthritis),a complex interaction of inflammatory cytokines interferes with the red cell lifecycle by impairing iron metabolism and inhibiting red cell precursors. The end result is a normocytic anaemia. Reticulocytes are an important cell in haematology as they increase in number following a haemorrhage, haemolytic anaemia or from treatment of a haematinic deficiency. They provide an excellent measure of red cell production and the age of the red cell population. In normal blood there is usually about 1 reticulocyte : 100 erythrocytes. Key point! marrow 3.5 Erythrocyte : after 1 week the mature erythrocyte emerges with no organelles and high haemoglobin content. Sequence: amplification and maturation of the erythrocyte Pronormoblast : This is the earliest and largest cell with a large nucleus and no haemoglobin Reticulocytes : Considered the “teenagers” of the the life cycle! This is the FINAL stage of development before full maturation. These cells are now anucleate and contain roughly 25% of the final haemoglobin total. They reside mostly in the marrow but in healthy individuals a small number can be found in the peripheral blood. They contain some cell organelles. Normoblasts : these cells go through a large number of progressive changes. Fundamentally they reduce in cell size but increase the haemoglobin concentration in the cytoplasm. The nucleus proportionally decreases until it is extruded before the cell is released in to the blood. blood

12 Partners in Global Health Education |haematinics Vitamin B 12 (cobalamin) and folate (pteroylglutamic acid ): These are key building blocks for DNA synthesis and essential for cell mitosis. DNA synthesis is reduced in all cells that are deficient in either folate or vitamin B 12. The bone marrow is the factory for blood cell production. In haematinic deficiency, DNA replication is limited and hence the number of possible cell divisions is reduced leading to larger red cells being discharged into the blood i.e. less DNA, less divisions and larger cells. This leads to enlarged, misshapen cells or megaloblasts in the marrow and macrocytic red cells in the blood. So what exactly are the haematinics? These are the key micronutrients that must be present if a red blood cell and its haemogoblin are to develop in a normal fashion. These major micronutrients, provided in a balanced diet, are iron, vitamin B 12 and folate A deficiency in any one of these micronutrients can result in anaemia through impaired red cell production within the bone marrow Assessing haematinic status is key to the investigation of the cause of anaemia haemoglobin deficiency; Click here see all key causes. iron life cycle; Click here to see the key stages Iron: At the centre of the haem molecule is an atom of iron which binds oxygen in a reversible manner. Haemoglobin concentration in the developing red cell is a rate limiting step for erythropoiesis. In iron deficiency, red cells undergo more divisions than normal and, as a result, are smaller (microcytic) and have a reduced haemoglobin content (hypochromic). Iron deficiency is the leading cause of anaemia worldwide. Click here to see a schematic diagram of vitamin B 12 absorption 2.4 Contents page 2.1. The erythrocyte: an overview Erythropoiesis 2.3. The red cell membrane 2.4 Haematinics Erthropoiesis is also regulated by the availability of haematinics “Check the haematinics” this is a phrase used frequently on the hospital ward!

13 Partners in Global Health Education |haematinics in haemoglobin Iron Protoporphyrin Globin Haem Haemoglobin Thalassaemia Iron deficiency Chronic inflammation Malignancy Click here to return Chronic infections and inflammatory disorders cause chronic anaemia as a result of; 1. slightly shortened red blood cell life span 2. sequestration of iron in inflammatory cells called macrophages Both procedures result in a decrease in the amount of iron available to make red blood cells. 2.4

14 Partners in Global Health Education |haematinics: the normal iron cycle Click here to return 2.4 Iron deficiency can be identified best by assessing the appearances of the red cells on a blood film. Iron indices in a blood sample are helpful to confirm a lack of iron. In order to interpret these indices, it is vital to understand how the body handles iron ….. Erythroid bone marrow (normoblasts) Reticuloendothelial system; Spleen & macrophages Duodenum Serum transferrin Fe Red blood cells Liver Iron is a key constituent of haemoglobin (60-70% of total body iron is stored here) and it’s availability is essential for erythropoiesis. In iron deficiency, there are more divisions of red cells during erythropoiesis than normal. As a result the red cells are smaller (microcytic) and have a reduced haemoglobin content (hypochromic). 2. Iron is then attached to a protein, transferrin in the serum (plasma), where it is transported to the bone marrow for haemoglobin synthesis. 1. Iron is absorbed from the small intestine in the ferrous state (Fe 2+ ; approx. 1mg/day). 3. Dying red cells are recycled by macrophages in the spleen and iron is recycled into the plasma for further use. Soluble transferrin receptors, sTfR are on the red cell surface. These can be measured and are increased in iron deficiency. An iron deficiency profile. Serum Iron: Reduced Serum total iron- binding capacity (TIBC): Increased- the body works hard to bind free iron. Serum ferritin: Reduced-since iron stores are low Serum soluble transferrin receptors: Increased-since red cells attempt to absorb more iron. In iron deficient states, bone marrow iron is reduced. START Some iron binds to apoferritin to form ferritin, a storage compound.

15 Partners in Global Health Education There are a number of key steps in the absorption of Vitamin B 12. The two key locations are the stomach and the terminal ilium. Dietary vitamin B 12 binds with intrinsic factor ( IF ) in the stomach, a transport protein produced by gastric parietal cells. The B12-IF complex then travels through the small intestine and is absorbed by special receptors in the distal ileum. This pathway is important when considering possible causes of Vitamin B 12 deficiency. Vitamin B 12 deficiency can take up to two years to develop as the body has sufficient stores for this period. Distal ileum Site of B 12 absorption Oesophagus Stomach IF Intrinsic factor Vitamin B 12 ingested |haematinics: vitamin B 12 Pernicious anaemia: the leading cause of B 12 deficiency. IgG autoantibodies target gastric parietal cells and its product IF causing an atrophic gastritis. This results in reduced secretion of intrinsic factor and therefore reduced B 12 -IF complex for absorption in the distal ileum. 2.4 Click here to return Causes of vitamin B12 deficiency 1.Pernicious anaemia 2.Inadequate intake 3.Poor absorption

16 Partners in Global Health Education | the red cell structure The red cell possesses an outer lipid bilayer membrane and a cytoskeleton that consists of a dense but collapsible lattice of specialised proteins. The lipid bilayer acts as a hydrophobic skin, whereas the proteins provide the strength, deformability and the biconcave shape of the cell. 2.3 There are 4 red cells proteins of importance: Contents page 2.1. The erythrocyte: an overview Erythropoiesis 2.3. The red cell membrane 2.1 Inherited disorders of erythrocyte membrane proteins result in a poorly deformable cell of normal size (normocyte) that cannot withstand the shear forces within the circulation. The membrane is then lost within the microcirculation creating spherical or elliptoid cells. These cells are then trapped and destroyed by macrophages within the spleen. This is one cause of haemolytic anaemia. Important examples are hereditary spherocytosis or elliptocytosis due to defects in the protein spectrin. ankyrin Protein 4.1 actin spectrin Key point! Click next slide to see flow diagram Link the components of red cell structure to red cell development and function LO

17 reduced spectrin synthesis dysfunctional spectrin abnormal spectrin gene Spectrin malfunction within erythrocyte membrane Erythrocytes are exposed to high sheer forces within the microcirculation Cytoskeleton function impaired; cell loses ability to deform Spherocyte: a small, more rigid, spherical erythrocyte results Cells are either destroyed within the microcirculation or detected and removed by the reticuloendothelial system of the spleen Haemolysis; premature red cell death occurs causing anaemia flow diagram: the process of spherocytosis in hereditary spherocytosis

18 Partners in Global Health Education Hexose monophosphate shunt. Red cells require a mechanism to detoxify the waste products (accumulated oxidised substrates) of the cell. This shunt provides this solution. It also provides 10% of glycolysis. However this metabolic pathway is also susceptible to pathology. The glycolytic pathway With no cell organelles and no mitochondria the fully developed erythrocyte relies on this aerobic pathway to gain energy (ATP) for the cell. 2.5 Contents page 2.1. The erythrocyte: an overview Erythropoiesis 2.3. The red cell structure Cell membrane DNA synthesis 2.4. Red cell metabolism Glucose Glucose- 6-P Fructose-6-P Lactate Pyruvate kinase Glucose-6-phosphate dehydrogenase NAPD NADPH+H + 2GSH H2OH2O O-O- GSSG Hexose monophosphate shunt Embden-Meyerhof glycolytic pathway Ribulose 5-P 6-PG Key point: Oxidant stress! CLICK HERE ADP ATP This is a sequence of biochemical reactions in which glucose is metabolised to lactate with the generation of 2 ATP molecules (providing energy for the cell). Pyruvate kinase deficiency: In rare circumstances there are defects within the critical glycolytic enzymes. 95% of these defects are associated with pyruvate kinase, a key enzyme within this pathway. The result is insufficient ATP production for cell life and therefore premature death (haemolysis). Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an X-linked disorder that is relatively common. The G6PD enzyme is a rate- limiting step within this pathway. If deficient, haemolysis occurs when the cell is placed under oxidative stress (e.g. by oxidative drugs, fava beans, infections) creating a potentially severe anaemia. Click OXIDATIVE STRESS for more info. |red cell metabolism Key point!

19 Glucose Glucose- 6-P Fructose-6-P Lactate Pyruvate kinase Glucose-6-phosphate dehydrogenase NAPD NADPH+H + 2GSH H2OH2O O-O- GSSG Hexose monophosphate shunt Embden-Meyerhof glycolytic pathway Ribulose 5-P 6-PG Oxidant stress! ADP ATP Red cell functioning adequately under normal conditions Drugs: e.g. antimalarials Fava beansInfection Red cell cannot produce enough NADPH via the HMP shunt Inadequate amounts of GSH to combat oxidant stress Oxidant damage to cell membrane Reduced red cell survival Haemolytic anaemia! RETURN

20 Partners in Global Health Education | haemoglobin and O 2 transport A key function of a red cell is to carry and deliver oxygen to the tissues and return CO 2 from the tissues to the lungs. As a result the red cell has developed a specialised molecule called haemoglobin (Hb). It is important to gain a basic understanding of its synthesis, functioning and metabolism as errors in these processes lead to a number of anaemic states. It’s waste products are also released when a red cell is destroyed prematurely and are therefore a valuable indicator of haemolysis. Contents page 2.1. The erythrocyte: an overview Erythropoiesis 2.3. The red cell structure Cell membrane DNA synthesis 2.4. Red cell metabolism 2.5. Haemoglobin and O 2 transport 2.6 2,3-DPG oxyhaemoglobin deoxyhaemoglobin A molecule called 2,3 – Diphosphoglycerate (2,3-DPG) sits between the  chains and when increased helps to offload oxygen to the tissues. For more information on foetal haemoglobin click here HAEM MOLECULE Each individual globin combines with one haem molecule. This molecule contains iron and binds oxygen in a reversible manner. A mature red cell (an erythrocyte) contains approximately 640 million haemoglobin molecules. GLOBIN CHAIN A normal adult haemoglobin (Hb A) molecule consists of 4 polypeptide (globin) chains:  1  2  1  2. Haemoglobinopathies Thalassaemia : reduced rate of synthesis of either  or  globin chains. Within this group of inherited conditions there may be both ineffective erythropoiesis and haemolysis resulting in a microcytic anaemia sometime also with hypochromia. Sickle cell disease : an inheritance of two abnormal  -globin genes (HbSS). The abnormality consists of a point mutation in the  globin gene. This results in Hb insolubility in it’s deoxygenated state with crystallization within the red cell causing sickling of the cell and vascular occlusion. A common problem that affects primarily the Afro-Caribbean populations. Key point! Oxygen (O 2 )

21 Partners in Global Health Education | haemoglobin in foetal haemoglobin 2,3-DPG oxyhaemoglobin deoxyhaemoglobin Oxygen requirements differ at different stages of development. The foetus displays a different type of haemoglobin to an adult. Foetal Hb (Hb F) and HbA 2 still contain two  chains but instead of  chains have two  and  chains respectively. HbF has a higher affinity for oxygen compared to maternal HbA. This is impart due to less binding of 2,3 – DPG. The change from HbF to HbA occurs at around 3-6months of age. RETURN 2.6

22 Partners in Global Health Education |haemoglobin and the oxygen dissociation curve Contents page 2.1. The erythrocyte: an overview Erythropoiesis 2.3. The red cell structure Cell membrane DNA synthesis 2.4. Red cell metabolism 2.5. Haemoglobin and O 2 transport PO 2 (mm Hg) Hb saturation (100%) 50 CO 2  pH  2,3-DPG  CO 2  pH  2,3-DPG  The sigmoid curve: this occurs because as O 2 is unloaded the beta chains are pulled apart and 2,3-DPG enters the space. This reduces the haemoglobin molecule’s affinity for O 2. The shape of this classic sigmoid curve will be dictated by the number of 2,3-DPG metabolites and CO 2 and H + ion concentration in the red blood cell. A shift to the left indicates an increased affinity for O 2. This makes it easier for Hb to bind to O 2, in the lungs and conversely more difficult for Hb to release O 2 in the tissues.. This occurs when there is a rise in pH (alkalosis), low CO 2 levels and with HbF. A shift to the right indicates a decreased affinity for O 2. This occurs when there are raised concentrations of 2,3-DPG, H + ions (acidosis) or CO 2 within the red blood cell. This results in greater release of O 2 to the tissues. 2.6

23 Partners in Global Health Education |ageing and death Haemolytic anaemias; This is an important group of anaemias. There are many important causes of premature red cell death resulting in anaemia and the increased products of haemolysis within the blood circulation and beyond. The next slide demonstrates the breakdown of the products of the red blood cell. This is an important pathway to consider whenever encountering a haemolytic anaemia. Haemolysis: any process that shortens the red blood cell lifespan to less than 120 days. A red cell shows signs of deterioration and reduced glycolytic rate from around 100 days of the cell’s cycle. Without any DNA or ribosomes, the cell is unable to generate new enzymes (like pyruvate kinase or G6PD that we have been introduced to). These ageing cells are eventually identified by the reticuloendothelial system. This is a system of white blood cells that are present within the spleen, liver and lymph nodes whose main role is to phagocytose damaged or ageing cells. The tired red cells are removed and recycled by macrophages in the spleen and liver. Normally red cell degradation and recycling is managed by the reticuloendothelial system on a daily basis without any problems. When a pathological process causes premature lysis of the red cells, the ability of the body to clear the increased number of waste products may be overloaded. 2.7 Contents 1. 1Introduction 1.2 use this module 1.3 Learning outcomes 2.1. The erythrocyte 2.2. Erythropoiesis 2.3. Red cell membrane 2.4. Haematinics 2.5. Red cell metabolism 2.6. Haemoglobin 2.7. Ageing and death Quiz Defining anaemia Prevalence 3.1. Clinical features Quiz Classifying anaemia 4.1. red cell indices Morphological classification 4.3. Aetiological classification 5.0. Blood film: a basic interpretation. Quiz Glossary 7.0. References please click on contents to repeat a section.

24 Haemoglobin Haem Unconjugated bilirubin Conjugated in the liver to the diglucuronide, water- soluble form that is secreted in the bile and then converted to stercobilinogen. Liver Some stercobilin and stercobilogen are reabsorbed from the intestine and excreted in the urine as urobilin and urobilinogen. Raised levels in the urine may indicate haemolysis. 3. Bilirubin Heamolysis results in excess bilirubin causing jaundice (typically lemon yellow colour ) and pigment gallstones. Globin Iron Attaches to transferrin F Is metabolized to amino acids Red blood cell Investigating haemolysis 1.Lactic acid dehydrogenase (LDH) 2.Reticulocyte count 3.Bilirubin 1. LDH is a nucleic enzyme which is released on red cell destruction. The concentration of LDH is measurable from a blood sample and provides an indicator of haemolysis. 3. LDH 2. Reticulocyte count will be elevated in response to the feedback loop during anaemia. The bone marrow increases red cell production. Reticulocytes are larger than mature red blood cells causing a rise in mean cell volume ( MCV). Flow diagram: products of red cell destruction. The protoporphyrin of haem is metabolised to the yellow pigment bilirubin, which is bound to albumin in the plasma. Stercobilinogen is excreted in the faeces Haptoglobins these proteins bind to any free haemoglobin. These proteins can become saturated in a haemolytic anaemia. Haemoglobin can then pass into the urine causing haemoglobinuria or converted to haemosiderinuria.

25 A normal red blood cell has an average lifespan of 80 days Erythropoietin is reduced in chronic hypoxia Iron is transported in the blood bound to apoferritin. High affinity haemoglobin would shift the oxygen dissociation curve to the left, thus limiting oxygen delivery to the tissues? Vitamin B 12 is absorbed in the jejunum. Folate and vitamin B 12 are key building blocks of haemoglobin. Chronic anaemia and malignancy prevent haem production. A deficiency in folate causes a macrocytic, megaloblastic anaemia. Adult haemoglobin is composed of 2 alpha and 2 beta globin chains. Increased reticulocytes is a key feature of a haemolysis. true / false Well done! You have come to the end of the first section. We suggest that you answer Quiz 1 to assess your learning so far. Please remember to write your answers on the mark sheet before looking at the correct answers! click to check answers

26 A red blood cell has an average lifespan of 80 days False! A red blood cell has an average lifespan of 120 days. This is short compared to other blood cells due to the cell having no nucleus or organelles and is thus unable to replace key enzymes and maintain cell function. Erythropoietin (EPO) production is reduced in chronic hypoxic states False! In chronic hypoxic states there is an increased production of EPO. This leads to an increase in the proportion of erythroblasts, expansion and eventually fatty deposition within the bone marrow. Iron is transported in the blood bound to apoferritin. T rue! JAK 2 is a receptor for erythropoietin. A point mutation (tyrosine kinase) in this receptor is implicated in the oncogenisis of several myeloproliferative neoplasm. (90% of Polycythemia vera patients). A low pH, a high CO 2 concentration in the blood and a high number of 2,3-DPG would shift the oxygen dissociation curve to the left False! It would shift to the right. All these factors would cause haemoglobin (Hb) to have a reduced affinity for O 2 and increase O 2 release fom Hb. Vitamin B 12 is absorbed in the jejunum False! Vitamin B 12 binds to intrinsic factor in the stomach, travels through the small bowel and the complex is absorbed in the distal ileum. Folate and vitamin B 12 are key building blocks of haemoglobin False! Vitamin B 12 and folate are key building blocks of DNA. Chronic anaemia and malignancy prevent haem production True! Chronic anaemia and malignancy block iron from being incorporated into the haem molecule. A deficiency in folate causes a macrocytic megaloblastic anaemia True! Both folate and vitamin B 12 are key micronutrients for DNA synthesis. Deficiencies cause a macrocytic megaloblastic anaemia. Adult haemoglobin is composed of 2 alpha and 2 beta chains True! The normal adult Hb contain 4 globin chains (often notated as α 2 β 2 ). Increased reticulocytes is a key feature of a haemolytic anaemia True! The cells will be elevated in response to our feedback loop during anaemia. With excessive destruction of red cells, the bone marrow increases production. true / false

27 Partners in Global Health Education What exactly is anaemia? Anaemia is defined as haemoglobin concentration less than the normal reference range. Reference ranges differ according to age, sex and altitude. However, in general, anaemia is defined as Hb concentration For adult males < 13.5 g/dl For adult women < 11.5 g/dl As well as reduced [Hb], anaemia is usually accompanied by a reduction in the number of red cells (red cell count) and packed cell volume (PCV). However this is not always the case. Red cell count and PCV may be normal in some patients with lower than normal haemoglobin levels (and hence anaemic). The total circulating haemoglobin concentration is therefore determined by…. the circulating plasma volume the total circulating haemoglobin mass. The following circumstances should therefore be taken in to consideration…… Welcome to section 2! | defining anaemia | Dehydration | Reduced plasma volume may mask anaemia. | Pregnancy or splenomegaly | These can produce an increase in plasma volume reducing the apparent haemoglobin concentration even though circulating haemoglobin levels are normal. | Acute significant blood loss | Following acute blood loss it may take up to a day for the plasma volume to be replaced and anaemia to present. Therefore, clinical features of shock and reduced blood volume may occur before a fall in haemoglobin concentration. Contents 1. 1Introduction 1.2 use this module 1.3 Learning outcomes 2.1. The erythrocyte 2.2. Erythropoiesis 2.3. Red cell membrane 2.4. Haematinics 2.5. Red cell metabolism 2.6. Haemoglobin 2.7. Ageing and death Quiz Defining anaemia Prevalence 3.1. Clinical features Quiz Classifying anaemia 4.1. red cell indices Morphological classification 4.3. Aetiological classification 5.0. Blood film: a basic interpretation. Quiz Glossary 7.0. References please click on contents to repeat a section. Contents 1. 1Introduction 1.2 use this module 1.3 Learning outcomes 2.1. The erythrocyte 2.2. Erythropoiesis 2.3. Red cell membrane 2.4. Haematinics 2.5. Red cell metabolism 2.6. Haemoglobin 2.7. Ageing and death Quiz Defining anaemia Prevalence 3.1. Clinical features Quiz Classifying anaemia 4.1. red cell indices Morphological classification 4.3. Aetiological classification 5.0. Blood film: a basic interpretation Anaemia cards Quiz Glossary 7.0. References please click on contents to repeat a section.

28 Partners in Global Health Education | prevalence Anaemia is thought to affect 1.62 billion people on a daily basis (WHO); this is 24% of the world’s population. Anaemia affects both developing and developed nations. However the main causes vary according to geographical region and from country to country. The WHO (World Health Organisation) has devised the most comprehensive global data bank on anaemia. Women (both pregnant and non-pregnant) and children suffer most from the condition. Developing nations A complex interaction of socio-economic conditions, nutritional deficiencies and co- existing disease (malaria, HIV) are key contributors to anaemia in developing nations (particularly within the tropics). Africa has the highest prevalence of anaemia. It occurs in 67.6% of preschool children, 57.1% of pregnant women and 47.5% of non-pregnant women. Click here to see WHO world map of the prevalence anaemia in non-pregnant women Click here to see WHO world map of the prevalence of anaemia in pre-school aged children Click here to see WHO world map of the prevalence of anaemia in pregnant women. Contents 1. 1Introduction 1.2 use this module 1.3 Learning outcomes 2.1. The erythrocyte 2.2. Erythropoiesis 2.3. Red cell membrane 2.4. Haematinics 2.5. Red cell metabolism 2.6. Haemoglobin 2.7. Ageing and death Quiz Defining anaemia Prevalence 3.1. Clinical features Quiz Classifying anaemia 4.1. red cell indices Morphological classification 4.3. Aetiological classification 5.0. Blood film: a basic interpretation. Quiz Glossary 7.0. References please click on contents to repeat a section.

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32 Partners in Global Health Education |clinical features of anaemia 1. The cardiovascular system Cardiac compensation is the major adaptation. Both stroke volume and heart rate increase mobilizing greater volumes of oxygenated blood to the tissues. This can present with palpitations, tachycardia and heart murmurs. Dyspnoea which occurs in severely anaemic patients may be a sign of cardio-respiratory failure. Contents 1. 1Introduction 1.2 use this module 1.3 Learning outcomes 2.1. The erythrocyte 2.2. Erythropoiesis 2.3. Red cell membrane 2.4. Haematinics 2.5. Red cell metabolism 2.6. Haemoglobin 2.7. Ageing and death Quiz Defining anaemia Prevalence 3.1. Clinical features Quiz Classifying anaemia 4.1. red cell indices Morphological classification 4.3. Aetiological classification 5.0. Blood film: a basic interpretation. Quiz Glossary 7.0. References please click on contents to repeat a section. Tissue hypoxia is the end result of the blood’s reduced oxygen carrying capacity. The compensatory mechanisms in response to hypoxia cause the clinical manifestations to develop. An anaemic individual will have the following two key compensatory mechanisms; 2. The skin A common sign is generalised pallor due primarily to vasoconstriction with redistribution of blood to key areas (brain, myocardium).

33 Partners in Global Health Education 1.A rapid onset: Anaemia that develops over a short period of time will cause more symptoms than more slowly progressing anaemia because there is less time for the O 2 dissociation curve of haemoglobin and the cardiovascular system to adapt. 2.Severity: Mild anaemia (Hb g/dL) often produces no symptoms or signs. In a young person, severe anaemia may not even present clinically. However this is notoriously unreliable and some patients with severe anaemia may compensate well while others with mild anaemia may present with severe symptoms. 3.Age: The elderly are less tolerable of anaemia mainly as a result of an inability to increase cardiac output. 4. Co-existent disease - often cardiac or pulmonary disease. |clinical features of anaemia In general, a healthy individual may compensate well for anaemia and remain mostly asymptomatic. However many of the following symptoms and signs are observable when the following occurs;

34 Partners in Global Health Education | clinical features of anaemia General symptoms and signs Contents 1. 1Introduction 1.2 use this module 1.3 Learning outcomes 2.1. The erythrocyte 2.2. Erythropoiesis 2.3. Red cell membrane 2.4. Haematinics 2.5. Red cell metabolism 2.6. Haemoglobin 2.7. Ageing and death Quiz Defining anaemia Prevalence 3.1. Clinical features Quiz Classifying anaemia 4.1. red cell indices Morphological classification 4.3. Aetiological classification 5.0. Blood film: a basic interpretation. Quiz Glossary 7.0. References please click on contents to repeat a section. General Symptoms Weakness and lethargy Shortness of breath: particularly on exercise. Headaches Palpitations Confusion and symptoms of cardiac failure in elderly Some specific signs Click images for explanation of signs! General Signs

35 Partners in Global Health Education | clinical features of anaemia This is a list of general symptoms and signs; we will cover more specific clinical features as we progress through the module. Signs: Pallor of mucous membranes (most common sign). This is a general sign. Beware: pallor is quite subjective and NOT a reliable clinical sign. Be careful not to exclude anaemia on the basis of absence of pallor alone RETURN

36 Partners in Global Health Education | clinical features of anaemia This is a list of general symptoms and signs; we will cover more specific clinical features as we progress through the module. Signs: Nail bed; demonstrating koilonychia (spoon-shaped nails). This is specific to iron deficiency. RETURN

37 Partners in Global Health Education | clinical features of anaemia This is a list of general symptoms and signs; we will cover more specific clinical features as we progress through the module. Signs Atrophic glossitis; red large swollen tongue. This is seen in both vitamin B 12 and folate deficiency. RETURN

38 Partners in Global Health Education | clinical features of anaemia This is a list of general symptoms and signs; we will cover more specific clinical features as we progress through the module. Signs Angular stomitis; fissuring at corners of mouth. This is seen in both vitamin B 12 and folate deficiency. RETURN

39 Partners in Global Health Education | clinical features of anaemia This is a list of general symptoms and signs; we will cover more specific clinical features as we progress through the module. Signs Dysphagia: pharyngeal web (Paterson-Kelly syndrome). This occurs in iron deficiency. RETURN

40 Partners in Global Health Education | clinical features of anaemia This is a list of general symptoms and signs; we will cover more specific clinical features as we progress through the module. Signs RETURN Peripheral oedema. A general sign.

41 Partners in Global Health Education | clinical features of anaemia This is a list of general symptoms and signs; we will cover more specific clinical features as we progress through the module. Signs High flow murmur, bounding pulse and/or tachycardia: All features of a compensatory hyperdynamic circulation. These are general signs! RETURN

42 Partners in Global Health Education An adult male with a haemoglobin concentraion (Hb) < 11.5 g/dl is anaemic. Within the developing world iron deficiency is the single most common cause of anaemia. The respiratory system is the main physiological compensator in anaemia. Koilonychia, glossitis and angular stomatitis are all general signs of anaemia. Some key signs associated with iron deficient anaemia are koilonychia and glosso- pharyngeal webbing. true / false Well done! You have come to the end of the second section. We suggest that you answer Quiz 2 to assess your learning so far. Please remember to write your answers on the mark sheet before looking at the correct answers! click to check answers Contents 1. 1Introduction 1.2 use this module 1.3 Learning outcomes 2.1. The erythrocyte 2.2. Erythropoiesis 2.3. Red cell membrane 2.4. Haematinics 2.5. Red cell metabolism 2.6. Haemoglobin 2.7. Ageing and death Quiz Defining anaemia Prevalence 3.1. Clinical features Quiz Classifying anaemia 4.1. red cell indices Morphological classification 4.3. Aetiological classification 5.0. Blood film: a basic interpretation. Quiz Glossary 7.0. References please click on contents to repeat a section. Contents 1. 1Introduction 1.2 use this module 1.3 Learning outcomes 2.1. The erythrocyte 2.2. Erythropoiesis 2.3. Red cell membrane 2.4. Haematinics 2.5. Red cell metabolism 2.6. Haemoglobin 2.7. Ageing and death Quiz Defining anaemia Prevalence 3.1. Clinical features Quiz Classifying anaemia 4.1. red cell indices Morphological classification 4.3. Aetiological classification 5.0. Blood film: a basic interpretation Anaemia cards Quiz Glossary 7.0. References please click on contents to repeat a section.

43 An adult male will be anaemic if they have a haemoglobin of < 11.5 g/dl on a full blood count. False! An adult male is anaemic if [Hb] is < 13.5 g/dl. An adult female will be considered anaemic if [Hb] is < 11.5 g/dl. Within the developing world iron deficient anaemia is the single greatest cause of anaemia True! The respiratory system is the main physiological compensator in anaemia. False! The cardiovascular system is the major adaptor. Both stroke volume and heart rate increase in an attempt to mobilize greater volumes of oxygenated blood to the tissues. Koilonychia, glossitis, angular stomatitis are all general signs of anaemia. False! Koilonychia is sign of iron deficiency. Glossitis and angular stomatits are a sign of vitamin B 12 and folate deficiency. Some key signs associated with iron deficient anaemia are koilonychia and glosso-pharyngeal webbing. True! Click here to continue module

44 Partners in Global Health Education Welcome to section 3! |classification of anaemia Essentially there are two ways to classify anaemia, by red cell size (morphological classification) or by cause (aetiological classification). Both have their purpose and both need to be fully understood to gain a rounded understanding of anaemia. Morphological classification This is a practical and clinically useful classification for establishing a differential diagnosis of anaemia. It is done by examining red cells in a blood stained smear and by automated measurements of red cell indices Aetiological classification This classification is based on cause and illuminates the pathological process underlying anaemia. *Key point : In order to understand this classification it is essential to understand red cell indices reported in the full blood count (FBC). There is great reward in understanding these indices as they enable one to identify some of the underlying processes leading to anaemia and, importantly, help to formulate a differential diagnoses. Contents 1. 1Introduction 1.2 use this module 1.3 Learning outcomes 2.1. The erythrocyte 2.2. Erythropoiesis 2.3. Red cell membrane 2.4. Haematinics 2.5. Red cell metabolism 2.6. Haemoglobin 2.7. Ageing and death Quiz Defining anaemia Prevalence 3.1. Clinical features Quiz Classifying anaemia 4.1. red cell indices Morphological classification 4.3. Aetiological classification 5.0. Blood film: a basic interpretation. Quiz Glossary 7.0. References please click on contents to repeat a section.

45 Partners in Global Health Education MCV: Mean cell volume; the average volume of the red cells. MCV does not provide an indicator of either haemoglobin concentration within the cells, or the number of red cells. It enables us to categorize red cells into the following; Microcytic (MCV <80fL) a small red blood cell. Normocytic(MCV of 80-99fL) a normal size red blood cell. Macrocytic (MCV > 99fL) a large red blood cell. This is a key index that is used daily in medical settings across the world to categorize the type of anaemia present. It is reliable in most cases; one exception is when two pathologies occur at the same time such as vitamin B 12 and Iron deficiency. MCV reports average cell volume; further assessment of cell size and how this varies within an individual can be ascertained from the red cell distribution width (RDW; see below). MCH: Mean corpuscular haemoglobin ( normal range pg/cell) : the average haemoglobin content of red blood cells. Cells with a reduced haemoglobin content are termed hypochromic and those with a normal level are termed normochromic (see below). |red cell indices RDW: Red cell distribution width; an index of the variation in sizes of the red cell population within an indiviual. This will be raised if two red cell populations are present. Occasionally useful if there is doubt about multiple causes of anaemia. A common cause for an increased RDW is the presence of reticulocytes. Normochromic implies normal staining of the cells in a thin blood film. The central area of pallor is normally about 1/3 of the cell diameter Hypochromic indicates reduced staining with increase in the central area of pallor These are the key measures of red cell indices. They relate to the haemoglobin content and size of the red blood cells.

46 Partners in Global Health Education |interpretation of red cell indices Microcytosis & hypochromia Normocytosis & normochromia Microcytic abnormally small red blood cells. Microcytic anemia is not caused by reduced DNA synthesis. It is not fully understood but is believed to be due reduced erythroid regeneration. Hypochromic hypochromic cells due to a failure of haemoglobin synthesis. Pathologies; Iron deficiency; iron is an essential building block of haem. Failure of globin synthesis; this occurs in the thalassemia's. Crystallization of haemoglobin: sickle cell disease and haemoglobin C. Normocytic Many processes causing anaemia do not effect the cell size or haemoglobin concentration within cells. Normocytic normochromic anaemia develops when there is a decrease in the production of normal red blood cells. Pathologies; anemia of chronic disease (some) aplastic anemia Haemolysis: a increased destruction (some) Hemolysis ;or loss of red blood pregnancy/fluid overload: an inbalance or an increase in plasma volume compared to red cell productionplasma Macrocytosis & megaloblastosis Macrocytic megaloblastic red blood cells have an unusual misshapen appearance, which is due to defective synthesis of DNA. This in turn leads to delayed maturation of the nucleus compared to that of the cytoplasm and the cells have a reduced survival time. Macrocytosis: The exact cause of the pathological mechanisms behind these large cells is not fully understood.. It is thought to be linked to lipid deposition on the red cell membrane. Alcohol is the most frequent cause of a raised MCV! Alcohol | Liver disease | hypothyroidism | Hypoxia | cytotoxic drugs | pregnancy | In clinical practice megaloblastic anaemia is almost always caused by a deficiency of vitamin B 12 or folate which are key building blocks in DNA synthesis.

47 Partners in Global Health Education | morphological classification of anaemia Anaemia type Red cell indices Common examples Microcytic hypochromic MCV < 80 fl MCH < 27 pg/L Iron deficiency Thalassaemia Sideroblastic Normocytic normochromic Macrocytic MCV > 98 fl Folate deficiency B 12 deficiency normal Haemolysis Chronic disease Marrow infiltration Megaloblastic Contents 1. 1Introduction 1.2 use this module 1.3 Learning outcomes 2.1. The erythrocyte 2.2. Erythropoiesis 2.3. Red cell membrane 2.4. Haematinics 2.5. Red cell metabolism 2.6. Haemoglobin 2.7. Ageing and death Quiz Defining anaemia Prevalence 3.1. Clinical features Quiz Classifying anaemia 4.1. red cell indices Morphological classification 4.3. Aetiological classification 5.0. Blood film: a basic interpretation. Quiz Glossary 7.0. References please click on contents to repeat a section.

48 Partners in Global Health Education |aetiological classification of anaemia This classification is based on cause and illuminates the pathogenic process leading to anaemia. You can look at anaemia from a production, destruction or pooling point of view. Reduced Production Insufficient production: If you consider the bone marrow to be the factory it must have enough raw material (Iron, vitamin B 12 and folate) to make new blood cells. These raw material are called haematinics. If there is not enough of the raw material (a deficiency of one or more of the haematinics), then there is insufficient production. Inefficient production (erythropoiesis): some problem with maturation of the erythroid in the marrow. Occurs in bone marrow infiltration (malignancy/leukaemia), aplastic anaemia or in the macrocytic megaloblastic anaemia. Destruction Reduced Cell lifespan This is either due to loss of red blood cells in a haemorrhage (a bleed) or the excessive destruction of red blood cells in haemolysis. Haemolysis is an important cause of red cell destruction and anaemia. Pooling: Hypersplenism. Contents 1. 1Introduction 1.2 use this module 1.3 Learning outcomes 2.1. The erythrocyte 2.2. Erythropoiesis 2.3. Red cell membrane 2.4. Haematinics 2.5. Red cell metabolism 2.6. Haemoglobin 2.7. Ageing and death Quiz Defining anaemia Prevalence 3.1. Clinical features Quiz Classifying anaemia 4.1. red cell indices Morphological classification 4.3. Aetiological classification 5.0. Blood film: a basic interpretation. Quiz Glossary 7.0. References please click on contents to repeat a section.

49 Partners in Global Health Education Reduced bone marrow erythroid cells aplastic anaemia Leukaemia or malignancy |classification of anaemia based on pathology Loss of red cells due to bleeding Increased destruction of red cells (haemolytic anaemia Failure of production of red cells by the bone marrow Dilution of red cells by increased plasma volume (e.g. hypersplenism) Nutritional (haematinic) deficiency Iron vitamin B 12 folate Ineffective red cell formation Chronic inflam. Thalassaemia renal disease immune Non- immune Autoimmune warm Autoimmune cold Adverse drug reaction Haemolytic disease of the newborn Malaria Burns Mechanical heart valve Hypersplenism PNH Abnormal red cell membrane Abnormal haemoglobin Abnormal red cell metabolism Sperocytes Elliptocytes Thalassaemia Sickle cell anaemia Pyruvate kinase deficiency G6PD deficiency Inherited / inside the cell Acquired / outside cell anaemia |classification of anaemia based on pathology Contents 1. 1Introduction 1.2 use this module 1.3 Learning outcomes 2.1. The erythrocyte 2.2. Erythropoiesis 2.3. Red cell membrane 2.4. Haematinics 2.5. Red cell metabolism 2.6. Haemoglobin 2.7. Ageing and death Quiz Defining anaemia Prevalence 3.1. Clinical features Quiz Classifying anaemia 4.1. red cell indices Morphological classification 4.3. Aetiological classification 5.0. Blood film: a basic interpretation. Quiz Glossary 7.0. References please click on contents to repeat a section.

50 Partners in Global Health Education |blood film: a basic interpretation A blood film is an essential investigation in classifying and diagnosing the cause of anaemia. A blood sample (anticoagulated venous sample) is smeared onto a glass slide, fixed and stained. Red cells are examined along with white cells, granulocyte precursors, blast cells and platelets. Red blood cells appear paler in the centre of the cell due to their biconcave shape. The pinkish colour one observes in a normal blood film is a result of the cells unique haemoglobin content. Shape, size and colour are the key variables to observe. Normal red cellMicrocytic hypochromic Macrocyte Target cell Basket case ElliptocyteFragments Tear drop poikilocyte Pencil cell Stomatocyte Sickle cell Spherocyte Acanthocyte Malarial parasite Please click on each cell to see the blood film and it’s causes. Please click here to compare blood films Contents 1. 1Introduction 1.2 use this module 1.3 Learning outcomes 2.1. The erythrocyte 2.2. Erythropoiesis 2.3. Red cell membrane 2.4. Haematinics 2.5. Red cell metabolism 2.6. Haemoglobin 2.7. Ageing and death Quiz Defining anaemia Prevalence 3.1. Clinical features Quiz Classifying anaemia 4.1. red cell indices Morphological classification 4.3. Aetiological classification 5.0. Blood film: a basic interpretation. Quiz Glossary 7.0. References please click on contents to repeat a section.

51 Normal red blood filmMicrocytic hypochromic Macrocytic megaloblastic Target cellsBite cells ElliptocyteFragments ‘Pencil’ cellsMalaria StomatocyteSickle cellSpherocyte Acanthocyte

52 Partners in Global Health Education |anaemia essential bites R.C.I: a microcytic hypochromic anaemia Epi:this is the most common cause of anaemia worldwide affecting around 500million daily. Aet:1. The most common cause of iron deficient anaemia is BLOOD loss 2. reduced intake (diet) 3. Increased demand (pregnancy) 4. Malabsorption (coeliac, gastrectomy) IX. FBC,  ferritin,  serum iron,  TIBC,  serum transferrin saturation. Endoscopy/colonoscopy if suspected blood loss. Si/Sy. Koilonychia, sore tongue, angular stomatitis, Plummer- Vinson syndrome (dysphagia due to oesophageal web), painless gastritis. Tx.Treat underlying cause, give ferrous sulphate until Hb and MCV normal (4-6months). iron deficieny R.C.I.: a microcytic hypochromic anaemia Epi:One of the most common autosomal inherited disorders. Common in Mediterranean, Africa and middle east. Gene carriers are protected from p.falciprum malaria. Path:Reduced beta globin (of haemoglobin) production. Ineffective erythropoiesis and haemolysis IX. blood film, Hb electropheresis Si/Sy. Heterozygotes: often asymptomatic, mild anaemia, low MCV. Homozygote: severe anaemia, failure to thrive in first 6 months of life, splenomegaly, bone hypertrophy (secondary to extramedullary haemopoisis). Tx. For major Thalassaemia treat with repeated blood transfusion and iron chelation. Β-Thalassaemia R.C.I.: a microcytic hypochromic anaemia Aet:A group of autosomal recessive genetic disorders due to a haemoglobin chain mutation. Part of the haemoglobinopathies that primarily affect those of African origin (sickel cell trait can afford some protection against malaria. Path: Abnormal haemoglobin (HbS) undergo a sickling transformation in a deoxygenated state and a permenant conformational change of shape. The red cell looses its ability to deform becoming rigid. This can cause occlusion of small vessels. These crises are precipitated by hypoxia, dehydration, infection and the cold. IX.Electropherisis, haemoglobin solubility test. Si/Sy: Bone pain, if chronic haemolysis- jaundice and pigment gallstones. Txt Supportive; analgesia, fluids and antibiotics if required. Sickle cell disease Epi: the most common cause of anaemia worldwide affecting around 500million daily. Aet: pernicious anaemia, malabsorpion, post total gastrectomy Ix.  B 12  MCV  platelets. IF antibodies, folate levels Si/Sy: Gradual deterioration, Irritability, Loss of memory, Painless jaundice, Loss of sensation, Feeling of pins and needles in extremities. ataxic Txt Intramuscular (IM) of 1mg of hydroxycobalamin (Vitamin B12). There is no oral form. Vitamin B 12 & Folate deficiency Epi: Aet: increased consumption (pregnancy), dietary deficiency, folate antagonist (drugs eg; methotrexate). Ix.  folate  MCV  transferrin saturation. Endoscopy/colonoscopy if suspected blood loss. Si/Sy: Gradual deterioration, Irritability, Loss of memory, Painless jaundice, Loss of sensation, Feeling of pins and needles in extremities. ataxic Txt Intramuscular (IM) of 1mg of hydroxycobalam in (Vitamin B12). There is no oral form. PathG6PD is a key enzyme in the hexose monophosphate shunt. An important funtion of the shunt is maintain a health haemoglobin by removing oxidant stresses. Wihtout the enzyme, Hb breakdown resulting in haemolytic aneamia. Aet:X-linked Ix.Direct assay during haemolysis Si/Sy: Koilonychia, sore tongue, angular stomatitis, Plummer- Vinson syndrome (dysphagia due to oesophageal web), painless gastritis. Rx Avoid precipitants of oxidative stress; drugs (anti-malarials, analgesics), fava beans. Tx. Blood transfusion if required. G6PD deficieny Epi: the most common cause of anaemia worldwide affecting around 500million daily. Aet:The most common cause of iron deficient anaemia is BLOOD loss reduced intake (diet) Increased demand (pregnancy) Malabsorption (coeliac, gastrectomy) Ix.FBC, ferritin,  serum iron,  TIBC,  transferrin saturation. Endoscopy/colonoscopy if suspected blood loss. Si/Sy: Koilonychia, sore tongue, angular stomatitis, Plummer- Vinson syndrome (dysphagia due to oesophageal web), painless gastritis. Txt Treat underlying cause, give ferrous sulphate until Hb and MCV normal. Hereditary spherocytosis; Microcytic anaemia Macrocytic anaemia Haemolytic anaemias Epi: the most common cause of anaemia worldwide affecting around 500million daily. Aet:The most common cause of iron deficient anaemia is BLOOD loss reduced intake (diet) Increased demand (pregnancy) Malabsorption (coeliac, gastrectomy) Ix.FBC, ferritin,  serum iron,  TIBC,  transferrin saturation. Endoscopy/colonoscopy if suspected blood loss. Si/Sy: Koilonychia, sore tongue, angular stomatitis, Plummer- Vinson syndrome (dysphagia due to oesophageal web), painless gastritis. Txt Treat underlying cause, give ferrous sulphate until Hb and MCV normal. Aquired Haemolytic anaemias; KEY R.C.I. Red Cell IndicesEpi. Epidemiology Aet. Aetiology Ix. Investigations Si/Sy. Signs and Symptoms Path. Pathology Tx. Treatment Contents 1. 1Introduction 1.2 use this module 1.3 Learning outcomes 2.1. The erythrocyte 2.2. Erythropoiesis 2.3. Red cell membrane 2.4. Haematinics 2.5. Red cell metabolism 2.6. Haemoglobin 2.7. Ageing and death Quiz Defining anaemia Prevalence 3.1. Clinical features Quiz Classifying anaemia 4.1. red cell indices Morphological classification 4.3. Aetiological classification 5.0. Blood film: a basic interpretation Anaemia cards Quiz Glossary 7.0. References please click on contents to repeat a section.

53 Partners in Global Health Education Well done! You have come to the end of the third and final section. We suggest that you answer Quiz 3 to assess your learning. Please remember to write your answers on the mark sheet before looking at the correct answers! click to check answers Microcytosis is MCV < 90fL The appearance of a hypochromic red blood cell is caused by reduced DNA synthesis In vitamin B 12 deficiency you would expect the MCV to be >99fL Both sickle cell anaemia and thalassaemia have abnormal haemoglobin A macrocytic blood film may indicate excess alcohol consumption or liver disease true / false Contents 1. 1Introduction 1.2 use this module 1.3 Learning outcomes 2.1. The erythrocyte 2.2. Erythropoiesis 2.3. Red cell membrane 2.4. Haematinics 2.5. Red cell metabolism 2.6. Haemoglobin 2.7. Ageing and death Quiz Defining anaemia Prevalence 3.1. Clinical features Quiz Classifying anaemia 4.1. red cell indices Morphological classification 4.3. Aetiological classification 5.0. Blood film: a basic interpretation Anaemia cards Quiz Glossary 7.0. References please click on contents to repeat a section.

54 Microcytosis is MCV < 90fL False! Microcytosis is MCV < 80fL. The appearance of a hypochromic red blood cell is caused by reduced DNA synthesis False! A hypochromic film is due to reduced haemoglobin content within red blood cells. In vitamin B 12 deficiency you would expect the MCV to be >99fL True Both sickle cell anaemia and thalassaemia have abnormal haemoglobin True! A macrocytic blood film may indicate excess alcohol consumption or liver disease True! Click here to return to beginning of module

55 Partners in Global Health Education |blood film: a basic interpretation Contents 1. 1Introduction 1.2 use this module 1.3 Learning outcomes 2.1. The erythrocyte 2.2. Erythropoiesis 2.3. Red cell structure Cell membrane DNA synthesis 2.4. Red cell metabolism 2.5.Haemoglobin 2.6 O 2 dissociation curve 3.0. Defining anaemia Prevalence 3.2 Clinical features 4.0. Classifying anaemia 4.1. red cell indices 4.2. Morphological 4.3 Aetiological classification 5.0 Blood film: a basic interpretation Blood film: a basic interpretation Glossary 7.0. Quiz A blood film can provide key evidence in diagnosing anaemia. It is therefore is an essential part of all investigations into anaemia. A blood sample (anticoagulated venous sample) will be smeared onto a glass slide, fixed and stained. Red cells are examined along with white cells, granulocyte precursors, blast cells. Red cells appear paler in their centre of the cell due to their biconcave. The pinkish colour one observes in a normal blood film is a result of the cells unique haemoglobin content. Shape, size and colour are the key variables to observe. Please click on each cell to see the blood film, causes and explanation. Normal red cellMicrocytic hypochromic Macrocyte Target cell Basket case ElliptocyteFragments Tear drop poikilocyte Pencil cell Stomatocyte Sickle cell Spherocyte Acanthocyte Malarial parasite Blood film RBC morphology: normocytic,normochromic. return Definitions Normocytic: A cell with an MCV within the normal range Normochromic:concentration of anaemia is within the normal range The biconcave red cell when stained shows a classical central area of pallor on a blood film.

56 Partners in Global Health Education |blood film: a basic interpretation Contents 1. 1Introduction 1.2 use this module 1.3 Learning outcomes 2.1. The erythrocyte 2.2. Erythropoiesis 2.3. Red cell structure Cell membrane DNA synthesis 2.4. Red cell metabolism 2.5.Haemoglobin 2.6 O 2 dissociation curve 3.0. Defining anaemia Prevalence 3.2 Clinical features 4.0. Classifying anaemia 4.1. red cell indices 4.2. Morphological 4.3 Aetiological classification 5.0 Blood film: a basic interpretation Blood film: a basic interpretation Glossary 7.0. Quiz A blood film can provide key evidence in diagnosing anaemia. It is therefore is an essential part of all investigations into anaemia. A blood sample (anticoagulated venous sample) will be smeared onto a glass slide, fixed and stained. Red cells are examined along with white cells, granulocyte precursors, blast cells. Red cells appear paler in their centre of the cell due to their biconcave. The pinkish colour one observes in a normal blood film is a result of the cells unique haemoglobin content. Shape, size and colour are the key variables to observe. Please click on each cell to see the blood film, causes and explanation. Normal red cellMicrocytic hypochromic Macrocyte Target cell Basket case ElliptocyteFragments Tear drop poikilocyte Pencil cell Stomatocyte Sickle cell Spherocyte Acanthocyte Malarial parasite Blood film RBC morphology: Microcytic hypochromic. Explanation Red cells are smaller and lighter than normal and displaying a typical ‘area of central pallor’. Cause Iron deficient anaemia Thalassaemia return

57 Partners in Global Health Education |blood film: a basic interpretation Contents 1. 1Introduction 1.2 use this module 1.3 Learning outcomes 2.1. The erythrocyte 2.2. Erythropoiesis 2.3. Red cell structure Cell membrane DNA synthesis 2.4. Red cell metabolism 2.5.Haemoglobin 2.6 O 2 dissociation curve 3.0. Defining anaemia Prevalence 3.2 Clinical features 4.0. Classifying anaemia 4.1. red cell indices 4.2. Morphological 4.3 Aetiological classification 5.0 Blood film: a basic interpretation Blood film: a basic interpretation Glossary 7.0. Quiz A blood film can provide key evidence in diagnosing anaemia. It is therefore is an essential part of all investigations into anaemia. A blood sample (anticoagulated venous sample) will be smeared onto a glass slide, fixed and stained. Red cells are examined along with white cells, granulocyte precursors, blast cells. Red cells appear paler in their centre of the cell due to their biconcave. The pinkish colour one observes in a normal blood film is a result of the cells unique haemoglobin content. Shape, size and colour are the key variables to observe. Please click on each cell to see the blood film, causes and explanation. Normal red cellMicrocytic hypochromic Macrocyte Target cell Basket case ElliptocyteFragments Tear drop poikilocyte Pencil cell Stomatocyte Sickle cell Spherocyte Acanthocyte Malarial parasite return Blood film RBC morphology: macrocytic,megaloblastic (More oval) Cause Macrocytic: Macrocytic megaloblastic: Liver disease Vitamin B 12 Alcoholism Folate

58 Partners in Global Health Education |blood film: a basic interpretation Contents 1. 1Introduction 1.2 use this module 1.3 Learning outcomes 2.1. The erythrocyte 2.2. Erythropoiesis 2.3. Red cell structure Cell membrane DNA synthesis 2.4. Red cell metabolism 2.5.Haemoglobin 2.6 O 2 dissociation curve 3.0. Defining anaemia Prevalence 3.2 Clinical features 4.0. Classifying anaemia 4.1. red cell indices 4.2. Morphological 4.3 Aetiological classification 5.0 Blood film: a basic interpretation Blood film: a basic interpretation Glossary 7.0. Quiz A blood film can provide key evidence in diagnosing anaemia. It is therefore is an essential part of all investigations into anaemia. A blood sample (anticoagulated venous sample) will be smeared onto a glass slide, fixed and stained. Red cells are examined along with white cells, granulocyte precursors, blast cells. Red cells appear paler in their centre of the cell due to their biconcave. The pinkish colour one observes in a normal blood film is a result of the cells unique haemoglobin content. Shape, size and colour are the key variables to observe. Please click on each cell to see the blood film, causes and explanation. Normal red cellMicrocytic hypochromic Macrocyte Target cell Basket case ElliptocyteFragments Tear drop poikilocyte Pencil cell Stomatocyte Sickle cell Spherocyte Acanthocyte Malarial parasite return Blood film RBC morphology: target cell Extra: it is also possible to see one neutrophil and two platelets. Cause Target cells are found in peripheral blood films in a number of conditions. 1.Liver disease (obstructive jaundice). 2.Thalassaemia major. 3.Sickle cell anaemia.

59 Partners in Global Health Education |blood film: a basic interpretation Contents 1. 1Introduction 1.2 use this module 1.3 Learning outcomes 2.1. The erythrocyte 2.2. Erythropoiesis 2.3. Red cell structure Cell membrane DNA synthesis 2.4. Red cell metabolism 2.5.Haemoglobin 2.6 O 2 dissociation curve 3.0. Defining anaemia Prevalence 3.2 Clinical features 4.0. Classifying anaemia 4.1. red cell indices 4.2. Morphological 4.3 Aetiological classification 5.0 Blood film: a basic interpretation Blood film: a basic interpretation Glossary 7.0. Quiz A blood film can provide key evidence in diagnosing anaemia. It is therefore is an essential part of all investigations into anaemia. A blood sample (anticoagulated venous sample) will be smeared onto a glass slide, fixed and stained. Red cells are examined along with white cells, granulocyte precursors, blast cells. Red cells appear paler in their centre of the cell due to their biconcave. The pinkish colour one observes in a normal blood film is a result of the cells unique haemoglobin content. Shape, size and colour are the key variables to observe. Please click on each cell to see the blood film, causes and explanation. Normal red cellMicrocytic hypochromic Macrocyte Target cell Basket case ElliptocyteFragments Tear drop poikilocyte Pencil cell Stomatocyte Sickle cell Spherocyte Acanthocyte Malarial parasite return Blood film RBC morphology: basket/blister cell. Explanation: Oxidant damage Cause: G6PD deficiency

60 Partners in Global Health Education |blood film: a basic interpretation Contents 1. 1Introduction 1.2 use this module 1.3 Learning outcomes 2.1. The erythrocyte 2.2. Erythropoiesis 2.3. Red cell structure Cell membrane DNA synthesis 2.4. Red cell metabolism 2.5.Haemoglobin 2.6 O 2 dissociation curve 3.0. Defining anaemia Prevalence 3.2 Clinical features 4.0. Classifying anaemia 4.1. red cell indices 4.2. Morphological 4.3 Aetiological classification 5.0 Blood film: a basic interpretation Blood film: a basic interpretation Glossary 7.0. Quiz A blood film can provide key evidence in diagnosing anaemia. It is therefore is an essential part of all investigations into anaemia. A blood sample (anticoagulated venous sample) will be smeared onto a glass slide, fixed and stained. Red cells are examined along with white cells, granulocyte precursors, blast cells. Red cells appear paler in their centre of the cell due to their biconcave. The pinkish colour one observes in a normal blood film is a result of the cells unique haemoglobin content. Shape, size and colour are the key variables to observe. Please click on each cell to see the blood film, causes and explanation. Normal red cellMicrocytic hypochromic Macrocyte Target cell Basket case ElliptocyteFragments Tear drop poikilocyte Pencil cell Stomatocyte Sickle cell Spherocyte Acanthocyte Malarial parasite return Blood film RBC morphology: basket cell. Explanation Oxidant damage G6PD deficiency Blood film RBC morphology: Elliptocyte. Blood film shows characteristic elliptical (elongated) red cells. Causes Hereditary elliptocytosis: due to a defective cell membrane protein (Spectrin, band 4.1).

61 Partners in Global Health Education |blood film: a basic interpretation Contents 1. 1Introduction 1.2 use this module 1.3 Learning outcomes 2.1. The erythrocyte 2.2. Erythropoiesis 2.3. Red cell structure Cell membrane DNA synthesis 2.4. Red cell metabolism 2.5.Haemoglobin 2.6 O 2 dissociation curve 3.0. Defining anaemia Prevalence 3.2 Clinical features 4.0. Classifying anaemia 4.1. red cell indices 4.2. Morphological 4.3 Aetiological classification 5.0 Blood film: a basic interpretation Blood film: a basic interpretation Glossary 7.0. Quiz A blood film can provide key evidence in diagnosing anaemia. It is therefore is an essential part of all investigations into anaemia. A blood sample (anticoagulated venous sample) will be smeared onto a glass slide, fixed and stained. Red cells are examined along with white cells, granulocyte precursors, blast cells. Red cells appear paler in their centre of the cell due to their biconcave. The pinkish colour one observes in a normal blood film is a result of the cells unique haemoglobin content. Shape, size and colour are the key variables to observe. Please click on each cell to see the blood film, causes and explanation. Normal red cellMicrocytic hypochromic Macrocyte Target cell Basket case ElliptocyteFragments Tear drop poikilocyte Pencil cell Stomatocyte Sickle cell Spherocyte Acanthocyte Malarial parasite return Blood film RBC morphology: basket cell. Explanation Oxidant damage G6PD deficiency Blood film RBC morphology: Elliptocyte. Causes Hereditary elliptocytosis Blood film RBC morphology: Fragments Cause Disseminated Intravascular Coagulation (DIC) Microangiopathy TTP Burns Cardiac valves

62 Partners in Global Health Education |blood film: a basic interpretation Contents 1. 1Introduction 1.2 use this module 1.3 Learning outcomes 2.1. The erythrocyte 2.2. Erythropoiesis 2.3. Red cell structure Cell membrane DNA synthesis 2.4. Red cell metabolism 2.5.Haemoglobin 2.6 O 2 dissociation curve 3.0. Defining anaemia Prevalence 3.2 Clinical features 4.0. Classifying anaemia 4.1. red cell indices 4.2. Morphological 4.3 Aetiological classification 5.0 Blood film: a basic interpretation Blood film: a basic interpretation Glossary 7.0. Quiz A blood film can provide key evidence in diagnosing anaemia. It is therefore is an essential part of all investigations into anaemia. A blood sample (anticoagulated venous sample) will be smeared onto a glass slide, fixed and stained. Red cells are examined along with white cells, granulocyte precursors, blast cells. Red cells appear paler in their centre of the cell due to their biconcave. The pinkish colour one observes in a normal blood film is a result of the cells unique haemoglobin content. Shape, size and colour are the key variables to observe. Please click on each cell to see the blood film, causes and explanation. Normal red cellMicrocytic hypochromic Macrocyte Target cell Basket case ElliptocyteFragments Tear drop poikilocyte Pencil cell Stomatocyte Sickle cell Spherocyte Acanthocyte Malarial parasite return Blood film RBC morphology: basket cell. Explanation Oxidant damage G6PD deficiency Blood film RBC morphology: Tear drop poikilocyte Definition: Poikilocyte; an individual cell of abnormal shape Cause Myelofibrosis Extramedullary haemopoiesis

63 Partners in Global Health Education |blood film: a basic interpretation Contents 1. 1Introduction 1.2 use this module 1.3 Learning outcomes 2.1. The erythrocyte 2.2. Erythropoiesis 2.3. Red cell structure Cell membrane DNA synthesis 2.4. Red cell metabolism 2.5.Haemoglobin 2.6 O 2 dissociation curve 3.0. Defining anaemia Prevalence 3.2 Clinical features 4.0. Classifying anaemia 4.1. red cell indices 4.2. Morphological 4.3 Aetiological classification 5.0 Blood film: a basic interpretation Blood film: a basic interpretation Glossary 7.0. Quiz A blood film can provide key evidence in diagnosing anaemia. It is therefore is an essential part of all investigations into anaemia. A blood sample (anticoagulated venous sample) will be smeared onto a glass slide, fixed and stained. Red cells are examined along with white cells, granulocyte precursors, blast cells. Red cells appear paler in their centre of the cell due to their biconcave. The pinkish colour one observes in a normal blood film is a result of the cells unique haemoglobin content. Shape, size and colour are the key variables to observe. Please click on each cell to see the blood film, causes and explanation. Normal red cellMicrocytic hypochromic Macrocyte Target cell Basket case ElliptocyteFragments Tear drop poikilocyte Pencil cell Stomatocyte Sickle cell Spherocyte Acanthocyte Malarial parasite return Blood film RBC morphology: basket cell. Explanation Oxidant damage G6PD deficiency Blood film RBC morphology: “Pencil” cell. These are thin elongated cells. Often occur alongside microcytic hypochromic cells, poikilocyte and occasional target cells. Explanation Iron deficiency

64 Partners in Global Health Education |blood film: a basic interpretation Contents 1. 1Introduction 1.2 use this module 1.3 Learning outcomes 2.1. The erythrocyte 2.2. Erythropoiesis 2.3. Red cell structure Cell membrane DNA synthesis 2.4. Red cell metabolism 2.5.Haemoglobin 2.6 O 2 dissociation curve 3.0. Defining anaemia Prevalence 3.2 Clinical features 4.0. Classifying anaemia 4.1. red cell indices 4.2. Morphological 4.3 Aetiological classification 5.0 Blood film: a basic interpretation Blood film: a basic interpretation Glossary 7.0. Quiz A blood film can provide key evidence in diagnosing anaemia. It is therefore is an essential part of all investigations into anaemia. A blood sample (anticoagulated venous sample) will be smeared onto a glass slide, fixed and stained. Red cells are examined along with white cells, granulocyte precursors, blast cells. Red cells appear paler in their centre of the cell due to their biconcave. The pinkish colour one observes in a normal blood film is a result of the cells unique haemoglobin content. Shape, size and colour are the key variables to observe. Please click on each cell to see the blood film, causes and explanation. Normal red cellMicrocytic hypochromic Macrocyte Target cell Basket case ElliptocyteFragments Tear drop poikilocyte Pencil cell Stomatocyte Sickle cell Spherocyte Acanthocyte Malarial parasite return Blood film RBC morphology: basket cell. Explanation Oxidant damage G6PD deficiency Blood film RBC morphology: Ring-forms in P.falciprum Intracellular malarial parasite Explanation A certain amount of haemolysis occurs with all types of malarial infection. It can lead to DIC and intravascular haemolysis. Malaria: Transmitted by the mosquito this disease causes up to 3 million deaths a year and is a major cause of anaemia within the tropics! See malaria module for more information.

65 Partners in Global Health Education |blood film: a basic interpretation Contents 1. 1Introduction 1.2 use this module 1.3 Learning outcomes 2.1. The erythrocyte 2.2. Erythropoiesis 2.3. Red cell structure Cell membrane DNA synthesis 2.4. Red cell metabolism 2.5.Haemoglobin 2.6 O 2 dissociation curve 3.0. Defining anaemia Prevalence 3.2 Clinical features 4.0. Classifying anaemia 4.1. red cell indices 4.2. Morphological 4.3 Aetiological classification 5.0 Blood film: a basic interpretation Blood film: a basic interpretation Glossary 7.0. Quiz A blood film can provide key evidence in diagnosing anaemia. It is therefore is an essential part of all investigations into anaemia. A blood sample (anticoagulated venous sample) will be smeared onto a glass slide, fixed and stained. Red cells are examined along with white cells, granulocyte precursors, blast cells. Red cells appear paler in their centre of the cell due to their biconcave. The pinkish colour one observes in a normal blood film is a result of the cells unique haemoglobin content. Shape, size and colour are the key variables to observe. Please click on each cell to see the blood film, causes and explanation. Normal red cellMicrocytic hypochromic Macrocyte Target cell Basket case ElliptocyteFragments Tear drop poikilocyte Pencil cell Stomatocyte Sickle cell Spherocyte Acanthocyte Malarial parasite return Blood film RBC morphology: basket cell. Explanation Oxidant damage G6PD deficiency Blood film RBC morphology: Stomatocyte Explanation Liver disease Alcoholism

66 Partners in Global Health Education |blood film: a basic interpretation Contents 1. 1Introduction 1.2 use this module 1.3 Learning outcomes 2.1. The erythrocyte 2.2. Erythropoiesis 2.3. Red cell structure Cell membrane DNA synthesis 2.4. Red cell metabolism 2.5.Haemoglobin 2.6 O 2 dissociation curve 3.0. Defining anaemia Prevalence 3.2 Clinical features 4.0. Classifying anaemia 4.1. red cell indices 4.2. Morphological 4.3 Aetiological classification 5.0 Blood film: a basic interpretation Blood film: a basic interpretation Glossary 7.0. Quiz A blood film can provide key evidence in diagnosing anaemia. It is therefore is an essential part of all investigations into anaemia. A blood sample (anticoagulated venous sample) will be smeared onto a glass slide, fixed and stained. Red cells are examined along with white cells, granulocyte precursors, blast cells. Red cells appear paler in their centre of the cell due to their biconcave. The pinkish colour one observes in a normal blood film is a result of the cells unique haemoglobin content. Shape, size and colour are the key variables to observe. Please click on each cell to see the blood film, causes and explanation. Normal red cellMicrocytic hypochromic Macrocyte Target cell Basket case ElliptocyteFragments Tear drop poikilocyte Pencil cell Stomatocyte Sickle cell Spherocyte Acanthocyte Malarial parasite return Blood film RBC morphology: basket cell. Explanation Oxidant damage G6PD deficiency Blood film RBC morphology: Sickle cell Explanation In sickle cell anaemia the red blood cell undergoes a “sickling” process due the cell containing haemoglobin S. In a deoxygenated state this haemoglobin undertakes a permanent conformational change creating large polymers. As a result these cells become rigid and unable to deform. The red cell eventually looses its cell membrane and becomes damaged as it travels through the circulation changing into the sickled shape we see. This eventually leads to an early cell death (hemolysis).

67 Partners in Global Health Education |blood film: a basic interpretation Contents 1. 1Introduction 1.2 use this module 1.3 Learning outcomes 2.1. The erythrocyte 2.2. Erythropoiesis 2.3. Red cell structure Cell membrane DNA synthesis 2.4. Red cell metabolism 2.5.Haemoglobin 2.6 O 2 dissociation curve 3.0. Defining anaemia Prevalence 3.2 Clinical features 4.0. Classifying anaemia 4.1. red cell indices 4.2. Morphological 4.3 Aetiological classification 5.0 Blood film: a basic interpretation Blood film: a basic interpretation Glossary 7.0. Quiz A blood film can provide key evidence in diagnosing anaemia. It is therefore is an essential part of all investigations into anaemia. A blood sample (anticoagulated venous sample) will be smeared onto a glass slide, fixed and stained. Red cells are examined along with white cells, granulocyte precursors, blast cells. Red cells appear paler in their centre of the cell due to their biconcave. The pinkish colour one observes in a normal blood film is a result of the cells unique haemoglobin content. Shape, size and colour are the key variables to observe. Please click on each cell to see the blood film, causes and explanation. Normal red cellMicrocytic hypochromic Macrocyte Target cell Basket case ElliptocyteFragments Tear drop poikilocyte Pencil cell Stomatocyte Sickle cell Spherocyte Acanthocyte Malarial parasite return Blood film RBC morphology: basket cell. Explanation Oxidant damage G6PD deficiency Blood film RBC morphology: Micro-Spherocyte. This slide shows spherocytes caused by hereditary spherocytosis. They sit amongst larger polychromatic red cells. Cause | Explanation Abnormality of cytoskeleton proteins. These cells are excessively permeable to sodium influx. Cell looses membrane on passage through reticuloendothelial system. Red cell osmotic fragility is characteristically increased.

68 Partners in Global Health Education |blood film: a basic interpretation Contents 1. 1Introduction 1.2 use this module 1.3 Learning outcomes 2.1. The erythrocyte 2.2. Erythropoiesis 2.3. Red cell structure Cell membrane DNA synthesis 2.4. Red cell metabolism 2.5.Haemoglobin 2.6 O 2 dissociation curve 3.0. Defining anaemia Prevalence 3.2 Clinical features 4.0. Classifying anaemia 4.1. red cell indices 4.2. Morphological 4.3 Aetiological classification 5.0 Blood film: a basic interpretation Blood film: a basic interpretation Glossary 7.0. Quiz A blood film can provide key evidence in diagnosing anaemia. It is therefore is an essential part of all investigations into anaemia. A blood sample (anticoagulated venous sample) will be smeared onto a glass slide, fixed and stained. Red cells are examined along with white cells, granulocyte precursors, blast cells. Red cells appear paler in their centre of the cell due to their biconcave. The pinkish colour one observes in a normal blood film is a result of the cells unique haemoglobin content. Shape, size and colour are the key variables to observe. Please click on each cell to see the blood film, causes and explanation. Normal red cellMicrocytic hypochromic Macrocyte Target cell Basket case ElliptocyteFragments Tear drop poikilocyte Pencil cell Stomatocyte Sickle cell Spherocyte Acanthocyte Malarial parasite return Blood film RBC morphology: basket cell. Explanation Oxidant damage G6PD deficiency Blood film RBC morphology: “Prickle” cell or small echinocytes. Especially prominent in postsplenectomy patients. Definition: Echinocyte: cell with abnormal blunt or sharp projections on surface. Can be up to 30 projections per cell. Explanation Pyruvate kinase deficiency

69 Partners in Global Health Education |glossary Anaemia: a haemoglobin concentration in peripheral blood below normal range for sex and age Haemoglobin : a metalloprotien inside a red blood cell that is responsible for oxygen delivery. It is composed of four globulin chains each containing an iron containing haem group. Macrocytic: Red cells of average volume (MCV) above normal. Mean cell volume: the average volume of circulating red cells Mean Corpuscular Haemoglobin (MCH): The average haemoglobin content of red blood cells. Microcytic: red cells of average volume (MCV) below normal Normoblast: nucleated red cell precursor normallyy found in the bone marrow Poikilocytosis: variation in shape of peripheral blood red cells Reticulocyte: a non-nucleated young red blood cell still containing RNA. Can be found in the peripheral blood and bone marrow. Stem cell: resides in the bone marrow and by division and differentiation gives rise to all the blood cells Sickle cell disease: an inherited disorder of haemoglobin of varying severity. The name arises from the deformed shape of the red blood cell takes when the abnormal haemoglobin inside them polymerizes at low oxygen concentrations. Thalassaemias: a spectrum of inherited disorders of haemoglobin where there is an inbalance in globin chain production. Contents 1. 1Introduction 1.2 use this module 1.3 Learning outcomes 2.1. The erythrocyte 2.2. Erythropoiesis 2.3. Red cell membrane 2.4. Haematinics 2.5. Red cell metabolism 2.6. Haemoglobin 2.7. Ageing and death Quiz Defining anaemia Prevalence 3.1. Clinical features Quiz Classifying anaemia 4.1. red cell indices Morphological classification 4.3. Aetiological classification 5.0. Blood film: a basic interpretation Anaemia cards Quiz Glossary 7.0. References please click on contents to repeat a section.

70 Partners in Global Health Education |references and links Contents 1. 1Introduction 1.2 use this module 1.3 Learning outcomes 2.1. The erythrocyte 2.2. Erythropoiesis 2.3. Red cell membrane 2.4. Haematinics 2.5. Red cell metabolism 2.6. Haemoglobin 2.7. Ageing and death Quiz Defining anaemia Prevalence 3.1. Clinical features Quiz Classifying anaemia 4.1. red cell indices Morphological classification 4.3. Aetiological classification 5.0. Blood film: a basic interpretation Anaemia cards Quiz Glossary 7.0. References please click on contents to repeat a section.

71 Partners in Global Health Education R.C.I: a microcytic hypochromic anaemia Epi:this is the most common cause of anaemia worldwide affecting around 500million people. Aet:1. The most common cause of iron deficient anaemia is blood oss 2. reduced intake (diet) 3. Increased demand (pregnancy) 4. Malabsorption (coeliac, gastrectomy) Ix. FBC,  ferritin,  serum iron,  TIBC,  serum transferrin saturation. Endoscopy/colonoscopy if suspected blood loss. Si/Sy. Koilonychia, sore tongue, angular stomatitis, Plummer-Vinson syndrome (dysphagia due to oesophageal web), painless gastritis. Tx.Treat underlying cause, give ferrous sulphate until Hb and MCV normal (4-6months). iron deficient anaemia; an overview Colon cancer microcytic hypochromic blood film. Return

72 Partners in Global Health Education R.C.I.: a microcytic hypochromic anaemia Epi:One of the most common inherited disorders. Common in Mediterranean, Africa and Middle East. Path:Reduced beta globin (of haemoglobin) production. Ineffective erythropoiesis and haemolysis Ix. blood film, Hb electrophoresis Si/Sy. Heterozygotes: often asymptomatic, mild anaemia, low MCV. Homozygote: severe anaemia, failure to thrive in first 6 months of life, splenomegaly, bone hypertrophy (secondary to extramedullary haemopoiesis). Tx. β-thalassaemia major requires repeated blood transfusion and iron chelation. Β-Thalassaemia Return

73 Partners in Global Health Education R.C.I.: a microcytic hypochromic anaemia Aet:Autosomal recessive genetic disorders due to mutation of the gene for HbA. Affect primarily people of African origin. Sickle cell trait (HbAS) affords strong protection against malaria. Path: Abnormal haemoglobin (HbS) undergoes a sickling transformation when in a deoxygenated state resulting in a permanent conformational change of shape. The red cell looses its ability to deform becoming rigid. This can cause occlusion of small vessels and result in sickle cell crises precipitated by hypoxia, dehydration, infection and the cold. IX.Electrophoresis, haemoglobin solubility test. Si/Sy: Bone pain, jaundice, pigment gallstones, leg ulcers, dactylitis in infants. Txt Supportive; analgesia, fluids and antibiotics during crises. Sickle cell disease (HbSS); an overview Dactylitis in a child Blood film: sickle cells Return

74 Partners in Global Health Education path: Vitamin B 12 binds to IF intrinsic factor in the stomach and is absorbed in the terminal ileum Aet: Pernicious anaemia, malabsorpion, post total gastrectomy Ix.  B 12  MCV  platelets. IF antibodies. Check folate levels. Si./Sy: Gradual deterioration, Irritability, Loss of memory, Painless jaundice, Loss of sensation, Feeling of pins and needles in extremities, ataxic. Txt. Intramuscular (IM) of 1mg of hydroxycobalamin (Vitamin B12). There is no oral form. Vitamin B 12 deficiency Aet: increased consumption (pregnancy), dietary deficiency, folate antagonist (drugs eg; methotrexate, alcohol). Ix.  serum folate,  red cell folate.  MCV Si/Sy: Jaundice. Weight loss. GI disturbances. Glossitis. Txt.Folic acid supplementation. Exclude Vitamin B 12 deficiency first. Folate deficiency Glossitis. Blood film; Microcytic hypochromic Return

75 Partners in Global Health Education PathG6PD is a key enzyme in the hexose monophosphate shunt. An important function of the shunt is maintain healthy haemoglobin by protection from oxidant stress. In G6PD deficiency, haemolytic anaemia occurs. Aet:X-linked Ix.Direct assay of G6PD activity Si/Sy: None other than those of acute / chronic anaemia Rx Avoid precipitants of oxidative stress; drugs (anti-malarials, analgesics), fava beans. Tx. Blood transfusion if required. G6PD deficient anaemia; an overview Drugs Fava beans Return

76 Partners in Global Health Education Epi:1 in 5000 people in Northern Europe. Aet:Autosomal dominant Path.Defective cell membrane protein (spectrin) causes a loss of cell membrane, progressive spherocytosis and eventually premature death (haemolysis). Increased sensitivity to infections such as parvo- virus. Ix.Blood film; spherocytes Increased osmotic fragility. negative antiglobulin test. Si/Sy: asymptomatic. Jaundice, splenomegaly General features of anaemia Txt Give ferrous sulphate, ferritin if deficiency Hereditary spherocytosis; an overview Return Blood film

77 Partners in Global Health Education WARM Aet:associated with the production of autoantibodies of IgG. They attach to the red cell at body temp and are removed early by the reticuloendothelial system. Path:Idiopathic or precipitated by drugs or autoimmune disease, leukaemia. IX.Bloods:  unconjugated haemoglobin,  LDH,  Reticulocytes. Positive direct antiglobulin test. Si/Sy: Jaundice, general features, splenomegaly Txt Steroids, splenectomy as 2 nd line. Vaccination against H. Influenza, Men C and Pneumococcus. Autoimmune haemolytic anaemia; an overview These anaemias can be split into ‘warm’ and cold’ types. This is dependent on the temperature at which the antibody reacts with the body. COLD Aet:Associated with the production of autoantibodies of IgM and are removed early by the reticuloendothelial system. Usually self-limiting. Path: Idiopathic or secondary to infection or lymphoma. IX.Bloods:  unconjugated haemoglobin,  LDH,  Reticulocytes. Positive direct antiglobulin test. Si/Sy: Worse in cold weather, acrocyanosis (purpling of skin), Reynaud's phenomenon. Txt Remove precipitants, keep patient warm, consider immunosuppression. Return


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