Module 1 | Anaemia an introduction

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

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.oQuiz 1 Anaemia; an overview

•3.0. Defining anaemia.•3.1. Prevalence of anaemia•3.2. Clinical features of anaemiaoQuiz 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.•5.1. Anaemia: essential bites oQuiz 3

Glossary

References

Contents1. 1Introduction 1.2 use this module1.3 Learning outcomes 2.1. The erythrocyte2.2. Erythropoiesis2.3. Red cell membrane2.4. Haematinics2.5. Red cell metabolism2.6. Haemoglobin2.7. Ageing and death

Quiz 1 3.0. Defining anaemia.3.1. Prevalence3.1. Clinical features

Quiz 2 4.0. Classifying anaemia 4.1. red cell indices.4.2. Morphological classification4.3. Aetiological classification

5.0. Blood film: a basic interpretation.5.1. Anaemia cardsQuiz 3.

6.0. Glossary

7.0. Referencesplease click on contents to repeat a section.

Please click here to move forwards or backwards through the module


| 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/dlFor 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




5.0. Blood film: a basic interpretation.

Quiz 3.

6.0. Glossary






6.0. Glossary


Image above: scanning electron microscope image of red blood cells.

Image left: Global WHO map of anaemia in preschool age children.


| 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





Quiz 3.

6.0. Glossary






6.0. Glossary



| how to use this module | 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 p

oin

t!

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.





Quiz 3.

6.0. Glossary






6.0. Glossary


Anaemia

essential bites.

These cards are designed to provide some essential information on key anaemias. These are accessible throughout the module.


| 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





Quiz 3.

6.0. Glossary






6.0. Glossary


L.O. We will place these objectives along the route to help direct your learning….


| 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!An erythrocyte is a fully

developed red blood cell!


| 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 O2.

Function The primary function of the erythrocyte is the carriage of oxygen from the lungs to the tissues and CO2 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


Kidney

Bone marrow

Red blood cells in circulationerythropoietin

Stem cells

Erythroid precursors

An erythrocyte is a fully developed, mature red blood cell. The adult human makes approximately 1012 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.

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.2.2. Erythropoiesis

2.2

2. 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


| 2.2. Erythropoiesis

Contents page


2.2

Key p

oin

t!

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 p

oin

t!

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


Stem cells

Kidney

Bone marrow

erythropoietin


Stem cells


|Red cell precursors and the sequence of erythropoiesis

Contents page


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!

Key p

oin

t!

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.

3.4. 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


|haematinics

Vitamin B12 (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 B12. 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 B12 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 anaemiahaemoglobin 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 B12 absorption

2.4

Contents page

2.1. The erythrocyte: an overview.2.2. Erythropoiesis2.3. The red cell membrane2.4 Haematinics

Erthropoiesis is also regulated by the availability of haematinics

“Check the haematinics” this is a phrase used frequently on the hospital ward!


|haematinics in haemoglobin

Iron Protoporphyrin

GlobinHaem

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


|haematinics: the normal iron cycle


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 (Fe2+; 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.


There are a number of key steps in the absorption of Vitamin B12. The two key locations are the stomach and the terminal ilium. Dietary vitamin B12 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 B12 deficiency.

Vitamin B12 deficiency can take up to two years to develop as the body has sufficient stores for this period.

Distal ileum

Site of B12 absorption

Oesophagus

StomachIF Intrinsic factor

Vitamin B12 ingested

|haematinics: vitamin B12

Pernicious anaemia: the leading cause of B12 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 B12-IF complex for absorption in the distal ileum.

2.4


Causes of vitamin B12 deficiency

1.Pernicious anaemia

2.Inadequate intake

3.Poor absorption


| 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.2.2. Erythropoiesis2.3. 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.

ankyrinProtein 4.1actinspectrin

Key

poin

t!

Click next slide to see flow diagram

Link the components of red cell structure to red cell development and functionLO

reduced spectrin synthesis

dysfunctional spectrin

abnormal spectrin gene

Spectrin malfunction within erythrocyte

membraneErythrocytes 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 spleenHaemolysis;

premature red cell death occurs

causing anaemia

flow diagram: the process of spherocytosis in hereditary spherocytosis


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.2.2. Erythropoiesis2.3. The red cell structure 2.3.1. Cell membrane 2.3.2. DNA synthesis2.4. Red cell metabolism

Glucose

Glucose- 6-P

Fructose-6-P

Lactate

Pyruvate kinase

Glucose-6-phosphate dehydrogenase

NAPD NADPH+H+

2GSH

H2OO-

GSSG

Hexose monophosphate shunt

Embden-Meyerhof glycolytic pathway

Ribulose 5-P

6-PG

Key point: Oxidant stress!CLICK HERE

ADP

ADP

ATP

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 p

oin

t!

Glucose

Glucose- 6-P

Fructose-6-P

Lactate

Pyruvate kinase

Glucose-6-phosphate dehydrogenase

NAPD NADPH+H+

2GSH

H2OO-

GSSG

Hexose monophosphate shunt

Embden-Meyerhof glycolytic pathway

Ribulose 5-P

6-PG

Oxidant stress!

ADP

ADP

ATP

ATP

Red cell functioning adequately under normal conditionsRed 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


| haemoglobin and O2 transport

A key function of a red cell is to carry and deliver oxygen to the tissues and return CO2 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.2.2. Erythropoiesis2.3. The red cell structure 2.3.1. Cell membrane 2.3.2. DNA synthesis2.4. Red cell metabolism2.5. Haemoglobin and O2 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 CHAINA normal adult haemoglobin (Hb A) molecule consists of4 polypeptide (globin) chains: 12 12.

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 p

oin

t!

Oxygen (O2)


| 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 HbA2 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


|haemoglobin and the oxygen dissociation curve

Contents page

2.1. The erythrocyte: an overview.2.2. Erythropoiesis2.3. The red cell structure 2.3.1. Cell membrane 2.3.2. DNA synthesis2.4. Red cell metabolism2.5. Haemoglobin and O2 transport

PO2 (mm Hg)

Hb

sa

tura

tion

(1

00

%)

50

50

• CO2

• pH

• 2,3-DPG

• CO2

• pH

• 2,3-DPG

The sigmoid curve: this occurs because as O2 is unloaded the beta chains are pulled apart and 2,3-DPG enters the space. This reduces the haemoglobin molecule’s affinity for O2.

The shape of this classic sigmoid curve will be dictated by the number of 2,3-DPG metabolites and CO2 and H+ ion concentration in the red blood cell.

A shift to the left indicates an increased affinity for O2. This makes it easier for Hb to bind to O2, in the lungs and conversely more difficult for Hb to release O2

in the tissues.. This occurs when there is a rise in pH (alkalosis), low CO2 levels and with HbF.

A shift to the right indicates a decreased affinity for O2. This occurs when there are raised concentrations of 2,3-DPG, H+ ions (acidosis) or CO2 within the red blood cell. This results in greater release of O2 to the tissues.

2.6


|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





Quiz 3.

6.0. Glossary

7.0. References

please click on contents to repeat a section.

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.

GlobinIron

Attaches to transferrin

FIs metabolized to amino acids

Red blood cell

Investigating haemolysis

1.Lactic acid dehydrogenase (LDH)2.Reticulocyte count3.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.

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 B12 is absorbed in the jejunum.

Folate and vitamin B12 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

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.

True! 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 CO2 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 O2 and increase O2 release fom Hb.

Vitamin B12 is absorbed in the jejunum

False! Vitamin B12 binds to intrinsic factor in the stomach, travels through the small bowel and the complex is absorbed in the distal ileum.

Folate and vitamin B12 are key building blocks of haemoglobin

False! Vitamin B12 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 B12 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 α2β2).

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


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.





Quiz 3.

6.0. Glossary

7.0. References






6.0. Glossary



| 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.





Quiz 3.

6.0. Glossary



|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.





Quiz 3.

6.0. Glossary


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).


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 O2 dissociation curve of haemoglobin and the cardiovascular system to adapt.

2.Severity: Mild anaemia (Hb 9.0-11.0 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;


| clinical features of anaemia

General symptoms and signsContents1. 1Introduction 1.2 use this module1.3 Learning outcomes 2.1. The erythrocyte2.2. Erythropoiesis2.3. Red cell membrane2.4. Haematinics2.5. Red cell metabolism2.6. Haemoglobin2.7. Ageing and death




Quiz 3.

6.0. Glossary


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



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




Signs:

Nail bed; demonstrating koilonychia (spoon-shaped nails). This is specific to iron deficiency.

RETURN




Signs

Atrophic glossitis; red large swollen tongue. This is seen in both vitamin B12 and folate deficiency.

RETURN




Signs

Angular stomitis; fissuring at corners of mouth. This is seen in both vitamin B12 and folate deficiency.

RETURN




Signs

Dysphagia: pharyngeal web (Paterson-Kelly syndrome). This occurs in iron deficiency.

RETURN




Signs

RETURN

Peripheral oedema. A general sign.




Signs

High flow murmur, bounding pulse and/or tachycardia: All features of a compensatory hyperdynamic circulation. These are general signs!

RETURN


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!






Quiz 3.

6.0. Glossary






6.0. Glossary


An adult male will be anaemic if they have a haemoglobin of < 11.5 g/dlon 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 B12 and folate deficiency.

Some key signs associated with iron deficient anaemia are koilonychia and glosso-pharyngeal webbing.

True!

Click here to continue module


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.





Quiz 3.

6.0. Glossary



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 B12 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 26.7-32.5pg/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.


|interpretation of red cell indices

Microcytosis & hypochromia Normocytosis & normochromia

Microcyticabnormally 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.

Hypochromichypochromic 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.

NormocyticMany 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 production

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 B12 or folate which are key building blocks in DNA synthesis.

http://en.wikipedia.org/wiki/Blood_plasma


| morphological classification of anaemia

Anaemia type

Red cell indices

Common examples

Microcytichypochromic

MCV < 80 flMCH < 27 pg/L

Iron deficiency

Thalassaemia

Sideroblastic

Normocyticnormochromic

Macrocytic

MCV > 98 fl

Folate deficiency

B12deficiency

normal

Haemolysis

Chronic disease

Marrow infiltration

Megaloblastic





Quiz 3.

6.0. Glossary



|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 B12 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 lifespanThis 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.





Quiz 3.

6.0. Glossary



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 B12

•folate

Ineffective red cell formation •Chronic inflam.•Thalassaemia•renal disease

immuneNon-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





Quiz 3.

6.0. Glossary



|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 cell Microcytic hypochromic

Macrocyte Target cell Basket case

Elliptocyte Fragments 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





Quiz 3.

6.0. Glossary

7.0. References


Normal red blood film Microcytic hypochromic Macrocytic megaloblastic Target cells Bite cells

Elliptocyte Fragments Fragments ‘Pencil’ cells Malaria



|anaemia essential bites

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


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 a naemia worldwide affecting around 500million daily.

Aet: pernicious anaemia, malabsorpion, post total gastrectomy

Ix. B12MCV 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 B12 & Folate deficiencyEpi:

Aet: increased consumption (pregnancy), dietary deficiency, folate antagonist (drugs eg; methotrexate).

Ix. folateMCV 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

hydroxycobalamin (Vitamin B12). There is no oral

form.

Path G6PD 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 lossreduced 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 lossreduced 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;

KEYR.C.I. Red Cell IndicesEpi. Epidemiology

Aet. Aetiology

Ix. Investigations

Si/Sy. Signs and Symptoms Path. Pathology

Tx. Treatment





6.0. Glossary


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!


Microcytosis is MCV < 90fL

The appearance of a hypochromic red blood cell is caused by reduced DNA synthesis

In vitamin B12 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





6.0. Glossary


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 B12 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



Contents1. 1Introduction 1.2 use this module1.3 Learning outcomes 2.1. The erythrocyte2.2. Erythropoiesis2.3. Red cell structure2.3.1. Cell membrane2.3.2 DNA synthesis2.4. Red cell metabolism2.5.Haemoglobin2.6 O2 dissociation curve 3.0. Defining anaemia.3.1. Prevalence3.2 Clinical features 4.0. Classifying anaemia 4.1. red cell indices4.2. Morphological 4.3 Aetiological classification

5.0 Blood film: a basic interpretation.


6.0. 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.





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.






6.0. Glossary

7.0. Quiz








Malarial parasite

Blood film

RBC morphology: Microcytic hypochromic.

ExplanationRed cells are smaller and lighter than normal and displaying a typical ‘area of central pallor’.

CauseIron deficient anaemia

Thalassaemia

return






6.0. Glossary

7.0. Quiz








Malarial parasite

return

Blood film

RBC morphology: macrocytic ,megaloblastic (More oval)

Cause

Macrocytic: Macrocytic megaloblastic:Liver disease Vitamin B12

Alcoholism Folate






6.0. Glossary

7.0. Quiz








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.






6.0. Glossary

7.0. Quiz








Malarial parasite

return

Blood film

RBC morphology: basket/blister cell.

Explanation:

Oxidant damage

Cause:

G6PD deficiency






6.0. Glossary

7.0. Quiz








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).






6.0. Glossary

7.0. Quiz








Malarial parasite

return

Blood film


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






6.0. Glossary

7.0. Quiz








Malarial parasite

return

Blood film


Explanation

Oxidant damage

G6PD deficiency

Blood film

RBC morphology: Tear drop poikilocyte

Definition: Poikilocyte; an individual cell of abnormal shape

Cause

•Myelofibrosis•Extramedullary haemopoiesis






6.0. Glossary

7.0. Quiz








Malarial parasite

return

Blood film


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






6.0. Glossary

7.0. Quiz








Malarial parasite

return

Blood film


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.






6.0. Glossary

7.0. Quiz








Malarial parasite

return

Blood film


Explanation

Oxidant damage

G6PD deficiency

Blood film

RBC morphology: Stomatocyte

Explanation

Liver diseaseAlcoholism






6.0. Glossary

7.0. Quiz








Malarial parasite

return

Blood film


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).






6.0. Glossary

7.0. Quiz








Malarial parasite

return

Blood film


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.






6.0. Glossary

7.0. Quiz








Malarial parasite

return

Blood film


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


|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.





6.0. Glossary



|references and links





6.0. Glossary



iron deficient anaemia; an overview

Colon cancer

microcytic hypochromic blood film.

Return



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



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


path: Vitamin B12 binds to IF intrinsic factor in the stomach and is absorbed in the terminal ileum

Aet: Pernicious anaemia, malabsorpion, post total gastrectomy

Ix. B12MCV 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 B12 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 B12

deficiency first.

Folate deficiency

Glossitis.

Blood film; Microcytic hypochromic

Return


Path G6PD 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


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; spherocytesIncreased osmotic fragility.negative antiglobulin test.

Si/Sy: asymptomatic.Jaundice, splenomegalyGeneral features of anaemia

Txt Give ferrous sulphate , ferritin if deficiency

Hereditary spherocytosis; an overview

Return

Blood film


WARMAet: 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 2nd line. Vaccination against H. Influenza, Men C and Pneumococcus.

Autoimmune haemolytic anaemia; an overviewThese anaemias can be split into ‘warm’ and cold’ types. This is dependent on the temperature at which the antibody reacts with the body.

COLDAet: 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

Module 1 | Anaemia an introduction

Documents

Transcript of Module 1 | Anaemia an introduction