Week 1 Flashcards
What is Haemotology?
study of blood, the blood-forming organs, and blood diseases
What is blood?
Blood is a specialized fluid (technically a tissue) composed of cells suspended in a liquid
The liquid is called plasma
What are the types of blood cells?
Red, white & platelets
Why do we need so many different types of blood cells?
Fight infection
Transport oxygen
Prevent bleeding
haematopoiesis (haemapoiesis or hematopoiesis)
The production of blood cells
What are the different sits of haematopoiesis in the embryo?
Yolk sac then liver then marrow
3rd to 7th month - spleen
What are the different sits of haematopoiesis at birth?
Mostly bone marrow, liver and spleen when needed
What are the different sits of haematopoiesis from birth to maturity?
number of actives sites in bone marrow decreases but retain ability for haematopoiesis
What are the different sits of haematopoiesis in adulthood?
not all bones contain bone marrow
haematopoiesis restricted to skull, ribs sternum, pelvis, proximal ends of femur (the axial skeleton)
erythropeiosis steps
Pronormoblast
Basophilic/early normoblast
Polychromatophilic/intermediate normoblast
Orthochromatic/late normoblast
Reticulocyte
mature red cell/erythrocyte
What do red blood cells do?
Carry oxygen
Other roles eg buffer CO2
What do platelets do?
Stop bleeding
What do white blood cells do?
Fight infection
Others e.g. cancer prevent
Granulocytes
Contain granules that are easily visible on light microscopy
–Eosinophils
–Basophils
–Neutrophils
Neutrophils function
Short life in circulation – transit to tissues.
–Phagocytose invaders
–Kill with granule contents and die in the process
–Attract other cells
–Increased by body stress – infection, trauma, infarction
Eosinophils structure
Usually bi-lobed
Bright orange/red granules
Eosinophils function
Fight parasitic infections
–Involved in hypersensitivity (allergic reactions)
–Often elevated in patients with allergic conditions (e.g. asthma, atopic rhinitis)
Basophils structure
Quite infrequent in circulation
Large deep purple granules obscuring nucleus
Basophils function
Circulating version of tissue mast cell –Role? –Mediates hypersensitivity reactions –FcReceptors bind IgE –Granules contain histamine
Monocytes structure
Large single nucleus
Faintly staining granules, often vacuolated
Monocytes Function
Circulate for a week and enter tissues to become macrophages
–Phagocyose invaders
–Attract other cells
–Much longer lived than neutrophils
Lymphocytes structure
Mature – small with condensed nucleus and rim of cytoplasm
Activated (often called atypical) – large with plentiful blue cytoplasm extending round neighbouring red cells on the film, nucleus more ‘open’ structure
Lymphocytes function
Numerous types and function (sub types of B, T, NK)!
–Cognate response to infection
–the brains of the immune system!
Immunophenotyping
Expression profile of proteins (antigens) on the surface of cells
Bio-assays
Culture in vitro and show lineage of progeny in different growth conditions
How to examine the haematopoietic system?
Look at the peripheral blood
Look at the bone marrow
Specialised tests of bone marrow
Look at other sites of relevance to blood production e.g. splenomegaly, hepatomegaly, lymphadenopathy.
Common sites for bone marrow aspiration and biopsy
Posterior illiac crests
Red cell membrane structure
Complex structure Not just a lipid bilayer Protein ‘spars’ Protein anchors Makes it flexible Like a hiking tent!
Sodium potassium pump in red blood cells
Red cells need energy to maintain specific ion concentrations gradient and keep water out
This pump keeps ion concentrations right & Keeps water out
But it needs ATP (energy)
Haemoglobin structure
A tetrameric globular protein
HbA is 2 alpha and 2 beta chains
Heme group is Fe2+ in a flat porphyrin ring & One heme per subgroup
One oxygen molecule binds to one Fe2+ (Oxygen does NOT bind to Fe3+)
Red cell production and how it leads to Erythropoieton production
Epo levels drop - hypoxia sensed by kindeys & so releases erythropoieton - erythropoieton stimulates rbc production in marrow.
Average life span of RBC
120 days (4 months)
Site of red blood cell destruction
Spleen (& liver)
RBC destruction steps
Normally occurs in spleen (and liver)
Aged red cells taken up by macrophages i.e. taken out of the circulation
Red cell contents are recycled - Globin chains recycled to amino acids & Heme group broken down to iron and bilirubin
Bilirubin taken to liver and conjugated
Then excreted in bile (colours faeces and urine)
The red cell’s challenges
No mitochondria - only glycolysis for energy
Glycolysis- a low energy yielding process
Lots of oxygen about - oxygen free radicals are easily generated
Free radicals are dangerous
Can oxidise Fe2+ to Fe3+ which doesn’t transport oxygen
Free radicals damage proteins
Why are free radicals dangerous to RBCs?
Can oxidise Fe2+ to Fe3+ which doesn’t transport oxygen
Free radicals damage proteins ~(remember we can’t repair/replace proteins as no machinery to do so -so once they’re damaged that’s it)
Reactive oxygen species
Reactive oxygen species such as superoxide and hydrogen peroxide are free radicals and have unpaired free electrons
They are capable of interacting with other molecules (proteins, DNA) and damaging their structure
Glutathione
Glutathione protects us from hydrogen peroxide by reacting with it to form water and an oxidised glutathione product (GSSG). This maintains the redox balance.
This can be replenished by NADPH which in turn is generated by the hexose monophosphate shunt
Majority of CO2 transport
60% bound to bicarbonate produced by RBCs
The second most common form of transport for CO2
Bound to haemoglobin (carbino-Hb)
How many O2 does Hb hold?
One oxygen is bound to the Fe2+ in the heme group
4 O2 molecules per Hb
Fully saturated 1g Hb will bind 1.34ml O2
Other forms of Hb have different subunits eg HbF (two alpha, two gamma
System requirements for oxygen transport by Haemoglobin
Hb needs to be able to bind oxygen easily when there is a lot about (ie lungs where pO2 is high)
Needs to hold on to it as the pO2 drops a little (ie in transport in blood vessels)
Needs to then release 02 in the tissues where the pO2 is low
Cope with extra demand when stressed and have spare capacity in the system to cope when anaemic
Different situations causing changes in the O2 saturation curve
What haemoglobin concentrations are for anemia?
The World Health Organisation (WHO) defines anaemia by the following haemoglobin (Hb) concentrations:
Males < 130 g/L (130-175 g/L)
Females < 120 g/L (120-155 g/L)*
What is the diagnostic haemoglobin concentration for anemia in pregnancy?
- In pregnancy, a Hb < 110 g/L is diagnostic.
What is anemia?
Strictly speaking, anaemia is defined as a reduction in circulating red blood cell mass. However, in clinical practice, anaemia is defined by more measurable variables such as:
Red blood cell (RBC) count
Haemoglobin (Hb) concentration
Haematocrit
What are the two classifications of anemia?
Aetological (ie anemia is a syndrome due to an underlying cause not diagnosis in itself)
Morphological
The aetological classification of anemia
The aetiological approach addresses the underlying mechanism leading to the reduction in Hb concentration.
Aetiologically, causes can be arranged into three groups:
Decreased RBC production
Increased RBC destruction
Blood loss
The morphological classification of anemia
The morphological approach categorises anaemia based on the size of RBCs (e.g. the mean corpuscular volume).
This approach arranges anaemia into three groups:
Microcytic (small RBCs)
Normocytic (normal sized RBCs)
Macrocytic (large RBCs)
Symptoms of anemia
Dyspnoea Fatigue Headache Dizziness Syncope Confusion Palpitations Angina
Signs of anemia
Bounding pulse Postural hypotension Tachycardia Conjunctival pallor Shock
Causes of insufficent production of RBCs in anemia
Insufficient production of RBCs occurs when the normal erythropoietic process is reduced or inhibited.
This may be due to a lack of required nutrients (e.g. iron), reduced hormonal influence (e.g. low EPO, hypothyroid), bone marrow suppression or bone marrow infiltration.
Causes for ineffective production of RBCs in anemia
Ineffective production of RBCs occurs due to abnormal erythropoiesis. There is a marked increase in the erythroid cell line in the bone marrow, but erythroid precursors do not mature properly and subsequently undergo apoptosis.
Conditions that lead to ineffective erythropoiesis include megaloblastic anaemias (e.g. folate and B12 deficiency), thalassaemias, myelodysplastic syndromes and sideroblastic anaemia.
Increased destruction of RBCs in anemia
Haemolysis refers to the destruction of red blood cells, which is broadly defined as a reduction in the lifespan of RBCs below 100 days (normal 110-120 days).
If RBC production in the bone marrow cannot keep pace with the level of haemolysis, then haemolytic anaemia with ensue. The haemolytic anaemias can be divided into inherited and acquired.
Classification of haemolytic anemias (increased destruction of RBCs)
Inherited and acquired
Inherited haemolytic anaemias can be further classified based on the site of inherited defect: what are these sites?
Membrane abnormalities (e.g. hereditary spherocytosis)
Metabolic deficiencies (e.g. G6PD deficiency)
Haemoglobin abnormalities (e.g. alpha-thalassaemia, beta-thalassaemia, sickle cell disease)
Classification of acquired haemolytic anemia
Immune and non-immune
Example of immune acquired haemmolytic anemias
Immune (e.g. warm and cold autoimmune haemolytic anaemia)
Example of non-immune acquired haemmolytic anemias
Non-immune (e.g. mechanical trauma, hypersplenism, infections, drugs)
What are the common causes if blood loss anemia in young females and the elderly?
Two common sources of blood loss include menstruation in young females and gastrointestinal bleeding in older populations
The morphological classification of anemia
Classifies the causes of anaemia based upon the mean corpuscular volume (MCV).
The MCV of RBCs
The MCV is a measure of the average volume of a RBC. The MCV is measured in femtolitres (fL) and usually resides between 82 and 99.
RBCs that are > 99 fL are referred to as macrocytes, RBCs that are < 82 fL are referred to as microcytes. A normal RBC is approximately 7 microns in diameter.
The MCV of RBCs in macrocytic anemia
RBCs that are > 99 fL are referred to as macrocytes,
The MCV of RBCs in microcytic anemia
RBCs that are < 82 fL are referred to as microcytes.
Microcytic anemia
Anaemia is described as microcytic when the MCV is < 82 fL.
Microcytic anaemia is commonly associated with a reduction in the mean corpuscular haemoglobin concentration (MCHC), which leads to the appearance of pale (hypochromic) RBCs.
The most common cause of microcytic anaemia
The most common cause of microcytic anaemia is iron-deficiency anaemia (IDA). This may be evaluated with iron studies (transferrin and serum iron) and serum ferritin.
Other important causes of microcytic anemia
Thalassaemia Anemia of chronic disease IDA Lead poisoning Sideroblastic anaemia
(TAILS)
Normocytic anemia
Anaemia is described as normocytic when the MCV is within normal limits (82-99 fL).
Causes of normocytic anemia
The causes of normocytic anaemia are extremely broad and it may reflect the early stages of either a microcytic or macrocytic anaemia.
Anaemia may be the first manifestation of a systemic disorder. One of the most common causes of a normocytic anaemia is ‘anaemia of chronic disease’.
Other common causes of a normocytic anaemia include blood loss, renal disease, cancer-associated anaemia and pregnancy.
Macrocytic anemia
Anaemia is described as macrocytic when the MCV is > 99 fL.
Common causes of macrocytic anemia
There are numerous causes of a macrocytic anaemia, but it is commonly secondary to folate and/or B12 deficiency. Folate and B12 deficiency cause a megaloblastic (immature) macrocytic anaemia and abnormal nucleic acid metabolism.
Drugs that interfere with nucleic acid metabolism may also cause a macrocytic anaemia (e.g. methotrexate).
Other important causes of a macrocytic anaemia include:
Alcohol abuse Liver disease Hypothyroidism Haematological malignancies Reticulocytosis
Folate and Vitamin B12 deficency too
Haematocrit
Ratio (or commonly expressed as the percentage) of the whole blood that is red cells if the sample was left to settle
Reticulcytosis
Increase red cell production =
Reticulocytosis
Reticulocytes
●Red cells that have just left the bone marrow
●Larger than average red cells
●Still have remnants of protein making machinery (RNA)
●Stain purple/deeper red as a consequence
●Blood film appears ‘polychromatic’
●Up regulation of reticulocyte production by the bone marrow in response to anaemia takes a few days
Total iron-binding capacity (TIBC)/transferrin in IDA.
Total iron-binding capacity (TIBC)/transferrin this will be high. A high TIBC reflects low iron stores. . Note that the transferrin saturation will however be low
Treatment for IDA
Oral ferrous sulfate: patients should continue taking iron for 3 months after the iron deficiency has been corrected in order to replenish iron stores.
Iron-rich diet: this includes dark-green leafy vegetables, meat, iron-fortified bread
Symptoms of haemolytic anemia
Fatigue Weakness Paraesthesia Dyspnoea Gastrointestinal symptoms (e.g. nausea, dyspepsia) Weight loss
Dark urine, abdominal pain (gallstones) & jaundice
Signs of haemolytic anemia
Atrophic glossitis Pallor Fever Splenomegaly Evidence of underlying disease
Haemolysis symptoms
Jaundice Abdominal pain (e.g. gallstones) Dark urine (e.g. haemoglobinuria secondary to intravascular haemolysis
Investigations in haemolytic anemia
FBC (inc. reticulocyte count) - causes a normocytic anaemia.
Blood film - Spherocytes (e.g. hereditary spherocytosis), Schistocytes (e.g. microangiopathic haemolytic anaemia) and Sickle cells (e.g. sickle cell disease)
LDH not specific
LFTs (bilirubin) - increased production of bilirubin
Serum haptoglobin - decrease in the level of haptoglobin
Hepatoglobin
Haptoglobin is a plasma protein, which binds to free haemoglobin within the blood. In the presence of intravascular haemolysis, free haemoglobin is mopped up by haptoglobin. The haemoglobin-haptoglobin complex is removed by the liver leading to a decrease in the level of haptoglobin. Importantly, haptoglobin is an acute phase reactant and as such levels my be raised despite significant haemolysis.
Erythrocyte membrane
The erythrocyte membrane is essential to allow RBCs to undergo deformation as they pass through the capillary bed and then recoil back into shape. It is also needed to regulate the entry of water and important cations (e.g. Na+, K+, Ca2+, and Mg2+).
Hereditary spherocytosis
Unstable / missing erythrocyte membrane proteins may be seen in hereditary spherocytosis or elliptocyosis.
Hereditary spherocytosis is the most common inherited form of haemolysis, which is usually transmitted in an autosomal dominant pattern. The condition is characterised by mutations that lead to defects within the RBC membrane resulting in cytoskeleton instability.
G6PD deficency
Defects in the metabolic apparatus can predispose RBCs to oxidative damage.
One of the most common causes worldwide is glucose-6-phosphate dehydrogenase deficiency (G6PD deficiency). This is an X-linked recessive disorder, which may lead to episodes of haemolysis in the presence of oxidative stressors.
Metabolic machinery
The metabolic apparatus is essential to generate energy in the form of ATP for the transfer of cations, function of 2,3-BPG and protection against oxidative stress.
Defects in the metabolic apparatus can predispose RBCs to oxidative damage. One of the most common causes worldwide is glucose-6-phosphate dehydrogenase deficiency (G6PD deficiency).
Sickle cell disease
Sickle cell disease is an autosomal recessive disease that occurs due to a point mutation within the beta-globin gene. The resultant haemoglobin (HbS) is 50x less soluble than HbA and is at risk of polymerising under low-oxygen tension, which further damages the RBC
Alpha-thalassaemia and beta-thalassaemia
Alpha-thalassaemia and beta-thalassaemia are characterised by a genetic deficiency of alpha and beta-globin chains, respectively. Both conditions are characterised by the absent or reduced production of normal globin chains leading to an imbalance in chain production, abnormal erythropoiesis and defective erythrocytes
Immune mediated haemolytic anemia
Occurs due to the binding of antibodies to components of the erythrocyte membrane, which can lead to fixing of complement and phagocytosis by macrophages.
Antibodies that bind to the erythrocyte membrane may be alloantibodies or autoantibodies.
Alloantibodies
Alloantibodies are antibodies produced by one individual that will react with antigens of another individual of the same species. May be seen in haemolytic transfusion reactions and haemolytic disease of the newborn
Autoantibodies
Autoantibodies, which are generated against components of the individuals own tissue, may be seen in AIHA. AIHA is further divided depending on the type of autoantibody present being ‘warm’ or ‘cold’.
Non-immune mediated acquired haemolytic anemia
Mechanical trauma - due to heart and large blood vessel pathology (e.g. prostheses).
Microangiopathic haemolytic anaemia (e.g. HUS, TTP, DIC).
Burns
Infections
Drugs & chemicals
Hypersplenism
Megaloblasts
Megaloblasts are immature red cells with large nuclei seen in B12 & folate deficiency.
Megaloblastic anaemia
Megaloblastic anaemia is characterised by the development of megaloblastic erythropoiesis, in which abnormal erythrocyte progenitors are seen (megaloblasts).
Vitamin B12
Vitamin B12 (cobalamin) is found in meats and diary products. It is an essential vitamin for DNA synthesis in cells undergoing rapid proliferation.
Vitamin B12 absorption
Absorption of vitamin B12 is a complex process; it is aided by a key glycoprotein, intrinsic factor (IF).
Parietal cells, found in the gastric epithelium, secrete IF. IF binds to vitamin B12 within the intestines. The subsequent vitamin B12-IF complex binds to receptors within the terminal ileum where it is absorbed.
Causes of vitamin B12 deficiency
Inadequate intake (e.g. strict vegetarians, vegans)
Inadequate secretion of intrinsic factor (e.g. pernicious anaemia, gastrectomy)
Malabsorption (e.g. Crohn’s, tropical sprue)
Inadequate release of B12 from food (e.g. gastritis, alcohol abuse)
Features of vitamin B12 deficiency
Peripheral neuropathy
Subacute degeneration of the cord
Focal demyelination
Depression
Personality change
Memory loss
Investigations in vitamin B12 defiency and macrocytic anemia
Blood tests usually reveal profoundly macrocytic anaemia with a raised MCV. Bilirubin and LDH may be slightly elevated - indicating increased turnover of abnormal progenitors in the bone marrow. If a bone marrow aspirate is taken, megaloblastic erythropoiesis, marked erythroid hyperplasia with ineffective erythropoiesis with the development of giant metamyelocytes, may be demonstrated.
Management of vitamin B12 defiency
Management involves B12 replacement & treatment of the underlying cause.
Treatment typically takes the form of intramuscular hydroxocobalamin. A dose of 1 mg, three times a week for two weeks, followed by maintenance of 1 mg every three months.
Importantly, in patients with co-existing folate deficiency, B12 must be replaced first as folate replacement in this setting may precipitate neurological complications (e.g. subacute degeneration of the cord).
Pernicious anemia
Pernicious anaemia (PA) refers to vitamin B12 deficiency as a result of autoimmune destruction of the gastric epithelium
Cause of pernicous defiency
Patients with PA typically develop chronic gastric inflammation, which may lead to gastric atrophy. Over time, the basal secretion of IF is severely decreased leading to the development of vitamin B12 deficiency.
Auto-antibodies in perncious anemia
Anti-parietal cell antibodies - directed against the parietal cell membrane; sensitive, but not very specific.
Anti-IF antibodies - directed against intrinsic factor; sensitivity less than that of anti-parietal cell antibodies (est. 50-70%), but a specificity of almost 100%.
Risk of having pernicous anemia
Patients with pernicious anaemia have an increased risk of gastric malignancy. The role of routine screening is currently inconclusive, but patients do warrant an initial assessment of the upper GI tract with endoscopy at the time of diagnosis.
Folate defiency
Folate (vitamin B9) is an important molecule which acts as a cofactor in amino acid metabolism and DNA/RNA synthesis.
Folate is commonly found in a variety of food sources, but due to its rate of loss being 10-20 times greater than B12, deficiency states can develop much more rapidly.
Folate deficiency & absorption
Folate is found in both animals and plants, and the daily requirement of folate is approximately 100-200 micrograms per day.
Absorption of folate occurs within the proximal part of the small intestines (e.g. duodenum & jejunum).
There are plenty of hepatic stores of folate (approx. 8-20 mg), but this reserve is lost rapidly from cellular metabolism and the shedding of epithelial cells. There is an estimated loss of 1-2% of stores per day. Therefore, folate deficiency can develop after months, compared to vitamin B12 deficiency, which tends to develop over years.
Causes of folate deficiency
Inadequate dietary intake
Malabsorption (e.g. coeliac disease, Crohn’s disease)
Increased requirements (e.g. pregnancy, malignancy)
Increased loss (e.g. Chronic liver disease)
Other (e.g. anti-convulsants, ETOH abuse)
features of folate defiency
Features of folate deficiency are primarily related to the underlying anaemia. Clinical features may include weakness, fatigue, pallor and other evidence of malnutrition.
Other clinical features will be related to the underlying cause of folate deficiency. For example, in Coeliac disease, there may be evidence of gastrointestinal symptoms such as diarrhoea, bloating, dyspepsia and abdominal discomfort
Folate deficiency investigations
Blood tests include: FBC, blood film, haematinics and red cell folate. Red cell folate is a better measure of levels than serum folate, since levels are affected even with a short period of deficiency.
Importantly, levels of folate may be affected by vitamin B12 deficiency and it may be difficult to distinguish between the two.
In general, normal levels of vitamin B12 make the diagnosis of folate deficiency most likely. If levels of vitamin B12 are normal/reduced then a Schilling’s test can help differentiate. In clinical practice, a trial with folic acid is often employed.
If B12 deficiency cannot be completely ruled out, then replacement of B12 and folate should occur together. This is because replacement of folic acid only in the presence of vitamin B12 deficiency may cause significant neurological disease.
Management of folate defiency
General management of folate deficiency is to treat the underlying cause if required and to provide supplemental folic acid.
Folic acid is usually given as a once daily oral dose of 5 mg for up to four months. Levels can be repeated in primary care. Importantly, pregnant women should receive folate supplementation prior to conception until 12 weeks (400 mcg or 5 mg daily) due to the risk of neural tube defects.
Non-megablastic anemias
A group of macrocytic anaemias that do not lead to megaloblastic erythropoiesis
Causes of non-megaloblastix anemias
Chronic alcohol use Hypothyroidism Haemolytic anaemia Medications (e.g. cyclophosphamide) Haematological malignancies
Most common cause of non-megaloblastic anemia
Chronic alcohol use is the most common cause of a non-megaloblastic anaemia. It is thought to be due to the toxic effects of acetaldehyde on erythrocyte progenitors.
Drugs that cause non-megaloblastic anemia (macrocytic anaemia)
Causative drugs include cyclophosphamide, hydroxyurea and azathioprine.
Causes of a microcytic anaemia
Iron-deficiency anaemia (IDA)
Anaemia of chronic disease
Thalassaemias (e.g. alpha / beta)
Iron defiency anemia
IDA is commonly seen in women of child-bearing age and children across the world. Premenopausal females are particularly at risk because of the loss of iron during menstruation and pregnancy.
In the developed world, it is estimated that 2-5% of adult men and postmenopausal women suffer from IDA.
Pathophysiology of IDA
Iron is an essential molecule for living organisms; it is vital for numerous cellular processes including oxygen transport & DNA synthesis.
The absorption of iron from enterocytes in the gastrointestinal tract is highly regulated to match the loss of iron from the body each day. When the rate of iron absorption cannot keep up with the rate of iron loss, it will lead to depletion of iron stores within the body and eventually IDA.
Iron content within the body
The total iron content within our body is approximately 3-4 grams, which is distributed among different structures:
Hb: 2-3 grams
Plasma iron (e.g. bound to transferrin): 3-7 mg
Iron-containing proteins (e.g. myoglobin): 300-400 mg
Stored iron (e.g. ferritin, haemosiderin): 1 gram
The major causes of IDA can be grouped into three categories: what are they?
Increased requirements (e.g. pregnancy, lactation) Increased loss (e.g. gastrointestinal bleeding) Decreased uptake (e.g. dietary deficiency, malabsorption)
Most common causes of IDA in the developed world
Chronic haemorrhage (e.g. increased iron loss) is one of the most common causes of IDA in the developed world. It is commonly due to excessive menstruation loss in premenopausal women but can be suggestive of underlying gastrointestinal pathology.
Signs and symptoms of IDA
Due to the chronicity of IDA, symptoms generally occur at low levels of haemoglobin concentration (e.g. < 80 g/L). These include fatigue, dyspnoea, dizziness, headache, nausea, bowel disturbance, and possible exacerbation of cardiovascular co-morbidities causing angina, palpitations, and intermittent claudication.
Classical signs of IDA include glossitis, koilonychia (spoon-shaped nails), angular stomatitis, and conjunctival pallor.
What are the investigations for microcytic anemia and thus IDA?
Iron studies include: serum iron, ferritin, and iron-binding globulin (transferrin).
Diagnosis of IDA
Management of IDA
Management of IDA should involve investigation into the underlying cause & replacement of iron.
Oral replacement of iron in the form of ferrous fumarate or ferrous sulfate are common pharmacotherapies. Follow-up blood tests should always be completed to assess for response to treatment and patients should be warned about side-effects. These may include constipation, black stools, diarrhoea, nausea, and dyspepsia/epigastric discomfort.
Anaemia of chronic disease (ACD)
Anaemia of chronic disease (ACD) is a complex and multi-factorial condition due to a chronic inflammatory process from underlying infection, malignancy or systemic disease.
Second most common cause of anaemia worldwide
ACD is the second most common cause of anaemia worldwide, and commonly seen among hospitalised patients.
Aetiology & pathophysiology of ACD
ACD is classically described as a normocytic, normochromic anaemia secondary to systemic diseases, infection or malignancy.
The pathophysiology of ACD is complex and a number of mechanisms have been proposed including altered hepcidin regulation, inhibition of erythropoiesis, low erythropoietin levels and increased phagocytosis of erythroid cells.
Hepcidin
Hepcidin is the normal regulator of iron absorption from enterocytes and the tissue distribution of iron. It is an acute phase protein that usually works to reduce the availability of iron from infecting microorganisms.
ACD clinical signs
The clinical presentation of ACD is generally that of the underlying disorder, and unless the haemoglobin concentration is severely reduced, patients may be asymptomatic.
If present, clinical features are typical of all anaemias including fatigue, headache and dizziness. If severely symptomatic, patients may develop palpitations, angina or dyspnoea.
Diagnosis of ACD
Management of ACD
In general, management should involve treatment of the underlying disorder and correct management of any complicating factors including iron, B12 and folate deficiency.
Other options for the treatment of ACD can include the use of erythropoietin, parenteral iron and transfusions as indicated.
Beta-thalassaemias
Beta-thalassaemias occur due to genetic mutations within the beta-globin genes, which are located on the short arm of chromosome 11.
This gene is termed the haemoglobin subunit beta (HBB) and it is essential for normal beta-globin chain production.
There are many hundreds of gene mutations within the HBB that lead to the development of thalassaemia. In general, mutations can lead to an absence of production (beta 0 thalassaemia) or a reduced production (beta + thalassaemia) of the beta-globin chain.
Beta-thalassaemia major
Patients with two abnormal alleles (homozygous) are said to suffer from beta-thalassaemia major and will have an absent or severely reduced production of beta-globin chains
Beta-thalassaemia minor
Patients with one abnormal allele (heterozygous) are said to suffer from beta-thalassaemia minor or ‘trait’ and have a mild reduction in beta-globin chain production.
Beta-thalassaemia major clinical features
Patients with beta-thalassaemia major tend to present in the first year of life as the production of foetal haemoglobin (HbF: two alpha / two gamma chains) is replaced by defective adult haemoglobin.
Clinical features tend to reflect the severity of beta-thalassaemia. Patients with beta-thalassaemia major tend to have marked extramedullary haematopoiesis and complications secondary to iron overload from repeated transfusions.
Extramedullary haematopoiesis signs
Hepatomegaly
Splenomegaly
Skeletal abnormalities
Iron overload signs in beta-thalassaemia major
Hypogonadism
Growth failure
Diabetes mellitus
Hypothyroidism
Beta-thalassaemia minor/trait clinical features
Patients with beta-thalassaemia minor/trait are usually entirely asymptomatic and found to have a microcytic anaemia on routine testing
Beta-thalassaemia investigations
Hb electrophoresis shows reduced or absent levels of HbA and the presence of increased HbF and HbA2. Importantly, HbA may be a present in patients who have recently been transfused.
Other laboratory tests are important in the workup of the beta-thalassaemias and involve an FBC, blood film, iron studies, haematinics, LDH, bilirubin (as part of LFTs) and haptoglobin.
The predominant finding is a profound microcytic anaemia (MCV < 75 fL) with evidence of microcytic, hypochromic erythrocytes on blood film and normal iron studies.
Beta-thalassaemia management
Management is variable and depends on the severity of beta-thalassaemia.
In general, patients with beta-thalassaemia trait do not require any treatment.
Patients with beta-thalassaemia major will require early, frequent blood transfusions. Other management options include splenectomy and hematopoietic stem cell transplantation. Patients receiving recurrent transfusions may suffer with iron overload and require iron chelation therapy
What transports iron to bone marrow?
Transferrin
Ferriten
Storage protein for iron
