Clinical haematology Flashcards
Define disseminated intravascular coagulation:
Disseminated intravascular coagulation (DIC) is a complex condition that describes the inappropriate activation of the clotting cascades, resulting in thrombus formation and subsequently leading to the depletion of clotting factors and platelets.
What is the epidemiology of disseminated intravascular coagulation?
DIC often occurs in the context of severe systemic disease (see aetiology below). DIC is often encountered in a hospital setting, particularly in intensive care units, surgical wards, and obstetric units due to the high prevalence of associated risk factors. It is associated with a high mortality rate, with the outcome is largely dependent on the prompt diagnosis and treatment of the underlying cause.
Causes of disseminated intravascular coagulation:
Major trauma or burns
Multi-organ failure
Severe sepsis or infection
Severe obstetric complications
Solid tumours or haematological malignancies
Acute promyelocytic leukaemia (APL) is an uncommon subtype of AML that is associated with DIC
Note: This comes up frequently in written exams
Signs and symptoms of disseminated intravascular coagulation:
Excessive bleeding e.g. epistaxis, gingival bleeding, haematuria, bleeding/oozing from cannula sites
Fever
Confusion
Potential coma
Physical signs include:
Petechiae
Bruising
Confusion
Hypotension
Oozing from a cannula size is a classic sign of DIC
What are the blood tests for disseminated intravascular coagulation?
FBC (thrombocytopenia)
Blood film may show schistocytes due to microangiopathic haemolytic anaemia (MAHA) - (fragmented red blood cells) on a blood film due to mechanical damage in small vessels from the clotting process
Raised d-dimer (a fibrin degradation product)
Clotting profile - increased prothrombin time (due to consumption of clotting factors), increased APTT, decreased fibrinogen (consumed due to microvascular thrombi)
What is the management for disseminated intravascular coagulation?
Management of DIC is primarily focused on treating the underlying cause. Supportive care is also essential to manage symptoms and prevent complications. This may include transfusions of platelets or clotting factors, and in some cases, anticoagulation therapy may be necessary.
What are the coagulation cascade findings in disseminated intravascular coagulation?
The low platelet count and fibrinogen are due to consumption, and prolonged PT due to the consumption of coagulation factors. APTT can be normal or prolonged
In DIC, PT is often prolonged because factor VII in the extrinsic pathway is rapidly depleted. aPTT may remain normal initially because the intrinsic pathway factors are not as quickly depleted or are compensated for by other mechanisms. This disparity reflects the differential sensitivity of these tests to factor consumption in the early phases of DIC.
define haemochromatosis:
Haemochromatosis is an iron storage disorder in which iron depositions in multiple organs (such as the liver, skin, pituitary, heart and pancreas) leading to oxidative damage. It is the most common genetic condition in the UK but may initially present with non-specific symptoms, leading to under-diagnosis.
How can haemochromatosis be classified?
Haemochromatosis can be primary (hereditary) or secondary (acquired) and classically presents in white, middle-aged males
What is the major cause of haemochromatosis?
The major cause of hereditary haemochromatosis is due to autosomal recessive mutations to the haemochromatosis (HFE) gene on chromosome 6.
The two main mutant alleles are C282Y and H63D.
Approximately 85-90% of HFE patients are homozygous for the C282Y allele
HFE mutations exhibit low penetrance :
Estimated 14% penetrance for homozygous males
Penetrance is even lower for females, attributed to menstruation and genetic variation in HLA subtypes (HFE is a HLA protein)
What is the pathophysiology of haemochromatosis?
Primary haemochromatosis is due to mutations in the HFE gene, each of which alter the regulatory pathways involved in hepcidin , an acute phase reactant protein that regulates iron stores.
HFE mutation→decreased hepcidin activity→ increased duodenal/jejunal iron absorption and release of iron from bone marrow macrophages → iron deposition in cells → Fenton reaction* and hydroxyl free radicals → DNA, lipid and protein damage → organ dysfunction
*Fenton reaction
Iron freely undergoes oxidation in cells from Fe2+ to Fe3+ as part of the Fenton reaction
In this process, hydroxyl free radicals are generated which then cause oxidative damage
A major mechanism of cell injury is free radical-induced lipid peroxidation which triggers apoptosis
What is the classification of primary haemochromatosis?
Classification is based on the mechanism of inheritance. All mechanisms interfere with the process of macrophage-liver communication, leading to decreased activity of hepcidin.
Type 1: Hereditary (HFE genotype) haemochromatosis
The cause over 90% of cases
Autosomal-recessive mutation to HFE gene (chromosome 6)
Only present in white populations
Type 2: Juvenile haemochromatosis: Presents in early adulthood (second and third decades) versus classic middle-aged patients of hereditary haemochromatosis.
Type 2A mutation of the haemojuvelin gene.
Type 2B mutation of the hepcidin gene A
Patients often have hypogonadism and cardiomyopathy.
Type 3: Transferrin receptor 2 haemochromatosis
Autosomal-recessive mutation in transferrin receptor 2 (chromosome 7)
Condition mimics HFE haemochromatosis clinically
Type 4: Ferroportin disease
Type 4A: low transferrin saturation and macrophage iron deposits
Type 4B: clinically similar to type 1 (HFE) haemochromatosis- high transferrin saturation and iron deposition in liver.
Name some causes of secondary haemochromatosis?
Frequent blood transfusions: each new transfusion introduces new iron which is recycled and stored
Iron supplementation: over-supplementing, particularly with concurrent vitamin C.
Diseases of erythropoiesis: ineffective erythropoiesis leads to iron accumulation
What are the early clinical manifestations of haemochromatosis?
Fatigue: This is one of the most common presenting symptoms, and often the most debilitating. It is usually chronic, non-refreshing and unrelieved by rest.
Arthralgia: Joint pain is another common symptom. This typically involves the metacarpophalangeal joints, wrists, knees, and ankles.
Impaired sexual function: Men may experience loss of libido or impotence due to gonadal failure, while women may experience menstrual irregularities or early menopause.
Abdominal pain: Patients may present with a non-specific, often chronic, abdominal pain. This can be due to hepatomegaly or pancreatic involvement.
Mood disturbances: Depression and irritability may be early manifestations of the con
What are the later clinical manifestations of haemochromotasis?
Skin hyperpigmentation: The skin may become bronzed or greyish due to increased melanin production. This sign is often mistaken for a tan, but is actually due to the combination of iron deposits and increased melanin in the skin.
Hepatomegaly and Cirrhosis: As iron accumulates in the liver, it can lead to liver enlargement (hepatomegaly) and eventually, cirrhosis. This can present as jaundice, ascites, and signs of portal hypertension.
Diabetes mellitus: Damage to pancreatic beta cells can result in insulin deficiency, leading to a form of diabetes known as ‘bronze diabetes’.
Cardiac disease: Cardiomyopathy due to iron deposition in the myocardium can present as congestive heart failure with signs such as dyspnea, orthopnea, and lower extremity oedema.
Arthropathy: A distinctive form of arthritis can develop, commonly affecting the second and third metacarpophalangeal joints. This can lead to the characteristic ‘iron fist’ sign, an important clue to the diagnosis.
Hypogonadism: Persistent gonadal dysfunction can lead to signs of hypogonadism in men and women.
chondrocalcinosis - deposition of calcium pyrophosphate dihydrate (CPPD) crystals in joint cartilage, and it is commonly associated with hemochromatosis.
What are the investigations for haemochromatosis?
Patients with clinical features, raised transferrin saturation and/or raised serum ferritin should then undergo molecular testing for HFE gene mutation . A C282Y mutation on the HFE gene (chromosome 6) is the most common cause of hereditary haemochromatosis.
Transferrin saturation is the superior screening test. It should also be remembered that ferritin is an acute phase protein and will be raised by inflammation, as well as alcoholism, metabolic syndrome and anaemia
Clinical evidence of liver involvement and/or serum ferritin >2247pmol/L must be referred to hepatology for liver biopsy to estimate hepatocyte iron content and assess extent of fibrosis or cirrhosis.
Depending on the presenting complaints, alternative tests include:
Fasting blood sugar (may be raised in liver/pancreatic involvement)
ECG (may show arrhythmia or decreased QRS amplitude)
Echocardiogram (assess iron deposition in conduction pathway and cardiomyopathy)
Testosterone, FSH, LH (may be low in gonadal/pituitary involvement)
What is the general management for haemochromatosis?
ll patients should receive advice on the following:
Avoid iron and iron-containing supplements
Avoid vitamin C supplements (and orange juice) (which increases the bioavailability of iron for enteric absorption), except in iron chelation therapy where it may increase therapeutic value
Limit or avoid alcohol
Consider hepatitis A and B vaccinations if no previous encounter.
What are the specific stages of haemochromotasis guiding management
Stage 0 and 1 can be managed in primary care and patients should receive counselling and support for their condition.
Describe phlebotomy treatment for haemochromotasis?
Phlebotomy , or venesection, is the process by which blood is removed from the patient to stimulate haematopoiesis, thereby utilising some of the excess iron for haem synthesis. It is performed in two stages:
Induction: weekly phlebotomy sessions in the secondary care setting to reduce iron levels to <50% transferrin saturation. This should be under the guidance of haematology or hepatology depending on the extent of liver disease). Induction can take several months or even longer depending on the iron burden.
Maintenance: infrequent (less than monthly) phlebotomy sessions to maintain normal iron levels (<50% transferrin saturation).
It is encouraged for maintenance phlebotomy to occur at blood donation banks under the NHS Blood & Transplant service if patients are ‘fit’ and do not have liver disease.
What is the treatment for haemochromotasis when phlebotomy is contraindicated in stages 2,3,4 (such as anaemia, cardiac disease or venous access issues)
Iron chelation therapy - Both oral agents (Deferasirox) and parenteral agents (Desferrioxamine) are available dependent on the patient’s likelihood of compliance and response.
Patients with end stage cirrhotic liver disease due to haemochromatosis are candidates for:
Liver transplantation. It is important to note that transplant outcomes are worse compared to other causes of cirrhosis.
What are the complications of haemochromatosis?
The main complications are a result of oxidative damage to organs. In addition, deranged iron scavenging increases susceptibility to certain organisms such as Listeria monocytogenes and haemochromatosis patients exhibit increased bone loss and osteoporosis which is multifactorial in nature.
Direct organ damage complications include:
Liver:
Fibrosis or cirrhosis
Hepatocellular carcinoma: cirrhosis patients have a 100 fold increased risk of developing liver cancer
Diabetes mellitus:
The risk is not significantly raised in these patients compared to population but this is due to the overwhelming obesity prevalence rather than iron overload itself not being a risk for progression of diabetes mellitus
Heart:
Arrhythmia due to iron deposition in conduction pathway
Cardiomyopathy: either dilated or dilated-restrictive
Chronic congestive heart failure
Hypogonadism:
Hypogonadotrophism can result from iron depositing in the pituitary direct damage to gonads
What is the prognosis of haemochromatosis?
Prognosis is dependent on severity of disease at diagnosis.
Patients without clinical symptoms of organ damage (such as cirrhosis or diabetes mellitus) at the time of diagnosis often have unchanged life expectancy from healthy individuals
However, large studies put the relative risk at over 2 and the mean survival at 21 years for patients who have cirrhosis at the time of diagnosis
Life-limiting complications
Cirrhosis at the time of diagnosis increases the risk of life-limiting complications such as hepatocellular carcinoma, diabetes mellitus and cardiac disease
Liver disease is exacerbated by additional liver injury (for example from alcohol and hepatitis infection).
Liver transplant is indicated for cirrhosis and cancer development but post-transplant prognosis (1- and 5-year survival) is significantly worse for haemochromatosis compared to other diseases that necessitate liver transplant
Which of complication of haemochromatosis would be most likely to show improvement with venesection?
Cardiomyopathy caused by haemochromatosis can significantly improve with regular venesection therapy.
Define anaemia:
Anaemia is a medical condition characterized by a deficiency in the number of red blood cells (RBCs) or a decrease in the concentration of haemoglobin (Hb) in the blood. This deficiency results in reduced oxygen-carrying capacity and impaired oxygen delivery to the body’s tissues and organs.
How is anaemia classified?
Anaemia can be classified according to the MCV, which is part of the FBC panel
What is macrocytic anaemia?
(MCV >100 fl)
Morphologically, macrocytic anaemia is usually typified by large RBCs due to abnormal RBC development, giant metamyelocytes and hypersegmented neutrophils (in the peripheral circulation).
Macrocytic anaemia may be megaloblastic or non-megaloblastic.
Name some causes of megaloblastic anaemia?
B12 deficiency
reduced intake (eg. dietary)
reduced absorption (eg. pernicious anaemia, inflammatory bowel disease, gastrectomy)
Folate deficiency
Drugs
hydroxycarbamide (previously called hydroxyurea)
azathioprine
cytosine arabinoside
azidothymidine
Name some causes of non-megaloblastic/normoblastic macrocytic anaemia?
Liver disease
Alcohol
Hypothyroidism
Myelodysplastic syndrome
Hypothyroidism
Pregnancy (usually a mild macrocytosis)
Name some causes of normocytic anaemia?
MCV 78–98 fl
Causes include:
Recent bleeding
Anaemia of chronic disease
Combined iron & B12/folate deficiency
Most non-haematinic-deficiency causes
Name some causes of microcytic anaemia?
Microcytic anaemia is defined as the presence of small, often hypochromic, RBCs in a peripheral blood smear
Causes include :
Iron deficiency
α-thalassaemia, β-thalassaemia, HbE, HbC
Anaemia of chronic disease (this more often causes normochromic normocytic anaemia)
Lead poisoning
Sideroblastic anaemias (rare)
What are the signs and symptoms of anaemia?
Shortness of breath
Fatigue
Pallor of the conjunctiva
Cold extremities
Increased cardiac output, palpitations, heart murmurs and cardiac failure
Severe anaemia can lead to chest pain and cognitive impairment
Name the investigations for anaemia:
Full Blood Count (FBC): This is the initial step in assessing anaemia. It provides information on haemoglobin levels, haematocrit, red blood cell count, and mean corpuscular volume (MCV). Abnormal MCV values help classify anaemia type.
Peripheral Blood Smear: A blood smear examination allows a closer look at the size, shape, and color of red blood cells. It can provide valuable clues, such as the presence of abnormal cell shapes (spherocytes, schistocytes) or specific inclusions (Heinz bodies).
Reticulocyte Count: Evaluating reticulocytes (immature red blood cells) can determine whether the bone marrow is appropriately responding to anaemia. Low reticulocyte counts may suggest decreased RBC production, while high counts could indicate haemolysis.
Iron Studies: Measuring serum iron, ferritin, total iron-binding capacity (TIBC), and transferrin saturation helps diagnose iron-deficiency anaemia and differentiate it from other forms.
Vitamin and Folate Levels: Assessing serum vitamin B12 and folate levels is essential for diagnosing megaloblastic anaemias, such as pernicious anaemia or folate deficiency anaemia.
Haemoglobin Electrophoresis: This test is crucial for identifying haemoglobinopathies like sickle cell disease and thalassaemia.
Specific Tests: In cases of suspected haemolytic anemia or underlying chronic diseases, additional tests may be required, including autoimmune markers, haptoglobin, and direct and indirect bilirubin measurements.
Bone Marrow Aspiration and Biopsy: These invasive procedures may be necessary when the underlying cause remains unclear or when bone marrow disorders, myelodysplastic syndromes, or aplastic anemia are suspected.
Name the management for anaemia:
Nutritional Support: For iron-deficiency anaemia, dietary adjustments or iron supplementation are essential. Correcting vitamin B12 and folate deficiencies through diet or supplements is critical for megaloblastic anaemias.
Erythropoiesis-Stimulating Agents: In chronic kidney disease-associated anaemia or anaemia related to chemotherapy, erythropoiesis-stimulating agents (ESAs) may stimulate red blood cell production.
Treating Underlying Conditions: Managing chronic diseases, such as inflammatory disorders or cancer, can alleviate anaemia. Specific treatments, such as corticosteroids for autoimmune haemolytic anaemia, may be required.
Blood Transfusions: In cases of severe anaemia, significant bleeding, or acute complications, blood transfusions can rapidly improve oxygen delivery. Transfusions are vital in haemolytic crises.
Haemolysis Management: When haemolysis is the cause, identifying and treating the underlying haemolytic disorder, along with managing complications like jaundice and anaemia, is crucial.
Bone Marrow Stimulants: In some anaemias, such as aplastic anaemia, bone marrow stimulants like granulocyte colony-stimulating factor (G-CSF) or erythropoietin-stimulating agents may be considered.
Supportive Care: Providing supportive care, including managing symptoms, optimizing nutrition, and addressing fatigue and quality of life, is a key aspect of anaemia management.
Regular Monitoring: Ongoing follow-up and monitoring are vital to track the response to treatment and ensure that haemoglobin levels are stable. Adjustments to the treatment plan may be needed based on patient progress.
Define iron deficiency anaemia:
Iron deficiency anaemia is a haematological disorder stemming from an insufficient supply of iron, which is vital for the synthesis of haemoglobin—a crucial component of red blood cells. Without adequate iron, the body struggles to produce a sufficient quantity of healthy red blood cells, leading to a reduction in oxygen-carrying capacity and subsequent symptoms of anaemia.
Name some causes of iron deficiency anaemia:
Dietary Insufficiency: Inadequate iron intake, especially in individuals with restrictive diets or limited access to iron-rich foods.
Chronic Blood Loss: Gastrointestinal bleeding, heavy menstrual periods, and other sources of chronic blood loss (e.g. angiodysplasia) can deplete iron stores.
Malabsorption Disorders: Conditions like coeliac disease, inflammatory bowel disease and atrophic gastritis can hinder iron absorption in the gut. Hookworms are a more prominent cause in tropical setting.
Increased Demand: During pregnancy and rapid growth phases, the body’s iron requirements can surpass the available supply. This can also occur if there is chronic haemolysis
What are the signs and symptoms of iron deficiency anaemia:
Tiredness
Lethargy
Weakness
Palpitations: An increased heart rate may be noticeable, especially when at rest.
Cognitive Impairment: Some patients may exhibit difficulty concentrating or memory issues.
Cold Intolerance
Headaches and dizziness
Brittle Nails: Changes in the nails, such as brittleness and spoon-shaped deformities (koilonychia), can be observed.
Angular stomatitis
Atrophic glossitis
Pica: Iron-deficiency anaemia may manifest as pica, with cravings for non-food substances like ice (pagophagia) or clay (geophagia). This is more common in children.
What will the blood film show in iron deficiency anaemia:
Hypochromic, microcytic red cells
Additional pencil cells
Occasional target cells
What investigations do we do specifically for iron deficiency anaemia:
Total iron binding capacity (TIBC) – Will typically be high as the body mobilises available iron stores owing to the iron deficiency
Ferritin – will be low as available iron stores in the body are mobilised to counteract the iron deficiency
Note: Ferritin should be measured alongside B12 and folate to assess possible coexisting haematinic deficiency
A low ferritin is diagnostic of iron deficiency; however, a normal or high ferritin does not exclude iron deficiency
Ferritin is an acute phase protein so levels can be masked/influenced by other conditions, particularly inflammation – It is good to check a C-reactive protein (CRP) at the same time
Iron deficiency anaemia in patients >60y should prompt suspicion colonic malignancy until proven otherwise and prompt FIT testing and subsequent 2 week wait referral if indicated according to NICE guidelines.
What is the management for iron deficiency anaemia:
Iron Supplementation: Oral or intravenous iron supplements are administered to correct iron deficiency. Intravenous iron is preferred in cases of severe deficiency or malabsorption. Important considerations of oral iron supplementation (usually a 3 month course) include:
Side effects - diarrhoea, constipation, black stools, abdominal pain, nausea
If it is not tolerated due to SEs, reduce the dose to one tablet on alternate days, or consider alternative oral preparations.
Iron supplements should be taken on an empty stomach (preferably one hour before a meal) with a drink containing vitamin C, such as a glass of orange juice or another juice drink with added vitamin C. This aids absorption.
Oral iron decreases the absorption of oral Levothyroxine. Therefore if both are prescribed, advise patients to take at least 4 hours apart.
Monitoring - recheck FBC within 4 weeks of starting treatment (haemoglobin concentration should rise by about 20 g/L over 3–4 weeks). Then check the FBC again at 2–4 months to ensure that the haemoglobin level has returned to normal. Once Hb is normal can continue supplementation for 3 further months, and then monitor at 3/6/12-monthly intervals.
What is pernicious anaemia?
Pernicious anaemia is a deficiency in RBCs caused by lack of vitamin B12 in the blood
In the strictest sense, it is caused by autoimmune impairment of intrinsic factor production
The term is also widely used to describe B12 deficiency-related anaemia secondary to other causes as well.
What is the pathophysiology of pernicious anaemia?
The pathophysiology of pernicious anaemia primarily revolves around the autoimmune destruction of gastric parietal cells, which play a central role in the absorption of vitamin B12. This complex process involves several key factors:
Autoimmune Attack: In pernicious anaemia, the body’s immune system mistakenly targets and destroys gastric parietal cells. These cells are responsible for producing intrinsic factor, a protein necessary for vitamin B12 absorption.
Intrinsic Factor Deficiency: As a result of autoimmune destruction, intrinsic factor levels decrease, leading to impaired vitamin B12 absorption in the ileum, the final part of the small intestine.
Vitamin B12 Deficiency: Reduced absorption of vitamin B12 results in a deficiency of this essential nutrient. Vitamin B12 is crucial for erythropoiesis (the formation of red blood cells) and the maintenance of the nervous system.
Megaloblastic Changes: Vitamin B12 deficiency leads to impaired DNA synthesis in developing blood cells. This results in megaloblastic changes, causing larger, structurally abnormal red blood cells (megaloblasts) in the bone marrow. These larger cells are less effective at carrying oxygen, leading to anaemia.
Haemolysis: Pernicious anaemia can lead to haemolysis (the breakdown of red blood cells) due to their structural abnormalities. .
What are the signs and symptoms of pernicious anaemia?
Fatigue
Pallor
Glossitis - inflammation of the tongue, leading to a smooth, beefy-red appearance.
Neurological Symptoms and subacute combined degeneration of the cord: Pernicious anaemia may cause neuropathy, affecting balance, sensation, and coordination.
Jaundice - due to haemolysis
Cognitive Impairment - memory problems, confusion, and mood changes may occur
What would a full blood count and blood smear show in pernicious anaemia?
Full Blood Count (FBC): Reveals macrocytic anaemia and may show hypersegmented neutrophils.
Low haemoglobin level
High MCV
High mean corpuscular haemoglobin (MCH)
Normal mean corpuscular haemoglobin concentration (MCHC)
Low reticulocyte count
abnormally large and oval-shaped RBCs
What are the specific investigations we do in pernicious anaemia?
Vitamin B12 Assays: Measure serum vitamin B12 levels, which are typically low in pernicious anaemia.
Intrinsic Factor Antibodies: These antibodies help confirm the autoimmune nature of the condition. This test is highly specific.
Parietal cell Antibodies: This test is highly sensitive.
Bone Marrow Aspiration and Biopsy: May show megaloblastic changes in erythropoiesis.
Pernicious anaemia is associated with atrophic body gastritis – diagnostic criteria are based on histologic evidence of gastric body atrophy associated with hypochlorhydria.
Note: ‘active’ vitamin B12 or holotranscobalamin is a more sensitive measure of vitamin B12 deficiency – total vitamin B12 is mostly bound to carrier proteins.
What is the management of pernicious anaemia?
Management of patients with pernicious anaemia is lifelong replacement by quarterly treatment with hydroxycobalamin and close monitoring to ensure early diagnosis of any subsequently unmasked iron deficiency. Folate replacement is also often necessary.
What are the complications of pernicious anaemia?
Patients should be advised about possible long-term gastrointestinal consequences, such as gastric cancer and carcinoid.
Vitamin B12 is required for the nervous system so, in vitamin B12 deficiency, always consider:
Peripheral neuropathy
Subacute combined degeneration of the cord
Optic atrophy
Dementia
Vitamin B12 deficiency can be associated with other autoimmune disorders such as hypothyroidism and vitiligo.
Name the causes of microcytic anaemia:
Iron Deficiency Anaemia (IDA): IDA is the most common cause of microcytic anaemia. It results from insufficient iron intake, malabsorption, chronic blood loss (e.g. gastrointestinal bleeding), or increased iron requirements (e.g. pregnancy).
Thalassaemias: Thalassaemias are a group of inherited haemoglobin disorders characterized by reduced production of normal globin chains, leading to microcytosis.
Anaemia of Chronic Disease (ACD): Chronic inflammatory conditions, such as rheumatoid arthritis and chronic infections, can cause ACD, which often presents as microcytic anemia.
Lead Poisoning: Exposure to lead, often through contaminated sources, can lead to microcytic anaemia, particularly in children.
Sideroblastic Anaemia: Sideroblastic anaemias are a heterogeneous group of conditions characterized by defective haem synthesis and the accumulation of iron within the mitochondria of erythroid precursors.
Define thalassaemia:
Thalassaemia is a group of inherited disorders characterised by abnormal haemoglobin production.
Defects in the four genes for α-globin result in α-thalassaemia in the two genes for β-globin result in β-thalassaemia
The absence/abnormality of the α- or β-globin genes leads to quantitative abnormality in globin chain production and an imbalance of the globin-chain synthesis
The clinical severity of the syndrome is proportional to the number of absent or abnormal genes
What is the inheritance pattern of alpha-thalassaemia?
Autosomal recessive inheritance
What is the pathophysiology of alpha thalassaemia?
α-thalassemia describes the spectrum of diseases caused by nonfunctioning copies of the four α-globin genes on chromosome 16.
Symptomatic disease results when two or more copies of the gene are lost
Patients with two defective copies have a mild asymptomatic anaemia – so-called α-thalassaemia trait
Those with three defective copies have symptomatic haemoglobin H disease
Microcytic anaemia (Hb approximately 70 g/l)
Haemolysis
Splenomegaly
Normal survival is to be expected
inheritance of four defective copies (hydrops fetalis) is incompatible with life
The lack of α-globin chains results in excess γ-chains (creating Hb Barts), which are poor carriers of oxygen owing to their high affinity for oxygen
It may affect the fetus in utero - Bart’s hydrops fetalis will generally present on antenatal ultrasound scans with increased amniotic fluid, increased nuchal translucency and other features of foetal fluid overload.
What is the management for alpha-thalassaemia?
Current treatment options for symptomatic thalassaemia include:
Blood transfusions
Stem cell transplantation
A splenectomy is an option, particularly in patients with HbH disease.
Regular folic acid can also be given, especially in those who are pregnant.
What is the inheritance pattern for beta-thalassaemia?
Autosomal recessive inheritance
What is the pathophysiology of beta-thalassaemia?
β-thalassemia describes the spectrum of diseases caused by nonfunctioning copies of the two β-globin genes
The mildest variant of β-thalassaemia is β-thalassaemia minor (also known as thalassaemia trait)
Patients typically have one functioning and one dysfunctional copy of the β-globin gene
The most severe form of β-thalassaemia (known as β-thalassaemia major) is caused by a complete absence of β-globin synthesis (null mutations in both copies of the β-globin gene)
What are the signs and symptoms of beta-thalassaemia?
β-thalassaemia minor - patients are typically asymptomatic
β-thalassaemia major:
Severe symptomatic anaemia at 3–9 months of age
Becomes evident when levels of HbF, which does not contain β-globin, fall and should be replaced by HbA (made up of two α- and two β-globin chains), which is lacking in β-thalassaemia major
Ineffective haematopoiesis results in extramedullary haematopoesis, which results in
Frontal bossing (hair-on-end appearance on Skull XR)
Maxillary overgrowth and prominent frontal/parietal bones (hypertrophy of ineffective marrow) - “Chipmunk facies”
Hepatosplenomegaly
Failure to thrive in infancy
What are the investigations and findings for beta-thalassaemia minor?
Isolated microcytosis (MCV approximately 63–77 fl) and mild anaemia (Hb typically not <100 g/l)
The degree of anaemia is often less severe than would be expected for the degree of microcytosis
Blood film - target cells and basophilic stippling
Increased red cell count
Hb electrophoresis (diagnostic) shows raised HbA2 (>3.5%) – can be lowered by the presence of iron deficiency
Can be confused with iron deficiency – ferritin in β-thalassaemia minor is usually normal or high
What are the investigations and findings for beta-thalassaemia major?
Profound microcytic anaemia; reduced MCV and reduced MCHC
Increased reticulocytes
Blood film – marked anisopoikilocytosis, target cells and nucleated RBCs. Teardrop cells from extramedullary haematopoeisis may also be present
Methyl blue stains – RBC inclusions with precipitated α-globin
High-performance liquid chromatography (HPLC) or electrophoresis (diagnostic) – mainly shows HbF
HbA2 may be normal or mildly elevated
Haemolysis
What is the management for beta-thalassaemia major?
Treatment is with regular blood transfusions
The most important long-term consideration in these patients is to reduce the risk of iron overload toxicity
A condition which primarily affects the heart, joints, liver and endocrine glands
Half of patients with β-thalassaemia major die before the age of 35 years, usually from cardiac failure secondary to iron overload
Iron overload can be prevented with iron chelating agents (eg. desferrioxamine/deferiprone/deferasirox)
Hydroxycarbamide (previously known as hydroxyurea) can also be used to boost HbF levels
Allogeneic bone marrow transplantation (BMT) from a sibling or matched unrelated donor
A potentially curative option
Should be done before significant organ damage has occurred due to iron overload
Risks of transplant include graft rejection, graft vs. host disease, infection and transplant-related mortality
These risks must balanced against the long-term benefits of transfusion independence and ‘cure’
What are the complications of beta-thalassaemia major?
Cardiomyopathy/cardiac arrhythmia/cardiac failure
Older patients are prone to atrial fibrillation
Urgent cardiac investigations (eg. ECG, echocardiogram, cardiac monitoring and chest X-ray) may be needed
Acute sepsis – bacterial sepsis (risk is further increased after splenectomy)
Consider central venous catheter infection (particularly with Klebsiella, Yersinia enterocolitica and encapsulated organisms
Give broad-spectrum antibiotics, and consider high-dependency unit input
Liver cirrhosis, portal hypertension and acute decompensation
Early liver unit input and careful fluid balance are required
Endocrine dysfunction
Hypocalcaemia with tetany due to hypoparathyroidism
Needs cardiac monitoring and IV calcium
Diabetes
Iron overload due to repeated blood transfusions. Presents similarly to Hereditary Haemochromatosis
Death is usually due to heart failure if it goes undiagnosed.
What is the definition of anaemia of chronic disease?
Anaemia of chronic disease is a type of anaemia characterised by low haemoglobin levels, decreased red blood cell production, and altered iron metabolism. It occurs in response to chronic inflammatory or infectious conditions, autoimmune disorders, and malignancies. In ACD, the body’s iron is sequestered in storage sites, leading to impaired availability for erythropoiesis, resulting in mild to moderate anaemia.
What is the epidemiology of anaemia of chronic disease?
ACD is a common form of anaemia and frequently occurs in individuals with chronic illnesses. Its prevalence varies based on the underlying diseases. Conditions such as rheumatoid arthritis, chronic kidney disease, cancer, and chronic infections are frequently associated with ACD. It can affect individuals of all age groups and backgrounds, with a higher prevalence in those with multiple comorbidities.
Inflammatory Conditions: Rheumatoid arthritis, systemic lupus erythematosus, and inflammatory bowel disease.
Chronic Infections: Tuberculosis, HIV, and osteomyelitis.
Malignancies: Leukaemia, lymphoma, and solid tumours.
Chronic Kidney Disease: Impaired erythropoietin production and iron metabolism.
Autoimmune Disorders: Systemic inflammation can lead to ACD.
Chronic Liver Disease: Hepcidin release is altered, impacting iron regulation.
What is the pathophysiology of anaemia of chronic disease?
Chronic disease can trigger the formation of inflammatory cytokines such as IL-1 and IL-6. Raised levels of IL-6 stimulate the release of hepcidin from the liver, which inhibits iron absorption by reducing the activity of ferroportin, an iron export channel located on the basolateral surface of gut enterocytes and the plasma membrane of reticuloendothelial cells (macrophages). This leads to a decrease in haemoglobin production and the onset of anaemia. In ACD you have good iron stores, however the chronic inflammation means you can’t access it. This results in a low TIBC, normal/low serum iron and normal/raised ferritin (falsely raised as it is acute phase reactant). See more in the investigations section.
What is the management of anaemia of chronic disease?
Management of ACD primarily involves treating the underlying condition causing the anaemia. In some cases, erythropoiesis-stimulating agents may be used to stimulate the production of red blood cells. This is because the production of EPO is blunted in ACD.
Iron supplementation is generally not effective due to the body’s impaired ability to absorb iron in this condition.
What is the definition of sideroblastic anaemia?
Sideroblastic anaemia is a group of blood disorders characterized by an impaired ability of the bone marrow to produce normal red blood cells. Instead, it produces ringed sideroblasts - red blood cells with iron-loaded mitochondria.
What causes sideroblastic anaemia?
Sideroblastic anaemia occurs due to ineffective erythropoiesis, leading to increased iron absorption and deposition within the bone marrow and other organs. The condition can be congenital, with X-linked, recessive, or dominant inheritance patterns depending on the gene involved. Acquired causes may be related to drug toxicity or myelodysplastic syndromes. Toxins and drugs associated with sideroblastic anaemia include chronic alcohol abuse, lead poisoning, and Isoniazid use.
What are the investigations for sideroblastic anaemia?
Full blood count: To assess the degree of anaemia and the size of the red blood cells.
Serum ferritin and iron levels: Typically elevated in sideroblastic anaemia.
Blood film examination: To identify sideroblastic inclusions within the red blood cell cytoplasm (see below).
Bone marrow biopsy: Can reveal increased iron deposition and ringed sideroblasts.
