Red Cells 1 & 2 Flashcards
What is anaemia?
Reduction in red cells or their haemoglobin content
Which substances are required for RBC production in the bone marrow?
- Metals: iron, copper, cobalt and manganese
- Vitamins: B12, folic acid, thiamine, B6, C and E
- Amino acids
- Hormones: erythropoietin, GM-CSF, androgens and thyroxine
Describe the process of red cell breakdown
- Occurs in the reticuloendothelial system (macrophages in the spleen, liver, lymph nodes, lungs etc.)
- Normal lifespan of RBCs is 120 days
- Globin (amino acids) is reutilised
- Haem: iron is recycled into haemoglobin and haem is brokendown into bilirubin
- The bilirubin is bound to albumin in the plasma
Describe the aetiology of congenital anaemias
- Genetic defects in the cell membrane, enzymes and in the haemoglobin
- Most reduce red cell survival and result in haemolysis
Describe the pathophysiology of Hereditary Spherocytosis
- Autosomal dominant
- Defects in 5 different structural proteins: ankyrin, alpha spectrin, beta spectrin, band 3 and protein 4.2
- Red cells are spherical
- Removed from circulation by the RE system
What is the clinical presentation of hereditary spherocytosis?
- Anaemia
- Jaundice (neonatal)
- Splenomegaly
- Pigment gallstones
- Less likely to be iron and B12 deficient
What are the treatment options for hereditary spherocytosis?
- Folic acid
- Transfusion
- Splenectomy
List the rare membrane disorders
- Hereditary elliptocytosis
- Hereditary pyropoikilocytosis
- South East Asian ovalocytosis
Name the two red cell enzymes that are important in red cell metabolism disorders
- 2,3 DPG (glycolysis)
- Glucose 6-phosphate dehydrogenase (pentose phosphate shunt - protects from oxidative damage)
What is the function of G6P dehydrogenase?
- Protects the red cell from oxidative damage
- Produces NADPH - vital for reduction of glutathione
- Reduced glutathione scavenges and detoxifies reactive oxygen species
Describe the aetiology and pathophysiology of G6PD deficiency
- Commonest disease causing enzymopathy: has many genetic variants
- Cells vulnerable to oxidative damage
- Confers protection against malaria
- X Linked: affects males, females are carriers
- Blister cells and bite cells under the microscope
How does G6PD deficiency present?
- Variable degrees of anaemia
- Neonatal jaundice
- Splenomegaly
- Pigment gallstones
- Usually a precipitant: drugs, broad beans and infection
- Intravascular haemolysis and haemoglobinuria
What triggers can cause haemolysis in G6PD deficiency?
- Infection
- Acute illness e.g. DKA
- Broad beans
- Drugs: antimalarials, antibacterials, analgesics (aspirin), antihelminthics, vitamin K analogues, probenecid and methylene blue
Describe the pathophysiology of pyruvate kinase deficiency
- Reduced ATP
- Increased 2,3-DPG
- Rigid cells
What is the presentation of pyruvate kinase deficiency?
-Variable
-Anaemia
-Jaundice
Gallstones
Describe the structure of normal adult haemoglobin
- Haem molecule
- 2 alpha chains (+ 2 alpha genes)
- 2 beta chains (+ 2 beta genes)
What are haemoglobinopathies and what causes them?
- Inherited abnormalities of haemoglobin synthesis
- Reduced or absent globin chain production: thalassaemia
- Mutations leading to structurally abnormal globin chain e.g. sickle cell
What is the inheritance of haemoglobinopathies?
Autosomal recessive
Describe the pathophysiology of sickle cell disease
- Haemoglobin still has all the components but the beta chains have a point mutation
- When the haemoglobin is exposed to low oxygen tension, the chain polymerises and this is what causes the sickle shape
- Once sickling happens it is irreversible
- Oxygen transport is unaffected
What are the consequences of sickle cell disease?
- Red cell injury, cation loss, dehydration
- HAEMOLYSIS
- Endothelial activation
- Promotion of inflammation
- Coagulation activation
- Dysregulation of vasomotor tone
- VASO-OCCLUSION
- Acute chest syndrome, stroke, pain episodes etc.
How does sickle cell disease present?
- Painful vaso-occlusive crisis
- Chest crisis
- Stroke
- Increased infection risk: hyposplenism
- Chronic haemolytic anaemia: gallstones and aplastic crisis
- Sequestration crises: spleen and liver
How can sickle cell be managed?
- Acute events/Painful crisis: analgesia, hydration, oxygen and consider antibiotics +/- blood transfusion
- Life long prophylaxis: vaccination, penicillin, malarial prophylaxis and folic acid
- Blood transfusion
- Disease modifying drugs: hydroxycarbamide
- Bone marrow transplantation
- Gene therapy
What are thalassaemias?
Reduced or absent globin chain production (alpha and beta most important)
What is an A+ mutation?
Two alpha chains from one parent but only one from the other
What is an A0 mutation?
Two alpha chains from one parent and none from the other
What happens if two parents have A0 mutations and pass them on to the foetus?
- This is not compatible with life
- The foetus cannot produce the alpha chains needed for foetal haemoglobin
What is the effect of a beta thalassaemia major?
- No beta chains
- Transfusion dependent anaemia
What is the effect of a thalassaemia minor?
- Trait or carrier state
- Hypochromic microcytic red cell indices
Describe the clinical presentation of beta thalassaemia major
- Severe anaemia
- Present at 3-6 months of age
- Expansion of ineffective bone marrow
- Bony deformities
- Splenomegaly
- Growth retardation
How can beta thalassaemia major be treated?
- Chronic transfusion support
- Need to correct iron overloading: iron chelation
- Iron Chelation therapy: S/C desferrioxamine or oral deferasirox
- Regular monitoring
- Ferritin and MRI scans
- Bone marrow transplation - curative
List the causes of sideroblastic anaemia that are a result of defects in the mitochondrial steps of haem synthesis
- ALA synthase mutations
- Hereditary
- Acquired
What causes porphyrias (build up of natural chemicals that produce porphyrins?
Defects in the cytoplasmic steps of haem synthesis
Which factors effect the normal range of haemoglobin?
- Age
- Sex
- Ethnic origin
- Time of day (cortisol level)
- Time taken to analysis (cells can swell)
What are the normal ranges for haemoglobin?
- Male 12-70 (140-180)
- Male > 70 (116-156)
- Female 12-70 (120-160)
- Female > 70 (108-143)
What are the clinical features of anaemia?
- Tiredness/pallor
- Breathlessness
- Swelling of ankles
- Dizziness
- Chest pain
- Evidence of bleeding: menorrhagia, dyspepsia and PR bleeding
- Symptoms of malabsorption: diarrhoea and weight loss
- Jaundice
- Splenomegaly/lymphadenopathy
What are the different pathophysiologies of anaemia?
- Bone marrow: cellularity, stroma and nutrients
- Red cell: membrane, haemoglobin and enzymes
- Destruction: blood loss, haemolysis and hypersplenism
Which red cell indices can give a morphological description of the anaemia?
- Mean cell haemoglobin (MCH)
- Mean cell volume (MCV)
In what three ways can the morphology of the anaemia be described?
- Hypochromic and microcytic
- Normochromic and normocytic
- Macrocytic
If an anaemia is hypochromic and microcytic which further test would you do?
Serum ferritin
If an anaemia is normochromic and normocytic which further test would you do?
Reticulocyte count (helps differentiate whether the bone marrow is working or not)
If an anaemia is macrocytic which further tests would you do?
- B12/folate
- Bone marrow
What are the causes of hypochromic microcytic anaemia?
- Iron deficiency (low ferritin)
- Thalassaemia, secondary anaemia and sideroblastic anaemia (normal or increased ferritin)
Describe the process of iron metabolism
- Absorbed iron is bound to mucosal ferritin and sloughed off or transported across the basement membrane by ferroportin
- It is then bound to transferrin in the plasma
- Stored as ferritin (mainly in the liver)
What is the role of hepcidin in iron metabolism?
- It is synthesised in hepatocytes in response to increased iron levels and inflammation
- Blocks ferroportin so reduces intestinal iron absorption and metabolism from reticuloendothelial cells
What features would suggest a diagnosis of iron deficiency anaemia?
- Dyspepsia/GI bleeding
- Other bleeding e.g. menorrhagia
- Diet
- Increased requirement e.g. pregnancy
- Signs of iron deficiency
- Abdo and rectal exam: atrophic tongue, koilonychia, angular cheilitis
What are the causes of iron deficiency anaemia?
- GI blood loss
- Menorrhagia
- Malabsorption: gastrectomy and coeliac disease
How can iron deficiency be managed?
- Correct the deficiency: oral iron (IV if intolerant to oral)
- Correct the cause: diet, ulcer therapy, gynae interventions, surgery etc.
What are the causes of normochromic normocytic anemia?
- Acute blood loss and haemolysis (increased reticulocyte count)
- Secondary anaemia, hypoplasia and marrow infiltration (normal or low reticulocyte count)
What is secondary anaemia and how is it caused?
- Anaemia of chronic disease
- Defective iron utilisation: increased hepcidin in inflammation and ferritin is often elevated
- Underlying disease: infection , inflammation or malignancy
Describe the process of haemolytic anaemia
- Accelerated red cell destruction
- Compensation by bone marrow (increased reticulocytes)
- Haemoglobin level: balance between red cell production and destruction
What are the causes of haemolytic anaemia?
- Congenital: hereditary spherocytosis, G6PD and haemoglobinopathies etc.
- Acquired: auto-immune haemolytic anaemia
- Mechanical e.g artificial valve
- Severe infection/DIC
- PET/HUS/TTP
Describe how a direct antiglobulin test works
- Detects antibody or complement on the red cell membrane
- Reagent either contains anti-human IgG or anti-complement
- Reagent binds to Ab or complement on red cell surface and cause agglutination in vitro
- Implies an immune basis for haemolysis
In an immune haemolysis what is are the potential causes if the autoantibody is warm?
- Auto-immune
- Drugs
- CLL
In an immune haemolysis what is are the potential causes if the autoantibody is cold?
- CHAD
- Infections
- Lymphoma
In an immune haemolysis what is are the potential cause if it is an alloantibody?
Transfusion reaction
What is likely to be seen under the microscope in an immune haemolysis?
- Spherocytes on the film
- Agglutination in cold AIHA
What is likely to be seen under the microscope in an intravascular haemolysis?
Red cell fragments - schistocytes
What investigations should be done if a patient is suspected to have haemolytic anaemia?
- FBC, reticulocyte count and blood film
- Serum bilirubin and LDH
- Serum haptoglobin
What should be done to determine the cause of the haemolytic anaemia?
- History and examination
- Blood film
- Direct antiglobulin test
- Urine for haemosiderin/urobilinogen
What is the management of haemolytic anaemia?
- Support marrow function: folic acid
- Correct cause: immunosuppression if autoimmune, remove site of red cell destruction (splenectomy)
- Treat sepsis, leaky prosthetic valve, malignancy etc.
- Consider transfusion
What are the causes of macrocytic anaemia?
- B12 and folate deficiency (megaloblastic)
- Myelodysplasia, marrow infiltration and drugs (non-megaloblastic)
Describe how vitamin B12 is absorbed?
- It binds to intrinsic factor in the stomach
- B12-IF complex attaches to specific IF receptors in distal ileum
- B12 is bound to transcobalamin II in the portal circulation for transport to bone marrow and other tissues
How does B12/folate deficiency present?
- Anaemia
- Neurological symptoms (subacute degeneration of the cord in B12 deficiency)
What are the causes of B12 deficiency?
- Pernicious anaemia
- Gastric/ilial disease
What are the causes of folate deficiency?
- Dietary
- Increased requirements (haemolysis)
- GI pathology (e.g. coeliac disease)
What is pernicious anaemia?
- Commonest cause of B12 deficiency
- Antibodies against intrinsic factor and gastric parietal cells
- Malabsorption of dietary B12
- Symptoms take 1-2 years to develop
How can B12 deficiency be treated?
B12 IM injection (loading dose + 3 monthly maintenance)
How can folate deficiency be treated?
- Oral folate replacement
- Ensure B12 is normal if there are neuropathic symptoms
What are the other causes of macrocytosis?
- Alcohol
- Drugs: methotrexate, antiretrovirals and hydroxycarbamide
- Disorder liver function
- Hypothyroidism
- Myelodysplasia
