Red Cells Flashcards
What’s more common; congenital or acquired anaemias?
Acquired
In broad terms, what are the causes of anaemia?
Blood loss
Increased destruction
Lack of production
Defective production
What substances are required for red cell production?
Metals- iron (also copper, cobalt, manganese)
Vitamins- B12, folic acid (also thiamine, B6, C and E)
Amino acids
Hormones- Erythropoietin (also GM-CSF, androgens and thyroxine)
How long do red cells last for and where are they broken down?
Red cells last for ~120 days before they are broken down in the reticuloendothelial system (macrophages mainly in spleen but also liver, lymph nodes, lung etc)
What are each of the components of red cells broken down in to?
- Globin- Amino acids –reutilised
- Haem- Iron-recycled into haemoglobin
- Bilirubin – bound to albumin in plasma
- From red cell breakdown -unconjugated
How are red cells structured?
Biconcave
Have a membrane, enzymes and haemoglobin
What kind of inheritance is displayed by congenital anaemias?
Most congenital anaemias are autosomal recessive
What is the clinical presentation of hereditary spherocytosis?
Varies but includes: Anaemia Jaundice (neonatal) Splenomegaly Pigment gallstones
What is the management of hereditary spherocytosis?
Folic acid supplements
Transfusion
Splenectomy if anaemia very severe (main sites of red cell destruction include spleen which is least vital for life so easiest to remove and reduce red cell destruction)
What is wrong with the red cells in hereditary spherocytosis?
Membrane disorder resulting in spherical red cells
What are the two main clinically significant enzyme pathways in red cells and what does each do?
Glycolysis- provides energy
Pentose phosphate shunt pathway- protects cells from oxidative damage
What is the function of the enzyme G6PD?
To protect red cells from oxidative damage
Where is G6PD deficiency most common and why?
In areas where malaria is/has been endemic as it confers protection against malaria
Pathologically, what happens in G6PD deficiency?
Blister cells and bite cells form, fragment in the circulation and die as they are not able to protect themselves from oxidative damage.
What is the clinical presentation of G6PD deficiency?
Variable degrees of anaemia
Neonatal Jaundice
Splenomegaly
Pigment Gallstones
What is the function of haemoglobin?
The function of haemoglobin is gas exchange, ensuring O2 is delivered to tissues and CO2 to the lungs
What does the oxygen dissociation curve shift in response to and why?
Acidosis
Hyperthermia
Hypercapnia
Does so so that more oxygen can be delivered to tissues when required
How is adult haemoglobin inherited?
Adult haemoglobin is composed of alpha and beta chains, which are coded for by alpha and beta genes. Alpha genes are on chromosome 16 and two genes are inherited from each of your parents. The beta genes are on chromosome 11 and only one gene is inherited from each parent
How does fetal haemoglobin recede with age?
With age, gamma chains are switched off and beta waves switched on to form more adult haemoglobin
Broadly speaking, what are the categories of haemoglobinopathies?
Reduced or absent globin chain production (thalassemia- named based on which globin chain affected (biggest groups are alpha and beta thalassemia))
Mutations leading to structurally abnormal haemoglobin chains (HbS- sickle cell)
In what populations are haemoglobinopathies most common?
From ethnic groups where malaria is/has been endemic due to protective function of carrier state. Most common in West Africa but can be present in any ethnic group
Describe the pathophysiology of sickle cell disease
Sickle cell disease is associated with a mutation in the beta chains, resulting in low oxygen tension in the affected haemoglobins (HbS), which crystallise inside the red cells and distort their shape. Sickling is irreversible but not all red cells will be affected
What are the consequences of haemolysis?
Endothelial activation
Promotion of inflammation
Coagulation activation
Dysregulation of vasomotor tone by vasodilator mediators (NO)
All contribute to vaso-occlusion
How does Sickle cell disease present?
Extremely varied:
Stroke
Chest crisis
Painful vaso-occlusive crisis (most often caused by sickling in bones)
Increased infection risk due to hyposplenism
Chronic haemolytic anaemia (gallstones, aplastic crisis)
Seqeustration crisis (red cells sticking in spleen or liver and rapid enlarging occurs)
Most common = bone pain
What are the features of a sickle cell chest crisis?
Worsening hypoxia Fever Chest pain Infiltration on CXR Close observation and transfusion required
How is a sickle cell painful crisis managed?
Analgesia
Hydration
Oxygen
Consider antibiotics
What treatment is given for sickle cell disease?
Life long prophylaxis: • Vaccination • Penicillin and malarial prophylaxis • Folic acid Disease modifying treatments: • Hydroxycarbamide • Bone marrow transplantation
What is the pathological cause of thalassemia?
Thalassemia is associated with reduced or absent globin chain production due to mutations or deletions
What is the difference between a alpha+ and alpha0 mutation?
Alpha+ is when one alpha gene is abnormal and one is normal from one parent.
Alpha0 is when no alpha chains are inherited from one parent. If both parents are Alpha0 this is not compatible with life.
What are the characteristics of homozygous alpha zero thalassaemia?
No alpha chains
Hydrops Fetalis –incompatible with life
What are the characteristics of beta thalassaemia major/homozygous beta thalassaemia?
No beta chains
Transfusion dependent anaemia
What are the characteristics of thalassemia minor?
Carrier state
Hypochromic microcytic red cell indices (small, pale cells)
Asymptomatic
How does beta thalassemia major present?
Presents by 3-6 months of age Severe anaemia Expansion of ineffective bone marrow Bony deformities Splenomegaly Growth retardation
How is beta thalassemia major treated?
Chronic transfusion every 4-6 weeks
Iron chelation
Bone marrow transplant curative
Why is iron chelation given in beta thalassemia major? How is it given?
To avoid iron overloading, which would cause death in 2nd or 3rd decades due to heart/liver/endocrine failure
IV desferrioxamine
Oral deferasirox
How do normal ranges for haemoglobin vary with age and sex?
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
What are useful red cell indices in anaemia and why are they useful?
Mean cell haemoglobin (MCH)
Mean cell volume (MCV)
Can give a morphological description of anaemia and a clue as to the cause
How can red cells be described using MCH and MCV?
Hypochromic microcytic
Normochromic normocytic
Macrocytic
What second line investigations should be done in hypochromic microcytic anaemia?
Serum ferritin as most common cause is iron deficiency. If ferritin is normal or raised then query thalassemia. Secondary anaemia can also cause hypochromic microcytic anaemia
What second line investigations should be done in normochromic normocytic anaemia?
Blood film and reticulocyte count (normal range 50-100), reticulocyte count can differentiate whether the marrow is working or not
What second line investigations should be done in macrocytic anaemia?
B12/folate and bone marrow (commonest cause B12/folate deficiency, if levels normal then look at bone marrow)
What is the function of hepcidin?
Regulates iron transportation through inhibition of ferroportin so that excess iron is not absorbed. Hepcidin is also synthesised in response to inflammation and so anaemia can occur in chronic disease.
What are the causes of iron deficiency anaemia?
GI bleeding Other bleeding, eg menorrhagia Diet (NB children and elderly) Increased requirement – pregnancy Malabsorption (gastrectomy, coeliac)
What are the clinical signs of iron deficiency anaemia?
Koilonychia
Atrophic tongue
Angular cheilitis (stomatitis?)
How is iron deficiency managed?
Managed with oral iron, although IV iron can be given if the patient is intolerant of oral methods. Blood transfusion is rarely indicated but may be required if the patient is bleeding. The cause should also be treated
When should a reticulocyte count be checked in anaemia?
A reticulocyte count should be checked if normochromic normocytic anaemia is present. If the reticulocyte count is increased then it is most likely acute blood loss or haemolysis. If the count is decreased or normal it is most likely secondary anaemia (by far most common), hypoplasia or marrow infiltration
What are the features of haemolytic anaemia?
Accelerated red cell breakdown (decreased Hb)
Increased reticulocytes due to compensation from the bone marrow
What are the causes of acquired haemolytic anaemia?
• Auto-immune haemolytic anaemia (extravascular)
• Intravascular (usually only in severely ill):
– Mechanical eg.artificial valve
– Severe infection/DIC
– PET/HUS/TTP
What is a direct antiglobulin test and what does it show?
Direct antiglobulin test = Coombs test.
Detects antibody or complement on red cell membrane.
Positive test indicates an immune basis for haemolysis, which is the extravascular causes. Intravascular causes are non-immune
What are alloantibodies?
Antibodies that the body has produced against transfused blood not their own.
What is present on blood film with immune haemolysis?
Spherocytes and agglutination
What is present on blood film with intravascular haemolysis?
Schistocytes, which are fragments of red cells
What investigations should be checked if the patient is haemolysing and how should each be affected?
FBC- anaemic Reticulocyte count- high Blood film Serum bilirubin- high Lactate dehydrogenase- high Serum haptoglobin- low
How should causes of haemolysis be checked?
History and examination
Blood film
Direct Antiglobulin Test (Coombs’ test)
Urine for haemosiderin/urobilinogen
How is haemolytic anaemia managed?
Support marrow function with folic acid
Correct cause:
– Immunosuppression if autoimmune (steroids)
– Remove site of red cell destruction (splenectomy)
– Treat sepsis, leaky prosthetic valve, malignancy etc. if intravascular
Consider transfusion
Which blood tests are known as the haematinics when grouped?
B12
Folate
Ferritin
What tests should be done in macrocytic anaemia and how are they interpreted?
B12/folate assay should be done and can be supplemented with a blood film or bone marrow check to see if the cells are megaloblastic or non-megaloblastic. If they are megaloblastic then B12 or folate deficiency are the likely causes. In non-megaloblastic it is probably due to myelodysplasia, marrow infiltration or drugs
What are the characteristics of folate/B12 deficiency?
Anaemia Neurological symptoms (subacute combined degeneration of the cord in B12 deficiency)
What are the causes of B12 deficiency?
Pernicious anaemia
Gastric/ileal disease
What are the causes of folate deficiency?
Dietary
Increased requirements (haemolysis)
GI pathology
What is pernicious anaemia?
Commonest cause of B12 deficinecy in the west
Autoimmune disease with antibodies against intrinsic factor (major) and gastric parietal cells (less specific).
How is B12/folate replacement given?
B12- B12 IM injection
Folate- oral folate replacement, ensure B12 normal if neuropathoc symptoms
Can give both if in doubt until sure cause is found
What are the other causes of macrocytosis other than anaemia?
Alcohol Drugs (Methotrexate, Antiretrovirals, hydroxycarbamide) Disordered liver function Hypothyroidism Myelodysplasia
