Red blood cells Flashcards
What is anaemia?
Reduction in red cells or their haemoglobin content
What are the aetiologies of anaemia?
- Blood loss
- Increased destruction
- Lack of production
- Defective production
What substances are required for red cell production?
- Metals: Iron, copper, cobalt, manganese
- Vitamins: B12, folic acid, thiamine, Vit.B6, C, E,
- Amino acids
- Hormones: Erythropoietin, GM-CSF, androgens, thyroxine, SCF
Describe red cell breakdown
○ Occurs in the reticuloendothelial system - Macrophages in Spleen, liver, lymph nodes, lungs etc ○ Globin - Amino acids –reutilised ○ Haem - Iron-reutilised - Haem – biliverdin→ bilirubin ○ Bilirubin – bound to albumin in plasma ○ From red cell breakdown -unconjugated
What are the functions of haemaglobin?
○ Gas exchange - O2 to tissues - CO2 to lungs ○ Oxygen dissociation curve - Shifts as a compensatory mechanism - “Bohr effect” □ Acidosis □ Hyperthermia □ Hypercapnia - HbF – higher O2 affinity than HbA
What are most congenital anaemias due to?
An abnormal product that breaks down in the circulation
Describe the genetic defects in red cell mebranes that cause congenital anaemias
□ Skeletal proteins are responsible for maintaining red cell shape and deformability
□ Defects in skeletal proteins can lead to increased cell destruction
□ Mutations in ankyrin >band 3 >spectrin (important)
Describe the genetic defects in metabolic pathways that cause congenital anaemias
□ Glycolysis ® provides energy ® Glucose 6-phosphate dehydrogenase □ Pentose Phosphate shunt ® protects from oxidative damage ® Pyruvate kinase
Give examples of congenital anaemia membrane disorders
□ Hereditary spherocytosis
□ Hereditary Elliptocytosis (milder)
□ Hereditary Pyropoikilocytosis (severe but rare)
□ South East Asian Ovalocytosis
What causes hereditary spherocytosis?
□ Most common forms autosomal dominant defects in 5 different structural proteins described ® Ankyrin ® Alpha Spectrin ® Beta Spectrin ® Band 3 ® Protein 4.2
What is hereditary spherocytosis?
□ Red cells are spherical
□ Removed from circulation by the RE system (extravascular)
What is the clinical presentation of hereditory spherocytosis?
□ Variable ® Anaemia ® Jaundice (neonatal) ® Splenomegaly ® Pigment gallstones
What is the treratment for hereditory spherocytosis?
® Folic acid (increased requirements)
® Transfusion (if you are ill and haemolysis is increased)
® Splenectomy (If you have a very severe condition)
Give examples of congenital anaemias that are due to metabolic disorders
- G6PD deficiency
- Pyruvate kinase deficiency
What does glucose 6 phosphate dehydrogenase (G6PD) do?
- Protects red cell proteins (Haemoglobin) from oxidative damage
□ Produces NADPH - Vital for reduction of glutathione
□ Reduced glutathione scavenges and detoxifies reactive oxygen species
what is G6PD deficiency?
□ Commonest disease causing enzymopathy in the world
® Many genetic variants
□ Cells vulnerable to oxidative damage
□ Confers protection against malaria ® Most common in malarial areas
□ X Linked
® Affects males
® Female carriers
What is the clinical presentation of G6PD deficiency?
□ Variable ® Neonatal Jaundice ® Drug, broad bean or infection precipitated jaundice and anaemia ® Intravascular haemolysis ® Haemoglobinuria ® Splenomegaly ® Pigment Gallstones
What is pyruvate kinase deficiency?
® Reduced ATP ® Increased 2,3-DPG ® Cells rigid ® Variable severity ◊ Anaemia ◊ Jaundice ◊ Gallstones
What are haemoglobinopathies?
- Inherited abnormalities of haemoglobin synthesis
- Reduced or absent globin chain production
□ Thalassaemia (alpha α, Beta β, delta δ, gamma γ) - Mutations leading to structurally abnormal globin chain
□ HbS (Sickle cell ), HbC, HbD, HbE, HbO Arab….. - Autosomal recessive inheritance
What is sickle cell disease?
□ Sickle haemoglobin (HbS) composed of haem molecule and:
® 2 α chains
® 2 β (sickle) chains
□ Once a red blood cell gets rid of its oxygen it becomes sickle shaped and the never turns back
What are the concequences of HbS polymerisation?
® Red cell injury, cation loss, dehydration results in haemolysis which results in:
◊ Endothelial activation
◊ Promotion of inflammation
◊ Coagulation activation
◊ Dysregulation of vasomotor tone by vasodilator ◊ Mediators (NO)
® All results in vaso-occlusion
What are the complications of sickle cell disease?
® Acute chest syndrome- vasoocclusive tissue damage
® Stroke- vasoocclusive tissue damage and cerebral vasculopathy
® Pain episodes- vasoocclusive tissue damage
® Lung disease- unknown
What is the presentation of sickle cell disease?
- Retinopathy
- Cardiomegaly -> congestive heart failure
- Cholelithiasis
- Renal infarcts -> haematuria
- Bone marrow hyperplasia
- Aseptic bone necrosis -> osteomyelitis
- Cerebral infarcts stroke -> mental retardation
- Pulmonary infarcts -> pneumonia
- Splenomegaly -> Splenic atrophy (autosplenectomy)
- Infarcts of the extremities
- Vaso occlusion
- Ulcer
- Painful Vaso-occlusive crises ◊ Bone
- Chest Crisis
- Stroke
- Increased infection risk
◊ Hyposplenism - Chronic haemolytic anaemia ◊ Gallstones
◊ Aplastic crisis - Sequestration crises (blood can go in but cannot get out resulting in pooling)
◊ Spleen
◊ Liver - Painful crisis
What are the signs and symptoms of chest crisis?
- Chest Pain
- Fever
- Worsening hypoxia
- Infiltrates on CXRay
What is the management of chest crisis?
- Respiratory Support
- Antibiotics
- IV Fluids
- Analgesia
- Transfusion – top up or exchange target HbS <30%
How are incidences of chest crisis reduced?
Incentive spirometry shown to reduce incidence
What is the management for painful crisis?
◊ Severe pain - often requires opiates - Analgesia should be given within 30 mins of presentation - Effective analgesia by 1hour - Avoid pethidine ◊ Hydration ◊ Oxygen ◊ Consider antibiotics
What is the life ecpectancy for people with sickle cell disease?
◊ US and UK cohorts survival to 18 years increased ◊ 85% in 2004 and 96% 2010
What is the management of actue events of sickle cell disease?
◊ Hydration ◊ Oxygenation ◊ Prompt treatment of infection ◊ Analgesia - Opiates - NSAIDs
What is the management of sickle cell disease?
® Lifelong prophylaxis ◊ Vaccination ◊ Penicillin (and malarial) prophylaxis ◊ Folic acid ® Blood transfusion ◊ Episodic and chronic ◊ Alloimmunisation ◊ Iron overload ® Disease modifying drugs ◊ Hydroxycarbamide ® Bone marrow transplantation ® Gene therapy
What is thalassaemia?
□ Reduced or absent globin chain production ® In alpha chain (alpha thalassaemia) ® In beta chain (beta thalassaemia)
What is homozygous alpha zero thalassaemia?
- (α0/α0 )
◊ No alpha chains
◊ Hydrops Fetalis –incompatible with life
What is beta thalassaemia (homozygous beta thalassaemia)
◊ No beta chains ◊ Transfusion dependent anaemia - Present at 3-6 months of age - Expansion of ineffective bone marrow - Bony deformities - Splenomegaly - Growth retardation - Life expectancy untreated or with irregular transfusions <10 years
What is the treament for beta thalassaemia
- Chronic transfusion support - 4-6 weekly
- Normal growth and development
- BUT - Iron overloading (must do chelation)
~ s/c desferrioxamine infusions (desferal)
~ Oral deferasirox (exjade)
~ Good adherence to chelation – life expectancy >40 years
~ Requires regular monitoring - Death in 2nd or 3rd decades due to heart/liver/endocrine failure if iron loading untreated
- Bone marrow transplantation- curative
What causes non-transfusion dependent thalassaemia?
A range of genotypes
What is thalassaemia minor?
◊ “Trait” or carrier state ◊ Hypochromic microcytic red cell indices (small red cells)
What are some rare defects in haem synthesis?
□ Defects in mitochondrial steps of haem synthesis result in sideroblastic anaemia
® ALA synthase mutations
® Hereditary (X-Linked)
® Acquired - Myelodysplasia
□ Defects in cytoplasmic steps result in porphyrias
