Flashcards in Haem: Haemolytic Anaemia Deck (56)
What is the normal lifespan of a RBC?
How may haemolysis be classified?
Intravascular - within circulation
Extravascular - removal/destruction by reticuloendothelial system
Inherited or Acquired
What are causes of extravascular haemolytic anaemias?
What are causes of intravascular haemolytic anaemia?
Mismatched blood transfusion (ABO)
Cold antibody haemolytic syndromes
Microangiopathic haemolytic anaemia e.g. haemolytic uraemic syndrome, thrombotic thrombocytopenic purpura
Paroxysmal nocturnal haemoglobinuria
What is the most common cause of intravascular haemolytic anaemia globally?
Malaria - plasmodium falciparum malaria (in severe forms depicted as black water fever).
What cause of intravascular haemolysis is linked to malaria?
G6PD deficiency - this is one of the most common genetic disorders worldwide
Describe the pathology of autoimmune haemolytic anaemia.
Antibodies fix and bind to RBCs. These are usually cold antibodies, particularly IgM.
Give an example of a drug that causes HA.
Describe the pathology of MAHA.
MAHA is characterised by damage to the endothelium and in turn to RBCs as they traverse the endothelium. MAHA includes HUS (common cause of acute renal failure in childhood) and TTP.
Describe the pathology of paroxysmal nocturnal haemoglobinuria.
PNH is due to an acquired genetic defect in synthesis of glycosylphosphatidylinositol anchor which is one of the GPI anchors. The GPI anchor is required for one cells to attach proteins to their surface.
How may hereditary haemolytic anaemias be categorized?
Disorders of the:
- Membrane - cytoskeletal proteins, cation permeability
- Red cell metabolism
- Haemoglobin - thalassaemia, sickle cell syndromes, unstable Hb variants
What is the most common cause of hereditary haemolytic anaemia?
Defects of haemoglobin.
RBCs have restricted metabolism that relies particularly on _______ ______ to meet energy needs by generating ____ . Defects in key metabolic pathways in RBCs, particularly _______ , may result in haemolysis.
RBCs have restricted metabolism that relies particularly on anaerobic glycolysis to meet energy needs by generating ATP. Defects in key metabolic pathways in RBCs, particularly ATP, may result in haemolysis.
Give examples of HHA due to Hb defects.
Quantitative defects - Thalassaemia
Qualitative defects - Sickle Cell
Structural defects - unstable Hb variants (rare)
What type of inheritance does hereditary spherocytosis have?
What are the main consequences of haemolytic anaemias?
Erythroid hyperplasia with increased rate of RBC production and circulating reticulocytes
Increased folate deman
Susceptibility to effect of parvovirus B19
Propensity to gallstones (cholelithiasis)
Increased risk of:
What may parvovirus B19 infection in hereditary spherocytosis result in?
What stain is used to stain for Iron?
Perl stain/Prussian blue stain
What may further increase risk of cholelithiasis in chronic haemolytic anaemia?
Coinheritance of Gilbert syndrome.
What is Gilbert's syndrome?
A benign variant where bilirubin conjugation is impaired resulting in higher level of unconjugated bilirubin and increased propensity to perform gall stones in the context of chronic haemolytic anaemia.
Gilbert syndrome is prevalent so co-existance with HA is quite common. It is due to a genetic morphism with a change to the promoter region. Instead of normal 6TA repeats in TATA box, which is an important regulatory element in the gene promoter, there is an extra dinucleotide on each allele with the genotype TA7/TA7 which is associated with reduction in transcription of UGT 1A1 gene, thus reduction of enzyme at protein level in the liver and less efficient bilirubin conjugation.
What are the clinical features of HA?
-Jaundice - due to increased generation of bilirubin
-Splenomegaly - spleen has important role in destruction of RBCs in patients with extravascular haemolysis or where there is extramedullary haemopoeisis with enlargement of the spleen and sometimes liver.
-Pigmenturia - refers to the appearance of abnormal urine colour.
What are the laboratory features of HA?
-Anaemia - variable feature
-Increased reticulocytes - almost always present except when there is parvovirus infection
-Polychromasia - cells which take up eosinophilic and basophilic dye and have a bluish/purpleish appearance. These correspond to reticulocytes which can only be seen on blood film using a special stain.
-Increased LDH - if there is increased RBC destruction, RBC enzymes will be released into the plasma. One of these is LDH glycolytic enzyme. This is a sensitive marker of intravascular haemolysis
-Reduced/absent haptoglobins - when there is intravascular haemolysis. Haptoglobins bind to Hb and the binding capacity is exceeded with haemolysis
-Haemosiderinuria - requires a special stain for iron such as Prussian blue stain of urine. Detects iron that is excreted from tubular cells. Implies indirectly the presence of intravascular haemolysis.
Absence or defects in which membrane proteins may lead to haemolytic anaemia?
Band 3, Ankryin, Band 4.2. GPI anchor.
Lipid bilayer rests upon a cytoskeletal scaffold made of spectrin. There are a number of proteins that link the lipid bilayer to the spectrin cytoskeleton. These include Band 3 (major anion transporter in RBCs and in kidneys). A number of other proteins, absence of which can produce haemolytic anaemia including Ankyrin and band 4.2.
What is the cause of paroxysmal nocturnal haemoglobinuria?
GPI anchor deficiency.
GPI anchor deficiency causes paroxysmal nocturnal haemoglobinuria. This is produced by biosynthesis, a highly conserved mechanism for attachment of a variety of biomolecules to the cell surface. This includes complement regulatory proteins – these protect the RBCs from complement damage. As a result of GPI anchor deficiency, the RBCs are destroyed by complement leading to intravascular haemolysis.
What 2 main HAs are due to red cell membrane disorders?
What protein defects lead to hereditary spherocytosis?
Proteins involved in vertical interactions - these proteins link the lipid bilayer and cytoskeleton
What protein defects lead to hereditary elliptocytosis?
Proteins involved in horizontal interactions.
What is the most common genetic defect of the RBC cytoskeleton?
Describe the inheritance pattern of hereditary spherocytosis.
Family history in 75% - typically autosomal dominant
25% recessive or de novo mutation