Haemolytic anaemia and Haemoglobinopathies Flashcards
What is haemolytic anaemia?
Anaemia due to shortened RBC lifespan.
How does the bone marrow respond to drop in RBC lifespan?
Usually bone marrow responds and increases erythropoiesis
Red cell production can increase 6 - 8 times
At what RBC lifespan does anaemia occur?
<15 days
What causes haemolytic anaemia?
RBC survival <15 days
Haematinic deficiency (esp. folate)
Bone marrow disease
What happens if haemolysis occurs in the blood vessels?
Hemoglobinemia
Methemalbuminemia
hemosiderinuna
Haemoglobinuria (It mixes with plasma and then gets excreted in urine)
What are signs of RBC destruction?
Increased bilirubin (haem breakdown)
Increased LDH (lactate dehydrogenase)
Reduced haptoglobins (Hb-haptoglobin complex)
What blood film evidence indicates red blood cell damage in haemolytic anaemia?
Spherocytes (no area of central pallor)
Fragmented red blood cells (schistocytes)
What blood film evidence indicates increased RBC production increase in haemolytic anaemia?
Increased reticulocyte production (polychromasia) [not ready yet]
Nucleated RBCs (they should be in bone marrow but are released early)
What are the clinical features of haemolytic anaemia?
Anaemia
Jaundice: bilirubin in plasma
Pigment gallstones may occur
Splenomegaly
Ankle ulcers: sickle cell anaemia
Expanded bone marrow
Aplastic crises: parvovirus
Megaloblastic anaemia
What are pigment gallstones caused by?
bilirubin is concentrated causing gallstones
What are ankle ulcers caused by?
Sickle cell anaemia
What is expanded bone marrow?
Erythroid hyperactivity causes increases in BM size (especially in young people)
What is aplastic crises? What is it caused by?
Caused by switching off of erythroid activity in the bone marrow. Can be caused by parvovirus infection
Why does haemolytic anaemia show up as megaloblastic anaemia as well?
It causes overactivity of folate use and that results in folate deficiency
What causes hereditary haemolytic anaemia?
Membrane defect: hereditary spherocytosis
Enzyme defect: G6PD (Glucose 6 phosphate dehydrogenase) deficiency
Globin chain defect: haemoglobiniopathies
What causes acquired haemolytic anaemia?
Immune haemolytic anaemia (most common acquired haemolytic anaemia)
Fragmentation haemolysis
Oxidative haemolysis
Liver disease
Infections, renal disease, other
Which membrane proteins are defected in hereditary spherocytosis?
Spectrin (peripheral protein)
Ankyrin
Band 3 (integral protein)
How is hereditary spherocytosis inherited?
Autosomal dominant
What is the most commonly inherited anaemia?
hereditary spherocytosis
Where are RBCs removed in hereditery spherocytosis?
In the spleen the RBCs lose their membrane and so red blood cells become spherical and then are destroyed
How does hereditary spherocytosis present in patients?
Fluctuating anaemia and jaundice
Sphenomegaly and gall stones
Lab tests show:
Spherocytes on blood film
Polychromasia
Negative DAT
Positive EMA (band-3) [Eosin 5 Maleimide which is a die that binds to band 3]
How is hereditary spherocytosis treated?
Splenectomy (spleen is the site of haemolysis)
Folic acid (to avoid folate deficiency)
cholecystectomy
What is a problem with splenectomy that should be considered?
People are more prone to bacterial infection when spleen is removed
What is hereditary elliptocytosis?
Autosomal dominant condition caused by mutations in spectrin.
It is asymptomatic in most people but 10% have haemolysis
What is G6PD deficiency?
Glucose 6 Phosphate Dehydrogenase deficiency
The most common red cell enzyme disorder worldwide (>200 million people affected)
What does G6PD do?
Enzyme in the hexose monophosphate shunt which generates reducing power as NADPH
What causes G6PD deficiency?
Mutation in gene on X-chromosome.making it more common in males than females
Does Australia have high G6PD deficiency?
No, But it must be known because it does exist in some people and people that migrate to australia
What is the problem with G6PD?
RBC susceptible to oxidant stress.
What triggers haemolysis in G6PD?
Oxidative stress caused by eating raw beans as well as infection, hypoxia, and drugs
What kind of red cells form on the blood film?
“Bite” or blister cells
What happens after oxidative stress is triggered?
Intravascular haemolysis and oxidised Hb is removed
How is G6PD deficiency treated?
Remove / stop / treat offending agent
Treat infection
Transfuse blood if necessary
What happens between crises caused by oxidative stress in G6PD deficiency?
RBC count returns to normal
What does pyruvate kinase do?
It is the enzyme that catalyses the last step of glycolysis and is required to make ATP
What results if pyruvate kinase is deficient?
Insufficient ATP leads to cell death resulting in haemolytic anaemia
How is pyruvate kinase deficiency inherited?
Autosomal recessive inheritance
How does pyruvate kinase present itself clinically?
Mild: occasional compensated haemolysis
Severe: can present in neonatal period with failure to thrive and splenomegaly
What do RBCs look like in pyruvate kinase deficiency?
Prickle-shaped RBCs
How is pyruvate kinase deficiency diagnosed?
Pyruvate kinase assay
What causes immune haemolytic anaemia?
It is idiopathic in most cases and in some cases it is caused by cancer cells (if leukemia/lymphoma is treated we can bring haemolysis under control)
Where does haemolysis take place in immune haemolytic anaemia?
In the spleen
What is allo-immune haemolytic anaemia?
Newborn blood damaged by antibodies to Rh in mother.
How can drugs cause immune haemolytic anaemia?
Antibody can form against a RBC-drug complex
Antibiotics
How can immune haemolytic anaemia be tested for?
Using a direct antiglobulin test:
Blood sample of someone with immune haemolytic anaemia containing antibodies attached to RBCs is put in a test tube.
Coomb’s reagent is then added to the mixture and agglutination gives a positive test result
What does autoimmune haemolytic anaemia look like on blood film?
Spherocytes are produced (this condition’s blood film is identical to spherocytosis)
Polychromasia with increased reticulocytes
Nucleated RBCs
Underlying disease (eg. leukemia)
What is fragmentation haemolysis?
A micro-angiopathic haemolytic anaemia where RBCs are damaged structurally
What causes fragmentation anaemia?
Heart valve pinhole lesion
Fibrin strands in vasculature (can be secondary damage)
Damaged blood vessels
Physically damaged RBCs due to mechanical movements of the body.
Red cell fragmentation
What kind of haemolysis does fragmentation haemolysis cause?
Intravascular haemolysis
What does fragmentation haemolysis look like on blood film?
Schistocytes
What does severe liver disease and renal dysfunction result in?
intravascular haemolysis
What cells are seen on blood film of severe liver disease?
Acanthocytes
What cells are seen on blood film of people with severe renal dysfunction?
Burr cells (echinocytes) [think of echidna]
What are echinocytes?
Echinocyte (from the Greek word echinos, meaning ‘hedgehog’ or ‘sea urchin’), in human biology and medicine, refers to a form of red blood cell that has an abnormal cell membrane characterized by many small, evenly spaced thorny projections. A more common term for these cells is burr cells.
What types of infections lead to severe haemolysis?
Severe bacterial sepsis
Malaria
Clostridium welchii: cause microspherocytes in PB film
What other conditions can severe bacterial sepsis cause?
Causes DIC and fragmented red cells
What species of plasmodium can cause anaemia?
P. vivax, falciparum, ovale, malariae
Trophozoites; schizonts; gametocytes
What does Clostridium welchii related anaemia look like on blood film?
Microspherocytes in PB film
Where are alpha and beta globin chains located in genome?
2 alpha genes on chromosome 16
2 beta genes on chromosome 11
What else does chromosome 11 contain around the beta globin chain?
The delta and gamma genes
What are the most common causes of monogenic diseases in the world?
Haemoglobinopathaties
What is thalassaemia caused by?
Deficient synthesis of globin chains
What are the classifications of thalassemia?
Trait: Carriers
Intermedia: shows up at times of stress
Major: symptomatic all the time
What is beta thalassemia caused by?
reduced beta chain production due to mutations in beta globin gene.
What happens when gene for beta thalassemia is homozygous?
When homozygous the condition is present at 3 - 6 months and causes severe anaemia due to loss of fetal gamma chain on which it was dependent.
What happens when gene for beta thalassemia is heterozygous?
Asymptomatic
Why does thalassemia cause swelling of the spleen and liver?
Because they are overworked trying to remove faults RBCs
How are beta thalassemia patients treated?
These people are transfusion dependent.for entire life (3 - 4 bags of packed blood cells a month) but transfusion brings in too much iron so iron is removed by iron chelators.
What do the faces of people with thalassemia major look like?
Hair standing on end and cheek bones are prominent
How many genes control alpha thalasemia?
4 alpha globin chains
How many alpha globin genes are missed in thalassemia minor?
1 or 2
How many alpha globin genes are missed in haemoglobin H disease?
3
How many alpha globin genes are missed in Hb barts hydrops fetalis?
4
What causes sickle cell anaemia?
A mutation encoding haemoglobin beta forming crystal and HbSS. Sickle shaped red cells can occlude blood vessels
