Haemolytic Anaemias + Haemoglobinopathies Flashcards
What is a Haemoglobinopathy?
Inherited disorders where expression of one or more of the haemoglobin chains are abnormal
2 Categories of Haemoglobinopathies
Abnormal haemoglobin variants
Thalassaemias
What causes Abnormal haemoglobin variants?
Mutations in genes for alpha or Beta globin chains
Altering stability and/or function
Example of a Haemoglobinopathy which causes Abnormal Haemoglobin Variants
Sickle Cell Disease
What are Thalassaemias?
A type of Haemoglobinopathy which causes in reduced/absent expression of normal A or B globin chainss
Causes reduced haemoglobin levels not abnormal haemoglobin
In what way are Haemoglobinopathies normally inherited?
Autosomal Recessive inheritance
What normally causes Abnormal variants of haemoglobin (sickle cell)
Mutations in coding region
What normally causes Thalassaemias?
Defects in the Regualtion of the expression of the genes for producing A and B globin chains
Sickle cell disease Inheritance:
What changes?
Autosomal Recessive
Glutamate —> Valine
Negative —> Neutral
A —> T
What is sickle cell disease caused by?
Single Base substitution on the B globin Gene
A substituted for T
In Sickle Cell Disease, what is the affect of substituting A for T on B globin gene
Glutamic acid (NEGATIVE) substituted to Valine (NEUTRAL)
Causes long twisted Haemoglobin polymers causes a deformation and sickle cell shape
Sickle Cell formation signs/symptoms
VASO-OCCLUSIVE EPISODES - (occlusion of small capillaries when sickle cells get trapped)
ANAEMIA - Sickle cells undergo haemolysis
JAUNDICE AND GALLSTONES (From excessive bilirubin from chronic haemolysis)
SPLENIC ATROPHY - Due to splenic infarction
What symptoms does Vaso-occlusive episodes cause?
Stroke
Acute chest syndrome
Chronic Kidney disease (renal medulla blood vessels blocked)
Joint damage from Avascular necrosis
What do Thalassaemias cause?
Imbalance in the composition of the 2 alpha and 2 beta tetramer in haemoglobin
B Thalassaemia affect on Haemoglobin
Reduced amount of Beta Globin polypeptide chain
Affect of being HETEROZYGOUS for B Thalassaemia of the Beta Globin gene
B Thalassaemia Trait
Rate of B globin production reduced
Microcytosis
Total blood haemoglobin same since bone marrow makes more RBC
Anaemia doesn’t really occur
What is B Thalassaemia Major?
When individual is HOMOZYGOUS for the mutation in the B globin gene
Synthesis of B GLobin Chain = ABSENT
How is someone with B Thalassaemia Major treated?
Dependant on BLood Transfusions after first few months of life
A Thalassaemia is caused by
Deletion or loss of function of 1 or more of the 4 alpha globin genes
What is the severity of Alpha Thalassaemia determined by?
The number of malfunctional Alpha globin chains
For Alpha Thalassaemia, what is the condition called when 3/4 of the Alpha globin genes are malfunctional?
Haemoglobin H disease
Haemoglobin H disease is categorised/indicated by:
Severe microcytosis
Anaemia
Haemolysis (Imbalanced tetramer of haemoglobin may affect function caused RBC to be destroyed)
Splenomegaly (Spleen works hard to increase RBC count to ensure blood haemoglobin levels don’t fall too low, EXTRAMEDULLARY HAEMOPOIESIS)
What are the 3 classifications of the Severity of Thalassaemias?
Thalassaemia Major (Transfusion Dependant)
Thalassaemia Intermedia (Transfusions Intermittently)
Thalassaemia Minor (don’t need Transfusions)
What is Haemolytic Anaemia?
The abnormal breakdown of RBC (Haemolysis) in:
-Blood vessels (Intravascular haemolysis)
-Spleen (extra vascular haemolysis)
The excess breakdown of RBC causes low blood haemoglobin concentration
2 General causes of Haemolytic anaemia?
Inherited (Gene defects)
Acquired (Damage to cells)
Inherited causes of Haemolytic Anaemia
(Metabolic defects in erythrocytes) 2
(Structural defects in erythrocytes) 2
PYRUVATE KINASE DEFICIENCY(Glycolysis defect) Limits ATP Production, Rely on GLycolysis for ATP
PENTOSE PHOSPHATE PATHWAY DEFECTS like G6PDH DEFICIENCY (NADPH can’t be regenerated so vulnerable to oxidative damage)
Hereditary Spherocytosis ( a membrane protein is abnormal)
HAEMOGLOBIN DEFECT (Sickle Cell)
How can cells be damaged causing Acquired Haemolytic anaemia?
Mechanical damage (Microangiopathic anaemia)
Anitbody damage (Autoimmune haemolytic anaemia)
Oxidant damage
Heat damage
Enzymatic damage
Chronic Increased haemolysis can cause:
SHortness of breath (Dyspnoea)
Fatigue
Jaundice (High bilirubin)
Gallstones (High bilirubin)
What is Microangiopathic haemolytic anaemia?
A group of Aquired Haemolytic Anaemias
Red cells are damaged by trauma
Causes of Microangiopathic haemolytic anaemias
RBCs getting snagged on Fibrin stands in blood vessels
Disseminated Intravascular Coagulation (DIC) - Bleeding and clotting happen at same time
Thrombotic thrombocytopenia purpura: Small clots in small blood vessels
Aortic Valve Stenosis - Shear stress from defective heart valve damages RBCs
What are shistocytes?
RBC fragments from mechanical damage
Relevance of schistocyte being present in blood sample
Indicated pathology
What can cause Autoimmune Haemolytic anaemias?
Infections
Lymphoproliferative Disorders (leukaemia and drug reactions)
What are the 2 classifications of Autoimmune haemolytic anaemias?
State why these are the classifications
Warm
Cold
Describes the temperature which the antibodies work best at
Which antibody is involved in WARM autoimmune haemolytic anaemia?
IgG
What happens in Warm Autoimmune Haemolytic Anaemia?
IgG antibodies recognise epitopes on red cell membrane
This marks red cells to macrophages in spleen
All destroyed or little membrane removed (SPheroycte forms)
Often cause Splenomegaly
Which antibody is involved in COLD Autoimmune Haemolytic Anaemia?
IgM
What happens in COLD Autoimmune Haemolytic Anaemia?
IgM autoantibodies and COMPLEMENT bind to RBC at cooler distal parts of body
IgM span over multiple RBC forming large agglutinates blocking capillaries
Causes ischaemic conditions like numb fingertips and earlobes, pallor, blue discolouration or gangrene when serious
What does the complement do that binds with IgM in COLD Autoimmune Haemolytic Anaemia?
Creates holes in membrane
Causes splenic macrophages to recognise+destroy cells
What does the Direct Coombs Test do?
Detects antibodies or complement bound to surface of RBCs
Used to see if patients haemolysis is immune related
Pyruvate Kinase deficiency in causing Inherited Haemolytic Anaemia
PKLR gene mutated
Pyruvate kinase essential to transfer phosphate from phosphoenolpyruvate to ADP to make ATP
Pyruvate Kinase deficiency = much less ATP from glycolysis
Why is Pyruvate Kinase Deficiency (Mutation on PKLR gene) so detrimental in RBCs
No mitochondria
Only form of ATP production = Glycolysis
How does lack of ATP in RBCs affect and cause cell death?
NA K ATPase pump can’t function
K moves into plasma
Cell shrinks and dies
G6PDH Deficiency causing Inherited Haemolytic Anaemia
Pentose Phosphate Pathway Ceases
No NADPH (No mitochondria so no Krebs Cycle)
Less Reduced Glutathione GSH
Less Protection Form Oxidative Stress
Hereditary Spherocytosis mode of inheritance
Autosomal Dominant
What happens in Hereditary Spherocytosis?
Abnormalities in membrane proteins of RBC inhibit their ability to change shape
4 Membrane proteins that causes Hereditary Spherocytosis when their gene is mutated
Spectrin
Ankyrin
Band 3
Protein 4.2
How does Hereditary Spherocytosis cause Inherited Haemolytic Anaemia?
Spherocytes get stuck and damaged in spleen (extravascular haemolysis)
Symptoms of Hereditary SPherocytosis
Anaemia (extravascular haemolysis)
Jaundice
Splenomegaly
Howell-Jolly bodies in RBCs (Nucleus fragments that aren’t removed)
