Haemolytic Anaemias + Haemoglobinopathies Flashcards by Callum Donoher

What is a Haemoglobinopathy?

Inherited disorders where expression of one or more of the haemoglobin chains are abnormal

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2 Categories of Haemoglobinopathies

Abnormal haemoglobin variants
Thalassaemias

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What causes Abnormal haemoglobin variants?

Mutations in genes for alpha or Beta globin chains
Altering stability and/or function

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Example of a Haemoglobinopathy which causes Abnormal Haemoglobin Variants

Sickle Cell Disease

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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

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In what way are Haemoglobinopathies normally inherited?

Autosomal Recessive inheritance

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What normally causes Abnormal variants of haemoglobin (sickle cell)

Mutations in coding region

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What normally causes Thalassaemias?

Defects in the Regualtion of the expression of the genes for producing A and B globin chains

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Sickle cell disease Inheritance:
What changes?

Autosomal Recessive

Glutamate —> Valine
Negative —> Neutral
A —> T

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What is sickle cell disease caused by?

Single Base substitution on the B globin Gene
A substituted for T

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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

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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

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What symptoms does Vaso-occlusive episodes cause?

Stroke
Acute chest syndrome
Chronic Kidney disease (renal medulla blood vessels blocked)
Joint damage from Avascular necrosis

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What do Thalassaemias cause?

Imbalance in the composition of the 2 alpha and 2 beta tetramer in haemoglobin

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B Thalassaemia affect on Haemoglobin

Reduced amount of Beta Globin polypeptide chain

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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

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What is B Thalassaemia Major?

When individual is HOMOZYGOUS for the mutation in the B globin gene
Synthesis of B GLobin Chain = ABSENT

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How is someone with B Thalassaemia Major treated?

Dependant on BLood Transfusions after first few months of life

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A Thalassaemia is caused by

Deletion or loss of function of 1 or more of the 4 alpha globin genes

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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)