S5: haemolytic anaemias + haemoglobinopathies & when haemopoiesis goes wrong

Question 1

Describe sickle cell disease

Answer 1

Autosomal recessive disease
Mutation of GAG -> GTG (glutamic acid replaced by valine)
Heterozygous carrier causes a mild asymptomatic anaemia
Homozygous sickle cell anaemia = most common cause of severe sickling syndrome
Problem occurs in low oxygen state as deoxy HbS forms polymers that cause red cells form a sickle shape

Question 2

What are the 4 types of alpha thalassemia?

Answer 2

(Number = alpha-globin genes deleted)

1) Silent carrier state (asymptomatic)
2) Alpha-thalassemia trait (minimal/no anaemia) = microcytosis and hypochromia in RBCs
3) Haemoglobin H disease (moderately severe) = microcytic, hypochromic anaemia with target cells and Heinz bodies
4) Hydrops fetalis (severe, intrauterine death) = all 4 alpha genes deleted, excess y-globin forms tetramers in foetus that is unable to deliver oxygen to tissues

Question 3

What are the 3 types of beta thalassemia?

Answer 3

Disease caused by mutation rather than deletion

1) B-thalassaemia minor/B-thalassemia trait (usually asymptomatic with a mild anaemia) = heterozygous with 1 normal and 1 abnormal gene
2) B-thalassemia intermedia (severe anaemia, but not enough to require regular blood transfusions) = genetically heterogeneous
3) B-thalassemia major (severe transfusion-dependent anaemia, becomes known 6-9 months after birth) = homozygous

Question 4

What are the consequences of thalassaemia?

Answer 4

Extramedullary haemopoiesis = impairs growth and causes classical skeletal abnormalities
Reduced oxygen delivery -> stimulation of EPO -> more defective RBCs
Iron overload = excessive absorption of dietary iron due to ineffective haematopoiesis & repeated blood transfusions required to treat the anaemia
Reduced life expectancy

Question 5

How is thalassemia treated?

Answer 5

Red cell transfusion from childhood
Iron chelation
Folic acid

Question 6

Give the three key lab findings for haemolytic anaemia

Answer 6

Raised reticulocytes = as the marrow tries to compensate
Raised bilirubin = breakdown of haem
Raised LDH = red cells rich in this enzyme

Question 7

Describe the 4 major types of myeloproliferative neoplasm and explain how these arise

Answer 7

1) Essential thrombocythaemia
2) Polycythaemia vera
3) Myelofibrosis
4) Chronic myeloid leukaemia
Arise due to overproduction of one or several blood elements with dominance of a transformed clone (many patients have a specific point mutation in one copy of the Janus kinase 2 gene (JAK2))

Question 8

Explain how acquired thrombocytopenia may arise and list the clinical signs of this condition

Answer 8

Decreased platelet production eg. B12 or folate deficiency, liver failure
Increased platelet consumption eg. massive haemorrhage, DIC
Increased platelet destruction eg. drug induced, hypersplenism, autoimmune condition
Not symptomatic until platelet count < 30; easy bruising, mucosal bleeding, purpura & petechiae

Question 9

What are the three sickle cell crises?

Answer 9

• vaso-occlusive: painful bone crises, organ (chest, spleen)
• aplastic (often triggered by parvovirus)
• haemolytic

Question 10

Name symptoms of sickle cell disease

Answer 10

Retinopathy 
Splenic atrophy
Avascular necrosis
Acute chest syndrome
Stroke

Question 11

What is thalassaemia?

Answer 11

Defects in the regulation of expression of globin genes -> result in abnormalities in both the relative and absolute amounts of globin chain proteins -> alpha/beta thalassemia

Question 12

What is haemolytic anaemia? What are the two types and give examples of each?

Answer 12

Abnormal breakdown of red blood cells reduces lifespan and can occur in blood vessels or spleen & wider RES
Inherited (defective gene): glycolysis defect, membrane protein, haemoglobin defect
Acquired defect (damage to cells): mechanical damage, antibody damage, oxidant damage

Question 13

What are the clinical signs of haemolytic anaemia?

Answer 13

Pigment gallstones = composed of bilirubin and calcium salts (small, irregular & dark)
Jaundice = high bilirubin causes yellowish discolouration of the skin & sclera of eye

Question 14

Describe the clinical signs and management of essential thrombocythaemia

Answer 14

Overproduction of platelets
Large and excess megakaryocytes in the bone marrow
Thrombotic events
Management: CVS factors managed, aspirin (high risk patients – return platelet count into normal range with drug such as hydroxycarbomide)

Question 15

Describe the clinical signs and management of polycythaemia vera

Answer 15

Overproduction of red blood cells
High haematocrit or raised red cell mass
Significant cause of arterial thrombosis
Venous thrombosis 
Pruritis 
Gout
Management: venesection to maintain the Hct < 0.45, aspirin unless contraindicated, manage CVS risk factors

Question 16

Describe the clinical signs of myelofibrosis

Answer 16

Cause of massive splenomegaly +/- hepatomegaly due to extramedullary haemopoiesis
Fatigue
Sweats
Consequences of massive splenomegaly

Question 17

Describe the clinical signs of chronic myeloid leukaemia

Answer 17

Symptomatic splenomegaly
Hyperviscosity (sticky blood)
Bone pain
Management: imatinib (tyrosine kinase inhibitor)