Sickle Cell and Thalassaemia

Question 1

What is sickle cell anaemia?

Answer 1

A chronic condition characterized by sickling of red blood cell due to production of abnormal Hb (HbS) instead of HbA

Question 2

What are the haplotypes of SCA?

Answer 2

· Sickle cell anaemia: homozygosity for HbS

· Sickle cell trait: Heterozygosity for HbS

· Sickle cell disease: broad group of diseases with possible compound heterozigosities, all resulting in sickling of cells (may be HbS/HbC or HbS/Bthalassaemia etc)

Question 3

What is the aetiology of SCA?

Answer 3

AR point mutation in B globin gene leading to production of Val instead of Glutamic acid on position 6 of B globin. This leads to hydrophobic interacitons within Hb molecule when it becomes deoxygenated – leading it to shrink into a sickle shape. These are frail and inflexible. They therefore are prone to:

· Breakdown in the spleen, therefore leading to shorter survival (20d)

· Occlusion of vessels causing hypoxia, which also causes further sickling

Question 4

What is the epidemiology of SCA?

Answer 4

Presents after 6months due to continued HbF production in that period. More common in Africa, middle east and Caribbean. 8% in Afrocaribbean are carriers.

Question 5

What are the symptoms of sca?

Answer 5

· Spleen: autonomous splenectomy, infarction of the spleen and necrosis. This leads to high susceptibility to infection.

o Abdominal pain, acute abdomen

· Bones: bone pain due to infarctions in painful crises. Leads to tender bones (dactilytis in children) arrest of growth and swelled joints, acute bony tenderness in crisis.

· Myalgia and arthralgia

· CNS: can cause fits or strokes

· Retina: visual loss

Exam:

· Bone: joint or muscle swelling due to avascular necrosis. Small digits.

· Retina: cotton wool spots (ischaemia) soft exudate.

Question 6

What are the findings in SCA sequestration crises?

Answer 6

· Spleen- splenomegaly then atrophy

· Liver causing anaemia

· Lungs: causing acute breathlessness, cough and fever.

· Corpora cavernosa: priapism and impotence

· Priapism

NB: apastic crisis in parvovirus B19 infection: sudden lethargy and pallor.

Question 7

What are the investigations of SCA?

Answer 7

Blood: FBC (anaemia, reticulocytes high in haemolytic crises and low in aplastic crises.) UEs.

Blood film: sickle cells. Anisocytosis and poklioccytosis. HYPOsplenism signs (Target cells and Howel Jelly bodies).

Sickle solubility test

Hb electrophoresis: separation vs control to detect HbS/HbA (according to polarity, HbS more? Polar therefore more migration????)

Xray for necrosis of bones. Ct head for neurological complications

Question 8

What is the management of SCA?

Answer 8

Acute painful crises: IV fluids, potent analgesia (IV opioids) oxygen.

Prophylactic antibiotics

Folic acid in haemolysis and pregnancy

Hydroxyurea to prevent sickle cell crises and increase HbF levels.

Exchange in transfusion for severe crises

Advice on avoidance of triggers/ BM transplantin severe patients / genetic counseling and pre natal planning.

Question 9

What are the complications of SCA?

Answer 9

Sickle cell crises, necrosis of bones/spleen. Aplastic crises (following pavovirus B19 infeciton). Haemolytic crises, pigment stones (+cholecystitis), renal papillary necrosis, leg ulcers.

Question 10

What is the prognosis of SCA?

Answer 10

Most survive >50 with good care. Major mortality for lung / CNS complications.

Question 11

What is the definition of thalassaemia?

Answer 11

Group of genetic disorders characterized by reduced/defective globin chain synthesis

Question 12

How may the globin genes be affected?

Answer 12

· Genes occur in clusters in different chromosomes: two on two different chromosomes: 2xa clusters, 2xb clusters

· Exception to one gene one protein rule: 2 alpha genes per alpha globin protein

o Chromosome 16 contiains 2x a genes, plus alpha embryonic gene (alpha pseudo genes)

o Adults therefore have a total of 4x alpha globin genes (2x maternal, 2x paternal)

· Chromosome 11 contains beta, delta, gamma genes (B cluster)

· Production combination from these gives rise to different haemoglobin types

· In disease, we may get b1d1 or y1d1, but not in health

Question 13

What is the aetiology of Thalassaemia?

Answer 13

Disorder in which there is reduced production of one of two types of globin chains (a/B) in Hb leading to imbalanced globin synthesis

· This leads to decreased speed of Hb production and therefore microcytic anaemia

· Mild forms can be compensated by the BM producing more red cells, but the more severe forms will lead to anaemia

Question 14

What are the types of chain deficiencies?

Answer 14

· 4-: produce only Hb Barts (y4 Hb) death in utero

· 3-1+: microcytic anaemia with splenomegaly

· 2/1-: microcytic cells but may not be anaemic, no splenomegaly.

Question 15

What is the difference between major, trait and intermedia?

Answer 15

· 2B-: Major: anamia presenting at 3-4 months (this is due to beginning HbA production (a2b2) at this time. Before this, HbF (a2y2) is the main type of Hb)

· 1b-: thalassaemia trait: may be astmptomatic or mild microcytic anaemia

· B thalassaemia intermedia: due to mild dysfunction in B globin synthesis. Microcytic anaemia and high ychain synthesis.

Question 16

What is the epidemiology of Thalassaemia?

Answer 16

5% are carriers WW. More Mediterranean.

Question 17

What are the symptoms of B major and trait on history and exam?

Answer 17

B major: anaemia presenting at 3-6 months. Failure to thrive and susceptibility to infections.

a/B trait: may be asymptomatic and picked up on routine FBC.

B major: palor, malaise, dyspnea, mild jaundice (haemolysis)

Frontal bossing and thalassaemic facies (areas of marroy hyperplasia)

Hepatosplenomegaly (extramedullary haemopoiesis and erythrocyte pooling)

Patients with B intermedia may have varying amounts of the above signs.

Question 18

What investigations would you do for thalassaemia?

Answer 18

FBC: low Hb, low MCV, low MCH

Blood film: macrocytic hypochromic anaemia, target cell, nucleated red cells and high reticulocyte count

Hb electrophoresis: low HbA and high HbF

BM: hypercellular with erythroid hyperplasia. Genetic testing or ocunselling fro couples.

Skull X ray: hair on end appearance due to expansion of medullary area.

Question 19

What is the management of thalassaemia?

Answer 19

a/B traits do not require treatment usually.

B thalassaemia major: regular blood transfusion + desoxyferramine for iron chelation. BM transplant from matched donor.

Surgical: splenectomy if blood transfusion requirements are very high, must be over 6yo and requires lifelong penicillin prophylaxis and vaccinations.

Question 20

What are the complications of thalassaemia?

Answer 20

Iron overload:

· Skin: slate grey pigmentation

· Liver: hepatomegaly due to secondary haemochromatosis

· Endocrine organs: failure (hypothyroidism, delayed puberty, short stature, DM)

· Heart: HF or arrhythmias.

Infections: mostly prone to encapsulated organisms.

Osteoporosis: due to expansion of marrow and endocrine complication

Question 21

What is the prognosis of thalassaemia?

Answer 21

Life expectancy normal with treatment. Mortality mainly by HF from iron overload and infection. BM transplant has 90% success rate.