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Haemoglobinopathies Flashcards

1
Q

The main differential of HbH disease is…

Ways to differentiate include

A

Beta thal intermedia
Hb 60 - 100g/L, MCV ~60
HbH disease has a higher retic count and lack of nRBCs compared to beta thal intermedia.

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2
Q

List possible causes of HbH disease

A

–/-α
α cs / α cs
–/α cs
–/α nd
- nd / - nd (homozygous for non-deletional alpha thal)
Non-deletional alpha thalassaemias (point mutations in a2) can give rise to a more severe reduction in alpha chain due to the lack of compensatory increase from the a1 gene.

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3
Q

Most common mutations for a+ thalassaemia

A

The most common mutations are α4.2 and α3.7

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4
Q

Most common mutations for a0 thalassaemia

A

–SEA, –FIL, –THAI, –MED

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5
Q

Diagnosis of HbH disease

A
  1. FBC with indices: Hb 60-100 g/L, MCV 60, raised RBC count, low MCHC
  2. Film - marked anisopoik, targets, micro hypo BUT lack of nRBCs and minimal basophilic stippling
  3. HbH inclusion bodies on supravital stain
  4. Hb electrophoresis and HPLC shows HbH (~10-40%), Hb Barts (1-5%) and reduced or normal HbA2.
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6
Q

Gene commonly mutated in acquired HbH disease

A

ATRX

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7
Q

Hb Constant Spring

A

Variant alpha globin (non-deletional alpha thal) with reduced chain synthesis (thalassaemic haemoglobinopathy). Results in anaemia with MCV in high 70s.
Prominent basophilic stippling.

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8
Q

Why do non-deletional alpha thalassaemias cause a more severe anaemia?

A

The non-deletional alpha thalassaemias are usually found on α2 gene. They give rise to a more severe reduction in alpha chain production due to the lack of compensatory increase from the α1 gene.

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9
Q

Pathophysiology of HbH disease

A
  • Greatly reduced rate of synthesis of alpha chain leading to beta tetramers (HbH) which have very high oxygen affinity.
  • These tetramers are soluble in the bone marrow and therefore erythropoiesis is more effective than in beta thalassaemia.
  • HbH is unstable and precipitates in red cells as they age
  • The inclusion bodies/precipitates cause red cell membrane damage and obstruction in the spleen leading to shortened RBC survival and haemolysis.
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10
Q

Causes of worsening of anaemia in HbH disease (5)

A
  1. Infection
  2. Oxidative drugs
  3. Pregnancy
  4. B12 or folate deficiency
  5. Aplastic crisis from Parvovirus B19
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11
Q

RBC indices and morphology in HbC disease

A

Hb 80 up to normal
MCV very low (50)
Target cells, irregularly contacted cells and HbC crystals (in RBCs otherwise devoid of haemoglobin)

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12
Q

Red cell indices and morphology in HbE disease

A

Hb 80 up to normal
MCV 60s
Target cells, irregularly contracted cells
**ddx is beta thal trait, beta thal/HbE and iron deficiency

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13
Q

Diagnosis of HbE disease

A 
Cellulose acetate (alkaline) - HbE runs with HbC and HbA2
Citrate agar (acid) - HbE runs with HbA
HPLC - HbE runs in HbA2 position
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14
Q

Where is HbC most prevalent?

A

West Africa

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15
Q

Where is HbE most prevalent

A

South East Asia

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16
Q

Genotypes in beta thalassaemia intermedia

A

Homozygous 𝛃+/𝛃+
Compound heterozygous 𝛃+/𝛃0
Compound heterozygosity for β thalassemia and another beta chain variant (eg, β-thal/HbE)
Beta thalassaemia trait worsened by addition of more alpha genes e.g. aa/aaaa
Homozygous beta thalassaemia ameliorated by alpha thalassaemia
Homozygous beta thalassaemia ameliorated by HPFH

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17
Q

Causes of sickle cell crisis (4)

A
  1. Vaso-occlusive
  2. Aplastic
  3. Hyper-haemolysis
  4. Sequestration
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18
Q

Why does vaso-occlusion occur in sickle cell? (4)

A
  1. Sickled cells get stuck in small vessels due to reduced deformability
  2. Free Hb mobs up NO so less vasodilation and slowing of blood
  3. Sickle cells get stuck to the endothelium
  4. Lower Protein S levels in sickle cell
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19
Q

Factors which make sickling better

A
  1. HbF > HbA2 > HbA
    - HbF may be due to S/B (5-15%), S/dB (15-25%), S/HPFH (20-30%) or treatment with hydroxyurea
  2. Concurrent alpha thalassaemia (more HbA)
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20
Q

Factors which make sickling worse

A
  1. HbC, HbD-Punjab, HbS Lepore and Hb O-Arab
  2. Fever
  3. Acidosis
  4. Exposure to cold (slowed blood through capillaries)
21
Q

Sickle cell disease in pregnancy

A
  1. Hb falls due to normal haemodilution
  2. Increased erythropoiesis - folate deficiency can develop
  3. Increased painful crises in third trimester
  4. Increased VTE risk
  5. Increased risk of pre-eclampsia
  6. Risk to fetus - IUGR, miscarriage, still birth, inheritance of sickle cell trait or compound heterozygous trait
  7. Increased risk of bacteruria and pyelonephritis
22
Q

Causes of death in sickle cell disease

A
  1. Respiratory failure - sickling
  2. Infection
  3. Stroke
  4. End-organ damage e.g. renal failure
23
Q

How does hydroxyurea improve sickle cell anaemia? (3)

A
  1. Increased HbF (stressed erythropoiesis)
  2. Increased MCV (better hydrated RBCs prevents sickling and adhesion to endothelium)
  3. Lower WBC count therefore reduced viscosity
24
Q

How would you investigate an unstable haemoglobin?

A
  1. Evidence of haemolysis
  2. FBC - bit and blister cells
  3. Heinz bodies (supravital stain)
  4. Isopropanol test or heat stability test (van der waal’s bonds are broken down and unstable haemoglobins are denatured quickly)
25
Why does HbF have a higher affinity for oxygen than HbA?
HbF has a weak affinity for 2,3-DPG
26
CADET turn Right to Reduce oxygen affinity
CO2 increased Acidosis 2,3-DPG increased Temperature increased
27
What is the definition of thalassaemia?
Reduced rate of globin chain synthesis resulting in an imbalance of alpha and non-alpha chains
28
What is a haemoglobinopathy?
Broad term encompassing both thalassaemia and haemoglobinopathies. Refers to a structurally abnormal globin chain which may or may not be clinically significant.
29
How does the beta variant charge affect the variant percentage?
Variants with a net positive charge have lower affinity for alpha chains ==> variant is <50% (usually around 40%) Variants with a net negative charge have higher affinity for alpha chains ==> variant is >50%.
30
How do you perform an HbH inclusion body stain?
Two drops whole blood + 2 drops of brilliant cresyl blue Incubate 2 hours Make 2 slides and examine for 20 mins (10mins each) N.B. the vital stain causes oxidative denaturation and precipitation of the unstable beta tetramers
31
How are haemoglobins quantified in haemoglobinopathy testing?
1. HPLC 2. Mini-cap 3. Gel electrophoresis ==> scanning densitometry ==> cut out band, elute it and run on spectrophotometer
32
QC in HPLC
Calibration using commercial HbA2 and HbF With each run a high and low control for both HbF and HbA2 are run. Tri-level HbA2 also run
33
Diagnosis of beta thalassaemia major
FBC and film - Hb 50g/L, MCV 50-60, many nRBCs and basophilic stippling, low MCHC Gel electrophoresis and HPLC - Increased HbA2, raised HbF, absent or reduced HbA Confirm diagnosis with PCR
34
Clinical consequences of beta thalassaemia major
1. Severe symptomatic anaemia 2. Failure to thrive with impaired growth and muscle wasting 3. Expanded and extramedullary haematopoiesis results in thalassaemic facies, splenomegaly and nerve compression 4. Cardiac failure 5. Iron overload from ineffective erythropoiesis and regular transfusions
35
Management of beta thalassaemia major
1. Regular transfusions - match for Rh and Kell antigens 2. Iron chelation 3. Folate supplementation and Vitamin D 4. Splenectomy 5. Monitor growth, endocrinopathies, cardiac function 6. Consider haematopoietic stem cell transplant
36
HPLC in compound heterozgous HbC/beta zero
Large HbC peak, slightly raised HbA2 and HbF ==> very similar to homozygous HbC ==> need genetic studies and family studies to distinguish
37
What is Hb-D-Punjab and when is it clinically significant?
Beta chain variant | Only clinical significance is when it is inherited with HbS ==> causes sickle cell disease
38
HPLC findings in heterozygous and homozygous deltabeta thalassaemia
``` Heterozgyous = increased HbF, low-normal HbA2 Homozygous = 100% HbF, no HbA2 ```
39
What is the hallmark of beta thalassaemia trait?
Raised HbA2 3.5-4% (some labs use a cut off of >4%)
40
Clinical features of sickle cell trait
Usually asymptomatic Can get sickling with hypoxia (high altitude, anaesthetic misadventure, flying in unpressurised plane) and high fever. Can get papillary necrosis and haematuria as oxygen tension is lower in the renal papillae. Women are at increased risk of bacteruria, pyelonephritis and pre-eclampsia with sickle cell trait.
41
Features of SC, SB and SS+alpha thal compared to SS
Less severe haemolysis therefore fewer gallstones Splenomegaly persists for longer ==> may not see hyposplenism until adulthood Vaso-occlussive complications occur with similar frequency (Hb is higher therefore more viscous) More proliferative retinopathy and osteonecrosis due to higher Hb
42
What is the differential diagnosis of Sickle cell anaemia (SS) with alpha thal trait?
Compound heterozygous for sickle cell and beta zero.
43
Indications for red cell transfusion (exchange or top-up) in sickle cell disease
1. Prophylaxis - primary and secondary stroke prevention - acute chest syndrome prevention not controlled by hydroxyurea - preoperatively - 3rd trimester of pregnancy 2. Treatment - severe anaemia (due to any cause) - acute stroke - acute chest syndrome - multiorgan failure
44
Presentation of high affinity haemoglobins?
Erythrocytosis / polycythaemia Normal EPO and JAK2 negative e.g. Hb Kempsey, Hb Yakima
45
Presentation of low affinity haemoglobins
Anaemia and cyanosis Enhanced delivery of oxygen to tissues but poor pick up of oxygen in lungs. Usually no treatment required. e.g Hb Kansas
46
Give three examples of an unstable haemoglobin | Why does it cause anaemia?
Hb Kohn, Hb Hammersmith, Hb Zurich | The unstable Hb precipitates and causes reduced RBC deformability and membrane damage ==> haemolysis
47
Why do unstable haemoglobins have increased or decreased oxygen affinity?
Altered binding to 2,3-DPG
48
Clinical features of an unstable haemoglobin
May have chronic or intermittent haemolysis Anaemia, jaundice Gall stones Splenomegaly Increased haemolysis with certain drugs, fever etc.

Disorders affecting red cells (3 decks)

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