4. Inherited Haemolytic Anemias- Haemoglobinopathies Flashcards
List two main types of factors that affect red blood cell survival
Intrinsic
Extrinsic
What are three intrinsic factors affecting red blood cell survival
Enzymes for glucose metabolism
Normal phospholipid membrane
Normal hemoglobin
What are the three types of hemoglobin that normal adult blood contains
Hemoglobin A (α2β2) Hemoglobin F (α2γ2) Hemoglobin A2 (α2δ2)
What percentage of adults hemoglobin does Hemoglobin A (a2β2) account for
98%
Describe a qualitative haemoglobin disorder
Structural defect of Alpha or Beta Globin Chain
Describe a quantitative haemoglobin disorder
Deficiency of alpha or beta globin chain
What is the diagnosis for:
A 2yr old boy that presents with
- Failure to thrive and progressive pallor
- Was well up to age 4 months
- Physical examination shows prominent maxillae
- Moderate splenomegaly noted
Beta Thalassemia
What is the definition of Thalassemia
A decrease in the production of either alpha or beta subunits
Which chromosome is affected in Beta Thalassemia
Chromosome 11
Which population is Beta Thalassemia most common in
Mediterranean
Middle Eastern
Asia
What type of mutation causes severe anemia in Beta Thalassemia?
Point mutation, where a stop codin is introduced early in the coding sequence and therefore terminates the protein sequence ( in this case Beta Globin sequence is terminated)
Is Beta Thalassemia Heterozygous or Homozygous
Both
What are the three types of Beta Thalassemia
Thalassemia Major (β0/β0)
Minor
Intermedia
Is Beta Thalassemia Major Heterozygous or Homozygous
Homozygous
Is Beta Thalassemia Intermedia Heterozygous or Homozygous
Heterozygous
Is Beta Thalassemia minor Heterozygous or Homozygous
Homozygous
What is the level of Microcytic RBCs in Beta Thalassemia minor
Increased Microcytic RBCs
What are the symptoms of Beta Thalassemia Minor
Asymptomatic or Mild Anemia
What are the changes in Adult Haemoglobin seen in Beta Thalassemia Minor
Haemoglobin A (α2 β2) decreases Haemoglobin A2 (α2 δ2) increases Haemoglobin F (α2 γ2) increases
Which test shows an increase in HbA2 and HbF in Beta Thalassemia Minor
Haemoglobin Electrophoresis
What is another name for Beta Thalassemia Major
“Cooley’s Anemia”
Which Anemia is known as “Cooley’s Anemia”
Beta Thalassemia Major
Is there Beta Globin production in Beta Thalassemia Major
Nope, None
What is the major Haemoglobin formed in Beta Thalassemia Major (β0/β0)
Haemoglobin F
What condition of the Spleen and Liver is evident in β Thalassemia Major (β0/β0)
Splenomegaly
Enlargement of Liver
Why is the liver and spleen enlarged in β Thalassemia Major
It is as a result of excessive red cell destruction
If both parents are the carrier of the β-Thalassemia trait, what is the chance of a β- Thalassemia Major offspring
1 in 4
What is the effect of the excessive α-chain precipitation in β-Thalassemia Major
The α - chains precipitate in erythroblasts and in mature red cells causing the severe ineffective erythropoiesis and hemolysis
What is the relationship between α-chain excess and anemia
Greater the α-chain excess the more severe the anemia
The production of which globin chain helps to “mop up” the excess α-chains in β- Thalassemia major?
γ-chains (gamma chains found in Haemoglobin F)
True or False
Thalassemia Major is often the result of inheritance of two different mutations, each involving β-globin synthesis
True
What are six clinical features of β-Thalassemia Major
Severe Anemia Enlargement of Liver and Spleen Expansion of Bones Iron overload (for patients sustained by blood transfusion) Increased susceptibility to infection Osteoporosis
Severe anemia in a β-Thalassemia Major patient becomes apparent at which age
3-6mths after birth
Why does β-Thalassemia Major become apparent at 3-6 mnths
Because this is when the switch from γ- to β-chain production should take place
One Clinical Feature of β-Thalassemia Major is splenomegaly, how does this affect the blood requirements
It increases blood requirements by increasing red cell destruction and pooling and by causing expansion of the plasma volume
What causes the expansion of bones in β- Thalassemia Major
Caused by intense marrow Hyperplasia (in an attempt to correct the anemia)
Leading to Thalassemic Facies
Expansion of bones is a clinical feature of β-Thalassemia Major
What effect does it have on bone structure, and bones like the maxilla and skull
Thins the bone cortex (increasing susceptibility to fracture)
Protruding Maxilla
Bossing of skull with hair- on - end appearance on X-ray
Which therapy is administered to β- Thalassemia Major patients along with their sustained blood transfusions to prevent iron overload
Chelation Therapy
What is the effect of iron overload
Failure of growth Delayed or absent puberty Diabetes Hypothyroidism Hypoparathyroidism
What changes in skin pigmentation are seen in an early stage of iron overload
Slately grey
What causes the Slate Grey appearance in an early stage or iron overload
Excess melanin and haemosiderin
Which test can be done to observe Iron overload in Liver or heart
T2 Magnetic Resonance Images
What is the reticulocyte percentage in β-Thalassemia
Raised
What type of anemia is seen in β- Thalassemia Major
Hypochromic
Microcytic anemia
Which iron test is used to assess iron overload
Serum Ferritin
For patients with Thalassemia Major you should attempt to keep the iron level in what range
1000 - 1500 ug/L
Normal is 30-620 ug/L in males
20-220 ug/L in premenopausalfemales
List eight treatment options for Thalassemia Major
1) Blood Transfusions
2) Regular Folic acid
3) Iron Chelation therapy
4) Vitamin C
5) Splenectomy
6) Endocrine Therapy
7) Immunization against Hep B
8) Allogenic bone marrow transplantation
How many units of blood and how often are these units administered to β- Thalassemic Major patients
2-3 units every 4-6 weeks
What type of blood is used in the Blood Transfusion for Beta Thalassemic Major patients
Fresh blood
No WBCs
If the Beta Thalassemic Major Pt has a folic acid poor diet what is the amount prescribed per day
5mg/day
List three options for Iron Chelators
Deferasirox ( oral ) - best option
Deferiprone (oral)
Deferoxamine (iv)
Why is Vitamin C apart of the treatment for Beta Thalassemia Major
It increases the excretion of iron by Deferoxamine
[It is believed that vitamin C can reduce both ferric (Fe(3+)) and ferrous (Fe(2+)) ions, and also facilitate the accessibility of iron to chelators through increase of iron release from the reticuloendothelial system.]
Splenectomy is a form of treatment for Beta Thalassemia Major, however this should not be performed in children until after what age
Age 6
Why is splenectomy an option for treatment in patients with Beta Thalassemia Major
To reduce blood requirements
(Remember the spleen destroys rbcs and releases the blood requirements back into the plasma, this is excessive in Beta Thalassemia Major)
Why is Endocrine Therapy an option for Beta Thalassemia Major pts
It is given either as replacement because of end organ failure
OR
To stimulate the pituitary if puberty is delayed
What is the blood picture of Beta Thalassemia minor
Hypochromic
Microcytic
What are the relative values for Mean Cell Volume MCV Mean Cell Haemoglobin MCH Red Cell Count RBC Haemoglobin
in Beta Thalassemia Minor
MCV is low
MCH is low
RBC is high
Haemoglobin is a bit low
A raised level in what type of Haemoglobin confirms the diagnosis for Beta Thalassemia Minor
Hb A2 (>3.5%)
Describe Thalassemia intermedia
Thalassemia of moderate severity who do not need regular transfusions
In β-Thalassemia Major Management the Haemoglobin is maintained at what level
12g/dl
True or False
All Beta Thalassemic Intermedia patients are transfusion dependent
False
Not all are
Diagnose this patient
Results
> Hb 8.0g/dl
> MCV 65fl ; MCH 18pg
> Blood film: hypochromic, microcytic with occasional nucleated RBCs
> Serum iron, TIBC normal (total iron binding capacity)
> Electrophoresis: Hb H
α-thalassemia
What is the genetic cause of α-thalassemia
All are due to gene deletion
What are Thalassemias
These are heterogenous group of genetic disorders that result from a reduced rate of synthesis of α or β chains
What is the effect of the loss of all four α globin genes on α-chain synthesis
Completely suppresses α-chain synthesis
Leads to death in utero (hydrops fetalis)
What is the result of 3 α gene deletions
Leads to a moderately severe microcytic, hypochromic anemia
What is the condition associated with Four gene deletion α-Thalassemia
Hydrops fetalis
What type of Haemoglobin is observed in α-Thalassemia
Hb H
[H (β4) - four β globulin chains]
What type of Haemoglobin is observed in α-Thalassemia of the fetus
[loss of all 4 α globin chains]
Hb Barts (γ4) (Hydrops fetalis)
Four gamma chains
Describe what causes α-Thalassemia trait
Caused by loss of one or two genes and are not usually associated with anemia
True or False MCV and MCH are low in α- Thalassemia trait
True
What is the cause of in utero death of fetuses with α-Thalassemia
Severe hypoxia due to Hb Barts (γ4) that has High oxygen affinity
Describe α+ trait thalassemia
1 α globulin gene deleted
Describe homozygous α+ trait
2 α globulin genes deleted
1 from opposite chromosomes
Describe heterozygous α0 thalassemia trait
2 α genes deleted
Both deleted genes from same chromosome
Describe Hb H disease
3 alpha globulin genes deleted
Diagnose this patient
Hb 7.5g/dl; sickled cells on film Wbc 28.6 x 10^9/L Plats 295 x 10^9/L Retic 18% Sickle solubility test positive Hb electrophoresis S and A2
Sickle Cell Disease
Define Sickle Cell Anemia
It is a group of hemoglobin disorders in which the sickle β-globin gene is inherited
What is the most common type of sickle cell anemia
Hb SS (homozygous sickle cell) (i.e. Hb α2β2 s)
What happens to Hb S when exposed to low oxygen tension
Forms crystals
Substitution of which amino acid causes the sickle β-globin abnormality
Substitution of Valine for Glutamic Acid in position 6 in the β chain
What percentage of West Africans have Sickle Cell Anemia
25%
Why is the 25% occurrence of sickle cell disease in West Africa maintained
Because of the protection against malaria that is afforded by the carrier state
Which Haemoglobin type gives up O2 more readily to tissues Hb S or Hb A
Hb S
O2 dissociation curve shifted to the right
List four clinical features of Sickle Cell Anemia
Painful Vaso-occlusive crises
Visceral sequestration crises
Aplastic Crises
Haemolytic Crises
What is vaso-occlusive crisis
When the microcirculation is obstructed by sickled RBCs, causing ischemic injury to the organ supplied and resultant pain
Painful vaso occlusive crises of the sickle cell anemic patient are often precipitated by what factors
Infection
Acidosis
Dehydration
Deoxygenation
What are some states of deoxygenation that can cause vaso occlusive crises in the sickle cell anemic patient
Altitude Operations Obstetric delivery Stasis of the circulation Exposure to cold Violent exercise
What are the most serious sites of vaso occlusive crises
Brain
Spinal cord
Which test can be used to detect abnormal blood flow that is indicative of arterial stenosis
Doppler Ultrasonography
What is typically the first presentation of sickle cell disease HbSS
‘Hand-foot’ Syndrome
What causes dactylitis in HbSS pts
Infarcts of the small bones
What causes sequestration crises
Sickling within organs and pooling of blood, often with severe exacerbation of anemia
What is the most common cause of death from Homozygous Sickle cell disease after puberty
Acute Sickle Chest Syndrome
What is the clinical presentation of Acute sickle chest syndrome
Dyspnoea
Falling arterial Po2
Chest pain
Pulmonary infiltrates on chest X ray
What is the treatment for Acute Sickle Chest Syndrome
Analgesia
Oxygen
Exchange transfusion and ventilatory support
What is Aplastic Crises
An aplastic crisis is when the body does not make enough new red blood cells to replace the ones that are already in the blood.
[These occur as a result of infection with parvovirus or from folate deficiencies]
How is Aplastic Crises characterized
Fall in reticulocytes
Fall in Haemoglobin
What is a Haemolytic crises
Increased rate of haemolysis with a fall in Haemoglobin but rise in reticulocytes
List four Laboratory Findings of Homozygous Sickle cell Disease HbSS
Haemoglobin is usually low (6-9g/dL)
Sickle cells and Target cells present in blood
Screening test for sickling positive when the blood is dehydrated
Haemoglobin Electrophoresis: in HbSS, no HbA detected
Moderate to severe normochromic anemia
Polychromasia and nucleated red cells
Leucocytosis
Thrombocytosis
List four prophylactic treatments for Homozygous Sickle Cell Anemia
Avoid factors known to precipitate crises
Folic acid
Good general nutrition and hygiene
Pneumococcal, haemophilus and meningococcal vaccine, also hep b
What are four simple treatments for HbSS crises
Rest
Warmth
Rehydration by oral fluids/ intravenous normal saline
Antibiotics if infection is present
Analgesics is administered to pts with HbSS crises, which drugs are suitable
Paracetamol
Non-steroidal anti-inflammatory agent and opiates
What is the role of Hydroxyurea treatment in HbSS treatment
Can increase Hb F levels and has been shown to improve the clinical course of children or adults who are having three or more painful crises each year
NB// hydroxyurea should NOT be used during pregnancy
Which treatment is know to cure HbSS
Stem Cell Transplantation
What is the mortality rate of stem cell transplantation
Less than 10%
What is the most common symptom of Sickle cell trait
Haematuria
Caused by minor infarcts of the renal papillae
List four varieties of Sickle Cell Disease
Sickle Cell Anemia (HbSS)
Sickle -Hb C disease
Sickle β 0 Thalassemia (S β0)
Sickle β+ Thalassemia (S β+)
List five reasons why Sickle Cell disease is clinically silent until age 6mths
Chronic hemolytic anemia of variable severity Ischemic strokes Pulmonary infection and infarction Chronic leg ulcers Impaired growth and development
What are the symptoms of Hand Foot Syndrome in HbSS crises
Sudden pain and swelling of extremities
Results in shortened digits in later life
