Haemoglobin Disorders II Flashcards
Sickle Cell disease
Sickle cell disease is a group of haemoglobin disorders in which the __________ is _________
sickle β-globin gene is inherited.
Sickle Cell disease
The sickle β-globin abnormality is caused by substitution of ______ for _________ in position ____ in the β globin-chain.
glutamic acid; valine
6
Sickle Cell disease
__________________ is the most common while the _______________________ also cause sickling disease.
Homozygous sickle cell anaemia (HbSS)
doubly heterozygote conditions of HbSC and Hb Sβthal
Homozygous Disease: Hb SS; Sickle cell anaemia.
The inheritance of 2 HbS gene one each from both parent.
T/F
T
Homozygous Disease: Hb SS; Sickle cell anaemia.
The disease was first described in 1904 by a Chicago based physcian, Dr. James Herrick who reported “ _______ and ______ shaped” red blood cells in a young man of _______ origin.
The patient had come to Dr. Herrick with complaints of shortness of breath, heart palpitations, abdominal pain, and _________ in his muscles.
He also felt _______ all the time, had _______, experienced attacks of ______, and had _____ on his legs. After noting these symptoms, the doctor took samples of his blood
peculiar elongated and sickle
Negroid
aches and pains; tired; headaches
dizziness; ulcers
Genetic basis of Sickle cell anaemia (HbSS)
•__________ mutation on the _____gene at _____ nucleotide, ____ Codon, aa in position _____, resulting in ______ instead of ________
• For comparison, Hb C a mutation at the same spot, leads to _____ instead of ———-
Single point
β
17th; 6th; 6
valine; glutamine
lysine; glutamine
Haemoglobin S production arises from _______________________ gene
Differ from HbA by ___________
an altered (mutated) “S” gene.
one amino acid substitution.
Pathogenesis
The substitution of a valine for a glutamine results in decreased _______ of (oxy or deoxy?) -HbS compared to (oxy or deoxy?) -HbA.
solubility ; deoxy
Deoxy
Pathogenesis
When _____genated, HbS tetramers form ———- which associate into _____ that ——————
deoxy
polymers
bundles
precipitate in the red cell
As long as HbS is in the oxygenated state it is (subtle or insoluble?)
solube
As long as HbS is in the _____genated state it is solube
oxy
Upon de-oxygenated, Hb becomes _______ and _______, _____ are formed which leads to _____.
Blood becomes more ________
insoluble and polymerise
tactoids
sickling
viscous
Consequences of polymerization of haemoglobin
Sickling of red cells
Loss of red blood cell ————-
__________ of red blood cells
________ of small vessels
_______damage
deformability
Haemolysis
Vaso-occlusion
End organ
Pathophysiologic effects of sickled cells.
Red cells carrying Hb S constantly ___________ on the arterial side to ________ on the venous side. Eventually, some cells become __________
switch from normal shape
sickled shape
irreversibly deformed,
Pathophysiologic effects of sickled cells.
Eventually, some cells become irreversibly deformed, resulting in:
1. ___________
2. ________ of ___________
Extra-vascular haemolysis
Compromise of micro circulation
Pathophysiologic effects of sickled cells.
- Extra-vascular haemolysis.
Conscientious function of the _____ to remove damaged or deformed cells targets the cells that ___________________________. The cells are trapped and removed by _________.
spleen
cannot traverse the narrow openings of the splenic sinusoids
macrophages
Pathophysiologic effects of sickled cells.
- Extra-vascular haemolysis.
◦ The deformed cells compromise the _______ of the spleen causing __________ and eventual _________
◦ Replacement of cells carrying HbS with the same abnormal cells causes ______ because of continuous _______ of the cells by the spleen and, later, by the ———-.
blood supply
repeated small infarctions
loss of splenic function.
anaemia; early destruction ; RES
Pathophysiologic effects of sickled cells.
Compromise of Microcirculation.
As red cells carrying HbS become ______ and lose their ability to ________. They create a ______ that ________.
sickled
traverse narrow passages; blockage
obstructs blood flow into the tissue
Pathophysiologic effects of sickled cells.
Compromise of Microcirculation.
The local anoxia that results from the blockage increase ____________and further aggravates the ________ and ___________ of abnormal haemoglobin.
oxygen extraction from the trapped red cells
deoxygenation and polymerization
Pathophysiologic effects of sickled cells.
Compromise of Microcirculation.
The compensatory action of the adjacent vessels releases more oxygen from the cells. This _____eases sickling and causes ————; of the situation.
incr
exacerbation
Pathophysiologic effects of sickled cells.
Compromise of Microcirculation.
Tissue damage from lack of oxygen is the cause of the ________ and _______ characteristic of sickle cell crises.
Vaso-occlusion promotes ___________________ injury
acute and chronic pain
ischemia-reperfusion (I-R)
Impaired rheology of the blood and aggregation of sickle erythrocytes with neutrophils, platelets, and endothelial cells causes stasis of blood flow and is referred to as _________
vaso-occlusion.
Factors promoting sickling
extreme heat/cold; cold
Dehydration
Acidosis
Factors promoting sickling
Hypoxemia: _______,________ ,______ , stasis of the circulation, , _______
altitude, operations, obstetric delivery,
violent exercise
Factors opposing sickling
The presence of non sickling haemoglobin:
Hb_____
Hb ______
F
A
Sickle-cell conditions are inherited from parents in much the same way as blood type, hair color and texture, eye color, and other physical traits.
T/F
T
The types of haemoglobin a person makes in the red blood cells depend on what hemoglobin genes are inherited from his parents
T/F
T
Inheritance
Sickle cell anemia is inherited in
an (Xlinked or autosomal?). (Dominant or recessive?) pattern, which means that __________ of the gene in each cell have mutations .
autosomal recessive
both copies
The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.
T/F
T
If one parent has sickle-cell anaemia (SS) and the other has sickle-cell trait (AS), there is a ____% chance of a child’s having sickle-cell disease (SS) and a ____% chance of a child’s having sickle-cell trait (AS).
50; 50
When both parents have sickle-cell trait (AS), a child has a ____% chance of sickle-cell anaemia (SS)
25
Clinical features of SS
Clinical features are of _________ punctuated by _______.
severe haemolytic anaemia
crises
Clinical features of SS
The symptoms of anaemia are often mild in relation to the severity of the anaemia because ________________________
HbS gives up oxygen (O2) to tissues relatively easily compared with HbA, its O2 dissociation curve being shifted to the right.
Clinical features of SS
The clinical expression of Hb SS is very variable, some patients having an almost normal life, free of crises but others develop severe crises even as infants and may die in early childhood or as young adults.
T/F
T
Sickle cell Anaemia: Consequences of Haemolysis
__________
_________
____________
——————-
Anaemia
Jaundice
Gallstones
Vasculopathies
Sickle cell Crises may be:
______ or _______
vaso-occlusive
Anaemic
Sickle cell Crises may be:
vaso-occlusive: eg ______
Pain
Sickle cell Crises may be:
Anaemic: _____,_____,_____,______
Sequestration, Aplastic, Hyperhaemolytic Megaloblastic.
Vaso-occlusive (Pain) crises
These are the most frequent and are precipitated by such factors as ———-,———,———,——— (e.g. altitude, operations, obstetric delivery, stasis of the circulation, exposure to cold, violent exercise).
Infarcts can occur in a variety of organs including the _______(____,____,____ are commonly affected), the ——— and the _________
infection, acidosis, dehydration or de-oxygenation
bones
hips, shoulders and vertebrae
the lungs and the spleen.
Vaso-occlusive (Pain) crises
The most serious vaso-occlusion is of the _____ ( _________ occurs in 7% of all patients) or _________.
brain
Ischemic stroke
spinal cord
Vaso-occlusive (Pain) crises
________________________ detects abnormal blood flow indicative of arterial stenosis. This predicts stroke in children. This can be largely prevented by ______________ in these cases.
Transcranial Doppler ultrasonography
regular blood transfusions
Vaso occlusive crises
_______
_______
________
Acute and chronic Pain
Painful dactylitis
Priapism
The ‘_______’ syndrome (painful dactylitis caused by infarcts of the _________) is frequently the first presentation of the sickle cell disease and may lead to __________
hand-foot
small bones
digits of varying lengths.
_____________ is frequently the first presentation of the sickle cell disease
painful dactylitis
Vaso-occlusive crises
PRIAPISM
Priapism is the ______,______,_________ erection of the penis.
It is relatively common in ________ with sickle cell anemia.
The onset may be in ________ or _____.
Recurrent or severe episodes can result in future ________.
Treatment is often not satisfactory
persistent, painful purposeless
young males
early childhood or adolescence
impotence
Visceral sequestration crises
These are caused by sickling within organs and _______, often with a severe exacerbation of _____.
pooling of blood
anaemia
Visceral sequestration crises
The _____________ is a feared complication and the most common cause of death after puberty.
acute sickle chest syndrome
Visceral sequestration crises
The acute sickle cell syndrome
It presents with ______, falling arterial Po2, _________, and _______ on chest X-ray.
Treatment is with _______ , ______, and _______ if necessary.
dyspnoea
chest pain and pulmonary infiltrates
analgesia, oxygen exchange transfusion and ventilatory support
Aplastic crises
These occur as a result of infection with _______ or from _______ deficiency and are characterized by a _________ in ______, usually requiring transfusion.
parvovirus
Folate
sudden fall in haemoglobin
Aplastic crises
They are characterized by a fall in ————- as well as _________.
reticulocytes
haemoglobin
Hyperhaemolytic crises
These are characterized by an increased ____________ with a fall in ______ but rise in _____________ and usually accompany a __________
rate of haemolysis
haemoglobin
reticulocytes
painful crisis.
Hyperhaemolytic crises Also complicates transfusion in some cases.
T/F
T
Other Clinical Features (Organ
Complications)
Skin:_____ of the _______ are common, as a result of vasculopathy resulting in _______ and ________. It is also seen in many haemolytic anaemia.
GIT: The spleen is ______ in infancy and early childhood but later is often _______ as a result of repeated infarcts ( ________ ).
Ulcers; lower legs; vascular stasis and local ischaemia
enlarged; reduced in size
autosplenetomy
Other Clinical Features (Organ
Complications)
The Liver is usually _______ throughout the years. A lot of abdominal crises are related to the enlarged liver. Chronic damage to the liver may occur through ____________________.
______,__________, and ________ following viral infections
.
enlarged
micro infarcts SCD hepatopathy.
Hepatitis, fibrosis and cirrhosis
Other Clinical Features (Organ
Complications)
The gall bladder: __________ tend to form like in all haemolytic conditions which can lead to chronic ________ and ———— of the common bile duct.
Pigment gall stones
Cholelithiasis
obstruction
Peptic ulceration is commoner in SCD than in normal population.
T/F
T
Other Clinical Features (Organ
Complications)
Avascular necrosis of femoral head is a hip joint problem where the blood supply to the _________ (____ portion) of the joint is reduced or obliterated. This causes this portion of the bone to necrose and collapse
femoral head (ball
Laboratory Findings
Blood film: ______chromic (haemoglobin still stains)
_____cytosis +++ (polychromatic macrocytes)
______cytosis (_____ cells, _____ cells and ______cytes). _______ red cells
Normo
Aniso; Poikilo
Sickle; target, acantho; Nucleated
Laboratory Findings
The haemoglobin is usually ______g/dL – low in comparison to symptoms of anaemia.
Bone Marrow- __________ to __________ hyperplasia (to compensate for lost RBCs)
6-9
normoblastic/megaloblastic
Laboratory Findings
Features of splenic atrophy (hypofunction):
_______Bodies; __________, _______ bodies, _________ bodies
Inclusion
Basophilic Stippling, Pappenheimer Bodies, Howell-jolly bodies.
Laboratory Findings
1. 2.
The haemoglobin is usually 6-9g/dL – low in comparison to symptoms of anaemia.
Blood film: Normochromic (haemoglobin still stains) Anisocytosis +++ (polychromatic macrocytes) Poikilocytosis (Sickle cells, Target cells and acanthocytes). nucleated red cells
Features of splenic atrophy (hypofunction): Inclusion Bodies; Basophilic
Stippling, Pappenheimer Bodies, Howell-jolly bodies.
Bone Marrow-normoblastic/megaloblastic hyperplasia (to compensate for lost RBCs)
Haemoglobin electrophoresis:
performed under (acidic or alkaline?) condition ( pH ____) using _______ in _____ buffer
alkaline
8.4
cellulose acetate
TRIS
Haemoglobin electrophoresis:
Principle:
a. Using a RBC _____, bands can be quantitated by scanning ______
b. HbS runs with Hb__ (which _________)
c. C migrates with ____ ((more or less?) predominant) and _____
lysate; densitometry
D; does not sickle
E; more ; A2
Electrophoresis uses ________ to separate _______________________ in the blood. Hemoglobin types have different electrical charges and move at different speeds.
electrical current
normal and abnormal types of hemoglobin
Hemoglobin electrophoresis
In Hb SS, Hb____ will be the predominant band, (little or no?) Hb A is detected.
The amount of Hb F is ____ and is usually ___-___%, larger amounts are normally associated with a milder disorder.
S; No
variable; 5-15
Hemoglobin electrophoresis
Trait (HbAS) is generally asymptomatic, carrying mostly Hb__(____%) and Hb__ (_____%)
A; 65
S; 35-40
Hemoglobin electrophoresis
Always less than ____% abnormal Hb if one normal gene
50
Factors affecting the result of hemoglobin electrophoresis are
Correct _____,
Correct _________ of the buffer
The ________ of the buffer
The _____ of the _______
pH; concentration
temperature
quality; carrier membrane
Management of SCD
- Prophylactic –avoid those factors known to precipitate crises, especially _______,______,________,________, and ________
2._________ (e.g. 5 mg once daily).
3. Good general nutrition and hygiene.
- _________ ,_______, and _______ vaccination and regular ________ are effective at reducing the infection rate with these organisms and should be strongly encouraged.
5.
dehydration, anoxia, infections, stasis of the circulation and cooling of the skin surface.
Folic acid
Pneumococcal, Haemophilus and meningococcal
oral penicillin
Management of SCD
Prophylactic antibiotics: _________ should start at diagnosis and continue at least until puberty.
_________ vaccination is also given as transfusions may be needed.
Oral penicillin
Hepatitis B
Management of SCD: MEDICATIONS
______
_______
________
_______
_______
Hydroxyurea (Droxia, Hydrea, Siklos).
•Crizanlizumab (Adakveo).
L-glutamine oral powder (Endari).
•Voxelotor (Oxbryta)
•Pain-relieving medications.
Management of SCD: MEDICATIONS
Hydroxyurea : Daily hydroxyurea reduces ______________ and might reduce the need for _________ and ________
the frequency of painful crises
blood transfusions and hospitalizations.
Management of SCD: MEDICATIONS
•Pain-relieving medications. ______ to help relieve pain during sickle cell pain crises. _____ and ______ is a challenge.
Narcotics
Opioid tolerance and addiction
Management of SCD: MEDICATIONS
•L-glutamine oral powder (Endari). The FDA recently approved this drug for treatment of sickle cell anemia. It helps in reducing the frequency of pain crises.
•Crizanlizumab (Adakveo). The FDA recently approved this drug for treatment of sickle cell anemia. Given through a vein, it helps reduce the frequency of pain crises. Side effects can include nausea, joint pain, back pain and fever
•Voxelotor (Oxbryta). The Food and Drug Administration (FDA) recently approved this oral drug to improve anemia in people with sickle cell disease. Side effects can include headache, nausea, diarrhea, fatigue, rash and fever
T/F
T
T
T
Hydroxyurea (____,______,______).
•Crizanlizumab (_____).
L-glutamine oral powder (_____).
•Voxelotor (_________)
Droxia, Hydrea, Siklos
Adakveo
Endari
Oxbryta
Other treatment options of SCD
Blood transfusions. This increases the number of _____________, which helps reduce symptoms and complications.
•Risks include
1)_________ to the donor blood, which can make it hard to _____________
2)________
3)excess _____ buildup in the body. Because excess iron can damage the heart, liver and other organs, with regular transfusions is the need for treatment to ______________
normal red blood cells
an immune response
find future donors (alloimmunization)
infection
iron; reduce iron levels.
Other treatment options of SCD
Stem cell transplant. Also known as ___________, this procedure involves ________________________________________________.
The procedure usually uses a matched donor, such as a _____, who doesn’t have sickle cell anemia.
.
bone marrow transplant
replacing bone marrow affected by sickle cell anemia with healthy bone marrow from a donor
sibling
Other treatment options of SCD
•Because of the risks associated with a bone marrow transplant, the procedure is recommended only for people, usually ______, who ( have or do not have?) significant symptoms and complications of sickle cell anemia.
The procedure requires a (short or long?) hospital stay.
After the transplant, patient will receive drugs to help prevent ____________. Even so, it might still happen, leading to life-threatening complications.
children
Have
Long
rejection of the donated stem cells
Sickle Cell trait (Hb AS)
This is a (benign or malignant?) condition with _____ anaemia and _____ appearance of red cells on a blood film.
Benign
no; normal
Sickle Cell trait (Hb AS)
__________ is the most common symptom and is thought to be caused by ______ of the ________
Haematuria
minor infarcts of the renal papillae.
Sickle cell trait (Hb AS)
Hb S varies from _____ to _____% of the total haemoglobin.
Care must be taken with anaesthesia, _______ and at (low or high?) altitudes.
35; 45
pregnancy
High
Combination of haemoglobin S with other genetic defects of haemoglobin (Compound heterozygotes)
The most common of these are ____________, and the ____________
Hb S/β-thalassaemia
sickle cell/C disease.
Combination of haemoglobin S with other genetic defects of haemoglobin (Compound heterozygotes)
In Hb S/β-thalassaemia, the MCV and MCH are (lower or higher?) than in homozygous Hb SS.
The clinical picture is of sickle cell anaemia; _________ is usual.
Lower
splenomegaly
Combination of haemoglobin S with other genetic defects of haemoglobin (Compound heterozygotes)
Patients with Hb SC disease have a particular tendency to _________ and ______, especially in _______.
thrombosis and pulmonary embolism
pregnancy
Hb SC
In general, when compared with Hb SS disease, they have a (lower or higher?) incidence of retinal abnormalities, (milder or more severe?) anaemia, splenomegaly and generally a (shorter or longer?) life expectancy.
Diagnosis is made by _________, particularly with family studies.
Higher
Milder
Longer
haemoglobin electrophoresis
Haemoglobin C
HbC is caused by substitution of ______ for _________ in the β-globin chain at the same point as the substitution in Hb __.
lysine
glutamic acid
S
Haemoglobin C’s point mutation occurs at a different point from the substitution in Hb S
T/F
F
Same
Haemoglobin C
Hb C tends to form _______ and in the homozygous state (HbCC) there is a ____________ with marked _______ formation, cells with _____ shape and ________.
The spleen is _______.
rhomboidal crystals
mild haemolytic anaemia
target cell
rhomboidal; microspherocytes
enlarged
The carriers (AC) show (plenty or a few?) target cells
A few target cells only
Haemoglobin D
This is a group of variants all with the same __________ that differ from the normal _________
electrophoretic mobility
adult Hb A.
Haemoglobin D
Heterozygote (HbAD) show ____ haematological abnormality while homozygote (HbDD) have ___________ and mild to moderate __________
no
a mild haemolytic anaemia
spleen enlargement.
Haemoglobin D
Co-inheritance of Hb D with Hb S or thalassaemia can produce conditions like ________ (_________ disease) or chronic haemolytic anaemia of moderate severity.
sickle cell anaemia
sickle haemoglobin D
The most frequent Hb D is _____________
Hb D Punjab.
Haemoglobin E disease
This the _____ most prevalent haemoglobinopathy worldwide.
This is the most common haemoglobin variant in __________ where it can reach a carrier frequency of ____-____%.
3rd
South-East Asia
60-80
Haemoglobin E disease
The possible malaria protective effects of this and other inherited haemoglobin abnormalities prevalent in these areas are the main cause of this high prevalence.
T/F
T
Haemoglobin E disease
In the homozygous state, there is a mild ____cytic, ____-chromic anaemia, ______ red cell survival, _______ MCV, target cells, _____ osmotic fragility.
micro
hypo
reduced
reduced
reduced
Haemoglobin E disease
HbE can cause serious disease when _________________
co-inherited with a beta- thalassaemia mutation.
Prenatal diagnosis of genetic haemoglobin disorders
It is important to give _______ to couples at risk of having a child with a major haemoglobin defect.
genetic counseling
Prenatal diagnosis of genetic haemoglobin disorders
If a pregnant woman is found to have a haemoglobin abnormality, her partner should be tested to determine whether he also carries a defect. When both partners show an abnormality and there is a risk of a serious defect in the offspring, particularly β-thalassaemia major, it is important to offer antenatal diagnosis when possible.
Several techniques are available, the choice depending on ________
the stage of pregnancy.
Prenatal diagnosis of genetic haemoglobin disorders
Other control strategies
Pre-_____/_____/pre-_____ screening
Pre- _____screening
_______ screening
______ counselling
school; school
Employment
marital
Population; Genetic
