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145
1.
A glutamic acid to valine substitution in
the beta-globin subunit of hemoglobin
causes which one of the following?
(A)
-thalassemia
(B)
-thalassemia
(C)
sickle cell disease
(D)
Hb Bart hydrops fetalis syndrome
2.
Individuals with sickle cell disease appear
healthy at birth. This is due to which one of
the following?
(A)
presence of HbF
(B)
presence of HbS
(C)
presence of HbA
(D)
presence of HbD
3.
Normal hematologic findings would be
expected with which on of the following?
(A)
0
-thalassemia
(B)
-thalassemia
(C)
thalassemia major
(D)
-thalassemia
4.
A severe form of
-thalassemia that
results in death in neonates is which one of
the following?
(A)
hemoglobin H disease
(B)
Hb Bart
(C)
thalassemia major
(D)
thalassemia minor
5.
Reduced or absent synthesis of
-globin
subunits of hemoglobin results in which one
of the following?
(A)
-thalassemia
(B)
0
-thalassemia
(C)
-thalassemia
(D)
sickle cell anemia
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146
1. The answer is (C).
Sickle cell disease results from a missense mutation in the second
nucleotide of the sixth codon, inherited in an autosomal recessive fashion, which results in
a glutamic acid to valine substitution in the
-globin subunit of hemoglobin. The resulting
hemoglobin S (HbS) molecule forms polymers that distort the cells and leave them poorly
deformable. The thalassemias, including Hb Bart result from deletions or mutations that
cause reduced or absent synthesis of hemoglobin subunits.
2. The answer is (A).
Fetal hemoglobin (Hb F) is the predominant form of hemoglobin in
prenatal life and persists at high levels for some time after birth. Hb F does not contain
-
globin subunits so it is unaffected by the mutation that causes sickle cell disease. Hb A is
the normal adult hemoglobin. HbS and HbD are both abnormal hemoglobins caused by
the common sickle cell mutation and coinheritance of another mutation in the same gene
respectively.
3. The answer is (B).
This is the silent carrier state for
-thalassemia, and in many cases, the
hematologic findings are normal.
4. The answer is (B).
Hb Bart is the most severe form of
-thalassemia and results from deletion
or dysfunction of all four
-globin alleles.
5.
The answer is (A).
-Thalassemia is defined by the absence or reduced synthesis of the
-globin subunits of hemoglobin.
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147
I. HEMOPHILIA A (FACTOR VIII DEFICIENCY)
A.
Hemophilia A is an
X-linked recessive
genetic disorder caused by a mutation in the
F8 gene
on
chromosome Xq28
for
coagulation factor VIII.
B.
Factor VIII participates in the
intrinsic pathway of hemostasis
(blood clotting) in the following
way: factor VIII binds to von Willebrand factor (vWF) in the circulation for stabilization (vWF
acts as a carrier protein for factor VIII); factor VIII is cleaved by thrombin, released from vWF,
and binds to activated platelet membranes where it interacts with factor IX; the factor VIII
and factor IX interaction activates factor X (which is a critical step in early hemostasis).
C.
Hemophilia A is most commonly (45% of cases) caused by the
F8 intron 22-A gene inversion
(“flip” inversion)
mutation. The remainder of cases are caused by missense, complete or par-
tial deletions, RNA splicing, nonsense, large insertion, sequence duplications, and frameshift
mutations.
D.
Hemophilia A is defined by a reduced factor VIII clotting activity in the presence of normal
vWF levels.
E. Prevalence
.
The prevalence of hemophilia A is 1/10,000 births in the US population.
F.
There are three clinically significant forms of hemophilia A:
1. Severe hemophilia A.
a.
Severe hemophilia A results from
1% of factor VIII clotting activity.
b. Clinical features include
:
usually diagnosed before 1 year of age, prolonged oozing after
injuries, renewed bleeding after initial bleeding has stopped, delayed bleeding, large
“goose eggs” after minor head bumps, abnormal bleeding after minor injuries, deep
muscle hematomas, episodes of spontaneous joint bleeding are frequent, and 2 to 5
spontaneous bleeding episodes/month without adequate treatment.
2. Moderately severe hemophilia A.
a.
Moderately severe hemophilia A results from 1% to 5% of factor VIII clotting activity.
b. Clinical features include:
usually diagnosed before 5 to 6 years of age, prolonged oozing
after injuries, renewed bleeding after initial bleeding has stopped, delayed bleeding,
abnormal bleeding after minor injuries, episodes of spontaneous joint bleeding are
rare, and one bleeding episode/month
→
one bleeding episode/year.
3. Mild hemophilia A.
a.
Mild hemophilia A results from 6% to 35% of factor VIII clotting activity.
b. Clinical features include:
usually diagnosed later in life, prolonged oozing after injuries,
renewed bleeding after initial bleeding has stopped, delayed bleeding, abnormal
bleeding after major injuries, episodes of spontaneous joint bleeding are absent, and 1
bleeding episode/year
→
1 bleeding episode/10years.
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148
BRS Genetics
II. HEMOPHILIA B (FACTOR IX DEFICIENCY; CHRISTMAS DISEASE)
A.
Hemophilia B is an X-linked recessive genetic disorder caused by a mutation in the
F9
gene
on
chromosome Xq27.1-q27.2
for
coagulation factor IX
.
B.
Factor IX participates in the intrinsic pathway of hemostasis (blood clotting) in the following
way: factor VIII is cleaved by thrombin, released from vWF, and binds to activated platelet
membranes where it interacts with factor IX; the factor VIII and factor IX interaction acti-
vates factor X (which is a critical step in early hemostasis).
C.
Hemophilia B is caused by a wide variety of mutations, which include: missense, complete or
partial deletions, RNA splicing, nonsense, and frameshift mutations.
D.
Hemophilia B is defined by a reduced factor IX clotting activity in the presence of normal
vWF levels.
E. Prevalence.
The prevalence of hemophilia B is 1/25,000 in the US population.
F.
There are three clinically significant forms of hemophilia B:
1. Severe hemophilia B.
a.
Severe hemophilia B results from
1% of factor IX clotting activity.
b. Clinical features include:
usually diagnosed before 1 year of age, prolonged oozing after
injuries, renewed bleeding after initial bleeding has stopped, delayed bleeding, large
“goose eggs” after minor head bumps, abnormal bleeding after minor injuries, deep
muscle hematomas, episodes of spontaneous joint bleeding are frequent, and 2 to 5
spontaneous bleeding episodes/month without adequate treatment.
2. Moderately severe hemophilia B.
a.
Moderately severe hemophilia B results from 1% to 5% of factor IX clotting activity.
b. Clinical features include:
usually diagnosed before 5 to 6 years of age, prolonged oozing
after injuries, renewed bleeding after initial bleeding has stopped, delayed bleeding,
abnormal bleeding after minor injuries, episodes of spontaneous joint bleeding are
rare, and one bleeding episode/month
→
one bleeding episode/year.
3. Mild hemophilia B.
a.
Mild hemophilia B results from 5% to 30% of factor IX clotting activity.
b. Clinical features include
: usually diagnosed later in life, prolonged oozing after injuries,
renewed bleeding after initial bleeding has stopped, delayed bleeding, abnormal
bleeding after major injuries, episodes of spontaneous joint bleeding are absent, and 1
bleeding episode/year
→
1 bleeding episode/10 years.
A.
VWD is a genetic disorder caused by a mutation in the
VWF gene
on
chromosome 12p13.3
for
von Willebrand factor (vWF).
B.
VWD is the most common inherited bleeding disorder. However, only a small number of
patients come to medical attention because of bleeding symptoms.
C.
vWF participates in the intrinsic pathway of hemostasis (blood clotting) in the following way:
vWf acts as a carrier protein for factor VIII; forms a bridge between vascular subendothelial
connective tissue and platelets by binding to the
platelet receptor Gp1b
at sites of endothelial
damage.
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Chapter 14
Genetics of Bleeding Disorders
149
t a b l e
14-1
Summary Table of Laboratory Findings in Bleeding Disorders
Lab Findings
Hemophilia A
Hemophilia B
VO
n Willebrand Disease
Platelet count
Normal
Normal
Normal
Bleeding time
Normal
Normal
Prolonged
Prothrombin time
Normal
Normal
Normal
Partial thromboplastin time
Prolonged
Prolonged
Prolonged or normal
Factor VIII
Low
Normal Normal
Factor IX
Normal
Low
Normal
v WF
Normal
Normal
Low
Ristocetin-induced platelet aggregation
Normal
Normal
Impaired
D.
The majority of mutations causing VWD are still undefined. A database of mutations is avail-
able at http://www.ragtimedesign.com/vwf/mutations. A mutation that has been reported in
a number of patients is a missense mutation, which results in a
normal cysteine S
S
arginine
at
position 386 (C386R).
E.
VWD is defined by a reduced synthesis or reduced functionality of vWF.
F. Prevalence
.
The prevalence of VWD is 1/10,000 worldwide. The prevalence of VWD is 1/1,200
births in the Veneto region in northern Italy.
G.
There are three clinically significant forms of VWD:
1. Type 1 VWD.
a.
Type 1 VWD is an autosomal dominant genetic disorder.
b.
Type 1 VWD results from a reduced synthesis of vW.
c.
Type 1 VWD accounts for 75% of the cases (i.e., the most common type of VWD).
d. Clinical features include:
can be diagnosed at any age; lifelong easy bruising; nose
bleeding (epistaxis); skin bleeding; prolonged bleeding from mucosal surfaces; heavy
menstrual bleeding; and mild to moderately severe bleeding symptoms, while some
patients are asymptomatic.
2. Type 2 VWD.
a.
Type 2 VWD is an autosomal dominant or autosomal recessive genetic disorder.
b.
Type 2 VWD results from a reduced functionality of vWF.
c.
There are four subtypes of Type 2 VWD: 2A, 2B, 2M, and 2N.
d.
Type 2A VWD accounts for 10% to 15% of the cases.
e. Clinical features include:
can be diagnosed at any age, lifelong easy bruising, nose
bleeding (epistaxis), skin bleeding, prolonged bleeding from mucosal surfaces, heavy
menstrual bleeding, and moderate to moderately severe bleeding.
3. Type 3 VWD.
a.
Type 3 VWD is an autosomal recessive genetic disorder.
b.
Type 3 VWD results from a reduced synthesis of vWF and factor VIII.
c.
Type 3 VWD is a rare disease but the most severe form of VWD.
d.
Clinical features include: nose bleeding (epistaxis); severe skin bleeding; severe bleed-
ing from mucosal surfaces; muscle hematomas; and severe joint bleeding.
IV. SUMMARY TABLE OF LABORATORY FINDINGS IN BLEEDING
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