TABLE OF CONTENT

PREFACE ............................................................................................i

TABLE OF CONTENT.......................................................................ii

TABLE OF PICTURE........................................................................iii

CHAPTER I: INTRODUCTION.........................................................1

1.1 Background.............................................................................1

1.2 Formulation of the problems..................................................1

1.3 Purpose...................................................................................2

CHAPTER II: CONTENT...................................................................3

2.1 Definition ………...................................................................3

2.2 Epidemiology ……….............................................................3

2.3 Etiology and Risk Factor ………...........................................4

2.4 Pathogenesis ………..............................................................5

2.5 Diagnosis………....................................................................7

2.6 Differential Diagnosis ………................................................9

2.7 Management ………............................................................10

2.8 Prevention ………................................................................11

2.9 Prognosis ………..................................................................13

CHAPTER III: CONCLUSION.........................................................15

REFERENCES...................................................................................16

i
 TABLE OF PICTURE

2.1 Increase numbers of patient identified with bleeding disorder

1999-2018)……………………….................................................4

2.2 Chromosome X flip tip inversion in hemophilia A. Cross-over

occur between F8A copy in gen F8 with one of two telomeric

copies. Cross-over with distal telomeric copy is more frequent

about 80% in inversion cases.*......................................................6

2.3 Gene inversion mechanism resulting in severe hemophilia A,

involving intron 22 F8 gene sequence. Recombination between

homologous intron 22 sequence and telomeric 400 kb gene

which is resulting in separation exon 1-22 from exon 23-26 with

reverse direction and relocation.*………………………..............7

ii
 CHAPTER I
INTRODUCTION

1.1 Background
Hemophilia is a disease that manifests itself with prolonged and excessive
bleeding that happen either spontaneously or after insignificant trauma.
Hemophilia A is a genetic disorder that is caused by factor VIII deficiency. Due
to this deficiency those who suffer from this disorder will bleed more when
injured because the blood cannot clot properly. The manifestation of this effect
can range from a simple wound that took longer to heal up to an unknown internal
bleeding that caused a lot of pain. This disease is known as one of the most
common hereditary disorder of hemostasis. It can occur in one out of 5000 males
and is responsible for 80% of hemophilia cases. More than 400.000 males
worldwide has Hemophilia A, many of whom remain undiagnosed. 
Hemophilia A is caused by an inheritied or acquired genetic mutation that
result in dysfunction or deficiency of factor VIII. An X linked, recessive
hemorrhagic trait or gene are the inducer of hemophilia A. It manifests itself as a
congenital absence or decrease in plasma clotting factor VII that is essential for
the clotting process at the site of disruption. These traits are often manifested in
males while females usually serve as carriers for his disease. Failure to either
diagnose or treat this illness may have dire consequences for it can lead to larger
life threatening hemorrhages and injuries. Recalling its urgency in the world of
medicine, further understanding on Hemophilia A is definitely needed.

1.2 Formulation of the Problems

1. What is Hemophilia A?

2. How is Hemophilia A spread?

1
 3. What are the causes of Hemophilia A and what are the risk factors?

4. How does Hemophilia A travel?

5. How do you diagnose Hemophilia A?

6. What is the differential diagnosis of Hemophilia A?

7. How is the management of Hemophilia A?

8. How to prevent Hemophilia A?

9. What is the prognosis for Hemophilia A?

1.3 Purpose
1. To find out the definition of Hemophilia A

2. To find out the spread of Hemophilia A

3. To find out the cause of Hemophilia A and what are the risk factors

4. To find out the course of Hemophilia A

5. To find out how to diagnose Hemophilia A

6. To find out the differential diagnosis of Hemophilia A

7. To find out the management of Hemophilia A

8. To find out how to prevent Hemophilia A

9. To find out the prognosis of Hemophilia A

2
 CHAPTER II
CONTENT
2.1 Definition
Hemophilia A is a genetic disorder caused by factor VIII (F VIII) deficiency
or classic hemophilia, a clotting protein. Although it is a genetic disease, about ⅓ of
cases are caused by a spontaneous mutation, a change in the F VIII gene. The gene
for hemophilia is carried on the X chromosome, inherited in an X-linked recessive
manner. This disease caused the blood does not clot normally. People with
hemophilia A will bleed more than normal after an injury, surgery, or dental
procedure. This disorder can be severe, moderate, or mild. Bleeding into the joint,
muscles, brain, or vital organs can cause pain and other serious complications.1,2

2.2 Epidemiology

Hemophilia A is the most common X-linked disease and most common

coagulation hereditary disorder after von Willebrand disease. Incidence rate of
hemophilia A is 1 case per 5000 males in the US and its prevalence of hemophilia A
is 20.6 cases per 100,000 males.3 Based on World Federation of Hemophilia (WHF),
there is increase number of people identified with bleeding disorder including
hemophilia A since 1999. In 2018, number of people with hemophilia A are 173,711
and in Indonesia, there are 2,035 people lived with hemophilia A.4

3
Figure 2.1 Increase numbers of patient identified with bleeding disorder 1999-2018.4

2.3 Etiology and Risk Factor

Hemophilia A is caused by an inheritied or acquired genetic mutation that

result in dysfunction or deficiency of factor VIII. Inadequate factor VIII results in the
insufficient generation of thrombin by the factor IXa and factor VIIIa complex by
means of the intrinsic pathway of the coagulation cascade. This mechanisme creates a
tendency for impaired clotting in response to trauma, especially in persons with
severe hemophilia, with spontanous bleeding. Hemophilia A is inherited in an X-
linked recessive pattern. The gene for factor VIII is located on the long arm of the X
chromosome. The factor VIII gene is one of the largest genes, compromising
approximately 0.1% of the DNA in the X chromosome. 
The biggest risk factor for hemophilia is to have family members with history
of hemophilia.Hemophilia A is inherited in an X-linked recessive pattern. Males only
have one X chromosome, that means one altered copy of the gene in each cell is
sufficient to cause the condition. Meanwhile females have two X chromosome, a
mutation would have to occur in both gene to cause the disorder. Thats why it is very

4
rare for females to have hemophilia. In X-linked recessive inheritance, a female with
one altered copy of the gene in each cell is called a carrier. Carrier females have
about half the usual amount of coagulation factor VIII, which is generally enough for
normal blood clotting.

2.4 Pathogenesis

In hemophilia A patient, an abnormality (defect) was found in the gene

structure of the coagulation protein, factor (F) VIII. FVIII is located in the X
chromosome. Hemophilia A patient will inherit this gene to their children. If a man
with hemophilia A married to a healthy and normal woman, on the second generation,
they will have a healthy male child and a hemophilia A-carrier female child, who
carries their father’s X chromosome, which contains the defect gene. Later, if this
hemophilia A-carrier woman married to a healthy and normal man, they will generate
the third generation, in which half of their male children will inherit their mother’s X
chromosome which contains the defect gene, and become hemophilia A patient,
meanwhile half of their female children will become hemophilia A carrier. If this
hemophilia A-carrier woman married to a man with hemophilia A, they will generate
the fourth generation, in which half of their female child and half of their male child
will become hemophilia A patients, and another half of their female child will
become hemophilia A carrier.5
Factor VIII (F8) Gene Defects in Hemophilia A
F8 defects associated with hemophilia A may be divided into several
categories: gross gene rearrangements, insertions or deletions of genetic sequence,
single DNA base substitutions resulting in either amino acid replacement
(“missense”), premature peptide chain terminator (“nonsense” or stop mutations), and
mRNA splicing defects. The single, clinically most important defect is a gene
rearrangement (an inversion) involving intron 22 F8, which is evident in
approximately 50% of all severe hemophilia A. In hemophilia A, intron which

5
divides exon 22 and 23 contain 2 additional transcripts named F8A and F8B. F8B is a
2.5 kb transcript that is transcribed in the same direction as the gene F8. F8A are
transcribed in the opposite direction to the F8 gene and two copies of F8A are found
at 300 kb and 400 kb of telomeric F VIII gene (Figure 2.2). 5,6

 
Figure 2.2 Chromosome X flip tip inversion in hemophilia A. Cross-over
occur between F8A copy in gen F8 with one of two telomeric copies. Cross-over with
distal telomeric copy is more frequent about 80% in inversion cases.5

In intron 22 F8 inversion, homologous recombination occurs between 9.5 kb

of intron sequence (int22h-1) and one of 2 intron sequence (int22h-2 and int22h-3).
Recombination occurs during the division of meiosis from spermatogenesis. It
produces large inversion and translocation of exon 1-22 and exon 23-26 (Figure 2.2).5

6
  
Figure 2.3 Gene inversion mechanism resulting in severe hemophilia A,
involving intron 22 F8 gene sequence. Recombination between homologous intron 22
sequence and telomeric 400 kb gene which is resulting in separation exon 1-22 from
exon 23-26 with reverse direction and relocation.5

2.5 Diagnosis

Diagnostic evaluation for person with hemophilia A usually comes with

family history of Hemophilia A, over bleeding time out proportion with traumatic
injury, or activated partial thromboplastin time which abnormal. 70% case of
hemophilia A related to family history can be evaluated at birth or after the first
episode of bleeding. Meanwhile, hemophilia A patient who do not have any family
history of hemophilia A can be diagnosed in lots of situations (circumcision, post
injection for vaccine or a drug, minor trauma leads to bruising, crawling and walking
cause ecchyosis in buttocks, and bleeding caused by torn frenulum). 7 By evaluating
and found the criteria increasing the suspicion of hemophilia A and should continue
with another examination related to hemophilia A.8
Patient with suspect hemophilia should do factor VIII an IX test to know
positive hemophilia and differentiate the type of hemophilia. If the test result showing
decrease level of factor VIII, we can suspect the patient with hemophilia A. Another
test should be done such as APTT (Activating Plasma Thromboplastin Time) with

7
prolonged APTT indicate hemophilia A. In order to exclude other disease, we can
also do some test such as platelet count, vWF  level, and PTT (Plasma Prothrombin
Time).9
Knowing the factor VIII level in patient can classify type of hemophilia A.
Mild hemophilia A (0.06 to 0.40 IU/mL or 6%-40% factor VIII) usually hard to
diagnose if using just clinical appearance, because it may only happen after surgery
or major trauma. Severe hemophilia A (0.02 to 0.05 IU/mL or 2% to 5% factor VIII)
can happen after mild to moderate trauma. And severe hemophilia A (less than 0.01
IU/mL or less than 1% factor VIII), spontaneous bleeding in intraarticular and
intramuscular can happen in severe hemophilia A.8
Clinical presentation in patient with hemophilia A can also be one of indicator
to diagnose the hemophilia A. Hemarthrosis or synovial joint bleeding can be indicate
of severe hemophilia A and become one of the best time to inject factor VIII. The
frequency of hemarthrosis episode will indicate the severity of Hemophilia A. The
most common joint who affected are knee, elbow, ankle, and wrist, while small joints
are less affected. Hematoma such as muscle hematoma (75% patient with severe
hemophilia A) who become major cause of disabilities in hemophilia A. Also, 10–
25% of bleeding episode in hemophilia A is muscle hematoma. After hematoma, it
leads to traumatic hematoma which related to superficial ecchymosis and sore. Some
detection test (keratin kinas, lactate dehydrogenase, aminotransferees, and aldolase),
CT Scan, and MRI can detect of necrosis in muscle.10
Central Nervous System (CNS) bleeding can also be indicator of hemophilia
A. Hemophilia A patient accompanied with CNS bleeding is serious case of mortality
and morbidity. Shock, anemia, lethargy, and hypotension can occur as unspesific
bleeding, while sudden problem in walking or arm movement, painful headaches or
neck pain, sleepiness and behavioral changes, repeated vomiting, seizures or
convulsions and double vision are severe sign of hemophilia A. Other bleeding such
as Gastro-Intestinal bleeding and hematuria can also indicate of hemophilia A.10

8
2.6 Differential Diagnosis

1.      Acquired Hemophilia

Acquired Hemophilia has similar laboratory findings to Hemophilia A, which

the bleeding time, prothrombin time (PT), and platelet count are normal, a
prolongation of activated partial thromboplastin time (aPTT), and also shows reduced
FVIII levels. Acquired hemophilia caused by the development of autoantibodies
related to plasma coagulation factors, mostly FVIII.

2.      Factor XI Deficiency

Factor XI Deficiency can manifest as an incidental laboratory abnormality, for

example activated partial thromboplastin time (aPTT) unexpected prolongation
happens. When abnormal bleeding occured, it tends to be much milder than in
hemophilia A and B, and to involve different tissues, typically involves mucosal
tissues (which are rich in fibrinolytic activity, for example in the oral and nasal
cavities and urinary tract). Severe case is rare, but commonly happens epistaxis and
menorrhagia in women.

3.      Von Willebrand Disease

Von Willebrand disease (vWD) are inherited, genetically, clinically

heterogeneous hemorrhagic disorder, and the most common differential diagnosis of
hemophilia A, which is caused by a deficiency or dysfunction of the protein termed
von Willebrand factor (vWF). Consequently, defective vWF interaction between
platelets and the vessel wall impairs primary hemostasis. vWF performs two major
roles in hemostasis. First, it mediates the adhesion of platelets to sites of vascular
injury. Second, it binds and stabilizes the procoagulant protein factor VIII (FVIII). 

9
 4.      Hemophilia B

This type of disease is commonly considered clinically indistinguishable with

hemophilia A. However, it differences in bleeding frequency, clinical scores, use of
prophylaxis, and need for orthopedic surgery have been reported, suggesting that the
bleeding tendency associated with factor IX deficiency may be less severe with
consequent better outcomes in the long term. The type of factor VIII/IX mutation is a
major determinant of the bleeding tendency. 11,12

2.7 Management
The primary aim of treatment in haemophilia is to prevent and treat bleeding
with deficient clotting factor. Specific factor deficiency should be treated with
specific factor concentrate principle of haemophilia, for example Factor VIII to treat
haemophilia A. 1 unit of factor VIII/kg will increase circulating factor VIII level by
2%. Therefore, 50 units/kg will give 100% correction to achieve the homeostasis. The
treatment is multidiscipline. Treatment is given by clinician (pediatric / internist),
clinical pathology, medical rehabilitator, orthopaedic and psycholog. Regular
standardized evaluation is performed at least every 12 months which can identify new
or potential problems in their early stages, so that treatment plans can be modified.13
Preparation on this therapy that can be used is cryoprecipitate, which contain
F. VIII, vWF, fibrinogen and F. XIII. Lypholized F.IX-prothrombin complex
concentrate which contain all of Vit K-dependent factor also can be used to treat
haemophilia A patient. Other preparation such as Lypholized F.VIII commercial is
made from pool donor and risky to patient, because it can transmit hepatitis and HIV. 
If acute bleeding occurs, it should be treated as quick as possible, preferably within
two hours. Bleeding in patients with mild and moderate haemophilia A can be treated
by administration of desmopressin (DDAVP), which can raise Factor VIII level
adequately about three to six times baseline levels. Desmopressin cause the release of

10
Von Willebrand’s antigen, a protein that carries factor VIII, from the platelets and the
cells that line the blood vessels where it is stored. The increasing of Von Willebrand’s
antigen and factor VIII will help to stop bleeding.14
Education is also necessary to prevent the disability with health education.
Patient should avoid trauma as minimal as possible and avoid intramuscular injection.
Rehabilitation also needed if joint damage occur. Pain could due to chronic
hemophilic arthropathy in patients who have not been adequately treated with clotting
factor concentrates for joint bleeding. Treatment needed to manage this pain includes
functional training, adaptations, and adequate analgesia. On the other hand, COX-2
inhibitors have a greater role in this situation.  Other NSAIDs should be avoided and
when pain is disabling, orthopaedic surgery may be indicated.14
Physical activity should be encouraged on patient to achieve physical fitness
and normal neuromuscular development. Main attentions of the activity are muscle
strengthening, coordination, general fitness, physical functioning, healthy body
weight, and self-esteem. Patients with significant musculoskeletal dysfunction can do
weight-bearing activities for their joint health and encouraging the development and
maintenance of good bone density. During activity, target joints can be protected with
braces or splints during activity, especially when there is no clotting factor coverage.
This joint treatment is performed to prevent ankylosis.14
Dental extraction or surgical procedures done in the oral cavity should have a
plan for hemostasis management, in consultation with the hematologist. Tranexamic
acid or epsilon aminocaproic acid (EACA) is often used after dental procedures to
reduce the need for replacement therapy. Dental care management on haemophilia A
patient can be safely carried out under local anesthesia using the full range of
techniques available to dental surgeons. Infiltration, intrapapillary, and intra-
ligamentary injections are often done under factor cover (20-40%).14

2.8 Prevention

11
 Since Hemophilia A is mostly a hereditary disase with mutation in the patients
gene, prevention in patients with Hemophilia A is mainly focusing on how to prevent
the spontaneous bleeding that occurs in muscle and joints. The spontaneous bleeding
in patients with Hemophilia A can occur when the patients are doing their daily
activity such as walking on the stairs, mainly because of the friction inside the joints.
There are several methods in preventing the occurence of bleeding in Hemofilia A
patients such as intravenous infusions of Factor VIII and or the use of Desmopressin
Acetate.
The administration of intravenous infusions of Factor VIII as a prophlyaxis of
spontaneous bleeding has shown an improvement in the clinical outcomes of the
patients, with three to four times procedures weekly, the Factor VIII levels can be
mantained to above 1 IU/dL. The prophylaxis are then divided into five types. The
first one is Episodic Treatment which is the treatment given only when the clinically
evident bleeding occurs. The second one is Primary Prophylaxis which is the
treatment started before the second clinically evident bleeding of the large joints
occurs or in the absence of documented osteochondral joint disease. The third is
Secondary Prophylaxis which is the treatment given when there is no onset of joint
disease while two or more bleeding in the large joints occurs. Next is Tertiary
Prophylaxis which is the treatment given when the joint disease is documented with
physical examination and radiographic imaging. The last one is Intermittent
Prophylaxis which is the treatment given to prevent bleeding in the recurrence lasting
less than 45 weeks in a year.
There are two main protocols in the administration and dosing of Hemophilia
A prophylaxis, the Malmo Protocol suggest to administer 25-40 IU/kg per dose in
three times per week for those with Hemophilia A, while the Utrecht Protocol suggest
to administer 15-30 IU/kg per dose in three times per week for those with Hemophilia
A.15 Study also shows that prophylaxis is best given in the morning before the daily
activity. However, the prophylaxis are not meant to heal the joint damage prefectly

12
but rather decrease the frequency of the bleeding and help to slow or prevent further
joint damage, thus improving quality of life.
Patient with Hemophilia A requires a lot of consultation when it comes to
doing a medical procedure that involves blood such as surgery, giving birth, and
vaccination. The role of prophylaxis is very important in every procedures to prevent
excessive bleeding. For example, when person with bleeding disorders is required to
do vaccination, the vaccination should be done subcutaneously rather than
intramuscularly or intradermally. When the vaccine can not be administered
subcutaneously, intramuscular and intradermal procedures can be done while using
the smallest needle possible (25-27 gauge), and covered with infusion of clotting
factor concentrates such as Factor VIII, then pressure should be applied to injection
site for at least five minutes after the procedure.15
Beside the treatment or prophylaxis of bleeding in Hemophilia A with the
injection of plasma-derived or recombinant concentrates for replacing the insufficient
emoint of factor VIII, the bleeding episodes in Hemophilia A can also be managed by
the use of Desmopressin Acetate which is a synthetic analogue of the hormone
vasopressin that works by stimulating the release of Factor VIII from its storage sites,
thus raise the level of Factor VIII and  controlling the bleeding in patients with mild
to moderate Hemophilia A. The Desmopressin Acetate can be administered
intranasally as treatment for bleeding episodes or as prophylaxis with the dose of 150
ug in patients weighing 50 kg or less, or 300 ug for patients weighing more than 50
kg.16

2.9 Prognosis

Based on the diagnosis, Hemophilia A can be mild, moderate, or severe,

depending on how much factor VIII is in the person’s blood. 50-60% of Hemophilia
A cases were found in severe conditions. In all stages of diagnosis, patients should
have a routine consultation with the doctor to evaluate the management and therapies.

13
An appropriate treatment and education to the patient and family, patients with
Hemophilia A can live healthy with a good quality of life. Presence of other health
conditions, such as chronic disease may affect life expectancy of the patients.16
Treatment of hemophilia have been discovered for nearly 50 years by
replacing the missing proteins of Factor VII, giving cryoprecipitate, or giving blood
transfusion. With early diagnosis and adequate treatment, most complications of
Hemophilia A can be avoided.17 
In few cases, life-threatening condition comorbid to severe Hemophilia may
occur, such as intracranial hemorrhage, and bleeding into the soft tissue around
important organs. Other cases may show chronic joint weakness. 18 Anemia, joint
deformity, neuritis and muscle atrophy may occur as side effect of severe bleeding or
improper blood transfusion. To prevent bad prognosis caused by the treatment, the
doctor should do anamnesis, diagnosis, and management clearly. 

14
 CHAPTER III
CONCLUSION

Hemophilia A is a genetic disorder caused by factor VIII (F VIII) deficiency

or classic hemophilia, a clotting protein. People with hemophilia A will bleed more
than normal after an injury, surgery, or dental procedure. This disorder can be severe,
moderate, or mild. Bleeding into the joint, muscles, brain, or vital organs can cause
pain and other serious complications.1,2 Hemophilia A is the most common X-linked
disease and most common coagulation hereditary disorder after von Willebrand
disease. Incidence rate of hemophilia A is 1 case per 5000 males in the US and its
prevalence of hemophilia A is 20.6 cases per 100,000 males.3 Hemophilia A is caused
by an inheritied or acquired genetic mutation that result in dysfunction or deficiency
of factor VIII. Inadequate factor VIII results in the insufficient generation of thrombin
by the factor IXa and factor VIIIa complex by means of the intrinsic pathway of the
coagulation cascade. FVIII is located in the X chromosome.
Hemophilia A patient will inherit this gene to their children. If a man with
hemophilia A married to a healthy and normal woman, on the second generation, they
will have a healthy male child and a hemophilia A-carrier female child, who carries
their father’s X chromosome, which contains the defect gene. Later, if this
hemophilia A-carrier woman married to a healthy and normal man, they will generate
the third generation, in which half of their male children will inherit their mother’s X
chromosome which contains the defect gene, and become hemophilia A patient,
meanwhile half of their female children will become hemophilia A carrier. If this
hemophilia A-carrier woman married to a man with hemophilia A, they will generate
the fourth generation, in which half of their female child and half of their male child
will become hemophilia A patients, and another half of their female child will
become hemophilia A carrier.5 There are two main protocols in the administration and
dosing of Hemophilia A prophylaxis, the Malmo Protocol suggest to administer 25-

15
40 IU/kg per dose in three times per week for those with Hemophilia A, while the
Utrecht Protocol suggest to administer 15-30 IU/kg per dose in three times per week
for those with Hemophilia A.15
Study also shows that prophylaxis is best given in the morning before the
daily activity. However, the prophylaxis are not meant to heal the joint damage
prefectly but rather decrease the frequency of the bleeding and help to slow or
prevent further joint damage, thus improving quality of life. Beside the treatment or
prophylaxis of bleeding in Hemophilia A with the injection of plasma-derived or
recombinant concentrates for replacing the insufficient emoint of factor VIII, the
bleeding episodes in Hemophilia A can also be managed by the use of Desmopressin
Acetate which is a synthetic analogue of the hormone vasopressin that works by
stimulating the release of Factor VIII from its storage sites, thus raise the level of
Factor VIII and  controlling the bleeding in patients with mild to moderate
Hemophilia A.

16
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2
Hemophilia A [Internet]. National Hemophilia Foundation. 2019 [cited 20
November 2019]. Available from: https://www.hemophilia.org/Bleeding-
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3
Hemophilia: Data & Statistics. Centers for Disease Control and Prevention.
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4
Report on the Annual Global Survey 2018. World Federation of Hemophilia.
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5
Repo.unand.ac.id . (2019). [online] Available at:
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7
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8
Dunn AL. Hemophilia A. In: Transfusion Medicine and Hemostasis. Elsevier
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11
Hemophilia A Differential Diagnoses [Internet]. Medscape. 2019 [cited 22
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Bakta I. Hematologi Klinik Ringkas. 6th ed. Jakarta: ECG; 2006.
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McDaniel M. Nurses' Guide to Bleeding Disorders. 6th ed. New York: National
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World Federation of Hemophilia. Guidelines for The Management of
Hemophilia. 2nd ed. Canada: World Federation of Hemophilia; 2012.
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Ludlam CA, Mahlangu JN, Mulder K, Poon MC, Street A. Guidelines for the
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18
Soucie J. Global Hemophilia Care: Data for Action. Annals of Internal Medicine.
2019;171(8):585.

18