A Brief History of Hemophilia

A project report submitted to the Department of Pharmacy, University

of Asia Pacific in partial fulfillment of the requirements for the degree
of

Master of Science in Pharmaceutical General

Submitted By

Registration No. PG-12-14-16-030

 Department of Pharmacy

State University of Bangladesh

LIST OF CONTENTS

Sl. No.
Name of the Topic
Page No.

Summary of Study
I
1.
Hemostasis
1
1.1
Mechanisms of Hemostasis
1
1.2
Clotting Factors in Blood
2
1.3
Mechanism of Blood Coagulation
3

4
Hemophilia

3.
History of Hemophilia
5
3.1
First Described and Identified
5
3.2
A Royal Disease
5-6
3.3
Treatment Breakthroughs
6-8
3.4
Timeline
8-9
4.
Types of Hemophilia
9-10
5.
Reasons for Hemophilia
10
5.1
Inheritance
10
5.1.1
Hemophilia Inheritation Through man
11-12
5.2
Acquired Hemophilia
13
5.2.1
Mutation
13
5.2.1.1
Genetic Mutations
13
5.2.1.2
Mutations in the Factor VIII and IX Genes
13-14
6.
Carriers and Women with Hemophilia
14
7.
Severity of hemophilia
14
8.
Disease symptoms
15-16
9.
Complications
17
9.1
Bleeding into Joints
17
9.2
Bleeding in the Brain
18
9.3
Inhibitor Antibodies
18
10.
Diagnosis of Hemophilia
19
10.1
Principles of Diagnosis
19
10.2
Prenatal Diagnosis of Hemophilia
19-20
10.3
Diagnosis of Hemophilia in Children and
20

Adults

10.3.1
Partial Thromboplastin time (PTT) and
20

Prothrombin Time (PT) Tests

10.3.2
Factor Assays
20
10.3.3
Factor Activity Test
20-21
10.3.4
Percent Activity
21
10.3.5
Screening Tests
21-22
11.
Management of Hemophilia
22
11.1
Principles of care
22-23
11.2
Fitness and Physical Activity
23-24
11.3
Adjunctive Management
24
11.4
Prophylactic Factor Replacement Therapy
25
11.5
Administration and Dosing Schedules for
26

Prophylaxis

11.6
Pain Management
26-27
11.7
Surgery and Invasive Procedures
27-29

12.
Definitive Treatment
29

12.1
Treatment with Replacement Therapy
29
12.1.1
Complications of Replacement Therapy
29-30

12.2.
Other Types of Treatment
30

12.2.1
Pharmacologic Options for Controlling
30-32

Bleeding
12.3.
Producing Recombinant Factor VIII and IX
33

12.4.
Gene Therapy
33-34

12.4.1
The Advantages of Gene Therapy for
34

Hemophilia

12.4.2
Gene Therapy in Humans
35
12.4.3
Risks of Gene Therapy
35-36

12.5.
Best Treatment Option Received by Parents
36-37

13.
Conclusion
37

Reference
38-41
LIST OF TABLES

Sl. No.
Name of the Topic
Page No.
1.
System for naming blood-clotting factors
2
2.
Some molecular and physiological characteristics of
9

hemophilia A and B

3.
Severity of haemophilia (ISTH criteria)
15
4.
Interpretation of screening tests
21
5.
Definitions of factor replacement therapy protocols
25
6.
Strategies for pain management in patients with
27

hemophilia

7.
Definition of adequacy of Hemostasis for surgical
28

procedures
LIST OF FIGURES

Sl. No.
Name of the Topic
Page No.

1.
The clotting mechanism. A, active form of clotting
4

factor. TPL, tissue Thromboplastin; TFI, tissue factor

pathway inhibitor.

2.
Inheritance Pattern for HemophiliaExample 1
12

3.
Inheritance Pattern for HemophiliaExample 2
12

4.
Clinical manifestations of haemophilia.
16

5.
After experiencing repeated hemophilic bleeding
15

episodes, joints can develop a chronic joint disease called

hemophilic arthropathy

6.
Intracranial bleeding is bleeding inside the brain.
18

7.
This diagram shows the ex vivo method of gene therapy.
33
Summary of Study

Hemophilia is a hereditary genetic disorder that impairs the bodys ability to control blood
clotting. People with Hemophilia have lower clothing factors level of blood plasma or
impaired activity of the coagulation factor needed for normal clothing process. Hemophilia A
(clothing factor VII deficiency); Hemophilia B (clotting factor IX deficiency) are the main
types of Hemophilia. Incidence of excessive or abnormal bleeding were 1st recorded
st
hundreds of years ago, in 1947 the main two types of Hemophilia were 1 distinguished. It is
sometimes referred to the royal diseases, because it affected the royal families to England,
th th
Germany, Russia and Spain in the 19 and 20 Century. The main reason for hemophilia
inheritance where affected male with no functioning factor VIII gene or IX gene have very
low to no factor in blood, carrier females have at least one functioning X chromosomes with a
normal factor VIII or IX gene that provide about 50% factor level. In acquired hemophilia the
main reason in genetic mutation of various types. Hemophilic pt. show different symptoms
and the level of severity of the disease depend on the amount clotting factor that is missing
from peoples blood. The disease may leads to complication like hemathrosis:

arthritis; intracranial bleeding and inhibitor antibodies .Prenatal cases can be done by

chorionic sampling and Aminiocentsis. In adult and children Haemophillia is diagnosised by

PTT; PT text; Factor assays and factor activity tests; screening test includes platelet count;
BT; PT and APTT. The primary aim of the management of a Haemophillic Pt. is to prevent
and treat bleeding in the deficient clothing factor. Prevention can be achieved by fitness and
physical activity; prophylactic factor replacement thereby etc. The definittive treatment for
the disease in replacement that includes concentration of clothing factor VIII or IX . There are
many pharmacologic options for controlling bleeding includes tramnexamic acid; Fibrin
pealet; calcium alginate; desmopressin etc. Now days, gene therapy represents a new type of
treatment for Hemophilia. Gene therapy gets right to the source of a genetic disease by trying
to correct the defective gene.
1. Hemostasis

In the word hemostasis, hemo means blood, and stasis means to stop. Hemostasis thus
describes how the body is able to stop the flow of blood after an injury. The process of
hemostasis begins about 20 seconds after an injury and is similar in all mammals (Raabe,
2008).

1.1 Mechanisms of Hemostasis

Hemostasis is maintained in the body via three mechanisms:

Vascular spasm - Damaged blood vessels constrict. Vascular spasm is the blood vessels' first
response to injury. The damaged vessels will constrict (vasoconstrict) which reduces the
amount of blood flow through the area and limits the amount of blood loss. This response is
triggered by factors such as a direct injury to vascular smooth muscle, chemicals released by
endothelial cells and platelets, and reflexes initiated by local pain receptors. The spasm
response becomes more effective as the amount of damage is increased. Vascular spasm is
much more effective in smaller blood vessels.

Platelet plug formation - Platelets adhere to damaged endothelium to form a platelet plug
and then degranulate. This process is regulated through thromboregulation. Plug formation is
activated by a glycoprotein called Von Willebrand factor (vWF), which is found in plasma.
Platelets play one of the biggest roles in the hemostatic process. As they adhere to the
collagen fibers of a wound, platelets become spiked and much stickier. They then release
chemical messengers such as adenosine diphosphate(ADP), serotonin and thromboxane A2,
causing more platelets to stick to the area, release their contents, and enhance vascular
spasms. As more chemicals are released more platelets stick and release their chemicals;
creating a platelet plug and continuing the process in a positive feedback loop. Platelets alone
are responsible for stopping the bleeding of unnoticed wear and tear of our skin on a daily
basis.

Blood coagulation - Clots form upon the conversion of fibrinogen to fibrin, and its addition
to the platelet plug. Coagulation: The third and final step in this rapid response reinforces the
platelet plug. Coagulation or blood clotting uses fibrin threads that act as a glue for the sticky
platelets. As the fibrin mesh begins to form the blood is also transformed from a liquid to a
gel like substance through involvement of clotting factors and pro-coagulants. The
coagulation process is useful in closing up and maintaining the platelet plug on larger
wounds. The release of prothrombin also plays an essential part in the coagulation process
because it allows for the formation of a thrombus, or clot, to form. This final step forces blood
cells and platelets to stay trapped in the wounded area (Barman et al., 2015).

1.2 Clotting Factors in Blood

Clotting factors are proteins in the blood that control bleeding. Many different clotting factors
work together in a series of chemical reactions to stop bleeding. This is called the clotting
process (WHF, 2014).

Table 1: System for naming blood-clotting factors

Factor

Names
I

Fibrinogen

II

Prothrombin

III
Thromboplastin

IV

Calcium

Proaccelerin, labile factor, accelerator globulin

VII

Proconvertin, SPCA, stable factor

VIII

Antihemophilic factor (AHF), antihemophilic factor A,

antihemophilic globulin (AHG)

IX

Plasma thromboplastic component (PTC), Christmas

factor, antihemophilic factor B

X

StuartPrower factor

XI

Plasma thromboplastin antecedent (PTA), antihemophilic,factor C

XII

Hageman factor, glass factor

XIII

Fibrin-stabilizing factor, LakiLorand factor

HMW-K
High-molecular-weight kininogen, Fitzgerald factor

Pre-Ka

Prekallikrein, Fletcher factor

Ka

Kallikrein
PL

Platelet phospholipid
1.3 Mechanism of Blood Coagulation

The loose aggregation of platelets in the temporary plug is bound together and converted into
the definitive clot by fibrin. Fibrin formation involves a cascade of enzymatic reactions and a
series of numbered clotting factors .The fundamental reaction is conversion of the soluble
plasma protein fibrinogen to insoluble fibrin. The process involves the release of two pairs of
polypeptides from each fibrinogen molecule. The remaining portion, fibrin monomer, then
polymerizes with other monomer molecules to form fibrin. The fibrin is initially a loose mesh
of interlacing strands. It is converted by the formation of covalent cross-linkages to a dense,
tight aggregate (stabilization). This latter reaction is catalyzed by activated factor XIII and
2+
requires Ca .

The conversion of fibrinogen to fibrin is catalyzed by thrombin. Thrombin is a serine protease

that is formed from its circulating precursor, prothrombin, by the action of activated factor X.
It has additional actions, including activation of platelets, endothelial cells, and leukocytes via
so-called proteinase activated receptors, which are G protein-coupled.

Factor X can be activated by either of two systems, known as intrinsic and extrinsic. The
initial reaction in the intrinsic system is conversion of inactive factor XII to active factor XII
(XIIa). This activation, which is catalyzed by high-molecular-weight kininogen and kallikrein
, can be brought about in vitro by exposing the blood to glass, or in vivo by collagen fibers
underlying the endothelium. Active factor XII then activates factor XI, and active factor XI
activates factor IX. Activated factor IX forms a complex with active factor VIII, which is
activated when it is separated from von Willebrand factor. The complex of IXa and VIIIa
2+
activate factor X. Phospholipids from aggregated platelets (PL) and Ca are necessary for
full activation of factor X. The extrinsic system is triggered by the release of tissue
thromboplastin, aproteinphospholipid mixture that activates factor VII. Tissue
2+,
thromboplastin and factor VII activate factors IX and X. In the presence of PL, Ca and
factor V, activated factor X catalyzes the conversion of prothrombin to thrombin. The
extrinsic pathway is inhibited by a tissue factor pathway inhibitor that forms a quaternary
structure with tissue thromboplastin (TPL), factor VIIa, and factor Xa (Barman et al., 2015).
Figure 1: The clotting mechanism. a, active form of clotting factor. TPL, tissue
thromboplastin; TFI, tissue factor pathway inhibitor.

2. Hemophilia

The word hemophilia comes from two Greek words: haima, meaning blood, and
philia, meaning affection. It is pronounced he-mo-feel-ia. Hemophilia is a genetic
condition that causes people to keep on bleeding for a long time unless treated. Hemophilia is
an almost always affects males .People with hemophilia do not bleed faster than anyone else;
but will bleed continuously at the normal rate until they are treated. A person with hemophilia
has low or non-existent levels of blood clotting protein called factor. This is because the
blood is unable to clot without any therapy. Internal bleeding is the major concern in
hemophilia. Bleeding is common into joints such as knees, ankles and elbows. This may be
caused by injury, but in severe hemophilia, can begin spontaneously. People with hemophilia,
commonly referred to as hemophiliacs, have a problem with clotting in their blood (Sona and
Lingam, 2010).
3. History of Hemophila

3.1 First Described and Identified

Incidences of excessive or abnormal bleeding were first recorded hundreds of years ago. The
nd
Talmud, a collection of Jewish rabbinical writings on laws and traditions, from the 2
century AD, stated that baby boys did not have to be circumcised if two of their brothers had
previously died from the procedure. The New Testament of the Bible mentioned a woman
who had hemorrhaged for 12 years, before touching the hem of Jesus garment, when she was
th
healed. Abulcasis, or Abu Khasim, a 10 century Arabian physician, described families
whose male relatives died from uncontrolled bleeding after trauma.

In 1803, John Conrad Otto, a Philadelphia physician, was the first to publish an article
recognizing that a hemorrhagic bleeding disorder primarily affected men, and ran in certain
families. He traced the disease back to a female ancestor living in Plymouth, New

Hampshire, in 1720. Otto called the males bleeders. In 1813, John Hay published a paper
in the New England Journal of Medicine proposing that affected men could pass the trait for a
bleeding disorder to their unaffected daughters. Then in 1828, Friedrich Hopff, a student at
the University of Zurich, and his professor Dr. Schonlein, are credited with coining the term

haemorrhaphilia for the condition, later shorted to haemophilia.

In 1926 Finnish physician Erik von Willebrand published a paper describing what he called

pseudohemophilia, a bleeding disorder affecting men and women equally. It was later
named von Willebrand disease. In 1957 Inga Marie Nilsson and researchers at the Malmo
University Hospital in Sweden determined that VWD was caused by low levels or deficient
von Willebrand factor.

In 1947, Dr. Alfredo Pavlovsky, a doctor in Buenos Aires, Argentina, distinguished two types
of hemophilia in his labA and B.
Factor I deficiency was first described in 1920. Factors II and V deficiency were identified in
the 1940s. The 1950s saw an explosion of work on rare factor deficiencies, as deficiencies of
FVII, X, XI and XII were first recognized. In 1960, FXIII deficiency was described (NHF,
2015).

3.2 A Royal Disease

Hemophilia is sometimes referred to as the royal disease, because it affected the royal
th th
families of England, Germany, Russia and Spain in the 19 and 20 centuries. Queen
Victoria of England, who ruled from 1837-1901, is believed to have been the carrier of
hemophilia B, or factor IX deficiency. She passed the trait on to three of her nine children.
Her son Leopold died of a hemorrhage after a fall when he was 30. Her daughters Alice and

Beatrice passed it on to several of their children. Alices daughter Alix married Tsar Nicholas
of Russia, whose son Alexei had hemophilia. Their familys entanglement with Rasputin, the
Russian mystic, and their deaths during the Bolshevik Revolution have been chronicled in
several books and films. Hemophilia was carried through various royal family members for
three generations after Victoria, and then disappeared (NHF, 2015).

3.3 Treatment Breakthroughs

In the early 1900s, there was no way to store blood. People with hemophilia who needed a
transfusion typically received fresh whole blood from a family member. Life expectancy was
13 years old.

In 1901, the US Surgeon Generals Catalogue listed lime, inhaled oxygen and the use of
thyroid gland or bone marrow, or hydrogen peroxide or gelatin, as treatments for hemophilia.
By the 1930s, it was discovered that diluting certain snake venoms caused blood to clot.
These treatments were used in patients with hemophilia.

By 1926, the US Surgeon Generals Catalogue contained an entire section on the use of blood
transfusions to replace missing clotting factors. Physicians discovered that patients responded
readily to infusions of plasma when given promptly after they sustained spontaneous joint and
muscle bleeding.

In 1937 Harvard physicians Arthur Patek and FHL Taylor published a paper describing anti-
hemophilia globulin found in plasma. It could decrease clotting time in patients with
hemophilia.

By the late 1950s and early 1960s fresh frozen plasma was transfused in patients in the
hospital. However, each bag of the plasma contained so little of the necessary clotting factor
that huge volumes of it had to be administered. Many children experienced severe joint bleeds
that were crippling. Intracranial hemorrhage could be fatal. By 1960, the life expectancy for a
person with severe hemophilia was less than 20 years old.
A paper written by Robert Macfarlane, a British hematologist, in the journal Nature in 1964
described the clotting process in detail. The interaction of the different factors in blood
clotting was termed the "coagulation cascade," now called the clotting cascade.

In 1965, Dr. Judith Graham Pool, a researcher at Stanford University, published a paper on
cryoprecipitate. In a major breakthrough, she discovered that the precipitate left from thawing
plasma was rich in factor VIII. Because cryoprecipitate contained a substantial amount of
factor in a smaller volume, it could be infused to control serious bleeding. Blood banks could
produce and store the component, making emergency surgery and elective procedures for
patients with hemophilia patients much more manageable.

By the 1970s, freeze-dried powdered concentrates containing factor VIII and IX became
available. Factor concentrates revolutionized hemophilia care because they could be stored at
home, allowing patients to self-infuse factor products, alleviating trips to the hospital for
treatment.

By the mid-1980s, it was confirmed that HIV/AIDS could be transmitted through the use of
blood and blood products, such as those used to treat hemophilia. Approximately half of the
people with hemophilia in the US eventually became infected with HIV through contaminated
blood products; thousands died. The overwhelming impact of HIV on the bleeding disorders
community was felt into the next few decades.

The hepatitis C virus (HCV) infection was also transmitted through contaminated factor
products, pooled from the blood of hundreds of thousands of donors. Before testing for HCV
began in 1992, an estimated 44% of all people with hemophilia had contracted it. With the
advent of more sophisticated screening methods and purification techniques, the risk of
contracting HCV through factor products is virtually nil.

Treatment for hemophilia and other bleeding disorders advanced in the 1990s. Factor
products became safer as tighter screening methods were implemented and advanced methods
of viral inactivation were used. In addition, synthetic (not derived from plasma) factor
products were manufactured using recombinant technologies. In 1992, the first recombinant
factor VIII product was approved by the Food and Drug Administration (FDA). In 1997, the
first recombinant factor IX product was granted FDA approval. Additional synthetic drugs,
such as desmopressin acetate (DDAVP), were also introduced to treat mild-to-moderate
hemophilia A and von Willebrand disease.

By 1995, prophylaxis, a preventive treatment regimen performed 2-3 times weekly in

children with hemophilia, became more common. Since the advent of prophylaxis, most
children in the developed world live with less pain, without the orthopedic damage associated
with chronic bleeding. As a result, most children born with hemophilia in the US today can
look forward to long, healthy and active lives.
However, some children develop inhibitors, or antibodies, to infused factor product. The
development of a bypassing agent in 1997 offered these patients an alternative product to help
stop bleeds and joint damage.

st
The early years of the 21 century have brought new recombinant products made without
human or animal plasma derivatives, lowering the possibility risk for allergic reactions to the
products or inhibitors? New longer-lasting products promise to decrease regular infusion rates
from 2-3 times per week to once-weekly or even less.

In 2013, three separate gene therapy trials were begun at institutions across the country. They
are testing the use of viruses as vector, or vehicles, to deliver factor IX genes into patients
livers, correcting their hemophilia. Because the factor VIII gene is larger and more
complicated to use, gene therapy clinical trials have not yet begun for patients with
hemophilia A (NHF, 2015).

3.4 Timeline

1828 - Term haemorrhaphilia first used. Later shortened to haemophilia.

1926 - Erik von Willebrand identifies a bleeding disorder, later called von Willebrand disease
(VWD)

1940s - Whole blood transfusions given at hospital

1948 - National Hemophilia Foundation (NHF) opens as The Hemophilia Foundation, Inc.
1952 - Researchers describe what is now called factor IX clotting protein

1954 - NHF establishes a Medical Advisory Council, later called Medical and Scientific
Advisory Council (MASAC)

1955 - First infusions of factor VIII in plasma form

1957 - Researchers in Sweden identify von Willebrand factor as the cause of VWD 1958 -
First use of prophylaxis for hemophilia A

1964 - Dr. Judith Graham Pool discovers cryoprecipitate

1968 - First FVIII concentrate available

1970s - Primary prophylaxis therapy experiments begin

1970s - Freeze-dried plasma-derived factor concentrates available

1977 - Desmopressin identified to treat mild hemophilia and von Willebrand disease 1980s -
Factor VIII, FIX and von Willebrand factor genes cloned

1982 - CDC reports first AIDS cases among people with hemophilia 1985 - First inactivated
factor concentrates available

1992 - FDA approves first recombinant FVIII products

1995 - Prophylaxis becomes standard of treatment in US

1997 - FDA approves first recombinant FIX products

1998 - First human gene therapy trials begin

2000s - FDA approves first recombinant factor products made without human or animal
plasma derivatives

2009 - FDA approves RiaSTAP to treat factor I deficiency

2011 - FDA approves Corifact to treat factor XIII deficiency

2013 - Gene therapy trials underway at three sites in the US (NHF, 2015).

4. Types of Hemophilia

Hempophilia A (Classic Hemophilia): A person with this type of hemophilia has low levels
of or is completely missing factor 8 (Also called FVIII or factor VIII deficiency) 80% of
people with hemophilia have Type A Hemophilia. Factor VIII deficiency usually manifests in
males.

In about 30% of cases, there is no family history of this bleeding disorder and it is just a
spontaneous genetic mutation. About 1 in 5,000 males born in the United States has
hemophilia. All economic groups and races are affected equally.

Hemophilia B (Christmas disease): This person has low levels of or is completely missing
factor 9 (Also called FIX or factor IX deficiency) 20% of people with hemophilia have Type B
Hemophilia. Factor IX deficiency usually manifests in males.

Hemophilia B was originally called "Christmas Disease" when it was first diagnosed in
1952. About 30% of cases of Hemophilia B are caused by spontaneous genetic mutation.
Hemophilia B is much less common than Hemophilia A. It occurs in about 1 in 25,000 male
births, and affects about 3,300 individuals in the United States. All races and economic groups
are affected equally (Singleton et al., 2010).

Table 2: Some molecular and physiological characteristics of hemophilia A and B

Type of
Deficient
Protein size
DNA
Half
Function in the
hemophilia
factor
(Kilodaltons)
length
life
coagulation

(bp)
(Hours)
cascade
Hemophilia

VIII
280
7056
8-12

Activated
by

thrombin
and activates to FX
Hemophilia

IX
68
1389
15-25
Activated by FXIa,

and activates to FX
Hemophilia type A and hemophilia type B are considered the only true hemophilia diseases.
However, two other bleeding disorders used to be confused with hemophilia, factor XI
deficiency, and von Willebrand disease. The bleeding disorder called factor XI deficiency
used to be called hemophilia C. The disease is caused by a deficiency in von Willebrand
factor (vWF), the blood protein that activates platelets and circulates in the blood holding the
three VIIIa protein fragments together. Deficiencies in factor VIII are observed in both
hemophilia A and vWD, which is why the difference between the two diseases was confusing
until it was demonstrated that vWF and factor VIII were two separate proteins. Unlike
hemophilia A and B, von Willebrand disease is autosomal (Raabe, 2008).

Hemophilia C: This person has low levels of or is missing completely factor 11 (Also called
FXI or factor XI deficiency) Hemophilia C is 10 times more rare than type A. Factor XI
deficiency is different because it can show up in both males and females.

Von Willebrands Disease: A bleeding disease similar to Hemophilia that affects both males
and females equally. It is caused by a deficiency of a blood clotting protein called Von
Willebrand factor. Von Willebrand factor circulates attached to factor VIII and is necessary to
form a clot.

Von Willebrands Disease occurs in 1 - 2% of the population. It is a genetic bleeding disorder

that can be inherited from either parent, unlike hemophilia. It affects males and females
equally.

Von Willebrand Disease can be difficult to diagnose. A blood clotting test can be performed to
measure the amount and characteristics of von Willebrand Factor. Because levels can vary,
sometimes a blood clotting test may need to be repeated. A person who might have von
Willebrand Disease should be referred to a hematologist who specializes in diagnosing and
treating bleeding disorders

5. Reasons for Hemophilia

5.1 Inheritance
The gene for factor VIII and IX are both located on the X chromosome. [Female (XX)
male (XY)]. Hemophilia is therefore said to be an X linked hereditary disorder. This
results in males being affected by the disease while females are carriers. While affected males
with no functioning factor VIII gene or IX gene have very low to no factor in blood , carrier
females have at least one (out of two) functioning X chromosomes with a normal factor VIII
or IX gene that provide about 50% factor levels. Carrier females who have excessive
lyonisation (inactivation) of the normal X chromosome can have very low levels of factors
and symptoms of bleeding.

Factor XI deficiency is usually an inherited condition, caused by a gene alteration. It is an

autosomal recessive disorder, meaning that both parents must carry the affected gene in order
to pass it to their children.

However, some people have bleeding symptoms when it is known that only one of their
parents was a carrier. In some cases, factor XI deficiency can occur spontaneously in people
with no known family history (NIH, 2008).

5.1.1 Hemophilia Inheritation Through man

A defect in one of the genes that determines how the body makes blood clotting factor VIII or
IX causes hemophilia. These genes are located on the X chromosomes (KRO-muh-somz).
Chromosomes come in pairs. Females have two X chromosomes, while males have one X
and one Y chromosome. Only the X chromosome carries the genes related to clotting factors.
A male who has a hemophilia gene on his X chromosome will have hemophilia. When a
female has a hemophilia gene on only one of her X chromosomes, she is a "hemophilia
carrier and can pass the gene to her children. Sometimes carriers have low levels of clotting
factor and have symptoms of hemophilia, including bleeding. Clotting factors are proteins in
the blood that work together with platelets to stop or control bleeding.

Very rarely, a girl may be born with a very low clotting factor level and have a greater risk for
bleeding, similar to boys who have hemophilia and very low levels of clotting factor. There
are several hereditary and genetic causes of this much rarer form of hemophilia in females.

Some males who have the disorder are born to mothers who aren't carriers. In these cases, a
mutation (random change) occurs in the gene as it is passed to the child.

Below are two examples of how the hemophilia gene is inherited.

Figure 2: Inheritance Pattern for HemophiliaExample 1

The image shows one example of how the hemophilia gene is inherited. In this example, the
father doesn't have hemophilia (that is, he has two normal chromosomesX and Y). The
mother is a carrier of hemophilia (that is, she has one hemophilia gene on one X chromosome
and one normal X chromosome).

Each daughter has a 50 percent chance of inheriting the hemophilia gene from her mother and
being a carrier. Each son has a 50 percent chance of inheriting the hemophilia gene from his
mother and having hemophilia.
Figure 3: Inheritance Pattern for HemophiliaExample 2

The image shows one example of how the hemophilia gene is inherited. In this example, the
father has hemophilia (that is, he has the hemophilia gene on the X chromosome). The mother
isn't a hemophilia carrier (that is, she has two normal X chromosomes).
5.2 Acquired Hemophilia

In rare cases, a person can develop hemophilia later in life. The majority of cases involve
middle-aged or elderly people, or young women who have recently given birth or are in the
later stages of pregnancy. This condition often resolves with appropriate treatment (WFH,
2012).

5.2.1 Mutation

These include point mutations, inversions, deletions, and unidentified mutations which
constitute 46%, 42%, 8%, 4%, respectively. It is of course also possible for a human to
acquire it spontaneously (de novo), rather than inheriting it, because of a new mutation in one
of their parents' gametes. Spontaneous mutations account for about of all hemophilia

(Sona, 2010).

5.2.1.1 Genetic Mutations

Hemophilia A is caused by a mutated factor VIII gene, and hemophilia B is caused by a

mutated factor IX gene. There are many ways that a mutation can be introduced into DNA.
First, before a cell divides to make a new cell, it makes a complete copy of its DNA to put
into the new cell. This process is called replication, and considering how many times it occurs
each day, it is surprisingly accurate. However, the process of replication is not perfect, and
mistakes are madeat a rate of one in every 1010 (10,000,000,000) nucleotides that are copied.
There are specific enzymes whose job it is to find and correct mistakes made during
replication, but they sometimes miss a few.

Outside sources can also be the cause of DNA mutations. When a piece of cloth becomes
stuck in between the teeth of a zipper, the zipper is no longer able to move. Similarly,
chemicals called mutagens can insert themselves into our DNA and prevent the replication
enzymes from copying the DNA code correctly. Mutations can also occur if a DNA strand is
cut, and chemicals, X- rays, radiation, and sunlight all have the potential to do this. When
DNA is cut, the damage may be so large that repair enzymes cannot figure out what the
original code was. Because they have to guess when they fill in the missing sections, they
may use incorrect nucleotides (Raabe, 2008).
5.2.1.2 Mutations in the Factor VIII and IX Genes

Not every person with hemophilia A has the same mutation, and the same is true for
hemophilia B. In fact, new mutations in the factor VIII and IX genes occur all the time, and
although almost every type of mutation has been observed in hemophiliac patients, the most
common types of mutations are deletions, insertions, and point mutations. A deletion
mutation is when part or all of a gene is missing. Because this type of mutation removes so
much information from the gene, a protein cannot usually be made, and the patient will
typically experience severe hemophilia. In an insertion mutation, new sections are added to a
gene. The effect of an insertion mutation is just as devastating as a deletion. Extra DNA
results in extra amino acids, which cause the length and shape of the protein to be incorrect.
This extra DNA could also insert a stop codon, causing translation to end prematurely and a
nonfunctioning protein to be made.

Another common mutation seen in hemophiliacs is a point mutation. A point mutation

involves a change in a single base pair. This change in one nucleotide can still result in an
amino-acid change. Whether a person will have hemophilia, and whether it will be severe or
mild, depends on the specific amino-acid change. For example, if the amino-acid change
created a stop codon, then a short protein would be made, which could result in severe
hemophilia. Another example would be if the amino-acid change allowed the protein to be
made, but the shape of the protein was altered enough that it could no longer function as an
enzyme or a cofactor. These types of changes would prevent the factor VIII or IX protein
from being activated during secondary hemostasis. A clotting factor that cannot be activated
is of no use, and hemophilia will result (Raabe, 2008).

6. Carriers and Women with Hemophilia

For many years, people believed that only men could have symptoms of hemophilia and that
women who "carry" the hemophilia gene do not experience symptoms themselves.

We now know that many carriers do experience symptoms of hemophilia. As our knowledge
about the disorder has increased, so has our understanding of why and how women can be
affected. Some women live with their symptoms for years without being diagnosed or even
suspecting they have a bleeding disorder. Through education and awareness-raising, the
World Federation of Hemophilia is working to close this gap in care.

7. Severity of hemophilia
The severity describes how serious a problem is. The level of severity depends on the amount
of clotting factor that is missing from a persons blood.
Table 3: Severity of haemophilia (ISTH criteria)

Severity

Factor VIII or IX

Clinical presentation

level
Severe

< 0.01 U/mL

Spontaneous

haemarthroses and
muscle haematomas

Moderate

0.010.05 U/mL

Mild trauma or surgery

causes bleeding

Mild

> 0.05 to 0.4 U/mL

Major injury or surgery

results in excess bleeding

(ISTH = International Society on Thrombosis and Haemostasis)

8. Disease symptoms

Hemophiliacs dont bleed faster than normal people they simply cannot stop bleeding.

Patients with severe hemophilia are usually diagnosed in the first year of life. They experience
heavy bruising and bleeding of the gums as their baby teeth come in, and they suffer unusually
severe bruises as they learn to walk. Throughout life, severe hemophiliacs experience
spontaneous bleeding episodes, which means that they bleed even though they have not
experienced an injury. These spontaneous bleeds occur most often in their joints, but also occur
in their muscles and under the skin. Severe hemophiliacs also experience frequent nosebleeds,
blood in their urine (from bleeding in their kidneys or the bladder), and blood in their feces
(from bleeding in their intestines or stomach).

On the knee X-ray, repeated bleeds have led to broadening of the femoral epicondyles, and there
is no cartilage present, as evidenced by the close proximity of the femur and tibia (A); sclerosis
(B), osteophyte (C) and bony cysts (D) are present. (HCV = hepatitis C virus). Inset (Massive
bruising).

People with moderate hemophilia usually do not have spontaneous bleeding episodes. Their
bleeding problems occur after suffering an injury, even a minor one. In many ways their
symptoms are similar to severe hemophiliacs, they just occur less frequently. People with
moderate hemophilia are all different when it comes to the disease symptoms they experience,
so bleeding episodes can range from once a month to once a year. Because the
symptoms of moderate hemophilia are still serious, patients are usually diagnosed before the
age of 5 or 6.
Figure 4: Clinical manifestations of haemophilia.

Many people with mild hemophilia are not diagnosed until later in life, when they are
adolescents or even adults. They do not experience spontaneous bleeding, but without
treatment, they can experience prolonged bleeding after major injuries, surgeries, and dental
procedures. If someone knows that they have mild hemophilia, they can receive clotting
factor prior to surgery or dental procedures to reduce their risk of bleeding. These may be the
only times when a person with mild hemophilia receives treatment for his or her disease
(Raabe,2008).
9. Complications

9.1 Bleeding into Joints

Hemarthrosis is the name given to a hemophilic bleeding episode that occurs in the joints.
There aremany joints in the human body, but 80% of hemarthroses occur in the knees,
elbows, and ankles.As a joint bleed begins, patients described an aura, or a feeling of
warmth and tingling as blood begins to flood the joint cavity. The aura may last about two
hours. As the bleed progresses, patients often report that they have a feeling of tightness in
the joint, but describe the feeling as uncomfortable rather than painful.

Many hemophiliacs have a joint known as their target joint. This joint seems to be one where
bleeding occurs most often. Over time, a hemophiliac can develop more than one target joint.
When the target joint developed, it was because the synovial membrane was being constantly
irritated by exposure to blood. Over time, repeated bleeding into the joint begins to irritate,
and cause inflammation in, the bones and cartilage of the joint. As a result, chronic joint
disease, or hemophilic arthropathy, develops. Cartilage is a dense tissue that is very similar in
structure to the outside of blood vessels. Over time, the cartilage can only take so much
abuse, and it begins to degrade. When it does, the bones now have no padding between them,
and bone rubbing on bone is very painful. This type of condition can occur in people without
hemophilia, in which case it is simply called arthritis.
Figure 5: After experiencing repeated hemophilic bleeding episodes, joints can develop a
chronic joint disease called hemophilic arthropathy.

Finally, because strong healthy muscles will help support and protect joints from bleeds,
patients should participate in a regular program of muscle stretching and strengthening
(Raabe, 2008).
9.2 Bleeding in the Brain

The brain is a very complex body organ that is divided into many different parts that perform
very specific functions, all of which are necessary for a normal life. This is why intracranial
bleeding (bleeding inside the brain) is very serious and can be life- threatening. In fact,
intracranial bleeding is a leading cause of death in hemophiliacs, with some estimates as high
as 25% of all hemopiliac deaths.

Figure 6: Intracranial bleeding is bleeding inside the brain.

Bleeding can occur on the surface of the brain or deep inside. First, when bleeding occurs
here, the blood accumulates in the space between the brain tissue and the membrane that
covers it. Second, when bleeding occurs deep into the inner sections of the brain, the blood
becomes trapped within the brain tissue. The bleeding and inflammation create swelling that
puts pressure on the many nerves of the brain. The severity of the bleeding episode
determines whether permanent brain damage or death results (Raabe, 2008).

9.3 Inhibitor Antibodies

A problem that many hemophilia patients have to deal with is the development of inhibitor
antibodies. Inhibitor antibodies are created in some hemophiliacs because their immune
systems begin to see the infused clotting factors as foreign, and therefore a threat. Their
bodies respond by producing antibodies that specifically attach to the clotting factors. The
antibodies coat the clotting factors and block them from participating in the chemical
reactions of secondary hemostasis. The antibodies also act to signal other cells of the immune
system that respond by quickly removing the infused factor VIII or IX from the bloodstream.
10. Diagnosis of Hemophilia

10.1 Principles of Diagnosis

A correct diagnosis is essential to ensure that a patient gets the appropriate treatment.
Different bleeding disorders may have very similar symptoms. The diagnosis of hemophilia
can be made before birth, in childhood, or later. Different tests are involved, depending on
when diagnosis is performed.

Understanding the clinical features of hemophilia and the appropriateness of the clinical
diagnosis.

Using screening tests to identify the potential cause of bleeding, for example, platelet count,
bleeding time (BT; in select situations), or other platelet function screening tests, prothrombin
time (PT), and activated partial thromboplastin time (APTT).

Confirmation of diagnosis by factor assays and other appropriate specific investigations

(Srivastava et al. 2012).

10.2 Prenatal Diagnosis of Hemophilia

There are two prenatal (before birth) hemophilia tests.

Chorionic villus sampling (CVS)

Amniocentesis

Chorionic villus sampling (CVS)

In the chorionic villus sampling (CVS) test, a cell sample is taken from the placenta and the
factor VIII and IX genes are checked for mutations. This test can be performed in the second
and third month of a pregnancy.

Amniocentesis

Amniocentesis is another prenatal test for hemophilia.. In amniocentesis, a small amount of

amniotic fluid is removed, and cells in the fluid are evaluated for mutations in the factor VIII
and IX genes. This test can be performed in the fourth month of a pregnancy.

Both the CVS and amniocentesis tests have risks associated with them, so they are not
performed unless the parents and their doctor decide they are medically necessary.

A mother who suspects that she is a carrier of hemophilia can also undergo two types of
testing for hemophilia. She can have genetic tests done, but this requires a sample from a
known carrier female in her family to see if they both have matching mutations. The mothers
blood can also be tested for levels of factor VIII and IX. While the values from these tests are
accurate, they are not reliable measures for whether that mothers child would be a
hemophiliac. In fact, carriers of hemophilia A and hemophilia B often have normal levels of
factor VIII and IX, respectively (Raabe,2008).

10.3 Diagnosis of Hemophilia in Children and Adults

For a physician to diagnose a child or adult with hemophilia, he or she must first obtain a
family history. Next, even though a diagnosis of hemophilia cannot be made based on clinical
symptoms alone, a bleeding history is taken as an important part of the overall medical
evaluation.

10.3.1 Partial Thromboplastin time (PTT) and Prothrombin Time (PT) Tests

The partial thromboplastin time (PTT) and prothrombin time (PT) tests can be done to
diagnose a bleeding disorder. The PTT test measures how well the intrinsic and common
pathways are working, while the PT test evaluates the extrinsic pathway. Each test is
performed in a similar manner.

Normal values differ depending on the laboratory that is doing the testing, but in general, 25
to 45 seconds is normal for the PTT test and 11 to 15 seconds for the PT test. Prolonged PTT
or PT values, such as a PTT time of 90 seconds or a PT time of 50 seconds, are indications of
a blood disorder (Raabe, 2008).

10.3.2 Factor Assays

Factor assay is required in the following situations: To determine diagnosis

To monitor treatment the laboratory monitoring of clotting factor concentrates is possible by

measuring pre-and post-infusion clotting factor levels.

Lower than expected recovery and/or reduced half-life of infused clotting factor may be an
early indicator of the presence of inhibitors.
To test the quality of cryoprecipitate It is useful to check the FVIII concentration present in
cryoprecipitate as part of the quality control of this product (Srivastava

et al., 2012).

10.3.3 Factor Activity Tests

The PTT and PT tests only indicate that a patient has a bleeding disorder; they do not tell that
the patient has hemophilia or indicate whether it is type A or B. Patients suspected of having a
bleeding disorder can undergo a coagulation factor test. These tests evaluate the activity of
factors VIII and IX in the patients blood and determine if they suffer from hemophilia A or
B. Factor activity tests can be described using two different values: units and percentage of
normal activity. The term unit may seem confusing, but all it really means is that one unit
is equal to 100% factor VIII or IX activity in 1 milliliter of normal blood. It is important to
understand that people without hemophilia do not have consistent factor VIII and IX activity
levels in their blood. Instead normal values range from 0.5 unit per milliliter to 2.0 units per
milliliter (Raabe, 2008).

10.3.4 Percent Activity

It is the more commonly used value for the coagulation factor tests because it quickly indicates
the severity of disease this patient may have. Recall thatpeople with less than 1% activity have
severe hemophilia, people with 1% to 5% activity have moderate hemophilia, and people with
greater than 5% activity have mild hemophilia (the range of normal percent activity is 50% to
200%). To calculate a patients percentage of normal activity, the patients activity in units per
milliliter is divided by the activity of a normal blood sample that is tested at the same time.

This number is then multiplied by 100%. For example, if the patients value was 0.01 units per
milliliter and the normal sample was 1.0 unit per milliliter, then

(0.01/1) 100 =1.0% activity

This person would be diagnosed with severe hemophilia (Raabe, 2008). 10.3.5 Screening Tests

Platelet count, BT, PT, and APTT may be used to screen a patient suspected of having a
bleeding disorder (Fischer et al., 2001)

Bleeding time lacks sensitivity and specificity and is also prone to performance-related errors.
Therefore other tests of platelet function such as platelet aggregometry are preferred when
available (Wu, 2011)

Table 4: Interpretation of screening tests

Possible

PT

APTT*

BT

Platelet

diagnosis

count
Normal

Normal

Normal

Normal

Normal

Hemophilia A or

Normal
Prolonged*

Normal

Normal

B**

VWD

Normal

Normal
or
Normal
or

Normal

prolonged*

prolonged

or
reduced

Platelet defect

Normal

Normal

Normal
or
Normal

prolonged

or
reduced
Results of APTT measurements are highly dependent on the laboratory method used for
analysis.

The same pattern can occur in the presence of FXI, FXII, prekallikrein, or high molecular
weight kininogen deficiencies.

Based on the results of these tests, the category of bleeding disorder may be partially
characterized to guide subsequent analysis.

These screening tests may not detect abnormalities in patients with mild bleeding disorders
including some defects of platelet function, FXIII deficiency, and those rare defects of
fibrinolysis, which may be associated with a bleeding tendency (Srivastava et al., 2012).

11. Management of Hemophilia

11.1 Principles of care

The primary aim of care is to prevent and treat bleeding with the deficient clotting factor.

Whenever possible, specific factor deficiency should be treated with specific factor
concentrate.

People with hemophilia are best managed in a comprehensive care setting

Acute bleeds should be treated as quickly as possible, preferably within two hours. If in
doubt, treat (Ingram et al., 1979).

Patients usually recognize early symptoms of bleeding even before the manifestation of
physical signs. This is often described as a tingling sensation or aura.
During an episode of acute bleeding, an assessment should be performed to identify the site
of bleeding (if not clinically obvious) and appropriate clotting factor should be administered.

In severe bleeding episodes that are potentially life-threatening, especially in the head, neck,
chest, and gastrointestinal tract, treatment with factor should be initiated immediately, even
before diagnostic assessment is completed.

To facilitate appropriate management in emergency situations, all patients should carry easily
accessible identification indicating the diagnosis, severity of the bleeding disorder, inhibitor
status, type of treatment product used, initial dosage for treatment of severe, moderate, and
mild bleeding, and contact information of the treating physician/clinic.
Administration of desmopressin (DDAVP) can raise FVIII level adequately (three to six times
baseline levels) to control bleeding in patients with mild, and possibly moderate, hemophilia
A. Testing for DDAVP response in individual patients is appropriate (Castaman et al., 2009).

Veins must be treated with care. They are the lifelines for a person with hemophilia 23-or 25-
gauge butterfly needles is recommended.

Never cut down into a vein, except in an emergency.

Apply pressure for three to five minutes after venipuncture.

Venous access devices should be avoided whenever possible but may be required in some
children.

Adjunctive therapies can be used to control bleeding, particularly in the absence of clotting
factor concentrates, and may decrease the need for them

If bleeding does not resolve despite adequate treatment, clotting factor levels should be
measured. Inhibitor testing should be performed if the level is unexpectedly low.

Prevention of bleeding can be achieved by prophylactic factor replacement.

Regular exercise and other measures to stimulate normal psychomotor development should be
encouraged to promote strong muscles, develop balance and coordination, and improve
fitness.

Patients should avoid activities likely to cause trauma.

Regular monitoring of health status and assessment of outcomes are key components of care.
Drugs that affect platelet function, particularly acetylsalicylic acid (ASA) and non-steroidal
anti-inflammatory drugs (NSAIDs), except certain COX-2 inhibitors, should be avoided.
Paracetamol /acetaminophen are a safe alternative for analgesia.

Factor levels should be raised to appropriate levels prior to any invasive procedure

Good oral hygiene is essential to prevent periodontal disease and dental caries, which
predispose to gum bleeding.

11.2 Fitness and Physical Activity

Physical activity should be encouraged to promote physical fitness and normal neuro-
muscular development, with attention paid to muscle strengthening, coordination, general
fitness, physical functioning, healthy body weight, and self-esteem (Gomis et al., 2009).
Bone density may be decreased in people with hemophilia.

For patients with significant musculoskeletal dysfunction, weight-bearing activities that

promote development and maintenance of good bone density should be encouraged, to the
extent their joint health permits

The choice of activities should reflect an individuals preference/interests, ability, physical

condition, local customs, and resources.

Non-contact sports such as swimming, walking, golf, badminton, archery, cycling, rowing,
sailing, and table tennis should be encouraged.

The patient should consult with a musculoskeletal professional before engaging in physical
activities to discuss their appropriateness, protective gear, prophylaxis (factor and other
measures), and physical skills required prior to beginning the activity. This is particularly
important if the patient has any problem/target joints.

Target joints can be protected with braces or splints during activity, especially when there is
no clotting factor coverage.

Activities should be re-initiated gradually after a bleed to minimize the chance of a re-bleed
(Iorio et al., 2007).

11.3 Adjunctive Management

Adjunctive therapies are important, particularly where clotting factor concentrates are limited
or not available, and may lessen the amount of treatment product required.

First aid measures: In addition to increasing factor level with clotting factor concentrates (or
desmopressin in mild hemophilia A), protection (splint), rest, ice, compression, and elevation
may be used as adjunctive management for bleeding in muscles and joints.
Physiotherapy is particularly important for functional improvement and recovery after
musculoskeletal bleeds and for those with established hemophilic arthropathy.

Anti fibrinolytic drugs (e.g. tranexamic acid, epsilon aminocaproic acid) are effective as
adjunctive treatment for mucosal bleeds and dental extractions.

Certain COX-2 inhibitors may be used judiciously for joint inflammation after an acute bleed
and in chronic arthritis.
11.4 Prophylactic Factor Replacement Therapy

Prophylaxis is the treatment by intravenous injection of factor concentrate in order to prevent

anticipated bleeding.

Prophylaxis prevents bleeding and joint destruction and should be the goal of therapy to
preserve normal musculoskeletal function.

Table 5: Definitions of factor replacement therapy protocols

Protocol

Definition

Episodic (on demand) treatment

Treatment given at the time of clinically evident

bleeding
Continuous prophylaxis

Regular continuous* treatment initiated in the

Primary prophylaxis

absence of documented osteochondral joint disease,

determined by physical examination and/or imaging

studies, and started before the second clinically

evident large joint bleed and age 3 years**

Secondary prophylaxis

Regular continuous* treatment started after 2 or more

bleeds into large joints** and before the onset of joint

disease documented by physical examination and

imaging studies

Tertiary prophylaxis

Regular continuous* treatment started after the onset

of joint disease documented by physical examination

and plain radiographs of the affected joints

Intermittent (periodic) prophylaxis

Treatment given to prevent bleeding for periods not

exceeding 45 weeks in a year

* continuous is defined as the intent of treating for 52 weeks/year and receiving a minimum of
an a priori defined frequency of infusions for at least 45 weeks (85%) of the year under
consideration.

**large joints = ankles, knees, hips, elbows and shoulders

It is unclear whether all patients should remain on prophylaxis indefinitely as they transition
into adulthood. Although some data suggest that a proportion of young adults can do well off
prophylaxis, more studies are needed before a clear recommendation can be made (Manco-
Johnson et al., 2007).
11.5 Administration and Dosing Schedules for Prophylaxis

There are two prophylaxis protocols currently in use for which there is long-term data:

The Malmo protocol: 25-40 IU/kg per dose administered three times a week for those with
hemophilia A, and twice a week for those with hemophilia B.

The Utrecht protocol: 15-30 IU/kg per dose administered three times a week for those with
hemophilia A, and twice a week for those with hemophilia B.

The protocol should be individualized as much as possible, based on age, venous access,
bleeding phenotype, activity, and availability of clotting factor concentrates.

One option for the treatment of very young children is to start prophylaxis once a week and
escalate depending on bleeding and venous access.

Prophylaxis is best given in the morning to cover periods of activity.

Prophylactic administration of clotting factor concentrates is advisable prior to engaging in

activities with higher risk of injury (Luchtman-Jones et al., 20006).

11.6 Pain Management

Acute and chronic pains are common in patients with hemophilia. Adequate assessment of

the cause of pain is essential to guide proper management.

Pain caused by venous access

In general, no pain medication is given.

In some children, application of a local anesthetic spray or cream at the site of venous access
may be helpful.

Pain caused by joint or muscle bleeding

While clotting factor concentrates should be administered as quickly as possible to stop

bleeding, additional drugs are often needed for pain control

Other measures include cold packs, immobilization, splints, and crutches

Post-operative pain

Intramuscular injection of analgesia should be avoided.

Post-operative pain should be managed in coordination with the anesthesiologist.

Initially, intravenous morphine or other narcotic analgesics can be given, followed by an oral
opioid such as tramadol, codeine, hydrocodone, and others.

When pain is decreasing, paracetamol/acetaminophen may be used.

Pain due to chronic hemophilic arthropathy

Chronic hemophilic arthropathy develops in patients who have not been adequately treated
with clotting factor concentrates for joint bleeding.

Treatment includes functional training, adaptations, and adequate analgesia.

COX-2 inhibitors have a greater role in this situation.

Other NSAIDs should be avoided.

When pain is disabling, orthopedic surgery may be indicated.

Patients with persisting pain should be referred to a specialized pain management team
(Tsoukas et al., 2006).

Table 6: Strategies for pain management in patients with hemophilia

1
Paracetamol/acetaminophen

If not effective

2
COX-2 inhibitor (e.g. celecoxib, meloxicam, nimesulide, and others)

or
Paracetamol/acetaminophen plus codeine (3-4 times/day)

or

Paracetamol/acetaminophen plus tramadol (3-4 times/day)

3
Morphine: use a slow release product with an escape of a rapid release.

Increase the slow release product if the rapid release product is used more

than 4 times/day

11.7 Surgery and Invasive Procedures

Surgery may be required for hemophilia-related complications or unrelated diseases. The

following issues are of prime importance when performing surgery on persons with
hemophilia.

Surgery should be scheduled early in the week and early in the day for optimal laboratory and
blood bank support, if needed.

If clotting factor concentrates are not available, adequate blood bank support for plasma
components is needed.
The dosage and duration of clotting factor concentrate coverage depends on the type of surgery
performed (Mathews et al., 2005).
Table 7: Definition of adequacy of hemostasis for surgical procedures

Excellent Intra-operative and post-operative blood loss similar (within 10%) to the non-
hemophilic patient.

No extra (unplanned) doses of FVIII/FIX/bypassing agents needed AND

Blood component transfusions required are similar to non-hemophilic patient

Good
Intra-operative and/or post-operative blood loss slightly increased over

expectation for the non-hemophilic patient (between 10-25% of expected),

but the difference is judged by the involved surgeon/anaesthetist to be

clinically insignificant.

No extra (unplanned) doses of FVIII/FIX/bypassing agents needed

AND

Blood component
transfusions required
are
similar to
the non-

hemophilic patient
Fair

Intra-operative and/or post-operative blood loss increased over expectation

(25-50%) for the non-hemophilic patient and additional treatment is needed.

Extra (unplanned) dose of FVIII/FIX/bypassing agents needed OR


Increased blood component
(within 2
fold) of
the anticipated

transfusion requirement
Poor/none

Significant intra-operative
and/or
post-operative
blood
loss
that is
substantially increased over expectation (>50%) for the non-hemophilic patient, requires
intervention, and is not explained by a surgical/medical issue other than hemophilia

Unexpected hypotension or unexpected transfer to ICU due to bleeding OR

Substantially increased blood component (> 2 fold) of the anticipated transfusion requirement
Patients with mild hemophilia A, as well as patients receiving intensive factor replacement
for the first time, are at particular risk of inhibitor development and should be re-screened 4
12 weeks post-operatively.

Infusion of factor concentrates/hemostatic agents is necessary before invasive diagnostic

procedures such as lumbar puncture, arterial blood gas determination, or any endoscopy with
biopsy (Kempton et al., 2010).

12. Definitive Treatment

12.1 Treatment with Replacement Therapy

The main treatment for hemophilia is called replacement therapy. Concentrates of clotting
factor VIII (for hemophilia A) or clotting factor IX (for hemophilia B) are slowly dripped or
injected into a vein. These infusions help replace the clotting factor that's missing or low.

Clotting factor concentrates can be made from human blood. The blood is treated to prevent
the spread of diseases, such as hepatitis. With the current methods of screening and treating
donated blood, the risk of getting an infectious disease from human clotting factors is very
small.

To further reduce the risk, you or your child can take clotting factor concentrates that aren't
made from human blood. These are called recombinant clotting factors. Clotting factors are
easy to store, mix, and use at homeit only takes about 15 minutes to receive the factor.

You may have replacement therapy on a regular basis to prevent bleeding. This is called
preventive or prophylactic (PRO-fih-lac-tik) therapy. Or, you may only need replacement
therapy to stop bleeding when it occurs. This use of the treatment, on an as-needed basis, is
called demand therapy.
Demand therapy is less intensive and expensive than preventive therapy. However, there's a
risk that bleeding will cause damage before you receive the demand therapy (NIH, 2015).
12.1.1 Complications of Replacement Therapy

Complications of replacement therapy include:

Developing antibodies (proteins) that attack the clotting factor

Developing viral infections from human clotting factors

Damage to joints, muscles, or other parts of the body resulting from delays in treatment
Antibodies to the clotting factor. Antibodies can destroy the clotting factor before it has a
chance to work. This is a very serious problem. It prevents the main treatment for hemophilia
(replacement therapy) from working.

These antibodies, also called inhibitors, develop in about 2030 percent of people who have
severe hemophilia A. Inhibitors develop in 25 percent of people who have hemophilia B.
When antibodies develop, doctors may use larger doses of clotting factor or try different
clotting factor sources. Sometimes the antibodies go away.

Researchers are studying new ways to deal with antibodies to clotting factors.

Viruses from human clotting factors. Clotting factors made from human blood can carry
the viruses that cause HIV/AIDS and hepatitis. However, the risk of getting an infectious
disease from human clotting factors is very small due to:

Careful screening of blood donors

Testing of donated blood products

Treating donated blood products with a detergent and heat to destroy viruses

Vaccinating people who have hemophilia for hepatitis A and B

Damage to joints, muscles, and other parts of the body. Delays in treatment can cause

damage such as:

Bleeding into a joint. If this happens many times, it can lead to changes in the shape of the
joint and impair the joint's function.
Swelling of the membrane around a joint.

Pain, swelling, and redness of a joint.

Pressure on a joint from swelling, which can destroy the joint (NIH, 2015).

12.2. Other Types of Treatment

12.2.1 Pharmacologic Options for Controlling Bleeding

Tranexamic Acid

Tranexamic acid is an antifibrinolytic agent that inhibits the activation of plasminogen to

plasmin. It promotes clot stability and is useful as adjunctive therapy in hemophilia. It is
valuable in controlling bleeding from mucosal surfaces (e.g., oral bleeding, epistaxis,
menorrhagia) in hemophilia (Chandy, 2005).

Fibrin sealant (glue)

Fibrin sealant has hemostatic, sealing, and healing properties. It is made by mixing fibrinogen
and thrombin, which mimics the last step in the blood coagulation cascade. A semi rigid to
rigid fibrin clot consolidates and adheres to the application site and acts as a fluid-tight
sealing agent able to stop bleeding. Fibrin sealant can be used for dental extraction,
circumcision, and to stop bleeding from mucous membranes. (Chandy, 2005).

Calcium alginate

There are several hemostatic agents in the dry form. Sailors and seaweed collectors have
known for ages of calcium alginates ability to stop bleeding and heal wounds. Calcium
alginate is a polysaccharide that can be extracted from brown seaweed and made into fibers
for swabs. When this material comes into contact with biological fluids, calcium alginate
++ +
exchanges its Ca ions with Na ions from the blood and gels. Several studies have shown a
hemostatic effect of this material, which can be used for epistaxis (Chandy, 2005)

Desmopressin (DDAVP)

DDAVP is a synthetic analogue to the natural hormone arginine-vasopressin 1-deamino-8-

Darginine vasopressin (desmopressin). It causes release of von Willebrand factor (vWF) from
endogenous stores in the endothelial cells and is effective in mild/moderate hemophilia and
Type 1 von Willebrand disease (vWD) but is not effective in Type 2 and Type 3 vWD as there
is no functional vWF. It is contraindicated in 2B and pseudo vWD.

The main advantage is that it is inexpensive and there is no risk of blood-borne viral
infections. The effect lasts for 6-8 hours and in a given patient is consistent on different
occasions. It is available in intranasal or intravenous (IV) forms. IV preparation strength is

4g/ml and this can also be given subcutaneously with the same effect. There is a two- to
sixfold increase in the vWF activity and factor VIII level within 15-30 minutes after
administration. The usual dose is 0.2-0.3 g/kg IV in a volume of 50-100 ml over 30 minutes.
For subcutaneous injection it is given at the same dose with a volume of <1.5 ml/site
(Lethagen, 2003).

Coagulation factor
Provision of some safe and affordable coagulation factor concentrates is essential for major
bleeding and surgery. Life-threatening bleeds in the central nervous system, upper airways,
etc. cannot be adequately managed without coagulation factor concentrates. Low dose
strategies for surgery in developing countries have been shown to be effective with
acceptable rates of bleeding (Srivastava et al., 1998).

Cryoprecipitate and plasma

Cryoprecipitate, fresh frozen plasma (FFP), and cryo-poor plasma are the only affordable
treatment options in many developing countries. However, they are usually not treated to
eliminate blood-borne viruses. (It is possible to apply some forms of virucidal treatment to
packs of FFP, and the use of treated packs is recommended.) Because of the risk of
transmitting disease, the use of plasma and cryoprecipitate which has not been viral
inactivated should be considered a temporary measure until adequate amounts of safe
concentrates can be procured (Chandy,2005).

Danazol

In a study by Gralnik et al, 200 mg of danazol was administered three times daily to 4 adults,
2 with hemophilia A and 2 with hemophilia B. In those with hemophilia A, their factor VIII
level rose from 1-3% to 3-8% and in those with hemophilia B the factor IX level rose from
5% to 14%. The level rose within 5-7 days and peaked at 7-13 days .This agent may be useful
for short-term administration following a central nervous system (CNS) bleed when
recurrence risk is high and for a target joint with recurrent hemarthrosis. It is also useful to
control intractable uterine bleeding in females with vWD ( Gralnick , and Rick,1983) .

Prednisone

Macroscopic upper hematuria, i.e. originating from the kidneys, can be resolved with
corticosteroids. This was shown in a series of cases in 1965. and there are also anecdotal
positive experiences from other centres, however a more recent study failed to show any
benefit of adding steroids to treatment with factor concentrate.Treatment can be given as
prednisone 0.5 mg/kg bodyweight daily for 5 days, then 0.25 mg/kg for another 5 days. The
advantages of prednisone compared to factor concentrates are the much lower cost and
absence of renal colic from blood clots passing down via the ureter (Rizza et al., 1997).

Amino glycosides

Clinical severity of hemophilia depends on the nature of the underlying mutations. Nonsense
mutations account for about 11.5% of all hemophilia A and B, resulting in a premature stop
codon. In addition, 5% of the mutations are that can possibly lead to a premature stop codon.
A slight increase in factor level (>1% of normal coagulant activity) can result in marked
clinical improvement.
Amino glycosides, such as gentamycin, can increase factor levels in patients with point
mutations, especially those with nonsense/frameshift mutations due to premature stop codons.
Amino glycosides act by incorporation of alternative amino acids at stop codons, thereby
producing some normal functional protein. The efficiency of read through depends on the
type of stop codon (TAA, TAG, and TGA). (Lillicrap et al., 2003).
12.3. Producing Recombinant Factor VIII and IX

In the 1980s, two separate research groups, at nearly the same time, succeeded at
synthesizing the entire factor VIII gene and expressing the recombinant protein. At 186,000
nucleotides long, this was the largest gene ever synthesized at that time, and the recombinant
proteins obtained were found to be just as effective at clotting blood as cryoprecipitates.
Recombinant factor VIII became commercially available in 1992, and recombinant factor IX
followed in 1997. Today, recombinant factor VIII and IX are some of the most commonly
used treatments for hemophilia. To produce a recombinant protein, there are many different
and unique molecular biology methods available for use. It is a little like baking a cake; there
is a lot of room for individuality. This is also why two separate research teams simultaneously
succeeded in producing recombinant factor VIII using different methods. There are, however,
basic steps common to producing recombinant proteins, which will be outlined next (Raabe,
2008).

Thus, second-generation therapies have been produced in which the HSA in the final
therapeutic material is replaced by nonprotein stabilizers. These second-generation products
wereRcFacto (Genetics Institute/Wyeth) and Kogenate FS/Kogenate Baye.

More recent third-generation products have been developed in which no exogenous bovine
and/or human protein is added to either the cell cultures or the final material. The
thirdgeneration types are BeneFIX (rFIX, produced by Genetics Institute/Wyeth), Advate
(rFVIII, Baxter Bioscience), and Xyntha (rFVIII, Wyeth) (Shima M and Yoshioka, 2014).

12.4. Gene Therapy

Gene therapy represents a completely new type of treatment for hemophilia. Gene therapy
gets right to the source of a genetic disease by trying to correct the defective gene.
Figure 7: This diagram shows the ex vivo method of gene therapy.
The process begins by inserting a healthy gene into the DNA of a virus. For hemophilia, a
normal clotting factor VIII or IX gene is used. In a laboratory, this virus is allowed to infect
cells that were collected from the patient. When these corrected cells are reintroduced back
into the patient, it is hoped that they will multiply and produce the proteins needed by that
patient.

In gene therapy, a functioning gene is transported into the body and cells of a patient. The
gene may insert itself into the patients DNA or it may remain independent; either way, the
hope is that the gene will produce the protein that is lacking in the patient, thereby curing the
patient of his or her disease. The following sections will cover the details of gene therapy
(Raabe, 2008).

12.4.1 The Advantages of Gene Therapy for Hemophilia

Gene therapy is still a new field of medicine. The research necessary to develop a gene-
therapy treatment is complicated and expensive. However, the disease hemophilia is an
excellent candidate for a successful gene-therapy treatment for two reasons.

First, it is a disease where only one gene is at fault. Delivering one gene into a person is more
straightforward than if the disease is the result of multiple mutated genes or, worse yet, if
entire chromosomes are defective.

Second, even if you achieve only a small increase in clotting factor activity levels, you could
improve a patients situation. For example, an increase in clotting-factor activity of only 1%
to 2% could be therapeutic enough to stop spontaneous bleeding episodes. Not only is it
scientifically possible to develop a successful gene-therapy treatment for hemophilia, but this
new treatment would be preferable to existing replacement treatments for a number of
reasons. First, gene therapy would eliminate any risks associated with using blood- derived
clotting-factor products. Many people are still using these products for reasons that range
from not having access to other products, not being able to afford the more expensive
recombinant clotting factors, or having developed inhibitor antibodies. While the blood
supply in developed countries is considered safe from HIV, hepatitis, and other viral diseases,
there always remains a small risk. Second, with current replacement treatments, severe
hemophiliacs require a great number of treatments, but with gene therapy, it is possible that
one treatment is all that a patient would need.
Third, with frequent factor treatments comes a very high price tag, so gene therapy could
potentially offer a less expensive treatment option. Last, successful gene therapy would
eliminate the problem of the development of inhibitor antibodies, which plague so many
hemophiliacs today (Raabe, 2008).
12.4.2 Gene Therapy in Humans

There have been five gene therapy trials for treatment of hemophilia in humans. Ex-vivo
transduction of fibroblasts or intravenous injection of a retroviral vector (Powell et al., 2003)
for hemophilia A had at most a marginal effect on FVIII levels, and these approaches are no
longer being pursued. Intravenous administration of a helper-dependent adenoviral vector
expressing FIX induced the acute phase response and was abandoned due to safety concerns.
The muscle-directed AAV vector-mediated gene therapy trial for hemophilia B did not
provide convincing evidence of expression, and enrolment has been stopped.

The liver-directed AAV-vector-mediated gene therapy trial was considered very promising, as
this approach resulted in 10% of normal FIX levels in dogs with hemophilia B. Indeed, one of
the patients who received the highest dose achieved 10% of normal activity during the first
month, and had reduced factor needs. The FIX activity fell at 1 month after transduction,
however, in conjunction with an increase in liver enzymes, which was believed to be due to a
cytotoxic T-lymphocyte response directed against AAV capsid proteins. This trial will be
modified to include immune suppression at the time of gene transfer (K.A. High, Childrens

Hospital of Philadelphia, Philadelphia, PA, USA, personal communication (Ponder, 2006).

12.4.3 Risks of Gene Therapy

Inhibitor formation is a very important concern for gene therapy. Although Chapel Hill dogs
with a missense mutation in their FIX gene that received liver-directed gene therapy have
generally not developed inhibitors, some dogs that were treated with muscle-directed gene
therapy have done so , suggesting that a muscle approach may be more immunogenic than a
liver approach. On the other hand, some Rhesus macaques have developed inhibitors to
human FIX despite the use of a liver-restricted promoter, and there are only 11 amino acid
differences between the human and the Rhesus macaque FIX sequences. Neonatal
administration of protein or gene therapy induced tolerance to human or canine FVIII in
mice; however, one out of five dogs that received neonatal gene therapy with a human FVIII
cDNA developed high-titer inhibitors. Thus, results in mice may not predict results in large
animals and humans. Patients have not developed inhibitors after gene therapy, although these
adults had been treated extensively with factor without inhibitor formation, and were likely to
be at low risk. Clearly, the problem of inhibitor development needs to be evaluated further.

A major concern for integrating vectors is the risk of cancer from insertional mutagenesis.
Although the common gamma chain used for gene therapy in patients with X-linked severe
combined immunodeficiency may have contributed to the leukemias that developed in 20%
of hese patients, integration of the retroviral vector near an oncogene also played a role. In
addition, integration within the Evi1 locus or other sites may have promoted clonal expansion
of hematopoietic cells in non-human primates or in humans with chronic granulomatous
disease after ex-vivo transduction of HSC. Thus insertional mutagenesis continues to be a
very serious concern for HSC transduction.

Most studies have not reported cancers in small or large animals that received gene therapy
with a viral or plasmid vector to the liver or muscle. One exception is the report that neonatal
intravenous injection of an AAV2 vector resulted in liver tumors in mice with
mucopolysaccharidosis VII. Another exception is the demonstration that fetal or neonatal
transfer of some lentiviral vectors resulted in liver tumors in adults, although administration
of other integrating vectors at the same ages was not carcinogenic. This suggests that there
was a specific oncogenic element present in the vectors that caused cancer. It will be
important to obtain long-term data in animals with therapeutic levels of expression to assess
this risk further (Donsante et al., 2001).

12.5. Best Treatment Option Received by Parents

The type of treatment you or your child receives depends on several things, including how
severe the hemophilia is, the activities you'll be doing, and the dental or medical procedures
you'll be having.

Mild hemophiliaReplacement therapy usually isn't needed for mild hemophilia.

Sometimes, though, DDAVP is given to raise the body's level of factor VIII.

Moderate hemophiliaReplacement therapy is needed only when bleeding occurs or to

prevent bleeding that could occur when doing certain activities. Your doctor also may
recommend DDAVP prior to having a procedure or doing an activity that increases the risk of
bleeding.

Severe hemophiliaYou usually need replacement therapy to prevent bleeding that could
damage your joints, muscles, or other parts of your body. Typically, replacement therapy is
given at home two or three times a week. This preventive
therapy usually is started in patients at a young age and may need to continue for life. For
both types of hemophilia, getting quick treatment for bleeding is important. Quick treatment
can limit damage to your body. If you or your child has hemophilia, learn to recognize signs
of bleeding.
Other family members also should learn to watch for signs of bleeding in a child who has
hemophilia. Children sometimes ignore signs of bleeding because they want to avoid the
discomfort of treatment (NIH, 2015).

13. Conclusion

Hemophilia is an X-linked congenital bleeding disorder caused by a deficiency of coagulation

factor VIII (in hemophilia A) or factor IX (in hemophilia B), is very hard to live with. As the
number of patients reported with hemophilia is comparatively less than other major diseases
like cancer, cardiac diseases, and diabetics it seems to be less concentrated area by
researchers. As technologies develop, tremendous advances have been made in the treatment
of hemophilia, and many patients can now lead full, healthy lives with careful management of
their condition.

The development of clotting factors made in the laboratory has virtually eliminated the
danger of infusion-related infection with HIV or hepatitis viruses from clotting factor
replacement therapy and regular home-based infusions have helped reduce chronic joint
problems. In the future, people with hemophilia may have access to continuous infusion of
clotting factors under the skin or in pill form. Some doctors are also encouraged by research
involving therapy. The days are not far away when hemophilia is treated with ease and even
complete cure possible.X
REFERENCES

In Barman SM, Barrett KE, Boitano S, Brooks H, Editors. Ganongs Review of Medical
Physiology. USA: McGraw-Hill Education, 2015; pp 531-533.

Castaman G, Mancuso ME, Giacomelli SH. Molecular and phenotypic determinants of the
response to desmopressin in adult patients with mild hemophilia A. Journal of Thrombosis
and Haemostasis, 2009; 7(11):1824-1831.

Chandy M. Pharmacologic options for controlling bleeding. In Schulman S, Editor. Treatment

Options in the Management of Hemophilia in Developing Countries, Hoboken: Blackwell
Publishing Ltd., 2005; pp 5-7.

Donsante A, Vogler C, Muzyczka N. Observed incidence of tumorigenesis in long-term

rodent studies of rAAV vectors. Gene Therapy, 2001; 8(3):13431346.

Fischer K, Van der Bom JG, Mauser-Bunschoten EP, Roosendaal G, Prejs R, Grobbee DE et
al. Changes in treatment strategies for severe haemophilia over the last 3 decades: Effects on
clotting factor consumption and arthropathy. Haemophilia, 2001; 7(5): 446-452.

Gomis M, Querol F, Gallach JE, Gonzalez LM, Aznar JA. Exercise and sport in the treatment
of haemophilic patients: A systematic review. Haemophilia, 2009; 15(1): 43-54.

Gralnick HR, Rick ME. Danazol increases factor VIII and IX in classical hemophilia and
christmas diseaseThe New England Journal of Medicine, 1983; 308(23):1393-1395.

Ingram GI, Dykes SR, Creese AL, Mellor P, Swan AV, Kaufert JK et al. Home treatment in
haemophilia: Clinical, social and economic advantages. Clinical & Laboratory Haematology,
1979; 1(1):13-27.
Iorio A, Fabbriciani G, Marcucci M, Brozzetti M, Filipponi P. Bone mineral density in
haemophilia patients: A meta-analysis. Seminars in Thrombosis and Hemostasis, 2010;
103(3): 596-603.

Kempton CL, Soucie JM, Miller CH, et al. In non-severe hemophilia A the risk of inhibitor
after intensive factor treatment is greater in older patients: a case-control study. The Journal
of Thrombosis and Haemostasis, 2010; 8(10): 2224-31.
Lethagen S. Desmopressin in mild hemophilia A: indications, limitations, efficacy, and safety.
Seminars in Thrombosis and Hemostasis, 2003; 29(1):101-106.

Liras A, Segovia C, Gabn AS. Advanced therapies for the treatment of hemophilia: Future
perspectives. Orphanet Journal of Rare Diseases, 2012; 7(97): 1-9.

Luchtman-Jones L, Valentino LA, Manno C. Recombinant therapy workshop participants

considerations in the evaluation of haemophilia patients for short-term prophylactic therapy:
A paediatric and adult case study. Haemophilia, 2006; 12(1):82-86.

Manco-Johnson MJ, Abshire TC, Shapiro AD. Prophylaxis versus episodic treatment to
prevent joint disease in boys with severe hemophilia. The Journal of Thrombosis and
Haemostasis, 2007; 357(6): 535-544.

Mathews V, Viswabandya A, Baidya S, George B, Nair S, Chandy M, Srivastava A. Surgery

for hemophilia in developing countries. Seminars in Thrombosis and Hemostasis, 2005;
31(5): 538-543.

National Hemophilia Foundation (NHF). History of Bleeding Disorders [Internet]. 2015

Available from: http://www.hemophilia.org/Bleeding-Disorders/History-of-Bleeding-
Disorders accessed on 12 July, 2015.

National Hemophilia Foundation (NHF). How Is Hemophilia Treated? [Internet]. 2015

Available from: http://www.nhlbi.nih.gov/health/health-topics/topics/hemophilia/treatment,
accessed on 12 July, 2015.

National Institutes of Health.(NHF). What Causes Hemophilia? [Internet]. Available

from:http://www.nhlbi.nih.gov/health/health-topics/topics/hemophilia/causes, accessed on 28
December, 2015.

Petrini P, Seuser A. Haemophilia care in adolescents compliance and lifestyle issues.

Haemophilia, 2009; 15(1):15-9.

Ponder KP. Gene therapy for hemophilia. Current Opinion in Hematology, 2006; 13(4): 301
307.

Powell JS, Ragni MV, White GC II. Phase 1 trial of FVIII gene transfer for severe hemophilia
A using a retroviral construct administered by peripheral intravenous infusion. Blood, 2003;
102(5): 20382045.
Querol F, Aznar JA, Haya S, Cid A. Orthoses in haemophilia. Haemophilia, 2002; 8(3): 407-
412.

In Raabe M, Editor. Hemophilia. New york: Infobase Publishing, 2008; pp 15-23, 48-49, 56-
69, 84-95.

Rizza CR, Kernoff PB, Matthews JM, McLennan CR, Rainsford SG. A comparison of
coagulation factor replacement with and without prednisolone in the treatment of haematuria
in haemophilia and christmas disease. Seminars in Thrombosis and Hemostasis, 1977; 28(37):
86-90.

Seuser A, Boehm P, Kurme A, Schumpe G, Kurnik K. Orthopaedic issues in sports for

persons with haemophilia. Haemophilia, 2007; 13(2): 4752.

Shima M, Yoshioka A. Products used to treat hemophilia: Recombinant products. In Lee CA,
Berntorp EE, Hoots WK, Editors. Textbook of Hemophilia. UK: John Wiley & Sons Ltd,
2014; pp 165-166.

Singleton T, Kruse-Jarres R, Leissinger C. Emergency department care for patients with

haemophilia and von Willebrand disease. The Journal of Emergency Medicine, 2010; 39(2):
158-165.

Sona PS, Lingam CM. Hemophilia - An overview. International Journal of Pharmaceutical

Sciences Review and Research, 2010; 5(1): 18-26.

Srivastava A, Chandy M, Sunderaj GD, Lee V, Daniel AJ, Dennison D et al. Low-dose
intermittent factor replacement for post-operative haemostasis in haemophilia. Haemophilia,
1998; 4(6): 799-801.

In Srivastava A, Mahlangu JN, Brewer AK, Bunschoten EPM, Mulder K, Key NS, Editors.
Laboratory Diagnosis: Guidelines for the Management of Hemophilia. Hoboken: Blackwell
Publishing Ltd., 2012; pp 29-31.
Tsoukas C, Eyster ME, Shingo S. Evaluation of the efficacy and safety of etoricoxib in the
treatment of hemophilic arthropathy. Blood, 2006; 107(5):1785-90.

Wallny TA, Scholz DT, Oldenburg J. Osteoporosis in haemophilia - An underestimated

comorbidity. Haemophilia, 2007; 13(1): 79-84.
World Federation of Hemophilia (WHF). About bleeding disorders [Internet]. 2014 Available
Form: http://www.wfh.org/en/page.aspx?pid=662, accessed on 5 September, 2015.

World Federation of Hemophilia (WFH). How do you get hemophilia? [Internet]. 2012
Available from: http://www.wfh.org/en/page.aspx?pid=644, accessed on 28 December, 2015.

Wu R, Luke KH, Poon MC, Wu X, Zhang N, Zhao L et al. Low dose secondary prophylaxis
reduces joint bleeding in severe and moderate haemophilic children: A pilot study in China.
Haemophilia, 2011; 17(1): 70-74.