Hemophilia A

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Hemophilia A is a hereditary blood disorder, primarily affecting males, characterized
by a deficiency of the blood clotting protein known as Factor VIII that results in
abnormal bleeding. Babylonian Jews first described hemophilia more than 1700 years
ago; the disease first drew widespread public attention when Queen Victoria
transmitted it to several European royal families. Mutation of theHEMA gene on the X
chromosome causes Hemophilia A. Normally, females have two X chromosomes,
whereas males have one X and one Y chromosome. Since males have only a single
copy of any gene located on the X chromosome, they cannot offset damage to that
gene with an additional copy as can females. Consequently, X-linked disorders such
as Hemophilia A are far more common in males. The HEMA gene codes for Factor VIII,
which is synthesized mainly in the liver, and is one of many factors involved in blood
coagulation; its loss alone is enough to cause Hemophilia A even if all the other
coagulation factors are still present.
Treatment of Hemophilia A has progressed rapidly since the middle of the last century
when patients were infused with plasma or processed plasma products to replace
Factor VIII. HIV contamination of human blood supplies and the consequent HIV
infection of most hemophiliacs in the mid-1980s forced the development of alternate
Factor VIII sources for replacement therapy, including monoclonal antibody purified
Factor VIII and recombinant Factor VIII, both of which are used in replacement
therapies today.
Development of a gene replacement therapy for Hemophilia A has reached the
clinical trial stage, and results so far have been encouraging. Investigators are still
evaluating the long-term safety of these therapies, and it is hoped that a genetic cure
for hemophilia will be generally available in the future.

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Hemophilia A

Hemophilia A is the most common type of hemophilia. It is also

known as factor VIII deficiency or classic hemophilia. It is largely
an inherited disorder in which one of the proteins needed to form
blood clots is missing or reduced. In about 30% of cases, there is
no family history of the disorder and the condition is the result of
a spontaneous gene mutation.
Approximately one in 5,000 males born in the United States has
hemophilia. All races and economic groups are affected equally.
When a person with hemophilia is injured, he does not bleed
harder or faster than a person without hemophilia, he bleeds
longer. Small cuts or surface bruises are usually not a problem,
but more traumatic injuries may result in serious problems and
potential disability (called "bleeding episodes").
Normal plasma levels of FVIII range from 50% to 150%. There
are different levels of hemophilia: mild, moderate, and severe,
depending on the amount of clotting factor in the blood:
People with mild hemophilia have 5% up to 50% of the
normal clotting factor in their blood. Most patients
usually have problems with bleeding only after serious
injury, trauma or surgery. In many cases, mild hemophilia
is not diagnosed until an injury, surgery or tooth
extraction results in prolonged bleeding. The first episode
may not occur until adulthood. Women with mild
hemophilia often experience menorrhagia, heavy
menstrual periods, and can hemorrhage after childbirth.
People with moderate hemophilia about, 15% of the
hemophilia population, have 1% up to 5% of the normal
clotting factor in their blood. They tend to have bleeding
episodes after injuries and some without obvious cause.
These are called spontaneous bleeding episodes.
People with severe hemophilia about 60% of the
hemophilia population, have <1% of the normal clotting
factor in their blood. They have bleeding following an
injury and may have frequent spontaneous bleeding
episodes, often into their joints and muscles.
Everyone inherits two sex chromosomes, X and Y, from his or her
parents. A female inherits one X chromosome from her mother
and one X chromosome from her father (XX). A male inherits one
X chromosome from his mother and one Y chromosome from his

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father (XY). The gene that causes hemophilia is located on the X

chromosome.
A woman who gives birth to a child with hemophilia often has
other male relatives who also have hemophilia. Sometimes, a
baby will be born with hemophilia when there is no known family
history. This means either that the gene has been "hidden" (that
is, passed down through several generations of female carriers
without affecting any male members of the family) or the change
in the X chromosome is new (a "spontaneous mutation").
There are four possible outcomes for the baby of a woman who is
a carrier. These four possibilities are repeated for each and every
pregnancy:
1. A girl who is not a carrier
2. A girl who is a carrier
3. A boy without hemophilia
4. A boy with hemophilia
With each pregnancy, a woman who is a carrier has a 25%
chance of having a son with hemophilia. Since the father's X
chromosome determines the baby will be a girl, all the daughters
of a man with hemophilia will be carriers. None of his sons, which
is determined by the father through his Y chromosome, will have
hemophilia.

Genetic counseling is available at most HTCs. These professionals

have information to help you make family planning decisions.
In general, small cuts and scrapes are treated with regular firstaid: clean the cut, then apply pressure and a band-aid.
Individuals with mild hemophilia can use a non-blood product
called desmopressin acetate (DDAVP) to treat small bleeds. Deep
cuts or internal bleeding, such as bleeding into the joints or
muscles, require more complex treatment. The clotting factor
missing (VIII or IX) must be replaced so the child can form a clot
to stop the bleeding.
Some factor products are made from human blood products such
as donated plasma. Others, called "recombinant factor," are
made in a laboratory and do not use human blood products. The
Medical and Scientific Advisory Council of the National Hemophilia
Foundation encourages the use of recombinant clotting factor
products because they are safer. Your doctor or your HTC will
help you decide which is right for you. All factor treatments are
injected or infused directly into the veins.
In cases of severe hemophilia, doctors sometimes recommend
giving a regimen of regular factor replacement treatments (a
therapy called prophylaxis) to prevent bleeding episodes before

they happen. The Medical and Scientific Advisory Council of the

National Hemophilia Foundation recommends prophylaxis as
optimal therapy for children with severe hemophilia A and B.
Notify your doctor or HTC if your child does not respond to the
usual dose of factor. In rare instances, people can develop an
inhibitor, to standard factor treatment. In the event this occurs,
your doctor or HTC will work with you to develop a special plan of
care.

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Hemophilia Foundation

2006 National

Haemophilia (2006), 12, (Suppl. 3), 5260

2006 The Author
52 Journal compilation 2006 Blackwell Publishing Ltdformation of alloantibodies is a
T-cell dependent
process involving class-switching and somatic hypermutation [6,7]. Two subtypes of THcells, i.e. TH1
and TH2 cells, are recognized and dened by the
released cytokines. TH1 cells secrete interleukin (IL)2, interferon-c and tumour necrosis factor (TNF)-b
and mediate the cell-mediated immune responses,
such as delayed type hypersensitivity and the activation of cytotoxic T-cells. TH2 cells
secrete IL-4, IL-5,
IL-6 and IL-10, promote B-cells activation and
mediate the humoral response. Cytokines secreted
by TH2 cells also mediate the characteristic immunoglobulin (Ig) class-switching to
IgG4. The exact
mechanism of how the TH1 and TH2 cells contribute
to the process of inhibitor development is not clear,
but the cytokine prole in animal models suggests
that both subsets of cells are involved [811].
The MHC class II phenotype provides a mechanism for individual variation in the
susceptibility to
inhibitor development. Another source of variability
is the T-cell repertoire in each subject. The normal
immune response to self-antigens, like FVIII and FIX
in utero, is the deletion of the T-cells recognizing
these antigens (autoreactive T-cells). However, in
patients with haemophilia, no FVIII or FIX antigen
will be present in the thymus and hence no MHC
peptide complexes created. FVIII/FIX-specic T-cells
will remain and provide a platform for a future

immune response to the exogenous factor [1214].

To elicit an optimal immune reaction and to
induce the resting T-cell to enter the cell cycle, the
interaction between the MHCpeptide complex and
the TCR-CD3 must be supported by co-stimulatory
signals mainly provided by the binding of CD80
(B7.1)/CD86 (B7.2) to CD28 (Fig. 2). Cytokines,
such as IL-2, IL-4 and IL-5, are released and
stimulate the up-regulation of additional surface
molecules on both B- and T-cells, including CD40
ligand (CD40L, CD154), CD28 and CD80/86. The
subsequent interactions induce B-cell proliferation,
differentiation and antibody production. Long-lived
memory T- and B-cells are also formed after which
they reside in the bone marrow, lymph nodes or
spleen. These memory B-cells usually have a higher
receptor afnity than native B-cells because of
somatic hypermutation.
The activation of T-cells is modulated and downregulated by the competitive binding of
cytotoxic
T-lymphocyte antigen 4 (CTLA4) with CD28 to the
B7 molecules. CTLA4 is expressed only on activated
T-cells and at a lower level than CD28. However, the
afnity for the B7 molecule is 20-fold greater. The
importance of the CD28/B7/CTLA4 pathway has
been substantiated in several studies. For example,
B7.2-decient haemophilic mice do not develop
FVIII antibodies and blocking the B7CTLA4 interaction with a fusion protein consisting
of CTLA4
and part of the heavy chain of IgG1 (CTLA4-Ig)
suppresses the formation of FVIII antibodies [15
17]. Blockade of the CD40CD40L pathway also
Fig. 2. Schematic model showing the principles of inhibitor formation in patients with
haemophilia A. Exogenous infused factor
VIII (FVIII) binds to the antigen-presenting cells (APC) (Step 1).
After endocytosis, oligopeptides will be formed by proteolytic
cleavage (Step 2). These peptides bind to the major histocompatibility complex (MHC)
class II molecules having the correct
recognition sequence. TheMHCFVIII peptide complexes are then
transferred to the cell membrane and presented to the T-cell
receptors (TCR) on the CD4+ TH-lymphocytes (Step 3). Co-stimulatory signals have to
be provided by the binding of B7.1 (CD80)
and B7.2 (CD86) to CD28 (Step 4a) to fully activate the
TH-lymphocytes and to stimulate the release of cytokines (Step 5).
The subsequent binding of these cytokines to the corresponding

receptors (CK-R) up-regulates immune response genes and costimulatory molecules on

the cell surfaces of both B- and T-cells
(Step 6). The enhanced action of cytokines and co-stimulatory
molecules, including the interaction between CD40 and CD40L,
induces B-cell proliferation, differentiation and FVIII antibody
production (Step 7). The activation of the TH-cells is down-regulated by the competitive
binding of cytotoxic T-lymphocyte antigen 4 (CTLA4) to the B7 molecules on the APC
(Step 4b).
Fig. 1. Summary of factors that may inuence the risk of inhibitor
formation in patients with haemophilia.
INHIBITOR DEVELOPMENT IN HAEMOPHILIA 53
2006 The Author
Journal compilation 2006 Blackwell Publishing Ltd Haemophilia (2006), 12, (Suppl. 3),
5260counteracts the immune response to FVIII and
preliminary data indicate that a humanized monoclonal anti-CD40L antibody may
modulate the
immune response to FVIII in patients with haemophilia A [1720]. Unfortunately, the
trial from which
these data derived was ended because of the risk of
thromboembolic side-effects before conrmatory
data could be obtained. It is clear from studies of
patients with autoimmune diseases, however, that
several of the co-stimulatory and regulatory molecules have the potential for being
pathophysiologically important and that they may confer
susceptibility to antibody-mediated diseases. An as
yet unexplained phenomenon is the presence of FVIII
specic T-cells and FVIII antibodies in healthy
subjects without a history of bleeding disorders
[2124]. This suggests that other regulatory mechanisms such as the formation of antiidiotypic antibodies may also inuence the immune response to
exogenous FVIII and FIX and hence the clinical
phenotype of patients with haemophilia [25].
Genetic factors
The importance of genetic factors has been reported
in several publications. Inhibitors are more prevalent
in siblings (50%) than in extended haemophiliac
relatives (9%), and in the Malmo International
Brother Study (MIBS), the rate of inhibitor concordance between siblings, i.e. either all
or none of the
siblings had a history of inhibitor development, was
78%, signicantly higher than expected based on
data from unrelated subjects [26,27]. A relative risk
of 3.2 for inhibitor development was calculated in
families with an older affected brother. Patients of
African heritage appear to be at higher risk for

experiencing inhibitors. In a meta-analysis of patients with severe haemophilia A, the

inhibitor incidence was 51.9% in African Americans compared
with 25.8% in Caucasians [28]. Genetic factors,
besides the TCR, that may inuence the outcome of
replacement therapy include the type of causative
gene mutation, the MHC class I and II phenotype
and polymorphisms of the genes coding for cytokines
and immune regulatory molecules.
Type of causative factor gene mutation
The frequency of inhibitors for each type of FVIII
mutation observed in the Bonn and HAMSTeRS
databases has been summarized by Oldenburg et al.
(Fig. 3) [29]. High-risk mutations with a reported
inhibitor incidence of 2188% are typically associated with no circulating antigen, e.g.
null mutations,
and include large deletions, inversions and nonsense
mutations. Missense mutations, small insertions/