|
Haemophilia or
hemophilia is the name of any of several hereditary
genetic illnesses that impair the body's ability to control
bleeding. Genetic deficiencies (or, very rarely, an
autoimmune disorder) cause lowered plasma clotting factor
activity so as to compromise blood-clotting; when a blood
vessel is injured, a scab will not form and the vessel can
continue to bleed excessively for a very long period of
time. The bleeding can be external, if the skin is broken by
a scrape, cut or abrasion, or it can be internal, into
muscles, joints or hollow organs. It might therefore present
visibly as skin bruises, or subtly as melena, hematuria, or
bleeding in the brain.
Forms
Haemophilia A - factor VIII
deficiency, "classic haemophilia" (X-linked)
Haemophilia B - factor IX deficiency, "Christmas disease"
(X-linked)
Haemophilia C - factor XI deficiency (Ashkenazi Jews,
autosomal recessive)
The unrelated type 1 and
type 2 von Willebrand disease (vWD) are milder than any of
the three haemophilias; only type 3 von Willebrand disease
expresses a severity similar to the haemophilias. vWD is
caused by mutations in the coagulation protein von
Willebrand factor. It is the most common coagulation
disorder present in 1% of the population.
Genetics
Haemophilia A and B are
inherited in an X-linked recessive pattern. They are caused
by mutations affecting the genes encoding one of the
clotting factors. The genes for both Haemophilia A and
Haemophilia B are located on the X chromosome; other
clotting factor deficiencies exist, but are not X linked
resulting in different clinical symptoms.
Females possess two X-chromosomes, whereas males have one X
and one Y chromosome. Since the mutations causing the
disease are recessive, a woman carrying the defect on one of
her X-chromosomes may not be affected by it, as the
equivalent allele on her other chromosome should express
itself to produce the necessary clotting factors. However
the Y-chromosome in men has no gene for factors VIII or IX.
If the genes responsible for production of factor VIII or
factor IX present on a male's X-chromosome is deficient
there is no equivalent on the Y-chromosome, so the deficient
gene is not masked by the dominant allele and he will
develop the illness.
Since a male receives his single X-chromosome from his
mother, the son of a healthy female silently carrying the
deficient gene will have a 50% chance of inheriting that
gene from her and with it the disease; and if his mother is
affected with haemophilia, he will have a 100% chance of
being a haemophiliac. In contrast, for a female to inherit
the disease, she must receive two deficient X-chromosomes,
one from her mother and the other from her father (who must
therefore be a haemophiliac himself). Hence haemophilia is
far more common among males than females. However it is
possible for female carriers to become mild Haemophiliacs
due to lyonisation of the X chromosomes. Haemophiliac
daughters are more common than they once were, as improved
treatments for the disease have allowed more haemophiliac
males to survive to adulthood and become parents.
Haemophilia is particularly dangerous in adult females
because of the recurring bloodflows involved in
menstruation.
As with all genetic disorders, 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 1/3 of all hemophilia A and 1/5 of all hemophilia B
cases. Genetic testing and genetic counseling is recommended
for families with hemophilia. Prenatal testing, such as
amniocentesis, is available to pregnant women who may be
carriers of the condition.
Probability
If a female gives birth to a
haemophiliac child, she is possibly a carrier for the
disease. Until modern direct DNA testing, however, it was
impossible to determine if a female with only healthy
children was a carrier or not. Generally, the more healthy
sons she bore, the higher the probability that she was not a
carrier, specifically
It is estimated that about
0.006% percent of the United States population suffers from
Haemophilia.
Treatment
Though there is no cure for
haemophilia, it can be controlled with regular injections of
the deficient clotting factor, i.e. factor VIII in
haemophilia A or factor IX in haemophilia B. Some
haemophiliacs develop antibodies (inhibitors) against the
replacement factors given to them, so the amount of the
factor has to be increased or non-human replacement products
must be given, such as porcine factor VIII. The increasing
availability of human recombinant replacement blood products
means the incidence of inhibitor formation is decreasing.
If a patient becomes refractory to replacement coagulation
factor as a result of circulating inhibitors, this may be
overcome with recombinant human factor VII (NovoSeven®),
which is registered for this indication in many countries.
In western countries, common standards of care fall into one
of two categories: prophylaxis or on-demand. Prophylaxis
involves the infusion of clotting factor on a regular
schedule in order to keep clotting levels sufficiently high
to prevent spontaneous bleeding episodes. On-demand
treatment involves treating bleeding episodes once they
arise.
As a direct result of the contamination of the blood supply
in the late 1970's and early 1980's with virologic agents
such as HIV and Hepatitis, new methods were developed in the
production of clotting factor products. The initial response
was to heat treat (pasteurize) plasma-derived factor
concentrate, followed by the development of monoclonal
factor concentrates which use a combination of heat
treatment and affinity chromatography to inactivate any
viral agents in the pooled plasma from which the factor
concentrate is derived. More recently, recombinant factor
products (which are typically cultured in Chinese hamster
ovaries and involve little, if any contact with human plasma
products) have become available and are widely used in
wealthier western countries. While recombinant clotting
factor products offer higher purity and safety, they are
also extremely expensive, and not generally available in the
developing world. In many cases, factor products of any sort
are difficult to obtain in developing countries.
Haemophilia figured prominently in the history of European
royalty. Queen Victoria passed the mutation to her son
Leopold and, through several of her daughters, to various
royals across the continent, including the royal families of
Spain, Germany and Russia. For this reason it was once
popularly called "the royal disease".
|
|