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Haemophilia
In the human body, each cell contains 23 pairs of chromosomes, one of
each pair inherited through the egg from the mother, and the other
inherited through the sperm of the father. Of these chromosomes, those that
determine sex are X and Y. Females have XX and males have XY. In addition
to the information on sex, 'the X chromosomes carry determinants for a
number of other features of the body including the levels of factor VIII
and factor IX.'1 If the genetic information determining the factor VIII and
IX level is defective, haemophilia results. When this happens, the protein
factors needed for normal blood clotting are effected. In males, the single
X chromosome that is effected cannot compensate for the lack, and hence
will show the defect. In females, however, only one of the two chromosomes
will be abnormal. (unless she is unlucky enough to inherit haemophilia from
both sides of the family, which is rare.)2 The other chromosome is likely
to be normal and she can therefore compensate for this defect.
There are two types of haemophilia, haemophilia A and B. Haemophilia A
is a hereditary disorder in which bleeding is due to deficiency of the
coagulation factor VIII (VIII:C)3. In most of the cases, this coagulant
protein is reduced but in a rare amount of cases, this protein is present
by immunoassay but defective.4 Haemophilia A is the most common severe
bleeding disorder and approximately 1 in 10,000 males is effected. The most
common types of bleeding are into the joints and muscles. Haemophilia is
severe if the factor VIII:C levels are less that 1 %, they are moderate if
the levels are 1-5% and they are mild if they levels become 5+%.5
Those with mild haemophilia bleed only in response to major trauma or
surgery. As for the patients with severe haemophilia, they can bleed in
response to relatively mild trauma and will bleed spontaneously.
In haemophiliacs, the levels of the factor VIII:C are reduced. If the
plasma from a haemophiliac person mixes with that of a normal person, the
Partial thromboplastin time (PTT) should become normal. Failure of the PTT
to become normal is automatically diagnostic of the presence of a factor
VIII inhibitor. The standard treatment of the haemophiliacs is primarily
the infusion of factor VIII concentrates, now heat-treated to reduce the
chances of transmission of AIDS.6 In the case of minor bleeding, the factor
VIII:C levels should only be raised to 25% with one infusion. For moderate
bleeding, 'it is adequate to raise the level initially to 50% and maintain
the level at greater that 25% with repeated infusion for 2-3 days. When
major surgery is to be performed, one raises the factor VIII:C level to
100% and then maintains the factor level at greater than 50% continuously
for 10-14 days.'7
Haemophilia B, the other type of haemophilia, is a result of the
deficiency of the coagulation factor IX - also known as Christmas disease.
This sex-linked disease is caused by the reduced amount of the factor IX.
Unlike haemophilia A, the percentage of it's occupance due to an abnormally
functioning molecule is larger. The factor IX deficiency is 1/7 as common
as factor VIII deficiency and it is managed with factor VIII concentrates.
Unlike factor VIII concentrates which have a half-life of 12 hours, the
half-life of factor IX concentrates is 18 hours. In addition, factor IX
concentrates contain a number of other proteins, including activated
coagulating factors that contribute to a risk of thrombosis. Therefore,
more care is needed in haemophilia B to decide on how much concentration
should be used.
The prognosis of the haemophiliac patients has been transformed by the
availability of factor VIII and factor IX replacement. The limiting factors
that result include disability from recurrent joint bleeding and viral
infections such as hepatitis B from recurrent transfusion.8
Since most haemophiliacs are male and only their mother can pass to
them the deficient gene, a very important issue for the families of
haemophiliacs now is identifying which females are carriers. One way to
determine this is to estimate the amount of factor VIII and IX present in
the woman. However, while a low level confirms the carrier status, a normal
level does not exclude it. In addition, the factor VIII and IX blood levels
are known to fluctuate in people and will increase with stress and
pregnancy. As a result, only a prediction of the carrier status can be
given with this method.
Another method to determine the carrier status in a woman is to look
directly at the DNA from a small blood sample of several members of the
family including the haemophiliacs. In Canada, modern operations include
Chorionic Villous Sampling (CVS) and it helps analyze the DNA for markers
of haemophilia at 9-11 weeks of pregnancy. (Fig. 1)9 A small probe is
inserted through the neck of the mother womb or through the abdomen under
local anaesthetics. A tiny sample from the placenta is removed and sent for
DNA analysis. Since this process can be done at 9-11 weeks after pregnancy,
the pregnancy is in it's relatively early stages and a decision by the
mother (and father) to terminate the pregnancy will not be as physically or
emotionally demanding on the mother than if she had it performed in the
late stages of the pregnancy.
Going back to the haemophiliacs, many have become seropositive for HIV
infections transmitted through factor VIII and IX concentrates and many
have developed AIDS. In Canada, the two drugs currently undergoing clinical
testing for treatment of HIV disease are AZT and DDI. For the use of AZT,
the major complication is suppression of normal bone marrow activity. This
results in low red and white blood cell counts.The former can lead to
severe fatigue and the latter to susceptibility to infections.10 DDI is
provided as a powder, which must be reconstructed with water immediately
prior to use. The most common adverse effect so far is the weakness in the
hands and legs. However, it appears that DDI is free of the bone marrow.11
AZT and DDI both represent the first generation of anti-retroviral drug
and it is the hope of many people that they will be followed by less toxic
and more effective drugs.
As it can be seen, haemophilia is one of those sex-linked diseases
that must involve the inheritance of both recessive and deficient
chromosomes. It is mostly found in males and since every male has a Y
chromosome, it is a general rule that the male will not pass it to his male
offsprings. Haemophiliacs can have either inherited the disease or they
could have had a mutation. In either case, these people must try to live a
normal life and must avoid any activities that can result in trauma.
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