Human DNA


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, hemophilia results. When this
happens, the protein factors needed for normal blood
clotting are affected. In males, the single X chromosome
that is affected 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 Hemophilia 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. Hemophilia 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 (2) Those with mild hemophilia bleed
only in response to major trauma or surgery. As for the
patients with severe hemophilia, they can bleed in response
to relatively mild trauma and will bleed spontaneously.
In hemophiliacs, the levels of the factor VIII:C are
reduced. If the plasma from a hemophiliac 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
hemophiliacs 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
Hemophilia B, the other type of hemophilia, 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 hemophilia A, the
percentage of its presence resulting from 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 (3) concentrates contain a number of
other proteins, including activated coagulating factors
that contribute to a risk of thrombosis. Therefore, more
care is needed in hemophilia B to decide on how much
concentration should be used.
The prognosis of the hemophiliac 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 hemophiliacs are male and only their mother can
pass to them the deficient gene, a very important issue for
the families of hemophiliacs 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 hemophiliacs.
In Canada, modern operations include Chorionic Villous
Sampling (CVS) and it helps analyze the DNA for markers of
hemophilia 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 anesthetics. A tiny sample
from the placenta is removed and sent for DNA analysis. (4)
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.
Unfortunately, many hemophiliacs 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 infectionts. 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.
Hemophilia is a disease 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. Hemophiliacs 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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