Hemophilia

(1)       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                                                                                                                                                                                                                                                                                                                                                                                                                                                           (2) 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                                                                                                                                                                                                                                                                                                                                                                                                                                                          (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 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.                                                                                                                                                                                                                                                                                                                                           (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.        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