Haemophilia B (Factor IX Deficiency)

Haemophilia B is also known as Christmas disease after the patient in whom it was classically described. Haemophilia A is due to a deficiency of clotting factor VIII whilst haemophilia B is due to a deficiency of clotting factor IX. They are both X-linked recessive conditions. By and large, haemophilia B tends to be similar to haemophilia A but less severe.
The gene locus is Xq27.1-q27.2. As is usual in such conditions, deficiency is not absolute but the lower the level of factor IX, the more serious will be the disease.^1,1

There is a variation called Leyden in which factor IX levels are below 1% until puberty when they rise, possibly reaching as high as 40 to 60% of normal.² This is thought to be due to the effects of testosterone at maturity.

Haemophilia A is about 5 times as common as haemophilia B. The latter has a prevalence of around 1 in 25,000 to 30,000 males.⁴ There are usually carrier females and affected males.

The reference level of factor IX is 5μ g/ml but the "normal" range is from half to twice that level.

• Severe disease occurs with a factor IX level below 1% of the reference and accounts for about 50% of cases.
• Moderate severity occurs with a level of 1 to 5% and accounts for around 30% of cases.
• Mild disease is with levels of 6 to 30% and accounts for around 20% of cases.

No race nor geographical area is exempt.

If a woman is a carrier there is a 1 in 2 chance that any son will be affected and a 1 in 2 chance that any daughter will be a carrier. If a man with the disease fathers a child, any daughter will be a carrier and any son will be unaffected and will not carry the gene. There is a report of a daughter of a man with the disease who had a factor IX level of 5% and haemarthroses and this was thought to be a manifestation due to Lyonisation in which one of the X chromosomes is inactive.^5,6 There are a few other isolated reports of females presenting with the disease.

A study from London of patients from Sweden showed that spontaneous mutation in both carrier females and affected males is not uncommon.⁷

As a general rule, platelet deficiency causes petechial haemorrhages and ecchymoses (bruising) whilst clotting factor deficiency produces haematomas and haemarthroses. Both haematomas in muscles and bleeding into joints can result from minor trauma and be very painful.

• Patients with severe disease suffer lifelong from infancy with spontaneous haemorrhages and haemarthrosis. They may even start from the trauma of delivery especially if instrumental. Ventouse delivery may produce an enormous haematoma.
• Patients with moderate disease suffer haemorrhage from minor trauma or surgery and sometimes spontaneous haemarthrosis.
• Patients with mild disease may suffer unexpected haemorrhage after trauma or surgery, or precipitated by the use of nonsteroidal anti-inflammatory drugs.
• If a patient presents with a history of diagnosed haemophilia, ascertain the type and the normal level of clotting factor.

For those who have not been diagnosed there are a number of presentations, normally in infancy, except in the mildest cases.

• There may be marked haematoma from delivery, especially after a Ventouse extraction.
• Infants may bleed excessively when blood is taken as for a Guthrie test. Circumcision may be the presenting sign of a problem. Traditional Jewish practice is to perform this on the 8th day from birth.
• Immunisations and tooth loss may lead to unexpected blood loss.
• Just the ordinary rough play of childhood, that tends to be more marked in little boys than little girls, may produce excessive bruising or spontaneous haemorrhage. With mild disease, haemorrhage is most likely to occur with trauma or surgery.
• Musculoskeletal problems may present as warmth, pain, stiffness, and refusal to use a joint due to muscle haematoma or haemarthrosis. Infants may not be able to complain in words but refusal to use a joint demands investigation.
• There may be headache, stiff neck, vomiting, lethargy, irritability, and spinal cord syndromes. There can be intracranial bleeding.
• Bleeding from the gut may produce haematemesis, melena, frank red blood per rectum, and abdominal pain.
• There may be microscopic haematuria or gross bleeding into the urinary tract.
• Other possible features include epistaxis, haemorrhage into the oral mucosa, haemoptysis, dyspnoea from a haematoma obstructing the airway, compartment syndromes, and contusions.

Physical signs

• There may be heat or swelling of a haematoma or an effusion.
• There may be obvious distress on palpation or passive movement of a joint.
• Bleeding into the CNS may cause neurological signs, including reduced level of consciousness.
• There may be pallor, dyspnoea, tachycardia and other features of exsanguination.

• Haemophilia A
• von Willebrand's disease
• Factor IX inhibitors
• Vitamin K deficiency
• Hepatic disease causing deficiency of clotting factors
• Platelet disorders
• Disseminated intravascular coagulation

It may be necessary to treat the bleeding disorder before establishing a full diagnosis. This should not be delayed. Although the treatment will probably nullify the value of coagulation tests taken soon after, curbing haemorrhage and saving the patient's life comes first. It is usually possible to take blood before any treatment is started but an accurate diagnosis may have to wait.

• Haemoglobin level may be normal for a child of that age, or low. Remember that in acute haemorrhage it takes time for haemodilution to occur.
• Note the white cell count in case the diagnosis is really leukaemia.
• Check platelets.
• Prothrombin time (PTT) will be normal.
• Activated partial thromboplastin time (aPTT) will be elevated although in mild disease it may be within the range of normal.
• Factor IX percentage activity.
• Factor IX inhibitors.
• Thromboelastography - a method of assessing clot formation characteristics - is being used in some centres to assist in determining bleeding tendency.⁸
• Imaging of the CNS may be in order, especially is there have been neurological signs. In acute haemarthrosis, x-ray does not add much but after years of recurrent haemarthrosis there is usually evidence of joint destruction.

• In the acute situation attention must be paid to trying to secure haemostasis. In the established patient, he may be able to administer factor concentrate himself. Get as much history as possible from the patient. He probably knows his disease well.
• If possible take blood for coagulation tests before starting any therapy but do not delay therapy. Blood transfusion may be required and so group and cross-match is necessary.
• Nowadays recombinant factor IX is available. For serious haemorrhage the aim is to correct the level to 100% but for more minor haemorrhage correction to 50% will suffice. A calculation of the dose required is based on the body weight, the baseline level of Factor IX and the desired level to be achieved. If it is impossible to get adequate recombinant factor IX in time, fresh frozen plasma and cryoprecipitate may still be used. Tranexamic acid as an inhibitor of fibrinolysis may also be of value.
• A further dose should be administered 24 hours after the first and is half of the initial calculated dose. Minor haemorrhage requires between 1 and 3 doses of factor IX. Major haemorrhage needs many doses and continued factor IX activity monitoring with the goal of keeping the trough activity level at least 50%. Continuous infusions of factor IX may be required.
• As the oral mucosa is rich in native fibrinolytic activity, antifibrinolytic therapy is used in addition to factor IX replacement for oral mucosal haemorrhage and prophylaxis. Amino-caproic acid is often employed.
• Patients should wear a Medicalert bracelet stating the disease, the normal level of factor IX and any other important information.
• Recently, liver transplant has been carried out successfully using high-purity Factor IX to control perioperative bleeding.⁹

Managing pain¹⁰

Haematoma and haemarthrosis can be very painful and require medication. The best route is oral but NSAIDs must not be employed for fear of GI haemorrhage. Opiates may well be needed and if given parenterally this must be IV or possibly SC but not IM. Intramuscular injection will produce a large and painful haematoma.

Prophylaxis³

There are both risks and benefits from the prophylactic use of factor IX therapy rather than simply treating emergencies. Intermittent prophylactic augmentation of factor IX levels may well have a beneficial effect on preventing haematoma and haemarthrosis formation. The frequency of administration and the dose to be given are an individual decision between the haematologist and the patient.

The main disadvantage of regular prophylactic administration of factor IX is the risk of inhibitors developing. They result from immune reactions as the introduced substance may present to the immune system as "not self". These inhibitors are less of a problem than with haemophilia A and occur in about 3% of severe cases. It may be possible to overcome them by using higher doses or it may be possible to induce immune tolerance .

Life style has to be adapted to accommodate the disease. Contact sports should be avoided as well as sports and pastimes in which there is significant risk of trauma. Manual labour should be avoided.

The bleeding can cause many problems, including neurological deficits but a very common finding is that recurrent bleeding into joints leads to destruction of the joint. The joints are painful to move and the range of movement is limited. Anyone who has taken blood from a patient with haemophilia A or B will probably have noticed that the patient is unable to extend the elbow fully.

Before the advent of recombinant factor IX, patients used to receive factor IX concentrate that was derived from the plasma of many donors. Before 1985 there was a significant risk that this product may be contaminated with hepatitis B or C or HIV. The risk was even greater for patients with haemophilia A, partly because it is usually a more severe condition and so treatment is probably needed more often but also because they required even more donors per treatment. Because of shortages, much of the product was imported from the USA where the incidence of these diseases is much higher and where the use of paid donors tends to produce a different type of donor in terms of lifestyle. A study published in 1998 found HIV antibody in 41% of patients with haemophilia A and 6% of haemophilia B. For the more severely affected patients the figures were 59% and 11% respectively.¹¹ In 1985 a viral inactivation process made the product much safer but the advent of recombinant "genetically engineered" factor IX has made a vast difference. Without it we may still be worried about transmission of other agents such as new variant Creutzfeldt-Jakob disease.¹²

Many haemophiliacs, including those with haemophilia B, are infected with both hepatitis C and HIV and the two viruses together produce a rather worse prognosis.¹³ There is a rising rate of death from liver disease and hepatocellular carcinoma.¹⁴

The life expectancy of patients with Christmas disease was around 60 years but the tragedy of infection, especially HIV as a result of their treatment, has curtailed many lives. The development of techniques such as liver transplant will help to improve the outlook but must be balanced against the development of conditions likely to be seen in an ageing haemophiliac population, such as nephrotic syndrome.¹⁵ A study of patients with severe haemophilia A or B not infected by HIV showed that mortality rates exceeded the general population by a factor of 2.69. In moderate/mild hemophilia, all-cause mortality did not change significantly during 1985 to 1999, and median life expectancy was 75 years. Mortality from bleeding and its consequences, and from liver diseases and Hodgkin disease, was increased, but for ischaemic heart disease it was lower.¹⁶

If a woman is known to be a carrier of the disease then it would be possible to perform selective abortion of any male fetus. This has two ethical objections. One is that 50% of aborted fetuses would be normal. The other is that abortion for a condition that is associated with a fairly normal life style with some restriction of "rough" activity and a life expectancy of 60 or more is ethically unsound. Reproductive choices for affected families are complex. There is the question of passing on the gene either from mother or father and the possibility of transmission of HIV if the man has been infected.¹⁷

New genetic tests are being developed which could aid the detection of the carrier state in women and also prenatal diagnosis.¹⁸ The measurement of plasma factor activity level and information from genotyping are helpful in assisting female carriers of options regarding the future of their pregnancy.¹⁹

For the future, this may well be an excellent disease for the use of gene therapy.

The disease was first recognised as different from haemophilia (now called haemophilia A) by Aggler et al in 1952²⁰ but the classical paper on the subject appeared at the end of that year.²¹ The name of the patient was Stephen Christmas. December 25 is Christmas Day, December 26th is the Feast of Stephen and the paper appeared in the Christmas edition of the BMJ on 27th December 1952.

The Leyden variation that improves at puberty was described in 1970.² The discovery in the early 1980s that many haemophiliacs with type A and, to a lesser extent, type B were infected with hepatitis viruses and HIV has been disastrous. However, without the treatment they would have died.

Recombinant factor VIII and factor IX has made an enormous difference but it is expensive. Gene therapy has been disappointing so far.²²