Synonym: Christmas disease

Introduction

Haemophilia B is due to a deficiency of clotting factor IX (haemophilia A is due to a deficiency of clotting factor VIII). 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

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.

Epidemiology³

Haemophilia B has a prevalence of around 1 in 25,000 to 30,000 males (about 5 times rarer than haemophilia A).⁴ There are usually carrier females and affected males.

The reference level of factor IX is 5 μg/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 any 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

Presentation³

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 non-steroidal anti-inflammatory drugs (NSAIDs).
• 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, which 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, melaena, 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 central nervous system (CNS) may cause neurological signs, including reduced level of consciousness.
• There may be pallor, dyspnoea, tachycardia and other features of exsanguination.

Differential diagnosis³

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

Investigations³

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.

Management^3,9

The major concerns, even with recombinant products, are the possibility of transmission of infections and inhibitor formation. If patients have never been exposed to plasma products then recombinant factor IX is first-line. If this is unavailable then plasma-derived factor IX or prothrombin complex concentrates are available. The latter should be avoided if at all possible, as it has been associated with an increased risk of thrombosis.⁹

• In the acute situation:
  • Attention must be paid to trying to secure haemostasis. In the established patient, he or she may be able to self-administer factor concentrate. Get as much history as possible from the patient, who probably knows his or her 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.
  • Use recombinant factor IX if available (it is first-line). 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.
  • 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 of at least 50%. Continuous infusions of factor IX may be required.
  • Haematoma and haemarthrosis can be very painful and require analgesic medication. The best route is oral but NSAIDs must not be employed for fear of gastrointestinal haemorrhage.¹⁰ Opiates may well be needed and, if given parenterally, this must be intravenously (IV) or possibly subcutaneously (SC) but not intramuscularly (IM). IM injection will produce a large and painful haematoma.
  • 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, e.g. tranexamic acid.
• In the chronic state:
  • Patient/carer information and consent, with advice regarding advantages and disadvantages of factor concentrates.
  • All patients should be offered vaccination against hepatitis A and hepatitis B - give SC, not IM (may also need to be offered to carers who might inject blood products).⁹
  • Patients should wear a MedicAlert® bracelet stating the disease, the normal level of factor IX and any other important information.
• Surgical considerations:
  • Any decision to proceed with surgery has to be a multidisciplinary one and the decision process should be aided by weighing up the risks and benefits for the patient.
  • Tranexamic acid inhibits fibrinolysis, without increasing thrombosis risk in healthy individuals undergoing cardiac or orthopaedic surgery, and so might be a useful adjunct.⁹
  • Recently, liver transplant has been carried out successfully using high-purity factor IX to control perioperative bleeding.¹¹

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 risk of transmission of infections from recombinant products arises from the use of human and animal products in the culture medium and stabiliser. In order to prevent any human/animal products, two viral inactivation and/or removal processes are used to improve safety of the products.⁹

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 1-3% of severe cases after 11 days of exposure (with a wide range of 2-180 days).⁹ In haemophilia B, inhibitor development is associated with anaphylaxis on exposure to any factor IX product (in half of the patients). Thus, first exposure should take place in a specialist centre.⁹ It may be possible to overcome them by using higher doses or it may be possible to induce immune tolerance, but there is a lack of evidence for this at present.

Lifestyle 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.

Complications³

The bleeding can cause many problems, including neurological deficits; however, 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 might be contaminated with hepatitis B or C or with 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, and 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 those with haemophilia B. For the more severely affected patients the figures were 59% and 11% respectively.¹² 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.¹³

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.¹⁴ There is a rising rate of death from liver disease and hepatocellular carcinoma.¹⁵

Prognosis

The life expectancy of patients with haemophilia B 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.¹⁶ 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 haemophilia, 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's disease, was increased, but for ischaemic heart disease it was lower.¹⁷

Prevention

If a pregnant woman is known to be a carrier of the disease then it would be possible to perform selective abortion of any male fetus she may be carrying. 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 lifestyle, with some restriction of 'rough' activity and a life expectancy of 60 years 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.¹⁸

New genetic tests are being developed which could aid the detection of the carrier state in women and also prenatal diagnosis.¹⁹ The measurement of plasma factor activity level and information from genotyping are helpful in informing female carriers of options regarding the future of their pregnancy.²⁰

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

Historical perspective

The disease was first recognised as different from haemophilia (now called haemophilia A) by Aggler et al in 1952²¹ but the classical paper on the subject appeared at the end of that year.²² 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 have made an enormous difference but they are expensive. Gene therapy has been disappointing so far.²³

Document references

1. Christmas Disease, Online Mendelian Inheritance in Man (OMIM)
2. Veltkamp JJ, Meilof J, Remmelts HG, et al; Another genetic variant of haemophilia B: haemophilia B Leyden.; Scand J Haematol. 1970;7(2):82-90.
3. Furlong BR et al; Type B Hemophilia, Medscape, Oct 2008
4. Connor JM, Pettigrew AF, Hann IM, et al; Application of an intragenic genomic probe to genetic counselling for haemophilia B in the west of Scotland.; J Med Genet. 1985 Dec;22(6):441-6. [abstract]
5. Lascari AD, Hoak JC, Taylor JC; Christmas disease in a girl.; Am J Dis Child. 1969 May;117(5):585-8.
6. X-linked inheritance, Genetic Interest Group, 2008
7. Montandon AJ, Green PM, Bentley DR, et al; Direct estimate of the haemophilia B (factor IX deficiency) mutation rate and of the ratio of the sex-specific mutation rates in Sweden.; Hum Genet. 1992 May;89(3):319-22. [abstract]
8. Chitlur M, Warrier I, Rajpurkar M, et al; Thromboelastography in children with coagulation factor deficiencies. Br J Haematol. 2008 May 19. [abstract]
9. Keeling D, Tait C, Makris M; Guideline on the selection and use of therapeutic products to treat haemophilia Haemophilia. 2008 Jul;14(4):671-84. Epub 2008 Apr 4. [abstract]
10. Haemophilia - Clinical Practice Guidelines, Royal Children's Hospital, Melbourne 2008
11. De Pietri L, Masetti M, Montalti R, et al; Use of recombinant factor IX and thromboelastography in a patient with hemophilia B undergoing liver transplantation: a case report. Transplant Proc. 2008 Jul-Aug;40(6):2077-9. [abstract]
12. No authors listed; Prevalence of antibody to HIV in haemophiliacs in the United Kingdom: a second survey. AIDS Group of the United Kingdom Haemophilia Centre Directors with the co-operation of the United Kingdom Haemophilia Centre Directors.; Clin Lab Haematol. 1988;10(2):187-91. [abstract]
13. Dolan G; Clinical implications of emerging pathogens in haemophilia: the variant Creutzfeldt-Jakob disease experience.; Haemophilia. 2006 Mar;12 Suppl 1:16-20. [abstract]
14. Wilde JT; HIV and HCV coinfection in haemophilia.; Haemophilia. 2004 Jan;10(1):1-8. [abstract]
15. Darby SC, Ewart DW, Giangrande PL, et al; Mortality from liver cancer and liver disease in haemophilic men and boys in UK given blood products contaminated with hepatitis C. UK Haemophilia Centre Directors' Organisation.; Lancet. 1997 Nov 15;350(9089):1425-31. [abstract]
16. Lambing A, Kuriakose P, Lanzon J, et al; Dialysis in the haemophilia patient: a practical approach to care. Haemophilia. 2008 Sep 8. [abstract]
17. Darby SC, Kan SW, Spooner RJ, et al; Mortality rates, life expectancy, and causes of death in people with hemophilia A or B in the United Kingdom who were not infected with HIV. Blood. 2007 Aug 1;110(3):815-25. Epub 2007 Apr 19. [abstract]
18. Oyesiku JO, Turner CF; Reproductive choices for couples with haemophilia. Haemophilia. 2002 May;8(3):348-52. [abstract]
19. Mitchell C, Mitchell CL, Krause A; New FACTOR IX linked marker alleles in African Haemophilia B patients. Haemophilia. 2007 Sep;13(5):642-4. [abstract]
20. Street AM, Ljung R, Lavery SA; Management of carriers and babies with haemophilia. Haemophilia. 2008 Jul;14 Suppl 3:181-7. [abstract]
21. Aggeler PM, White SG, Glendenning MB, et al; Plasma thromboplastin component (PTC) deficiency; a new disease resembling hemophilia. Proc Soc Exp Biol Med. 1952 Apr;79(4):692-4.
22. Biggs R, Douglas AS, Macfarlane RG, et al; Christmas disease: a condition previously mistaken for haemophilia. Br Med J. 1952 Dec 27;2(4799):1378-82.
23. Coutelle C, Themis M, Waddington SN, et al; Gene therapy progress and prospects: fetal gene therapy--first proofs of concept--some adverse effects.; Gene Ther. 2005 Nov;12(22):1601-7. [abstract]

Internet and further reading

• Batlle J, Villar A, Liras A, et al; Consensus opinion for the selection and use of therapeutic products for the treatment of haemophilia in Spain. Blood Coagul Fibrinolysis. 2008 Jul;19(5):333-40. [abstract]

Acknowledgements