- Haemophilia is a rare inherited disorder that leads to abnormal bleeding, and specifically the inability to stop bleeding.
- Mutations to genes on the X-chromosome cause deficiencies of certain blood clotting factors: Factor VIII in the case of haemophilia A and Factor IX in the case of haemophilia B (‘Christmas disease’).
- All affected patients, for practical purposes, are males who can have mild, moderate or severe disease depending on the blood level of the clotting factor. Females carrying the defective genes are obligate carriers.
- Haemophiliacs have a tendency to bleed easily after minor trauma, or even to bleed spontaneously, depending on the level of clotting in their blood.
- Bleeding into joints (haemarthroses) and muscles occurs spontaneously, whereas bleeding from other sites is usually precipitated by minor trauma.
- Haemophilia is diagnosed when patients who present with a compatible clinical picture (often with a positive family history), are found to have abnormally low levels of Factor VIII (or IX) on blood assays.
- Treatment involves the intravenous administration of Factor VIII (or IX) concentrates, along with painkillers and orthopaedic surgery for damaged joints. If at all possible, all drugs causing bleeding, including aspirin and nonsteroidal anti-inflammatory drugs should be avoided.
- Preventive measures include carrier detection among females and antenatal diagnosis by means of molecular analysis of foetal tissue, obtained by means of chorionic villus biopsy.
- Complications of the disease and therapy include HIV and other viral infections attained via infected (usually not adequately tested) blood products, cerebral haemorrhage, orthopaedic problems and inactivating Factor VIII antibodies. Viral infections are uncommon currently as all plasma derived concentrates are adequately screened and subjected to virucidal treatment.
What is haemophilia?Haemophilia is inherited deficiency of coagulation (‘blood clotting’) factor. Three forms are recognised. Haemophilia A is due to Factor VIII deficiency, Haemophilia B is due to Factor IX deficiency and Haemophilia C is due to Factor XI deficiency. Haemophilia A is the most common of the three affecting approximately one in 10 000 newborn males.
The coagulating factor deficiency in haemophilia results in failure of blood to clot and therefore a tendency to bleed spontaneously, after minor trauma and after major trauma and surgery.
Haemophilia affects males and females are obligate carriers. This is because the genes that cause haemophilia are carried on the X-chromosome, leading to a so-called ‘X-linked’ inheritance. Men are clinically afflicted, when the abnormal gene is inherited, as males have only one X-chromosome and one Y-chromosome (compared to the two X-chromosomes and no Y-chromosome in females). Women only ‘carry’ the disease to their children, as they have two X-chromosomes. Sons always inherit the disease from their mothers. Mothers may pass on carrier status to their daughters, who in turn may pass the disease to their male offspring.
What causes haemophilia?In a normal individual haemostasis, the ability to ‘stop bleeding’, is a complex and finely regulated process that depends on the interaction of three components: blood vessels, blood platelets and coagulation (‘clotting’) factors.
Clotting factors are multiple plasma proteins (numbered I to XIII) that cause ’cascades’ of enzymatic reactions in blood plasma. Basically, these cascades of reactions are often divided into an ‘intrinsic’, an ‘extrinsic’ and a ‘common’ pathway.
Patients with haemophilia A have a mutation (an abnormality) of the gene coding for coagulation Factor VIII, leading to abnormally low plasma levels of Factor VIII. This factor is involved in the ‘intrinsic’ pathway of coagulation.
Haemophilia B is the result of mutations of the gene coding for clotting Factor IX. As this factor is also involved in the ‘intrinsic’ pathway of coagulation, it is not surprising that low levels of Factor IX give rise to a disease identical to haemophilia A.
What are the main symptoms and signs of haemophilia?Patients with either form of haemophilia have abnormal haemostasis and so suffer from a tendency to bleed. There are considerable variations in the degree of this bleeding tendency among patients. Very mild forms of the disease are sometimes observed in female ‘carriers’, but for practical purposes all severely affected patients are male.
The features of haemophilia A depend on the levels of Factor VIII:
Levels of less than 1% are associated with frequent and often severe spontaneous bleeding from early life.
These patients are particularly prone to certain forms of bleeding:
- Bleeding into joints, called haemarthroses, causes pain, redness and swelling of the larger joints (often the knee). Repeated episodes can lead to joint deformity that can be crippling without adequate treatment.
- Muscular haematomas, bleeding into muscle, is common, either after relatively minor trauma or intramuscular injections. This should be avoided in these patients.
- Deep visceral (‘internal organs’) bleeds are occasionally seen.
Levels of less than 5% are associated with severe bleeding following injury and occasionally spontaneous bleeding (as described above).
Levels of above 5% produce only mild disease, usually with bleeding only after injury or surgery. These patients can still bleed badly once haemostasis has failed. Diagnosis in this group is often delayed until quite late in life.
The features of haemophilia B are very similar to those described above.
How is haemophilia diagnosed?
A family history is helpful, but this is lacking in up to one third of all new cases. The absence of affected male family members does not therefore exclude the disease.
The pattern of bleeding (for example, involving joints rather than isolated nose bleeding) usually alerts the attending physician to the possibility of underlying haemophilia.
The clotting profile:This is a common test and shows certain suggestive (but not specific) abnormalities in the case of haemophilia. There is prolongation of the PTT (‘partial thromboplastin time’) with a normal INR (‘international normalised ratio’). These two tests give an indication of the time it will take the blood to clot.
The bleeding time:An abnormal bleeding time points towards possible platelet or blood vessel defects. This test is normal in (isolated) haemophilia.
The clotting factors (factor assays):Tests for specific clotting factors are not performed in all patients presenting with a bleeding tendency, but is certainly indicated when haemophilia is considered. Patients with haemophilia A have reduced levels of Factor VIII; those with haemophilia B have reduced levels of Factor IX. Other factors (including the so-called Von Willebrand-factor) are normal. Von Willebrand-factor is one of the components in the blood, which promotes clotting during the normal clotting cascade.
Final diagnosisHaemophilia is diagnosed if patients who present with a consistent compatible clinical picture (often with a positive family history) are found to have abnormally low levels of Factor VIII (or IX) on blood assays. Sometimes further tests (like correction tests, for example) are required.
How are haemophiliacs treated?
Important principlesHaemophilia cannot be cured, but their bleeding episodes can be adequately controlled. This requires great insight and motivation, from both the patient and healthcare workers. There are some tenets regarding the treatment of bleeding in haemophiliacs:
- Symptoms often precede objective evidence of bleeding
- Bleeding may not appear until several days after well-documented trauma
- It is of paramount importance to avoid aspirin or other drugs that may impair blood platelet function and cause severe bleeding
Factor VIII concentrates Factor VIII concentrates have revolutionised the treatment of haemophilia, having a major positive impact on joint deformity and allowing major surgery in these patients. This modality is currently available in many different forms, with significant differences in price and safety.
Two types of Factor VIII concentrates are available, namely plasma-derived (from blood donated by blood donors) and recombinantly produced (produced in the laboratory):
- Plasma-derived concentrate: This is prepared from multiple donors and undergoes extensive testing and virucidal treatment before it is supplied as a powder. It can be refrigerated and reconstituted just before use. Intermediate purity Factor VIII is currently available in South Africa.
- Recombinant Factor VIII concentrate: Recombinant Factor VIII concentrate is now well established as the treatment of choice in people with haemophilia. It is the safest modality, but is unfortunately very expensive, preventing its worldwide use.
Treatment of bleeding patients with Factor VIII concentrates:
- Minor bleeding: The Factor VIII level should be raised to 20 to 30%.
- Moderate bleeding: The Factor VIII level should be raised to 50 to 80%
- Severe bleeding: The Factor VIII level should be raised to 80 to 100% pre-operatively and maintained above 50% until healing has occurred.
- Severe bleeding: The Factor VIII level should be raised to 100% pre-operatively and maintained above 50% until healing has occurred.
Administration of Factor VIII concentrates:Factor VIII concentrate can be stored in domestic refrigerators at 4 degrees Celsius and should be administered via intravenous infusion by the patient immediately after bleeding has started. This reduces the need for hospital care. Haemophiliacs and their immediate family should know when and how to administer Factor VIII concentrate. This should be done at least twice daily to maintain an adequate therapeutic level.
Prevention of bleeding:The majority of severely affected patients are now given prophylactic treatment three times a week from early childhood, in an attempt to prevent bleeding and joint damage.
Local therapy to joints
The local therapy to joints is usually under the supervision of a multi-disciplinary team including a haematologist, physiotherapist and orthopaedic surgeon. It may include initial immobilisation, followed by joint mobilisation and physical therapy. Joint replacements are sometimes required.
Other treatment modalities for haemophiliacs
Synthetic vasopressin (DDAVP) can be administered intravenously, subcutaneously or intranasally to produce a transient rise in Factor VIII concentration in mild haemophiliacs. Avoiding the potential complication of blood products, this modality is useful to treat bleeding in mild cases of haemophilia. It can even be used as prophylaxis before minor surgery.
The treatment of haemophilia BThe general principles are similar to haemophilia A, with administration of Factor IX concentrates during bleeding. Blood products are still used (including fresh frozen plasma). Newer modalities, such as recombinant Factor IX, are being developed.
How is haemophilia prevented?Haemophilia is a so-called ‘X-linked’ inherited disorder. The male offspring of a female carrying the mutated gene are either healthy (50%) or have the disease (50%). Half of her female offspring will be carriers; the other half will have two normal genes. All daughters of haemophiliacs are carriers and all sons are healthy (they inherit their X-chromosome from the mother and therefore do not have the disease). Because women have two X-chromosomes, they inherit one affected X-chromosome from their father and one normal X-chromosome from their mother.
This information is important as it provides a valuable basis of preventive (genetic) medicine.
Determining the carrier status in females depends on a detailed family history and the results of coagulation studies, which are mildly abnormal in carriers. Newer molecular techniques that test for mutations are also currently available, although not widely used.
When a known female carrier falls pregnant, an early antenatal diagnosis is now possible by means of molecular analysis of foetal tissue at 9-11 weeks into the pregnancy.
Couples should consider the option of a ‘therapeutic’ abortion in case of affected male offspring. Paediatricians should be alerted to the diagnosis if the couple decides to go to term with the pregnancy.
What is the outcome of haemophilia?The most frequent cause of premature death in individuals with severe haemophilia is cerebral haemorrhage.
Other complications of the disease and treatment include:
Antibodies to Factor VIIIThe problem of inactivating antibodies is encountered in up to 10% of haemophiliacs, often those with an extremely low plasma level of Factor VIII. In some individuals who receive transfusions with Factor VIII, the immune system may produce antibodies against Factor VIII, because this may be recognised as a foreign substance. This problem is very difficult to manage and patients are usually under direct supervision of an experienced specialist haematologist. Treatment modalities include the use of factor bypassing agents such as FEIBA and recombinant Factor VIIa.
Viral infectionsWith the aggressive use of blood screening procedures and treatment of blood with virucidal procedures, the risk of infections trannsmitted by the plasma-derived factor concentrate is low. Blood products have the potential to transmit HIV and hepatitis A, B and C infections.
Orthopaedic problemsWith repeated bleeds, almost all joints are ultimately damaged with consequent joint arthritis and destruction. Available therapeutic modalities include joint replacements and aggressive physiotherapy.
When to see your doctor
- A family history of haemophilia, especially if a pregnancy or major surgery is planned, can be seen as indications for evaluation.
- Unexplained frequent bleeding or easy bruising.
- Previous surgery complicated by bleeding.
- Planned pregnancy with family history of bleeding.
The following are some symptoms that also require further evaluation:
- Unexplained bleeding after minor (or no) trauma
- Prolonged bleeding after minor surgical procedures, including dental extractions
- Severe/excessive menstrual blood loss or blood loss during birth
- Easy or spontaneous bruising
Reviewed by Dr Johnny Mahlangu MBBCh, BSc(Lab Med), FCPath(SA), Cert Clin Haem(SA), Department of Molecular Medicine and Haematology, University of the Witwatersrand and National Health Laboratory Service, Johannesburg Hospital. May 2007