What are inhibitors?
An inhibitor is a type of antibody. The function of an antibody is to destroy substances in the body that it does not recognise. In a person with haemophilia the antibody may be created following treatment with factor VIII or IX. This is because the person with haemophilia does not recognise factor VIII or IX as a normal protein. It will attach itself to the factor and inhibit its ability to stop bleeding. Developing an antibody is a normal reaction of the body and is usually a good thing - for example developing antibodies to common illnesses after vaccination or getting the disease prevents you from infection or re-infection.
An inhibitor may be detected during routine screening at regular check-ups. More often an inhibitor may be suspected when bleeding does not respond to treatment as well as it has in the past. The United Kingdom Haemophilia Centre Doctors' Organisation (UKHCDO) suggests that a test for inhibitors be done in children every three months up to the age of 10 years and for two years after changing products at any age.
How common are inhibitors and are there differences between haemophilia
A and B?
It is estimated that up to one third of people with severe or moderately severe haemophilia A (less than 5% clotting factor) may develop an inhibitor at some time in their lives. However, among people with haemophilia B, inhibitors seem only to affect less than 5% of people with severe or moderately severe haemophilia. Inhibitor development is rare among people with mild haemophilia. It is thought that inhibitors may run in families, although having one child or adult with an inhibitor in a family does NOT mean that other family members will necessarily get one.
The risk of developing inhibitors does not remain the same throughout the life of the person. Historically inhibitors have tended to develop more frequently during childhood, when treatment begins. This is also the time at which the body is making most antibodies to childhood illnesses and the immune system reacts as if factor VIII or IX is a protein that it should fight.
High and low titres - What do they mean?
The presence of an inhibitor is usually confirmed using a blood test called the Bethesda inhibitor assay. The amount of antibody is measured and is reported as a Bethesda unit or titre. The higher the titre, the more antibody or inhibitor is present. People with a high titre inhibitor are also known as high responders. About 40% of people who develop inhibitors have a low titre (less than 5 Bethesda Units). Low responders may just need a double or treble dose of clotting factor to overcome the inhibitor's effects. In many such cases the inhibitor will spontaneously disappear over time. However, among high responders even very high doses of clotting factor can be ineffective. Bleeding then has to be controlled by other means (see How are bleeding episodes treated below).
If someone with an inhibitor is not treated with clotting factor for some time, the amount of inhibitor may fall and a high titre inhibitor may change to a low titre. However, if factor concentrate is then given, the titre may rise again and can go very high. As the immune system has a rest from the stimulus of clotting factor the production of antibodies falls. When it is stimulated again by clotting factor it reacts by boosting production of antibodies again. This is known as the anamnestic response.
Are inhibitors more common with recombinant than factor derived treatment?
Recent studies on children with haemophilia A who have only received recombinant factor VIII seemed to show that inhibitors develop at a younger age and after fewer treatments than among those who were historically treated with plasma derived clotting factor. However among those treated with recombinant factor only, less than half the inhibitors were high responding and up to one third disappeared on their own. These are known as transient inhibitors and are not usually significant. With the use of plasma derived products about 80% of inhibitors were high responding and very few were transient. These findings are likely to be due to the careful scientific way in which the introduction of recombinant factor VIII was studied. There is less information available about inhibitors to factor IX, as there are very few inhibitors in patients with haemophilia B. However, in haemophilia B the inhibitors often occur in parallel with allergic reactions and this may make home treatment difficult or impossible.
Inhibitors are known to develop only against certain part of the factor VIII or IX protein, whether they are high or low responding and whether or not the factor VIII or IX is recombinant or plasma derived.
How are bleeding episodes treated?
In people with low titre inhibitors it is often possible to treat bleeds with higher and more frequent than usual doses of factor VIII or IX. However, for high responders a different approach will be used:
1. Recombinant factor VIIa
This genetically engineered clotting factor is a `by-passing' agent used to treat bleeds in people with haemophilia A and B who have inhibitors. It is effective in the treatment of both minor and life-threatening bleeds and in prevention of surgical bleeding. However, it has a very short half-life (i.e. it loses half its effectiveness approximately every two hours) and doses need to be infused every two to four hours. There is no risk of viral transmission and the risk of excessive thrombosis also seems to be low especially in children.
2. Activated prothrombin complex concentrates e.g. Feiba
These products contain other activated clotting factors that can stimulate the formation of a clot and stop bleeding. They bypass the specific need for factor VIII or IX. However, used in high doses they have been associated with excessive clotting including thrombosis of the veins in the legs (Deep Vein Thrombosis), heart attack, blood clots in the lung (pulmonary embolism) and disseminated intravascular coagulation (blood clots in small vessels throughout the body)
3. Porcine factor VIII
This is a highly purified factor VIII produced from pigs' blood which can
be very effective in controlling bleeding in people with inhibitors to human
factor VIII, where the antibody does not react much with porcine factor VIII.
It can cause allergic reactions and a temporary drop in platelet count (though
this does not usually cause problems). Porcine factor VIII is ineffective
in those with factor IX inhibitors, as factor VIII does not stop bleeding
in people with factor IX deficiency. It will also be ineffective in those
patients with factor VIII inhibitors who have, or develop, strong antibodies
(inhibitors) against porcine factor VIII. At the moment there is an extreme
shortage of porcine factor VIII. Some Muslims and Jews may have religious
or cultural issues about using porcine factor.
How can we get rid of inhibitors?
Immune tolerance therapy aims to train the body to accept treatment with the missing clotting factor. Regular doses of factor VIII are administered twice daily, daily or every other day over a period of weeks, months or even years, sometimes together with immunosuppressive drugs such as steroids or immunoglobin. This approach gradually accustoms the body to accept the missing factor. Inhibitors to Factor IX can also be treated with immune tolerance therapy.
Because immune tolerance therapy calls for frequent intravenous injections many people will be fitted with a port-a-cath, which is a small chamber inserted under the skin under general anaesthetic and connected by a tube to a vein in the neck. This makes it possible to give intravenous injections easily and quickly. Very rigid sterile procedures must be adopted as there is a risk of infection in the port-a-cath. For more information see our new fact sheet Information on Ports.
Surgery with inhibitors
Some people with haemophilia and an inhibitor have severe arthropathy affecting their joints and causing disability. Surgery is possible on people with inhibitors though the risks are higher as it is more difficult to achieve satisfactory clotting function with bypassing agents than with fVIII or fIX in non-inhibitor patients. There are also cost issues as surgery on people with inhibitors is extremely expensive and different hospitals have different policies on authorising such surgery. Some will only authorise emergency surgery and very often proposed surgery will have to be approved by the funding authority.
Children with inhibitors
Just because you have an inhibitor does not mean you will bleed more often or for any longer than a person with haemophilia but no inhibitors. However, when you have bleeds they will be more difficult to treat. Children with inhibitors may need to restrict their activities more than other children who have haemophilia. However, it is important to maintain fitness to keep the muscles strong to support weak joints. Most inhibitors develop at quite a young age and caring for a child with an inhibitor can be very demanding. If you feel the need to talk to someone else who has been through the same situation the Haemophilia Society can put you in touch with someone from our Volunteer Support Network.
Further Information:
| The Haemophilia Society Chesterfield House 385 Euston Road London NW1 3AU Tel: 020 7380 0600 Freephone: 0800 018 6068 Email: info@haemophilia.org.uk Web site: www.haemophilia.org.uk |
Scottish Office PO Box 26706 Glasgow G3 6ZB Tel: 0141 548 8081 Fax: 0141 548 8001 Email: helenlawrie@haemophilia.org.uk |
| The Volunteer Telephone Support
Network: Need a listening ear? Talk in confidence to someone with similar experiences. Freephone: 0800 018 6068 |
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| Further Reading: | |
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Introduction to Haemophilia and Related Bleeding Disorders (produced by the Haemophilia society 2001) |
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Living with Haemophilia by Dr. Peter Jones (5th edition 2002) |
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Inhibitors - Factors that matter (a leaflet produced by Bayer 2000) |
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Inheritance of Hemophilia (produced by the National Hemophilia Society USA) |
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Raising a Child with Haemophilia. A Practical Guide for Parents (produced by Laureen Kelly) |
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Information on Ports (a fact sheet published by the Haemophilia Society) |
A full publications list is available from the Society
This fact sheet can only give basic general information drawing on medical opinion and evidence available at the time of writing. Different people may give you different advice on certain issues and there may be some variations in the way care is managed in different hospitals and in different areas. It is important that you contact your own doctor(s) and nurses(s) for further information and advice on your own individual circumstances.
The Society would like to thank Dr. Brian Colvin, Haemophilia Centre Director
at the Royal London Hospital and Kate Khair, Haemophilia Nurse Specialist
at Great Ormond Street Hospital for Children for their help in producing this
factsheet.
August 2003
