Patterns of inheritance

Haemophilia is an inherited genetic condition. However, approximately 30% of people with it are unable to trace back any family history, suggesting a spontaneous gene mutation. The cells of human beings contain chromosomes which are have genes on them. These genes are the things that carry the information needed to generate the features of a person such as an ability to make clotting factors. Most people have 23 pairs of chromosomes and the one that defines gender is described as either XX for women or XY for men. The Y chromosome is described as a Y because it is literally missing a leg that would turn it into an X and the blood-clotting gene is on this missing leg.

Some genes are ‘dominant’ over others. This means that we only need one copy of the gene – inherited from either the father or the mother – for it to work and decide how the body functions.

The haemophilia gene is not dominant but ‘recessive’. Generally recessive genes only work if we inherit a copy of the gene from both parents.

However because the blood-clotting gene is on the ‘missing leg’ of the X, men inherit it exclusively from their mothers. Women have two X’s so have one copy of the gene if the other chromosome is defective.

However men possess only one X chromosome. If it is the recessive haemophilia gene rather than the dominant normal gene then the single copy on that chromosome will decide those features in that man, because there is no dominant gene on the Y chromosome to correct it.

This means that women can carry the gene for haemophilia without suffering the symptoms. Any son of such a carrier would have a one in two chance of inheriting the condition from them. Their daughters would have a one in two chance of being also becoming a carrier of the disorder. A man with haemophilia cannot pass it on to his sons but will inevitably pass it to his daughters who will become carriers. Thus haemophilia is usually only expressed in men however carriers may have a lower than normal level of factor VIII or IX but it is only usually a cause for concern at times of major operations or childbirth and even then treatment may not be required. This description of bodily genetics is highly simplified and as human beings are extremely complex organisms do not expect the case of every person with haemophilia to follow this pattern exactly.

Von Willibrand's Disease (vWD) is inherited in a more complex manner, and can affect men and women equally. Over 67% of cases of diagnosed vWD occur in women, mainly because heavy and prolonged periods are amongst the most recognisable and frequent symptoms of the condition (Lee). Paradoxically this may also be a reason why vWD is rarely diagnosed, as few doctors are aware that clotting disorders can affect women. Menorrhagia, slow healing cuts and easy bruising experienced by women with vWD are often dismissed as just a part of life, and not recognised as symptoms of a potentially serious clotting disorder.

The most well-known example of haemophilia passed through a family is to be seen in the extended family of Queen Victoria. The British Royal Family was, by the end of the nineteenth century, related to the majority of the royal families of Europe. Victoria had nine children and, unbeknown to her, she was a carrier of the haemophilia A gene. Although only one of her sons, Leopold, actually developed haemophilia, she passed the gene on to her daughters as eventually the condition emerged in the Spanish, Greek and Russian royal families and many smaller princely families (Zeepyat). The condition was a factor in both the communist revolution in Russia in 1917 and the civil war in Spain by adding to an environment of uncertainty about the strength and future of the monarchy in both countries (Potts).

The effects of haemophilia

The common misconception about haemophilia is that when someone has a cut (e.g. whilst shaving) they are in danger of bleeding to death. Whilst such cuts need to be treated, they are seldom a major problem. The real danger lies in internal bleeding into muscles, joints and body cavities. Internal bleeding can occur spontaneously or as a result of an injury. Once an internal bleed starts, without treatment it can cause irreparable damage to the joints or muscles. Blood is toxic to bone, therefore untreated bleeds into joints can cause chronic arthritis.

Bleeding episodes cause the joint or muscle to swell, causing acute and often permanent damage and can be excruciatingly painful as blood pumps uncontrollably into the area. Bleeds into the vital organs can be fatal. The pain, arthritis and the limited movement after frequent bleeding lead to a need for surgery to the joints. Ankle and knee replacements are common in adults with haemophilia although the hope is that the next generation will have far less surgery after a lifetime of prophylactic treatment to prevent bleeding. This is why so many adults with haemophilia have difficulty walking or an unusual gait.

Treatment for haemophilia

Prior to the Second World War the only treatment available was bed rest, and waiting for the bleed to stop and the blood to drain away. This could take weeks, or even months. Some, more alternative remedies, such as snake venom and peanut oil were available, but with questionable effectiveness. During the war, large quantities of blood plasma were collected to treat heavy casualties on the battlefield. During the process of storing this plasma at low temperatures, a thick, brown sediment was seen to form. This cryoprecipitate turned out to be very rich in clotting factors, and so formed the basis of the first effective haemophilia therapy. During the seventies it became technologically possible to isolate individual factors and pool them to create batches of factor concentrate. These concentrates could then be self-administered intravenously at home, either at the onset of a bleed to stop it, or alternatively prophylactically, in an attempt to prevent bleeds altogether.

The development of factor concentrates and home treatment was heralded as one of the major breakthroughs and success stories of post war medical technology. The effect of concentrates was to transform the lives of people with haemophilia. Home treatment with factor concentrates meant not having to automatically face all the most serious problems of haemophilia, such as acute and chronic pain, crippling disability and the prospect of spending over one quarter of one's life confined to bed. People with haemophilia could now become active, independent members of the community, able to engage in all aspects of society.

The treatment of von Willibrand's Disease is dependant on the type of von Willebrands and severity of the bleeding. For some women with mild type 1 disease oral contraceptives may be the only treatment they require. Desmopressin is used mainly for people with mild type 1 von Willebrands, to boost the levels of clotting factors in the blood. Tranexamic acid is used for minor bleeding problems such as nose bleeds and may be used in conjunction with Desmopressin or factor concentrates to help stabilise a clot. Usually only people with severe vWD are treated with cryoprecipitate or Factor concentrates.

Factor concentrates, like many blood products, are made from pooled plasma. They are produced by a number of commercial pharmaceutical companies, the Red Cross and, in England, by the Bio-Products Laboratory (BPL). It can take up to 30,000 donations of blood to make one batch of factor concentrate. As a result of relying upon such a huge donor pool, blood products have always been susceptible to contamination by viruses. Injecting factor concentrates has been likened, in terms of the risks of exposure to HIV, to having unprotected sex, or sharing needles with tens of thousands of people every time you take treatment. All people with haemophilia treated with factor concentrates during the 1970s and early 1980s were exposed to infection with the hepatitis viruses B and C.

This was already a problem in the UK, where donations were always voluntary, but in the USA, and some other countries where blood donors have usually been paid, the rates of infection were far higher. It was as a result of the use of hepatitis infected, imported commercial factor concentrates that, in 1977, the then Labour Government made a commitment to UK self sufficiency in factor concentrates and other pooled plasma blood products.

Scotland did become self-sufficient, but England and Wales did not. During this period pharmaceutical companies pioneered various systems of treating concentrates in an attempt to eliminate viral contamination such as the hepatitis viruses. The most successful was heat treatment, a form of pasteurisation developed in 1978 by Behringewerke Atkionsgesellschaft in Germany. However, despite the high incidence of hepatitis in the haemophilia population, heat treatment was not prioritised, mainly because of cost. As a result of a drug company and public health policy failure to recognise the need to virally inactivate factor concentrates, HIV was spread unknowingly to tens of thousands of people with haemophilia worldwide through what was then being hailed as a life saving treatment.

Haemophilia and AIDS

Despite the fact that it was known that a person with haemophilia died in the United States in 1981 from what is now termed an AIDS-related illness, the association between factor concentrates, AIDS and viral contamination was not made until 1983. In early 1984 in Britain there were at least two reported cases of AIDS in people with haemophilia and later that year, after months of prevarication by the pharmaceutical companies and authorities over whether to heat treat factor concentrates or not, the Haemophilia Foundation in the USA instructed the 20,000 people with haemophilia in the United States to refuse to use all non heat-treated product. The UK Haemophilia Society threatened to follow suit. By the end of 1984 all imported, commercial concentrate in the UK was heat-treated. By mid-1985 domestic product was also treated to destroy the virus. Earlier there had been an attempt to encourage donors who may have been at risk of exposure to AIDS, such as people who had lived in sub-Saharan Africa, gay men and intravenous drug users, not to give blood.

When the test for HIV was pioneered, people with haemophilia were routinely tested. The enormity of the disaster became clear. In the United States, around 10,000 of the 20,000 people with haemophilia were diagnosed as seropositive. In the United Kingdom of the 7,000 people with haemophilia 1,246 were infected, representing 42% of those with severe haemophilia and 6% of those with moderate or mild haemophilia (UKHCDO). As a general rule, people were infected in proportion to the amount of commercial concentrate used, the more severe the haemophilia, the more concentrate used, the more the risk of infection. HIV infection through blood products is discussed in more detail in HIV transmission.

The UK Haemophilia Society eventually assumed the responsibility of advising and assisting people with haemophilia affected by HIV in the UK. In 1984 the Society was a small organisation with one full-time employee. The HIV recompense campaign in effect forced the Society to come of age.

Living with HIV and haemophilia

Most adults with haemophilia in the UK have had to incorporate HIV and viral hepatitis into living with their haemophilia. In the early years of the AIDS crisis this, along with the compensation campaign, led to charges from certain quarters of separatism and allegations that the haemophilia community was claiming to be more deserving than other people affected by AIDS. However, within the haemophilia community in the UK, with the possible exception of a few healthcare professionals, there were no public assertions that they were the innocent victims of AIDS. The Haemophilia Society's policy has always been that all the communities affected by AIDS should be treated equally, but at the same time have their specific and differing needs met. Since haemophilia affects a range of people with different backgrounds it should not, though, be assumed that they are not affected by the prevalent views and circumstances within society. Homophobia and indeed homosexuality are as common amongst people with haemophilia as everybody else.

The haemophilia community has responded differently to the AIDS crisis from other affected communities. People with haemophilia are already living with a pre-existing, potentially disabling and fatal condition. Many people, and particularly those with severe joint damage, have a major disability, which, in its own right, affects mobility, and care needs. At the advent of the AIDS crisis, 30% of people with haemophilia were already dependent upon state benefits and because of the genetic nature of the condition, the associated poverty, like the disease itself, tends to run through families.

Once blood products were heat-treated,the haemophilia community effectively ceased to be at risk of HIV infection from their treatment. Those with haemophilia and HIV are therefore a finite group of people. After mid-1985, at the very latest, no person should have been infected with HIV in the UK through the use of factor concentrates. Naturally people with haemophilia remain as much at risk of contracting HIV sexually or through sharing needles as everyone else.

A primary concern for the haemophilia community has also always been the safety of the blood product supply. The extent to which people with haemophilia rely upon uncontaminated factor concentrates cannot be underestimated. This concern has been long-standing and about much more than just HIV. After contaminations with hepatitis viruses, HIV and recent concerns about transmission of variant Creutzfeldt-Jakob Disease (vCJD).  In September 2003 the Department of Health conducted a patient notification exercise asking haematologists to inform all their patients who had received blood products made from British blood donors that they was a risk of contracting vCJD. No person with haemophilia had contracted the disease but one person had died of vCJD after receiving a blood transfusion from a donor who went on to develop and die from the disease.

These concerns have led to ongoing campaigns for the widespread use of recombinant factor concentrates, manufactured from transgenic animal cell cultures. Not being produced from human blood, these factor concentrates should be free of human viruses. From April 2003 in Britain a three-year programme of funding began to make recombinant factor concentrates available to everyone with haemophilia A and B who wanted it. Recombinant factor products are not effective in people with von Willebrands and so products made from plasma continue to be used.

People with haemophilia usually attend specialist centres seeing a consultant haematologist for their haemophilia so when they were diagnosed with HIV they often had a pre-existing life-long relationship with a hospital. Many Haemophilia Centres have incorporated control of HIV-related health issues into their general management of haemophilia while others have referred their patients to HIV clinics. Some are still treated for their HIV by haemophilia consultants while other centres have joint clinics with HIV clinicians. It is also worth noting that over 95% of those with haemophilia and HIV are co-infected with Hepatitis C - with all the attendant health and treatment complications that can ensue (see below).

People with haemophilia and HIV are scattered across the country and even though it is possible to speak of the haemophilia community as a generic term, the community exists around a medical and not a social condition. Haemophilia is neither confined to, nor generally more prevalent in any one social or ethnic grouping. HIV has also affected people with haemophilia of all ages. From a health education perspective the response has had to reflect this diversity. Elderly as well as paediatric HIV has had to be tackled, as has AIDS in schools. They are also predominantly heterosexual men, which historically is not the case for HIV epidemic in England and Wales and so often had different specific needs for information and support. The ability for men with HIV to have children as safely as possible with their partner is an obvious example of something which has been an issue for many years but only recently started to become part of the services of some HIV clinics.

All these differences, and the small number of people still alive probably accounts for the lack of integration between people with haemophilia and HIV into the more general community of people with HIV. However, the rest of this manual remains relevant for them as they will not only have similar concerns regarding adherence, side-effects and safer sex but will also have to bear the same discrimination and ignorance as everyone else with HIV.

Treatment issues

As a group, people with haemophilia and HIV seem to be responding well to combination therapy. Everyone has now been living with a positive diagnosis for over twenty years. However, antiretroviral therapies have a few particular problems for people with bleeding disorders. In addition to the normal side-effects of HIV medicines there is the complication of bleeding related to the use of protease inhibitors. There are also some haemophilia-specific issues for people with HCV coinfection.

Protease inhibitor-related bleeding episodes

Since 1996 there have been reports that protease inhibitors cause an increase in spontaneous bleeding for people with haemophilia and other clotting disorders (FDA). The reasons for this remain unclear, as all other factors such as platelet counts and prothrombin times remain normal. Studies have also shown that people with haemophilia and HIV on PIs tend to increase their use of clotting factor concentrates by up to or in excess of 50%. Figures suggest that between 16 - 52% of people with haemophilia and HIV on PIs develop these side-effects to a greater or lesser degree (Martinez; Stanworth).

The cause of this side-effect has not been identified and the sites of these bleeds are often abnormal or in places in which the person with haemophilia has rarely if ever experienced bleeds in the past. Most people with severe haemophilia are prone to spontaneous bleeds into weight- bearing joints, especially knees and ankles, as well as elbows and some larger muscles. However, PI related bleeding seems to occur in additional areas such as toe and finger joints, and smaller muscle groups in the face, hands, and feet. The incidence of these atypical bleeds seems to drop off after people discontinue treatment with PIs (Yee; Stanworth) but should be expected to return if someone recommences therapy including PIs.

The management of these complications seems to involve a significant increase in clotting factor prophylaxis. Most people with haemophilia and HIV seem to manage fairly well with this, although it may not fully control all the atypical bleeding. For many the trade-off between improved health and an increased incidence of bleeding is worthwhile. For others it has been a major deterrent to starting treatment. The bleeding seems to occur equally in people with haemophilia A, B or von Willebrands disease and for all PIs. The bleeding seems to diminish or disappear after a few months of treatment in the majority of people with haemophilia (Wilde) but for a small minority, the bleeding is so extreme that the only course is to stop PI therapy altogether, and to look at alternative regimes (Stanworth). Many people with haemophilia take PIs and have no problems of excess bleeding, though and the fear of it should not be seen as a reason to deny access to these important medications.

Hepatitis C complications

Another major issue is the tolerance of drug regimes by people with active HCV related hepatitis. Over 5,000 people with haemophilia have HCV infection acquired from blood products in the UK - this includes the vast majority of those who are HIV-positive. A number were also infected with hepatitis B which may have become a chronic infection. The section below looks only at the haemophilia specific issues regarding hepatitis coinfection and not at all the general issues for people with HIV and viral hepatitis which are covered elsewhere.

The initial problem for people with haemophilia and HCV, with or without HIV, has been the efficacy of having a liver biopsy. This is where a needle is inserted through the skin and a section of the liver taken away for analysis in order to understand how well the liver is coping with the hepatitis virus. A biopsy result can be very important in deciding whether to take treatment for viral hepatitis. In people with haemophilia a biopsy should always be done under the cover of treatment and can be done with the guidance of an ultrasound to follow the path of the needle inside the body. Despite this a number of haemophilia clinicians are understandably reticent about biopsies being performed on people with haemophilia.

The treatment of choice for people with haemophilia and HIV is pegylated interferon as it is for everyone with hepatitis C. The only haemophilia-specific issue with treatment concerns potential bleeding issues with interferon. Whether the use of interferon has no effect, increases the number of bleeds someone has, possibly from the subcutaneous injection, or reduces the number of bleeds as the person is less active if they are experiencing major side-effects is unsubstantiated but has been discussed at meetings of people with haemophilia.

For those whose liver disease is more advanced, liver transplants can be an option. There are a few centres in the UK that will offer transplants to co-infected people with haemophilia, and there are people with haemophilia, HIV and HCV living comfortably over three years after a successful liver transplant but so few operations have been done since the advent of HIV combination therapy, it is difficult to estimate survival rates.

In addition, the liver transplant also cures the haemophilia (Factor VIII & IX are synthesised in the liver). However, the new liver will once again be infected by HCV, although with treatment advances, and the slow progression of HCV, the limited evidence so far suggests that those who have successfully received transplants can have several years of reasonably good quality life ahead.

Effectively, the clinical management of HIV in those with haemophilia actually involves the management of three chronic and life-threatening illnesses. Psychologically, the stress of this cannot be underestimated. For the person with haemophilia and HIV/HCV co-infection, their families and their carers, the problem of overcoming one illness, only to be faced with another, and then when that is apparently under control, to be faced with yet another, can be devastating. However their continued survival and ability to cope with these conditions on top of the usual work, and life stresses can also be seen as a sign of resilience.