Haemophilia -- darkest hours before the dawn
We have the technology to make plentiful and relatively safe supplies of coagulation factors, and a cure may be within our grasp
MJA 1996; 164: 453
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Haemophilia is often considered to be our community's most expensive
disease because of the life-long need for frequent replacement of
coagulation factors VIII (haemophilia A) and IX (haemophilia B). The
incidence of haemophilia in Australia is one in 7000 males -- the same
in all ethnic groups. Its prevalence is much reduced because of
premature death from bleeding in pre-replacement- therapy days and
past transmission of infections such as HIV and hepatitis B and C
through unsterilised pooled plasma concentrates.
History's most famous person with haemophilia, the Tsarevitch Alexei, had almost reached his likely lifespan of 20 years when he was murdered in 1917. His frequent crippling haemarthroses and muscle bleeds are obvious from photographs. Today, because of major technical advances in coagulation factor production, most boys born in Australia with haemophilia can expect a normal lifespan and lifestyle, with neither plasma-derived viral infection nor disabling progressive arthropathy.
Reducing viral transmission
In Australasia, concentrates are prepared from plasma collected and
screened for viral markers by State Red Cross Blood Banks,
fractionated by CSL Ltd and sterilised by terminal dry heating at 80ûC
for 72 hours. No case of HIV transmission from concentrates has been
identified in the haemophilia population since 1985.
Between 1981 and 1984, 245 people with haemophilia contracted HIV, at least 98 of whom have died (figures courtesy of the Mark Fitzpatrick Trust), and patients in all Australian States and Territories have received recompense payments for HIV infection. Because of the high prevalence of hepatitis C virus in pooled plasma before appropriate screening and increased heat technologies became available, most patients who received concentrates before 1989 were also infected with this virus, leading to serious comorbidity with HIV infection, chronic liver disease and hepatocellular carcinoma. Despite many improvements and sequential application of multiple virucidal technologies, some human viruses, such as parvovirus B19, may remain in plasma concentrates. Novel techniques, such as viral nanofiltration and partitioning during fractionation, are being developed, but a threat known as the TNV (the next virus!) to the safety of human-derived products always remains.
The genes for factor VIII and IX, which occur on the tip of the long arm of the X chromosome, were sequenced in 1984 and 1985.1 By 1988 recombinant human factor VIII expressed in rodent cell lines was available for human trial.2 This product is now licensed and has been used in Australia since January 1995, so with political goodwill and financial support the supply of factor VIII may finally match demand. The possibility of human virus transmission is not completely abolished as, presently, recombinant factor VIII is resuspended in human serum albumin (although this product has not yet been reported to transmit such infec tions). Recombinant factor IX concentrates are now in clinical trial overseas.
In the past, the approach to haemophilia treatment was to arrest
bleeding after it had occurred. This is called "on-demand" therapy.
Unfortunately, this strategy is like shutting the gate after the
horse has bolted, as it fails to prevent the significant joint damage
caused by the reaction of the synovial membrane to blood. It is
possible, however, to shut the gate somewhat earlier with
"prophylactic therapy". In patients whose factor VIII level is
greater than 1%, there is seldom spontaneous bleeding into joints.
Hence, prophylactic therapy aims to maintain factor VIII levels at
more than 1% at all times. As the factor VIII half-life is
approximately 12 hours, this can be achieved by giving factor VIII
concentrates in a dose of 25-40 IU/kg body weight three times a week.
Reports from Sweden3 and the
United States4 have
demonstrated the effectiveness of such a regimen, and virtually all
eligible children in Australia can now potentially receive
prophylaxis, although Victoria is the only State to have matched
Commonwealth Government funding for this therapy to date.
A recent review of the results of prophylactic treatment at the Royal Children's Hospital, Melbourne, has confirmed a dramatic reduction in the incidence of joint bleeding and the number of hospital visits and, consequently, a reduction in morbidity from haemophilia (H E, unpublished results). The cost to the community of treating haemophilia patients prophylactically, in current costs for recombinant factor VIII, is no less than $100 000 per year (for an average of 100 000 units per patient). There are, however, significant cost savings from a reduced need for medical and allied health professional treatment, and the prospects that, without joint damage, young men will be able to pursue active and productive lives without the need for pension support.
Despite the advances in treatment, there are patients with severe
haemophilia who develop allo-antibodies to infused factor VIII, and
then do not respond to human factor VIII. In some instances, these
patients face forms of treatment which are barely superior to those
which were practised in the days of Rasputin, and suffer high
morbidity and mortality compared with patients who do not develop
these antibodies or inhibitors. While 20% of individuals with severe
haemophilia (factor VIII activity < 1%) develop such antibodies,
only half of those have high enough levels of antibodies to inactivate
the infused factor VIII. Thus, one in 10 patients with severe disease
are at risk of having no effective factor VIII replacement therapy. At
present, Australians with this problem are more disadvantaged than
similar patients in countries such as the United States, Canada or
Western Europe. The only product available for treating their
life-threatening or organ-threatening bleeds is porcine factor
VIII. Its use has to be approved by the Therapeutic Goods
Administration (TGA), and its usefulness is often offset by the
development of antiporcine factor VIII antibodies, which restricts
its use to bleeds that threaten life, limb or an organ and, even then,
for a short time only.
The only other products presently available are activated prothrombin complex concentrates, which are of unpredictable efficacy and can only be obtained with TGA approval. Because these products are costly and infrequently used, they are not always available in Australia. A new and recombinant product, activated factor VIIa (Novo Seven), has been shown to be the most effective in the treatment of inhibitors, including cover for surgery -- this product is not currently registered by the TGA5 and is no longer available for compassionate use. This is a serious situation for patients who are otherwise "untreatable".
Treating bleeding in patients with activated prothrombin complex concentrates or recombinant VIIa is a form of on-demand therapy. European workers have shown conclusively that, in most patients newly diagnosed as having factor VIII inhibitors, giving factor VIII in a daily dose of 100-200 IU/kg body weight can often suppress the inhibitor to non-detectable levels, with normal factor VIII recovery in the plasma. 6 This is known as "tolerising therapy" and is a form of prophylaxis. Unfortunately, there is insufficient factor VIII in Australia to use it for this indication, even though tolerising is the most logical way to prevent the morbidity associated with poorly controlled bleeding, and it is cost-effective in comparison with on-demand therapies.
It is to be hoped that the working parties currently convened by Australian Health Ministers to investigate optimum therapies for patients with haemophilia and factor VIII inhibitors will recommend funding for tolerising therapy in all newly diagnosed patients with inhibitors. These patients are usually children, thus small, requiring much less product than adults with established inhibitors.
Genetic technology can be used to detect female relatives who are at risk of being carriers, and to detect haemophilia antenatally. In the long term the tantalising prospects of "cure" of this molecular disease by gene therapy is stimulating much research into mechanisms of vector biology which allow efficacious, safe and continuous expression of factors VIII and IX.
Fortunately, the days when patients with haemophilia could be treated only by Rasputin are over. Comprehensive care centres in each State coordinate surgical, medical and dental management while providing counselling and diagnostic services. With the potential for plentiful and safe factor supplies for prophylactic, surgical and inhibitor- suppressing programs, and hope of a cure by gene therapy, the future for our children with haemophilia is bright.
Alison M Street
© 1997 Medical Journal of Australia.