Paul LF Giangrande
BSc MD FRCP FRCPath
Oxford Haemophilia Centre and Thrombosis Unit
Haemophilia is a congenital disorder of coagulation; it affects approximately one in 10,000 males worldwide. Haemophilia A is due to a deficiency of Factor VIII in the circulating blood, and haemophilia B (also known as Christmas disease) is a clinically identical disorder caused by Factor IX deficiency. The clinical severity is critically determined by the level of circulating Factor VIII (or IX) in the blood, and severe haemophilia is defined by a clotting factor level of <1IU/dl. The hallmark of severe haemophilia is recurrent and spontaneous haemarthrosis. Recurrent bleeds into a joint lead to synovitis and joint damage, resulting in crippling arthritis. There is also a significant risk of internal haemorrhage (including intracranial) in severe haemophilia, which was a significant cause of mortality in the past when treatment was not so readily available. Higher levels of Factor VIII or IX (>5IU/dl) are associated with a milder form of the disease, with no spontaneous joint bleeds but a definite risk of bleeding, after even relatively minor injury. Haemophilia care is delivered through a network of designated comprehensive care centres (of which there are 23 in the UK). These provide round-the-clock multidisciplinary care for patients with haemophilia and related disorders.
Treatment of bleeding episodes involves the intravenous injection of coagulation factor concentrates; the total dose and frequency of treatment will also be determined by the severity and site of bleeding. There is an increasing move to prophylactic therapy, in which the patient receives infusions of coagulation factor concentrate two or three times a week to prevent bleeds, rather than just treating on demand when bleeds occur. Patients on prophylactic therapy experience few or even no spontaneous bleeds and, thus, progressive joint damage and arthritis can be avoided. The quality of life of patients on prophylaxis may be greatly enhanced, allowing them to lead much more independent lives. Approximately 15% of patients with severe haemophilia A can be expected to develop inhibitory antibodies to Factor VIII at some stage, although inhibitor development in haemophilia B is encountered in less than 1% of patients.
The development of blood products for the treatment of haemophilia has dramatically altered the prognosis for those patients who live in affluent countries and have regular access to safe products. In Sweden, the median life expectancy for people with severe haemophilia increased by five times, from just 11 years during the period 1831–1920 to 56.8 years during the period 1961–1980. In more recent years, of course, infection with HIV and/or hepatitis C (HCV) has had a significantly negative impact. The issue of bovine spongiform encephalo‑pathy (BSE) and the variant form of Creutzfeldt–Jakob disease (vCJD) has, once again, raised concerns about the use of plasma-derived products in the haemophilia community around the world. However, no cases of either the classical or vCJD have been reported in haemophiliacs anywhere in the world.
In recent years, the relative merits of plasma vs recombinant products have been a major topic of debate, and there is now an irreversible growth in the use of recombinant products in preference to plasma-derived products in more affluent countries. The arguments focus primarily on safety with regard to transmission of pathogens, which must be of prime concern in the selection of products for the treatment of haemophilia. In fact, all patients in the UK now exclusively receive these products, with effect from April 2005. An important positive consequence of the progressive switch to recombinant products in developed countries is that it will help to secure effective and safe treatment for people in developing countries, as manufacturers of plasma-derived products will be forced to seek new markets in the developing world and these will also have to be competitively priced.
The application of recombinant technology has, up to now, been limited to simply copying the normal Factor VIII and IX molecules. In the future, it is likely that modified molecules with enhanced properties such as reduced immunogenicity and increased half-life will be developed. Possible strategies for increasing the duration of activity of Factor VIII in the circulation include generating forms of Factor VIII with mutations at the sites that are the natural targets for specific proteolytic inactivation by activated protein C (APC) or Factor IXa and Xa. Clearance of Factor VIII in the circulation is normally mediated by low-density lipoprotein receptor-related protein (LRP), a hepatic clearance receptor with broad ligand specificity. Suppression of the interaction between Factor VIII and these catabolic receptors could thus, theoretically, prolong the half-life of Factor VIII. The development of inhibitory antibodies in haemophilia remains a significant problem, and the creation of less immunogenic molecules would be a welcome development. The major targets for binding of inhibitory antibodies are within the A2 and C2 domains of Factor VIII.
The development of transgenic dairy animals also offers the potential for the production of recombinant products at low cost through extraction from their milk. In order to express a recombinant protein in the milk of an animal, expression vectors containing a gene encoding the protein of interest are fused to milk-specific regulatory elements and introduced by microinjection of a one-cell embryo. The mammary gland-specific transgene is transmitted in a Mendelian fashion following integration into the germline. If expressed, it becomes a dominant genetic characteristic that will be predictably inherited by offspring of the animal, and the yield of transgenic protein in the milk is often high, in the range of grams per litre.
Haemophilia provides an attractive model for correction by gene therapy, and several clinical trials in both haemophilia A and B are already underway. The basic principle involves gene transfer using viral vectors. The first study involved eight patients with haemophilia B who received an intramuscular injection of a transfected adeno-associated viral vector. A favourable but transient effect on plasma levels, paralleled by a reduction in concentrate requirement, was reported in three of the subjects. The use of viral vectors was circumvented in another study, in which fibroblasts from six patients with haemophilia were cultured ex vivo and transfected with Factor VIII DNA. The autologous fibroblasts were then reimplanted in the omentum at laparoscopy, and detectable levels of Factor VIII in the range of 0.2–4% were observed in three subjects.
While gene therapy undoubtedly offers the prospect of a true cure for haemophilia, it is clear that much work still remains to be done, and it probably will not be a realistic option for at least another 20 years.
It is clear that much has been achieved with regard to the treatment of haemophilia in the last few decades, but equally the prospect of a true cure for this disorder remains elusive. Perhaps the current position is best summed in words borrowed from Sir Winston Churchill: “Now this is not the end. It is not even the beginning of the end. But it is, perhaps, the end of the beginning.”