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Haemophilia, a well-known rare disease

  1. Top of page
  2. Haemophilia, a well-known rare disease
  3. Side-effects of treatment
  4. Forty years of haemophilia treatment in the Netherlands
  5. Haemophilia care for different age groups
  6. Actual challenges in haemophilia treatment
  7. Haemophilia care in developing countries
  8. The cost of haemophilia treatment
  9. A safe, blood supply
  10. Conclusion
  11. Disclosures
  12. References

Haemophilia is one of the most well-known rare diseases. It is so well known that most people do not even realise that haemophilia is a rare disease. Haemophilia is an X-linked genetic bleeding disorder caused by a deficiency of coagulation factor VIII (haemophilia A) or factor IX (haemophilia B). Severe forms are characterized by major bleeding after minor trauma.

Effective treatment for haemophilia has become available in the last 45 years and consists of the administration of the deficient coagulation factor via intravenous administration. In the first decades, the coagulation factors were purified from human plasma. From the 1990s, recombinant (genetically engineered, rDNA) factor VIII or IX is gradually replacing the plasma products. When patients suffer severely from haemophilia, they are treated with prophylactic infusions a couple of times a week. The patients most often treat themselves at home or with the assistance of a family member. Monitoring of treatment usually takes place in centres of reference with a multidisciplinary approach. Advisory guidelines are developed for appropriate treatment [1].

An important factor that has contributed to an effective control strategy of the disease is the existence of patient support groups that are present in most countries collaborating with medical advisors. Most of today’s haemophilia societies are organized within the World Federation of Haemophilia (WFH), founded by Frank Schabel in 1963.

In the past, treatment of haemophilia has been involved with transmission of viral infections (hepatitis C, AIDS). Nowadays, the used coagulation factors are protected in such a way that transmission of hepatitis C or AIDS is hardly possible, especially with fully licensed products. The next important step for curative treatment in the future is gene therapy, although early clinical studies have to deal with serious drawbacks. Another promising area of research could be the use of transgenic animals, especially to make a larger supply available, which is of utmost importance for developing countries.

Side-effects of treatment

  1. Top of page
  2. Haemophilia, a well-known rare disease
  3. Side-effects of treatment
  4. Forty years of haemophilia treatment in the Netherlands
  5. Haemophilia care for different age groups
  6. Actual challenges in haemophilia treatment
  7. Haemophilia care in developing countries
  8. The cost of haemophilia treatment
  9. A safe, blood supply
  10. Conclusion
  11. Disclosures
  12. References

As mentioned before, severe forms of haemophilia are characterized by major bleeding after minor trauma. These haemorrhages often occur in joints, eventually causing arthropathy. This is the most important complication of haemophilia, which can be prevented when treatment is available. But, especially for developing countries where treatment is most often not available or only in urgent situations, severe joint impairment still is the most important complication of this disease.

A second complication of haemophilia, when treatment is available, is the occurrence of neutralizing antibodies to factor VIII or IX (inhibitors), either in the past or the present. In a Dutch study of 2001, inhibitors were reported by 13% (52/420) of patients with severe haemophilia [2].

The third, and most tragic complication of treatment of the disease, is the transmission of bloodborne viruses by the blood products used for haemophilia in the past, like AIDS (HIV), hepatitis B (HBV) and hepatitis C virus (HCV, the former non-A, non-B hepatitis). Of the Dutch patients with severe haemophilia who were treated with plasma-derived clotting factors before 1985, 17% became infected with HIV and more than 50% with HCV. Plasma-derived products have been safe for HBV and HIV since 1985, and also for HCV since 1992 [2].

HIV infections in the Netherlands have been relatively low, compared to other EU countries and the United States. This difference in seropositivity rates can be explained by the high rate of self-sufficiency in blood clotting products prepared from the blood of voluntary, unpaid donations by the Dutch Red Cross at that period in the 1980s.

Forty years of haemophilia treatment in the Netherlands

  1. Top of page
  2. Haemophilia, a well-known rare disease
  3. Side-effects of treatment
  4. Forty years of haemophilia treatment in the Netherlands
  5. Haemophilia care for different age groups
  6. Actual challenges in haemophilia treatment
  7. Haemophilia care in developing countries
  8. The cost of haemophilia treatment
  9. A safe, blood supply
  10. Conclusion
  11. Disclosures
  12. References

There are very few long-term studies to prove the value of treatment for patients with haemophilia since its beginning. In the Netherlands, a series of five national postal surveys have been performed from 1972 onward, with a sixth survey being planned for 2011. In the first five studies this study, the most important medical and social developments over the last decades of haemophilia treatment have been evaluated. The data from this study show the improvement of mortality, morbidity and quality of life of Dutch patients with haemophilia [2].

It can also be seen from these data that the total number and duration of hospital stays decreased tremendously. Children with haemophilia can go to normal schools nowadays, most jobs are open to them, full participation in society is possible through employment, marriage and having children.

The life expectancy of haemophiliacs is almost normal, namely 71 years compared to 76 years for the male population in the Netherlands without haemophilia [3]. Not only the life expectancy increased in this time period of 30 years also labour participation increased substantially over the years. In the beginning of this study, the average age where patients with severe haemophilia were no longer able to participate in the labour force was 32 years, nowadays this average age is 49 years [2].

Haemophilia care for different age groups

  1. Top of page
  2. Haemophilia, a well-known rare disease
  3. Side-effects of treatment
  4. Forty years of haemophilia treatment in the Netherlands
  5. Haemophilia care for different age groups
  6. Actual challenges in haemophilia treatment
  7. Haemophilia care in developing countries
  8. The cost of haemophilia treatment
  9. A safe, blood supply
  10. Conclusion
  11. Disclosures
  12. References

The increased life expectancy in haemophilia also has its implications for the age distribution of the patient group [4]. Figure 1 illustrates the age distribution for the patients with severe haemophilia who are supervised in one of the bigger haemophilia centres in the Netherlands, the Van Creveld Clinic in Utrecht from 1975 to 2009. In 1975, they treated 82 patients with severe haemophilia, and in 2009, this number was 338 (E. P. Mauser-Bunschoten, personal communication).

image

Figure 1.  Proportion of patients (%) with severe haemophilia in different age groups from 1975 to 2009, data from the Van Creveld Clinic, Utrecht, the Netherlands.

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Younger generations will grow up with little medical problems with the exclusion of the development of inhibitors. Joint and muscle bleeding will not appear that much because of the prophylactic treatment they receive and they are safeguarded from viral complications.

For the younger generations, the disease implies that – after a training period – they will treat themselves at home and visit a haemophilia treatment centre only once or twice a year for a control visit. If all goes well with home treatment, they are not very familiar with the sometimes serious complications of the disease. The same is true for newer generations of haematologists. When they – in contrast to their colleagues from the past – seldom see the serious complications of haemophilia, expertise will disappear [5]. Also, the interest of haematologists will focus on other, more serious haematological diseases, like leukaemia and related blood problems in oncology.

However, because of the increased life expectancy, the haemophilia community is now for the first time in history dealing with a new category of patients: the seniors [4]. These seniors were young at the time when no proper treatment for haemophilia existed. Since the 1960s, these patients with haemophilia could receive intravenous factor VIII and IX replacement therapy prepared from plasma and later recombinant DNA sources and subsequently more and more treatment became available. This implies that in their youths, these men suffered from severe bleedings that caused permanent joint damage, and this damage could not be reversed through later treatment. The only option here is intensive physiotherapy and orthopaedic operations, like hip and knee replacements. On top of that part of the Dutch haemophilia population was infected with HIV and/or HCV before the development of adequate viral inactivation of blood products in the late eighties, early nineties.

At present, these seniors with haemophilia not only have to live with premature arthropathy and HIV/HCV infection, they are also confronted with age-related ailments. Progressive arthritis and declining fitness may lead to an increasing dependency on medical treatment, a growing number of hospital visits and loss of independency. In connection with the physical aspects of ageing older patients may encounter psychosocial problems which may be triggered by early retirement, loss of health and altered family dynamics.

Actual challenges in haemophilia treatment

  1. Top of page
  2. Haemophilia, a well-known rare disease
  3. Side-effects of treatment
  4. Forty years of haemophilia treatment in the Netherlands
  5. Haemophilia care for different age groups
  6. Actual challenges in haemophilia treatment
  7. Haemophilia care in developing countries
  8. The cost of haemophilia treatment
  9. A safe, blood supply
  10. Conclusion
  11. Disclosures
  12. References

The history of haemophilia also gives an indication of other, important policy issues surrounding this disease, like the treatment possibilities in developing countries. The issue of viral transmission (HIV, HCV) is an indication to address once more the worldwide problem of a safe, blood supply. As a consequence of safety issues in blood transfusion, the cost of haemophilia products have risen substantially. The rise in cost of modern haemophilia treatment in combination with the current economic problems will become a big concern for a lot of health care providers and governments.

Haemophilia care in developing countries

  1. Top of page
  2. Haemophilia, a well-known rare disease
  3. Side-effects of treatment
  4. Forty years of haemophilia treatment in the Netherlands
  5. Haemophilia care for different age groups
  6. Actual challenges in haemophilia treatment
  7. Haemophilia care in developing countries
  8. The cost of haemophilia treatment
  9. A safe, blood supply
  10. Conclusion
  11. Disclosures
  12. References

Only about 30% of the patients with haemophilia in the world are diagnosed and receive treatment. The majority of those people live in the more prosperous countries, where comprehensive haemophilia care is included in the national health care system.

One of the main goals of the WFH is to help and encourage haemophilia care in developing countries together with national haemophilia organizations, health care providers and governmental officials to assess their needs and develop a national plan for haemophilia care [6]. Improving the possibility of treatment of haemophilia in developing countries also means that there is an opportunity to improve the infrastructure of a national blood transfusion system and as a consequence the development of some basic, plasma-derived blood products. When there is a good screening programme for HBV, HCV and HIV, the use of plasma-derived products for haemophilia can contribute to the treatment of haemophiliacs in the developing world, without the need to import the 10–20% more expensive rDNA clotting products. From such a development, also other patient groups who are dependent on a safe blood supply could profit, like patients with sickle cell and thalassaemia.

Companies in several developing countries, for instance in Iran and India, are now working on the further development of transgenic animals which are able to produce enough quantities of factor VIII or IX. Also, companies in the USA and New Zealand are working on this. Especially after the approval by the FDA in February 2009 of the first genetically engineered transgenic product Atryn, prospects for this technology are improving. Atryn is an anticoagulant therapy produced in the milk of genetically engineered goats to prevent blood clots in people with hereditary antithrombin deficiency, a rare coagulation disorder.

Another exciting approach could be the use of the large quantities of factor VIII and IX that are no longer fractionated in the Western world, because of the switch to rDNA clotting products. The Canadian Hemophilia Society is pushing this idea to help haemophiliacs in South Africa, and also, the Dutch fractionator Sanquin is looking into ways how this unused material can be distributed to a former Dutch colony: Indonesia.

The cost of haemophilia treatment

  1. Top of page
  2. Haemophilia, a well-known rare disease
  3. Side-effects of treatment
  4. Forty years of haemophilia treatment in the Netherlands
  5. Haemophilia care for different age groups
  6. Actual challenges in haemophilia treatment
  7. Haemophilia care in developing countries
  8. The cost of haemophilia treatment
  9. A safe, blood supply
  10. Conclusion
  11. Disclosures
  12. References

Recently, European health systems of all types have been concerned with controlling total spending in pharmaceuticals [7]. The cost of treating patients with haemophilia has increased substantially over the last decades because of the introduction of new production methods (e.g. recombinant DNA clotting products) and new governmental regulations asking for viral inactivation safety procedures to protect users of blood and blood coagulation products from the transmission of viruses (e.g. hepatitis A, B, C, HIV and more recently Variant Creutzfeldt-Jakob Disease (vCJD)). The treatment of haemophilia is costly. A patient with mild symptoms costs about € 30 000, and a patient with severe symptoms about € 125 000.

Around 2005, the WHO strongly questioned the issue whether haemophilia products should be any longer on the WHO list of essential medicines [8]. The arguments that have been exchanged during this discussion certainly reflect concerns over the costs of modern haemophilia treatment. It is therefore that the international haemophilia community should be aware that they take the initiative to control compliance with treatment regimens and that they look for ways to control the costs of modern products. But even more important, they should also play a stimulating role in promoting research in other areas that could limit or end the consequences of the disease, like gene therapy or the use of transgenic animals.

A safe, blood supply

  1. Top of page
  2. Haemophilia, a well-known rare disease
  3. Side-effects of treatment
  4. Forty years of haemophilia treatment in the Netherlands
  5. Haemophilia care for different age groups
  6. Actual challenges in haemophilia treatment
  7. Haemophilia care in developing countries
  8. The cost of haemophilia treatment
  9. A safe, blood supply
  10. Conclusion
  11. Disclosures
  12. References

The tragic occurrence of viral transmission (HIV, HCV) in haemophiliacs all over the world, clearly demonstrated the need of a safe, blood supply. There has been a long, historical debate about the pros and cons of a blood transfusion system with voluntary, unpaid versus paid blood donors. And this debate has not ended, as was illustrated by a recent article in Transfusion Today, where Claudine Hossenlopp wrote a memorial devoted to Charles Salmon, the former Secretary General of the International Society of Blood Transfusion (ISBT). In her article Hossenlopp questions whether the 21st century will succeed in avoiding commercialization of the human body. And she concludes: ‘Blood is certainly one element of the human body and as such cannot be considered as a merchandise. However, once considered outside the human body, i.e. once drawn, it becomes a product and can be submitted to legal requirements as well as to market forces. This paradox remains true for the future’ [9]. Also, Volkow [10] and Del Rio addressed the topic again in several recent articles. In one of these articles, they conclude that a safe blood supply based on voluntary, unpaid donors is barely a footnote in the global plan to control HIV.

This paid versus unpaid debate started about four decades ago when commercial blood banks and pharmaceutical companies had gained a strong position in the supply of plasma and plasma products in the United States and some other industrialized countries. The debate became well known with the publication of Richard Titmuss’s book ‘The gift relationship: from human blood to social policy’ in 1970 and republished in 1997 [11]. Also, the books of Piet J. Hagen (1982) and Douglas Starr (1998) contain a lot of information on this debate [12,13]. Hagen also wrote a ‘white paper’ on the topic of blood transfusion in Europe for the Council of Europe, which was published in 1993 [14]. Other more recent publications on this topic are from Van der Poel, James and Cruz, which indicate that a blood supply based on volunteer, unpaid donors is still relevant for safety reasons [15–17].

For all people in the world, who need a blood transfusion today, tomorrow or the day after tomorrow the issue of a safe, blood supply is still relevant [18]. Therefore, it is even more tragic to see that in this period of economic crises, people have to sell their plasma again to earn a living. And more personally, I feel that it is even insulting to those blood transfusion recipients who were transmitted by HCV and HIV that companies go on with these practices 40 years after the first warnings by Richard Titmuss and others.

Conclusion

  1. Top of page
  2. Haemophilia, a well-known rare disease
  3. Side-effects of treatment
  4. Forty years of haemophilia treatment in the Netherlands
  5. Haemophilia care for different age groups
  6. Actual challenges in haemophilia treatment
  7. Haemophilia care in developing countries
  8. The cost of haemophilia treatment
  9. A safe, blood supply
  10. Conclusion
  11. Disclosures
  12. References

In the last 45 years, the treatment possibilities for people with haemophilia improved a lot. The tragedy of bloodborne viral transmissions led to an increase of safety measures, which led also to a sharp increase of the cost of the clotting products for haemophilia. The burden of these ‘safety’ costs should not be burdened again on the shoulders of those with haemophilia. They already have to bear the impact of the HIV and HCV tragedy.

Instead, the haemophilia community and the producers should strive for more efficient ways of treatment, e.g. improvement of the efficiency of the existing clotting products or more investments in new technologies, like gene therapy and transgenic methods of production. The last method especially could lead to a potential enlargement of existing stock of treatment products, so that treatment becomes an option also for developing countries.

References

  1. Top of page
  2. Haemophilia, a well-known rare disease
  3. Side-effects of treatment
  4. Forty years of haemophilia treatment in the Netherlands
  5. Haemophilia care for different age groups
  6. Actual challenges in haemophilia treatment
  7. Haemophilia care in developing countries
  8. The cost of haemophilia treatment
  9. A safe, blood supply
  10. Conclusion
  11. Disclosures
  12. References
  • 1
    Mauser-BunschotenEP, Van Den BergM, SmitC, De Knecht-van EekelenA (editors): From Haemophilia Treatment to Haemophilia Coaching: Changing Perspectives for Patients and Physicians. Utrecht, 2005
  • 2
    Plug I, Van Der Bom JG, Peters M, Mauser-Bunschoten EP, De Goede-Bolder A, Heijnen L, Smit C, Zwart-van Rijkom JEF, Willemse J, Rosendaal FR: Thirty years of hemophilia treatment in the Netherlands, 1972–2001. Blood 2004; 104(12):34943500
  • 3
    Plug I, Van Der Bom J.G., Peters M, Mauser-Bunschoten EP, De Goede-Bolder A, Heijnen L, Smit C, Willemse J, Rosendaal FR: Mortality and causes of death in patients with haemophilia, 1992–2001: A prospective cohort study. J Thromb Haemost 2006; 4(3):510516
  • 4
    Mauser-Bunschoten EP, De Knecht-van Eekelen A, Smit C: Ageing with Haemophilia: Medical and Psychosocial Impact. Utrecht, Van Creveldkliniek, 2007
  • 5
    Mauser-Bunschoten EP, De Knecht-van Eekelen A, Smit C: Rare Bleedings in Haemophilia. Utrecht, Van Creveldkliniek, 2002
  • 6
  • 7
    SaltmanRB, BusseR, FiguerasJ (editors): Social Health Insurance Systems in Western Europe. European Observatory on Health Systems and Policies Series. Maidenhead (Berkshire, England), Open University Press, 2005
  • 8
    WHO Expert Committee on the Use of Essential Drugs. WHO Model List of Essential Medicines: 14th list, March 2005. Geneva, World Health Organisation, 2005
  • 9
    Hossenlopp C: Charles Salmon (1925–2009): ethical considerations. Transfusion Today 2009-4, ISBT, 2009
  • 10
    Volkow P, Del Rio C: Paid donation and plasma trade: unrecognized forces that drive the AIDS epidemic in developing countries. Int J STD AIDS 2005; 16:58
  • 11
    Titmuss RM: The Gift Relationship: From Human Blood to Social Policy. London, George Allan & Unwin Ltd, 1970. Republished in 1997 by the London School of Economics. LSE Books, 1997
  • 12
    Hagen PJ: Blood: Gift or Merchandise. New York, Alan R. Liss, Inc., 1982
  • 13
    Starr D: Blood: an Epic History of Medicine and Commerce. New York, Alfred A. Knopf, 1998
  • 14
    Hagen PJ: Blood Transfusion in Europe: A ‘White’ Paper. Strassbourg, Council of Europe Press, 1993
  • 15
    Van Der Poel C: Paying for blood donations, still a risk? Vox Sanq 2002; 83:285293
  • 16
    James RC, Mustard CA: Geographic location of commercial plasma donation clinics in the United States. Am J Public Health 2004; 94(7):12241229
  • 17
    Cruz JR: Seeking a safer blood supply. Lancet 2005; 365:14631464
  • 18
    Pollack A: Is money tainting the plasma supply? NY Times 2009; Dec 6:BU1