Hemophilia on the treshold of the 21st century
Plug, I.Citation
Plug, I. (2005, September 6). Hemophilia on the treshold of the 21st century. Retrieved from https://hdl.handle.net/1887/3389
Version: Corrected Publisher’s Version
License: Licence agreement concerning inclusion of doctoral thesis in theInstitutional Repository of the University of Leiden Downloaded from: https://hdl.handle.net/1887/3389
Chapter 1
Introduction
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General introduction
Hemophilia
Hemophilia is a hereditary clotting disorder which is caused by a deficiency of factor VIII (hemophilia A) or IX (hemophilia B). In the Netherlands the prevalence is around 10 per 100,000, resulting in about 1600 patients1. The severity of the disease is determined by the residual clotting factor activity. Patients with mild hemophilia (>0.05-0.40 IU/ml) show little spontaneous bleeding and bleed excessively only after major trauma; patients with moderate hemophilia (0.01-0.05 IU/ml) may show excessive hemorrhages after minor trauma, while severe hemophilia (<0.01 IU/ml) is characterized by major bleeding occurring spontaneously or after minor trauma. Frequent bleeding in joints results into damage of the synovial tissue and arthropathy. Hemophilia is a genetic recessive X-linked trait and therefore patients are mostly men. Female family members can be carriers of the disorder, which is characterized by a 25% chance of having a son with hemophilia, and a decreased clotting factor activity level.
History
Although effective treatment has only become available in the recent decades, hemophilia was known to the ancient world. The earliest written references to what appears to be hemophilia are encountered in Jewish texts of the second century AD. Rabbinical rulings exempted male boys from circumcision if two previous brothers had died of bleeding after the procedure2. The first modern description of hemophilia is attributed to Dr John Conrad, who clearly appreciated the three cardinal features of hemophilia: an inherited tendency of males to bleed3. However, the first use of the word "hemophilia" appears in an account of the condition written in 1828 by Hopff (Über die haemophilie oder die erbliche Anlage zu tödliche
Chapter 1
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members of royal families in Europe were affected by it. Queen Victoria had no ancestors with the condition but soon after the birth of her eighth child, Leopold in 1853 it became evident that he had hemophilia. Two of Queen Victoria's daughters were also carriers of hemophilia. The condition was transmitted through them to several Royal families. Perhaps the most famous affected individual was the son of Tsar Nicolas II of Russia, Tsarevich Alexis, who was born in 19044.
Treatment and complications
M any reputable scientist claimed early success in treatment with unusual substances. As recently as 1964 a report in Lancet claimed that peanut flour was effective for the treatment of hemophilia5. The first hint of success came from Dr R.G. M acfarlane in 1934, who discovered that snake venom could accelerate the clotting of hemophilic blood6. Plasma derived factor VIII and IX preparations became available in the early 1960s7. Ever since the discovery by Dr Judith Pool of cryoprecipitate, replacement therapy with factor concentrates has been the most important component of hemophilia care. This treatment rapidly improved the medical and social situation of patients with hemophilia and considerably increased life expectancy8,9. In the early 1980s major side-effects became manifest when many patients became infected with the human immunodeficiency virus (HIV)10. M oreover, of all patients treated before 1992 with plasma-derived clotting factor preparations, 80 percent became infected with hepatitis viruses11. Today, clotting factor preparations are virtually safe regarding blood-borne viruses12, and the risk of hepatitis and HIV transmission must be considered negligible,
whereas the development of neutralizing antibodies (‘inhibitors’) against the infused factor VIII or IX is an important issue13,14.
Introduction
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human blood and therefore even theoretically incapable of transmitting human blood-borne pathogens, has further stimulated the use of prophylactic treatment. In the Netherlands since the late 1970s treatment of hemophilia has consisted of the intravenous infusion of clotting factor concentrates performed either on demand (at the moment of bleeding) or
prophylactically. Prophylactic treatment is primarily prescribed to patients with severe hemophilia. The rationale for prophylaxis in hemophilia is that patients with a factor level of 0.01-0.04 IU/ml rarely develop chronic joint changes. By maintaining the plasma
concentration of clotting factors at a level above 0.01 IU/ml hemophilia can be converted from a severe to a milder form15-17.
Outline of this thesis
Chapter 1
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introduced in the early 1990s. Despite the serious side effects of plasma-derived clotting products these new products were not accepted as quickly as expected. In Chapter 2.5 factors influencing the use of recombinant factor VIII were studied.
Introduction
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References
1. Rosendaal FR, Briët E: The Increasing Prevalence of Hemophilia. Thrombosis and Haemostasis 1990;63:145.
2. Rosner F: Haemophilia in the Talmud and Rabbinic writings. Ann Intern Med 1969;70:833-837. 3. Otto J.C: An account of a hemorrhagic disposition existing in certain families. Med Repos 1803;6:1-4. 4. Rosendaal FR, Smit C, Briët E: Hemophilia treatment in historical perspective: a review of medical and
social developments. Ann Hematol 1991;62:5-15.
5. Mainwaring D, Keldon S.E: Peanut flour in haemophilia. Lancet 1964;19:647.
6. Macfarlane R.G, Barnett B: The haemostatic possibilities of snake-venom. Lancet 1934;2:985-987. 7. Pool JG, Hershgold EJ Pappenhagen AR. High-potency antihaemophiliac factor concentrate prepared from
cryoglobulin precipitate. Nature (203), 312.
8. Larsson SA: Life expectancy of Swedish haemophiliacs, 1831-1980. Br J Haematol 1985;59:593-602. 9. Triemstra M, Rosendaal FR, Smit C, Van der Ploeg HM, Briët E: Mortality in patients with hemophilia.
Changes in a Dutch population from 1986 to 1992 and 1973 to 1986. Ann Intern Med 1995;123:823-827. 10. Chorba TL, Holman RC, Strine TW, Clarke MJ, Evatt BL: Changes in longevity and causes of death among
persons with hemophilia A. Am J Hematol. American Journal of Hematology 1994;45:112-121.
11. Van der Poel CL, Reesink HW, Mauser-Bunschoten EP, Kaufmann RH, Leentvaar-Kuypers A, Chamuleau RA, Schaasberg W, Bakker E, Exel-Oehlers PJ, Theobalds I, .: Prevalence of anti-HCV antibodies confirmed by recombinant immunoblot in different population subsets in The Netherlands. Vox Sang 1991;61:30-36.
12. Teitel JM: Safety of coagulation factor concentrates. Haemophilia 1998;4:393-401.
13. Berntorp E: The treatment of haemophilia, including prophylaxis, constant infusion and DDAVP; in Lee C.A. (ed): Clinical Haematology. 96 A.D., vol 9, pp 259-273.
14. Wight J, Paisley S: The epidemiology of inhibitors in haemophilia A: a systemic review. Haemophilia 2003;9:418-435.
15. van Creveld S: Prophylaxis of joint hemorrhages in hemophilia. Acta Haematologica 1971;45:120-127. 16. van den Berg MH, Fischer K: Prophylaxis for severe hemophilia: experience from Europe and the United
States. Seminars in Thrombosis and Hemostatis 2003;29:49-54.
17. Nilsson I M, Berntorp E, Lofqvist T, Petterson H: Twenty-five years' experience of prophylactic treatment in severe haemophilia A and B. Journal of Internal Medicine 1992;232:25-32.
18. Rosendaal FR, Varekamp I, Smit C, Bröcker-Vriends AHJT, Van Dijck H, Vandenbroucke JP, Hermans J, Suurmeijer TPBM, Briët E: Mortality and causes of death in Dutch haemophiliacs 1973-1986. British Journal of Hematology 1989;71:71-76.
