Hemophilia and von Willebrand's disease: 2. Management

Canadian Medical Association Journal 1995; 153: 147-157

[résumé]

Reprint requests to: Dr. Man-Chiu Poon, Division of Hematology and Hematologic Malignancies, Department of Medicine, Foothills Provincial General Hospital, 1403-29th St. NW, Calgary AB T2N 2T9

© 1995 Canadian Medical Association

• Abstract
• Introduction
• Management of hemophilia A and B
• Management of von Willebrand's disease
• Complications of treatment
• Additional aspects of management
• Validation
• Priorities for future research
• References

Abstract

Options: Prophylactic and corrective therapy with hemostatic and adjunctive agents: DDAVP (1-desamino-8-d-arginine vasopressin [desmopressin acetate]), recombinant coagulation products (human Factor VIII and human Factor VIIa) or virally inactivated plasma-derived products (high- or ultra-high-purity human Factor VIII or human Factor VIII concentrate containing von Willebrand factor activity, porcine Factor VIII, high-purity human Factor IX, human prothrombin-complex concentrate, human activated prothrombin-complex concentrate), adjunctive antifibrinolytic agents, topical thrombin and fibrin sealant. The induction of immune tolerance in patients in whom inhibitors develop should also be considered.

Outcomes: Morbidity and quality of life associated with bleeding and treatment.

Evidence: Relevant clinical studies and reports published from 1974 to 1994 were examined. A search was conducted of our reprint files, MEDLINE, citations in the articles reviewed and references provided by colleagues. In the MEDLINE search the following terms were used singly or in combination: "hemophilia," "von Willebrand's disease," "Factor VIII," "Factor IX," "von Willebrand factor," "diagnosis," "management," "home care," "comprehensive care," "inhibitor," "AIDS," "hepatitis," "life expectancy," "complications," "practice guidelines," "consensus statement" and "controlled trial." The in-depth review included only articles written in English from North America and Europe that were relevant to human disease and pertinent to a predetermined outline. The availability of treatment products in Canada was also considered.

Values: Minimizing morbidity and maximizing functional status and quality of life were given a high value.

Benefits, harms and costs: Proper prophylactic or early treatment with appropriate hemostatic agents minimizes morbidity and functional disability and improves quality of life. Economic gains are realized through the reduction of mortality and morbidity and their associated costs. The patient has a better opportunity to contribute to society through gainful employment and the fulfilment of social roles. Potential harms include HIV infection, hepatitis B, hepatitis C and the development of inhibitor antibodies to clotting-factor concentrates. The risk of viral transmission has been minimized through the development of procedures for the viral inactivation of plasma-derived clotting-factor concentrates and through the use of recombinant coagulation-factor concentrates and other non-plasma-derived hemostatic agents.

Recommendations: DDAVP is the drug of choice for patients with mild hemophilia or type 1 or 2 (except 2B) von Willebrand's disease whose response to DDAVP in previous testing has been found to be adequate. Therapeutic blood components of choice include recombinant products and virally inactivated plasma-derived products. In Canada the recommended products are recombinant Factor VIII for hemophilia A, high-purity plasma-derived Factor IX for hemophilia B and plasma-derived Factor VIII concentrates containing adequate von Willebrand factor (e.g., Haemate P) for von Willebrand's disease. Dosages vary according to specific indications. Adjunctive antifibrinolytic agents, topical thrombin and fibrin sealant are useful for the treatment of oral or dental bleeds and localized bleeds in accessible sites. In patients with inhibitor antibodies, high-dose human or porcine Factor VIII is usually effective when the inhibitor titre is less than 5 Bethesda units/mL. In nonresponsive patients, or in those whose inhibitor titre is higher, "bypassing" agents (e.g., activated prothrombin-complex concentrate and recombinant Factor VIIa) are useful. Long-term management may include immune-tolerance induction.

Validation: These recommendations were reviewed and approved by the Association of Hemophilia Clinic Directors of Canada (AHCDC) and the Medical and Scientific Advisory Committee of the Canadian Hemophilia Society. No similar consensus statements or practice guidelines are available for comparison.

Sponsors: These recommendations were developed at the request of the Canadian Blood Agency, which funds the provision of all coagulation-factor concentrates for people with congenital bleeding disorders, and were developed and endorsed by the AHCDC and the Medical and Scientific Advisory Committee of the Canadian Hemophilia Society.

[Table of Contents]

The development of management recommendations by the Association of Hemophilia Clinic Directors of Canada (AHCDC, formerly the Canadian Hemophilia Clinic Directors Group) was initially requested by the Canadian Blood Agency, which provides funding for the purchase of all coagulation-factor concentrates for the management of congenital coagulation disorders. A writing committee consisting of the three principal coauthors was established. We developed an outline of the topics to be considered and reviewed relevant clinical studies and reports published from January 1974 to April 1994. (This period was extended to September 1994 for the purposes of this article.) We searched our own reprint files, the MEDLINE database, citations in articles reviewed and references provided by colleagues. For the MEDLINE search we used the following terms singly or in combination: "hemophilia," "von Willebrand's disease," "Factor VIII," "Factor IX," "von Willebrand factor," "diagnosis," "management," "home care," "comprehensive care," "inhibitor," "AIDS," "hepatitis," "life expectancy," "complications," "practice guidelines," "consensus statement" and "controlled trial." We reviewed in depth only literature written in English from North America and Europe that was relevant to human disease and to our outline. The availability in Canada of treatment products was also considered. We then wrote an initial draft that was critiqued by the five members of the executive committee of the AHCDC, who provided input and approved a revised draft for circulation to members of the AHCDC and the Medical and Scientific Advisory Committee of the Canadian Hemophilia Society. Each member of the AHCDC and the chair of the advisory committee critiqued the document. Many AHCDC members also relayed critiques made by their clinic nurse coordinators.

These comments and revisions were incorporated into another draft circulated to each member of the AHCDC. This draft was discussed and approved in May 1994 at the AHCDC annual meeting, held in Quebec City. After minor revisions, a final document was circulated to the Canadian Hemophilia Society's Medical and Scientific Advisory Committee, whose members include representatives of hemophilia clinic nurse coordinators, physiotherapists, social workers, dentists and physicians. The advisory committee met in June 1994 and endorsed the document.

Randomized clinical trials that could provide evidence at levels I and II7 regarding the clinical efficacy of agents for the management of hemophilia and von Willebrand's disease have not been done. Because the efficacy of hemostatic agents correlates closely with the clotting-factor levels (and, in von Willebrand's disease, reduced bleeding time) that they induce, clinical trials are usually preceded by pharmocokinetic studies to determine in-vivo half-life and recovery. All ultra-high-purity and recombinant Factor VIII concentrates used in the treatment of hemophilia A, and all high-purity Factor IX concentrates used in the treatment of hemophilia B, have been evaluated in pharmacokinetic studies according to the study design and data analysis guidelines established by the Scientific and Standardization Committee of the International Society for Thrombosis and Haemostasis.(8) These guidelines take into account sample size, the need for randomized patient crossover with an adequate washout period, the clinical status of the study participants, dosage, methods of potency assessment, and statistical models and methods for half-life and recovery analyses. The efficacy of Haemate P, a product recommended for the correction of bleeding time in von Willebrand's disease, has been compared with that of a number of other Factor VIII concentrates in randomized crossover studies.(9) Crossover comparison of Haemate P with cryoprecipitate was not deemed ethically acceptable because cryoprecipitate, unlike all Factor VIII concentrates, does not undergo a viral inactivation process.(10) The development of inhibitors (alloantibodies that inhibit clotting-factor activity) in patients receiving recombinant Factor VIII concentrates(11,12) has been evaluated prospectively (but without randomization) in studies involving previously untransfused patients.

[Table of Contents]

Management of hemophilia A and B

DDAVP

Therapeutic use

The response of Factor VIII and von Willebrand factor to DDAVP decreases progressively when closely spaced repeated infusions are given; this is particularly the case in patients with hemophilia A.(17,24) Thus, DDAVP is especially useful in situations in which only a single dose is required. During major surgery or episodes of prolonged bleeding it may be necessary to alternate DDAVP with supplemental coagulation products.

Side effects

Blood components

In Canada coagulation products for the management of inherited bleeding disorders are licensed by the Bureau of Biologics, funded by the Canadian Blood Agency and purchased and distributed by the Canadian Red Cross Society Blood Services. The AHCDC makes requests with regard to the classes of concentrates that are made available for patient care, but the purchase and distribution of specific brands depends on contract negotiations that take several considerations, including cost, into account. Table 1 gives details on coagulation-factor concentrates currently funded by the Canadian Blood Agency and available through the Canadian Red Cross Society Blood Services. To obtain products not licensed by the Bureau of Biologics, Emergency Drug Release approval by the Bureau of Biologics is required.

Factor VIII concentrates (hemophilia A)

• Recombinant Factor VIII (rFVIII) concentrate. The clotting factor is produced in cultured hamster cells, purified with the use of procedures including immunoaffinity chromatography on murine monoclonal antibodies, and stabilized in human serum albumin.
• Ultra-high-purity plasma-derived Factor VIII concentrate purified by immunoaffinity chromatography and stabilized in human serum albumin.
• High-purity plasma-derived Factor VIII concentrate stabilized in human serum albumin.

Side effects
Concerns about the possibility of viral transmission have already been discussed. Rarely, allergic reactions, and hemolysis caused by contaminating red cell antibodies, occur. Inhibitors may also develop. Recently, there was some concern that previously untransfused patients receiving rFVIII may be at higher risk of inhibitor development than those receiving the plasma-derived product. Clinical trials suggest that the incidence of inhibitors in previously untransfused hemophilia A patients receiving rFVIII was between 19.4% and 28.6%.(11,12) Many of these inhibitors are of low titre, and some are evanescent. Whether the incidence rate of inhibitor development among patients receiving rFVIII is really higher than that among patients receiving the plasma-derived product is uncertain, given that patients receiving rFVIII in the clinical trials were prospectively monitored at more frequent intervals (every 3 months) than any previous patient population. Indeed, more recent studies suggest that the use of plasma-derived Factor VIII products may also result in a higher incidence rate of inhibitor development than the previously reported figure of 3.6% to 20%.(27,28)

Recommendation
In general, rFVIII concentrate, which carries a negligible risk of viral transmission, is recommended for the management of hemophilia A. The use of ultra-high-purity Factor VIII concentrates has recently been reported to delay the decline of CD4+ cell counts in asymptomatic HIV-infected patients when compared with less pure plasma-derived Factor VIII.(29,30) Whether this preservation of CD4+ cells is associated with a slower progression of HIV-related disease or increased survival in these patients is unknown. Data from prospective randomized trials are available only on ultra-high-purity plasma-derived Factor VIII concentrates purified by immunoaffinity chromatography. This type of Factor VIII concentrate is therefore available for HIV-infected patients who prefer it. Retrospective analysis of trial data suggests that among patients who received rFVIII, the rate of decline in CD4+ cell counts was no greater among those with HIV infection than among those who were not infected with HIV.(31)

Factor IX concentrates (hemophilia B)

• High-purity plasma-derived Factor IX concentrates containing a negligible amount of other vitamin-K-dependent clotting factors (i.e., Factors II, VII and X).
• Prothrombin-complex concentrate. This product has an intermediate degree of purity and contains a significant amount of other vitamin-K-dependent clotting factors.

Side effects
As with all plasma-derived concentrates, the potential for viral transmission and allergic reactions exists. In a minority (up to 6.3%) of patients receiving Factor IX therapy, inhibitors may also develop.(32) The development of thrombosis and disseminated intravascular coagulation may be associated with the use of prothrombin complex concentrates(33) and may be related to zymogen overload and the presence of small amounts of activated factors (e.g., Factor Xa) or other thrombogenic contaminants (e.g., phospholipids).(34,35) The thrombotic risk is not predictable but is particularly significant when the product is used in large, repeated doses (e.g., more than 75 U/kg for more than three to four doses at intervals of less than 12 hours) or in the treatment of neonates, patients with bone fractures or patients with crush injuries, extensive intramuscular bleeding or hepatocellular dysfunction.

Recommendation
The use of high-purity Factor IX whenever possible is recommended.

Adjunctive hemostatic agents

• Antifibrinolytic agents such as e-aminocaproic acid (Amicar) and tranexamic acid (Cyklokapron). These products inhibit plasminogen activation and plasmin activity, thus preventing clot lysis. They are best used for the treatment of mucosal, oral and dental bleeds(36-39) (Table 2). A short course (5 days) of antifibrinolytic therapy (Amicar 75 mg/kg [up to 4 g] every 6 hours or Cyklokapron 25 mg/kg every 8 hours) is also effective in the management of epistaxis. These agents should not be used to treat urinary tract hemorrhage, in which an unlysed clot may cause urinary tract obstruction, or bleeding into a closed space where hemostatic monitoring is difficult. Antifibrinolytics can be administered orally, intravenously or topically for oral and dental bleeds.
• Topical thrombin and fibrin sealant. These agents are useful for the control of localized, accessible bleeding from lacerated tissues or after dental extraction, particularly when blood products are not effective (e.g., when inhibitors have developed). Bovine thrombin powder can be applied directly or on a gelatine sponge.

Treatment of bleeding episodes

Antiplatelet drugs (e.g., acetylsalicylic acid) and intramuscular injections should be avoided. Major surgery and major bleeding episodes should be managed in institutions with full coagulation-monitoring facilities.

[Table of Contents]

Management of von Willebrand's disease

Blood components

In rare instances the use of Factor VIII concentrates fails to stop a bleeding episode. In such cases the use of cryoprecipitate or platelet concentrates, or both, should be considered.(46)

[Table of Contents]

Complications of treatment

Inhibitor development

Among patients with hemophilia A whose inhibitor titre is below 5 Bethesda units, the infusion of large doses of human Factor VIII concentrate (100 to 200 U/kg) will sometimes be effective.(47) If this approach fails and the patient's Factor VIII antibodies have been shown to have reduced reactivity against porcine Factor VIII, the next option is to use porcine Factor VIII at a dose of 50 to 100 U/kg.(48,49) In either case it must be remembered that most patients will subsequently have a marked increase in the titre of their neutralizing antibodies.

If the initial inhibitor titre is greater than 5 to 10 Bethesda units, high doses of human or porcine Factor VIII can be tried in conjunction with an antibody-removal protocol such as the use of extracorporeal immunoadsorption with a staphylococcal protein A column or plasma exchange.(50,51) More commonly, effective treatment for this patient group will require the infusion of one of several available "bypassing" concentrates. Prothrombin-complex concentrates and activated prothrombin-complex concentrates in doses of 100 U/kg at 12-hour intervals (no more than three to four doses, to minimize the risk of thrombosis)(52,53) and recombinant human Factor VIIa(54,55) have been reported to be effective in the treatment of bleeding in these patients.

In the long-term management of patients who have inhibitors the induction of immune tolerance to their therapeutic concentrate should be considered. Conventional immunosuppressive regimens are not successful in these patients, but about 50% will respond favourably to infusion protocols.(56,57) Nonresponsive patients will require continued management with bypassing concentrates.

Viral disease transmission

[Table of Contents]

Additional aspects of management

[Table of Contents]

Validation

[Table of Contents]

Priorities for future research

Research efforts should aim at clarifying whether inhibitors develop more commonly in patients treated with rFVIII than in those treated with plasma-derived Factor VIII.(11,12,27,28) Well-designed, randomized studies are needed to identify the best and most cost-effective treatment of bleeding in patients with inhibitors and to improve methods for eliminating inhibitors once they have developed. Whereas immune-tolerance induction is effective in eliminating inhibitors in about 50% of affected patients,(56,57) additional research is required to identify the optimal dosage, timing and method of administration (e.g., pulse v. continuous) of clotting factors in immune-induction protocols. Research into the basic immunologic and pathogenic features of inhibitors is also critical. Understanding inhibitor formation and its management will have an impact on the development of gene therapy for coagulation disorders, as this will also involve the delivery of rFVIII and therefore has the potential to result in inhibitor formation.

Recent studies suggest that prophylactic infusion to maintain clotting-factor levels above 0.01 U/mL (more than 1% activity) at all times prevents most episodes of spontaneous bleeding into joints and preserves joint function.(13-16) Randomized studies are needed to confirm the efficacy and cost-effectiveness of this mode of management. Studies are also needed to assess the safety, efficacy and cost-effectiveness of continuous versus pulse coagulation-product infusion in prophylactic therapy.

Continued efforts to develop new products that are safe and effective in the management of coagulation disorders is needed. Such products could include recombinant clotting factors from which viral contamination is virtually eliminated. Alternative stabilizing agents for recombinant clotting-factor concentrates should be sought to replace the plasma-derived human albumin currently in use. Research should also look into better and more convenient methods for the administration of these products.

Hemophilia would appear to be well suited to gene therapy because severe disease can be converted to mild disease with only a minor increase in the clotting-factor level (to 0.05 U/mL, or more than 5% activity). Successful gene therapy would eliminate the need for replacement therapy even though the patient would not necessarily be "cured." Considerable research is still required before this goal can be achieved.

Research should be directed toward the development of effective methods and modalities for the prevention and management of HIV infection, hepatitis and other bloodborne diseases. Protective vaccines against HIV and hepatitis C virus should also be developed.

Finally, patient-outcome research to document the efficacy and cost-effectiveness of current treatment modalities is important in the present context of shrinking health care resources.

[Table of Contents]

References

1. Levine P: Efficacy of self-therapy in hemophilia: a study of 72 patients with hemophilia A and B. N Engl J Med 1974; 291: 1381-1384
2. Ingram GIC, Dykes SR, Creese AL et al: Home treatment in haemophilia: clinical, social and economic advantages. Clin Lab Haematol 1979; 1: 13-27
3. Smith PS, Keyes NC, Forman EN: Socioeconomic evaluation of a state-funded comprehensive hemophilia-care program. N Engl J Med 1982; 306: 575-579
4. Smith PS, Levine PH: The benefits of comprehensive care for hemophilia: a 5 year study of outcomes. Am J Public Health 1984; 74: 616-617
5. Jones P: Comprehensive care in hemophilia. In Seghatchian MJ, Savidge GF (eds): Factor VIII -- von Willebrand Factor, vol 2, CRC Press, Boca Raton, Fla, 1989: 135-144
6. Association of Hemophilia Clinic Directors of Canada: Hemophilia and von Willebrand's disease: 1. Diagnosis, comprehensive care and assessment. CMAJ 1995; 153: 19-25
7. Sackett DL: Rules of evidence and clinical recommendations on the use of antithrombotic agents. Chest 1986; 89 (suppl): 2S-3S
8. Morfini M, Lee M, Messori A, and the Factor VIII/Factor IX Scientific and Standardization Committee of the International Society for Thrombosis and Haemostasis: the design and analysis of half-life and recovery studies for Factor VIII and Factor IX. Thromb Haemost 1991; 66: 384-386
9. Mannucci PM, Tenconi PM, Castaman G et al: Comparison of four virus-inactivated plasma concentrates for treatment of severe von Willebrand disease: a cross-over randomized trial. Blood 1992; 79: 3130-3137
10. Mannucci PM: Clinical evaluation of viral safety of coagulation Factor VIII and IX concentrates. Vox Sang 1993; 64: 197-203
11. Lusher JM, Arkin S, Abildgaard CF et al: Recombinant Factor VIII for the treatment of previously untreated patients with hemophilia A. N Engl J Med 1993; 328: 453-459
12. Bray GL, Comperts ED, Courter S et al: A multicenter study of recombinant Factor VIII (Recombinate): safety, efficacy, and inhibitor risk in previously untreated patients with hemophilia A. Blood 1994; 83: 2429-2435
13. Nilsson IM, Berntorp E, Löfqvist T et al: Twenty-five years' experience of prophylactic treatment in severe haemophilia A and B. J Intern Med 1992; 232: 25-32
14. Carlsson M, Berntorp E, Bjorkman S et al: Pharmacokinetic dosing in prophylactic treatment of hemophilia A. Eur J Haematol 1993; 31: 247-252
15. Brackmann HH, Eickhoff HJ, Oldenburg J et al: Long-term therapy and on-demand treatment of children and adolescents with severe haemophilia A: 12 years of experience. Haemostasis 1992; 22: 251-258
16. Petrini P, Lindvall N, Egberg N et al: Prophylaxis with factor concentrates in preventing hemophilic arthropathy. Am J Pediatr Hematol Oncol 1991; 12: 280-287
17. Mannucci PM: Desmopressin: a nontransfusional hemostatic agent. Annu Rev Med 1990; 41: 55-64
18. Mannucci PM, Vicente V, Alberca I et al: Intravenous and subcutaneous administration of desmopressin (DDAVP) to hemophiliacs: pharmacokinetics and Factor VIII responses. Thromb Haemost 1987; 58: 1037-1039
19. Rodeghiero F, Castaman G, Di Bona E et al: Consistency of responses to repeated DDAVP infusions in patients with von Willebrand's disease and hemophilia A. Blood 1989; 74: 1997-2000
20. Köhler M, Hellstern P, Miyashita C et al: Comparative study of intranasal, subcutaneous and intravenous administration of desamino-d-arginine vasopressin (DDAVP). Thromb Haemost 1986; 55: 108-111
21. Rose EH, Aledort LM: Nasal spray desmopressin (DDAVP) for mild hemophilia A and von Willebrand disease. Ann Intern Med 1991; 114: 563-568
22. Holmberg L, Nilsson IM, Borge L: Platelet aggregation induced by 1-desamino-d-arginine vasopressin (DDAVP) in type IIB von Willebrand's disease. N Engl J Med 1983; 309: 816-821
23. Takahashi H, Nagayama R, Hattori A et al: Platelet aggregation induced by DDAVP in platelet-type von Willebrand's disease. N Engl J Med 1984; 310: 722-723
24. Mannucci PM, Bettega D, Cattaneo M: Patterns of development of tachyphylaxis in patients with haemophilia and von Willebrand disease after repeated doses of desmopressin (DDAVP). Br J Haematol 1992; 82: 87-93
25. Desmopressin and arterial thrombosis. [editorial] Lancet 1989; 1: 938-939
26. Mannucci PM, Lusher JM: Desmopressin and thrombosis. [letter] Lancet 1989; 2: 675-676
27. Ehrenforth S, Kreutz W, Scharrer I et al: Incidence of development of Factor VIII and Factor IX inhibitors in haemophiliacs. Lancet 1992; 339: 594-596
28. Addiego J, Kasper C, Abildgaard C et al: Frequency of inhibitor development in haemophiliacs treated with low-purity Factor VIII. Lancet 1993; 342: 462-464
29. Seremetis SV, Aledort LM, Bergman GE et al: Three-year randomised study of high-purity or intermediate-purity Factor VIII concentrates in symptom-free HIV-seropositive haemophiliacs: effects on immune status. Lancet 1993; 342: 700-703
30. De Biasi R, Rocino A, Miraglia E et al: The impact of a very high purity Factor VIII concentrate on the immune system of human immunodeficiency virus-infected hemophiliacs: a randomized, prospective, two-year comparison with an intermediate purity concentrate. Blood 1992; 78: 1919-1922
31. Mannucci PM, Brettler DB, Aledort LM et al: Immune status of human immunodeficiency virus seropositive and seronegative hemophiliacs infused for 3.5 years with recombinant Factor VIII. Blood 1994; 83: 1958-1962
32. Briët E: Factor IX inhibitors in haemophilia B patients: their incidence and prospects for development with high purity Factor IX products. Blood Coagul Fibrinolysis 1991; 2 (suppl 1): 47-50
33. Kasper CK: Postoperative thromboses in hemophilia B. [letter] N Engl J Med 1973; 289: 160
34. Giles AR: By what mechanisms could prothrombin complex concentrates promote Factor VIII bypassing activity in vivo? [review] Transfus Med Rev 1987; 1: 131-137
35. Giles AR, Nesheim ME, Hoogendoorn H et al: The coagulant-active phospholipid content is a major determinant of in vivo thrombogenicity of prothrombin complex (Factor IX) concentrates in rabbits. Blood 1982; 59: 401-407
36. Walsh PN, Rizza CR, Matthews JM et al: Epsilon-aminocaproic acid therapy for dental extractions in haemophilia and Christmas disease: a double blind controlled trial. Br J Haematol 1971; 20: 463-475
37. Sindet-Pedersen S, Stenbjerg S: Effect of local antifibrinolytic treatment with tranexamic acid in hemophiliacs undergoing oral surgery. J Oral Maxillofac Surg 1986; 44: 703-707
38. Sindet-Pedersen S, Dahl M, Ingerslev J: Fibrinolysis and hemostasis in the oral cavity. [abstract 38] Paper presented at the 21st International Congress of the World Federation of Hemophilia, Mexico City, Mexico, Apr 24-29, 1994
39. Sindet-Pedersen S, Stenbjerg S, Ingerslev J: Control of gingival hemorrhage in hemophilic patients by inhibition of fibrinolysis with tranexamic acid. J Periodontal Res 1988; 23: 72-74
40. Bona RD, Weinstein RA, Weisman SJ et al: The use of continuous infusion of factor concentrates in the treatment of hemophilia. Am J Hematol 1989; 32: 8-13
41. Martinowitz U, Schulman S, Gitel S et al: Adjusted dose continuous infusion of Factor VIII in patients with haemophilia A. Br J Haematol 1992; 82: 729-734
42. Harrison JA, Powell JS, Abildgaard CF: Constant infusion of recombinant Factor VIII (Kogenate) for surgery in hemophilia. [abstract] Thromb Haemost 1993; 69: 1099
43. Logan LJ, Gilbert PK, Sanders NL et al: Delivery of Alphanine by continuous infusion for surgical operations. [abstract] Transfusion 1993; 33: 876-877
44. Rodeghiero F, Castaman G, Meyer D et al: Replacement therapy with virus-inactivated plasma concentrates in von Willebrand disease. Vox Sang 1992; 62: 193-199
45. Berntorp E, Nilsson IM: Use of a high-purity Factor VIII concentrate (Hemate P) in von Willebrand's disease. Vox Sang 1989; 56: 212-217
46. Castillo R, Monteagudo J, Escolar G et al: Hemostatic effect of normal platelet transfusion in severe von Willebrand disease patients. Blood 1991; 77: 1901-1905
47. Kasper CK: Complications of hemophilia A treatment: Factor VIII inhibitors. Ann N Y Acad Sci 1991; 614: 97-105
48. Kernoff PBA: The clinical use of porcine Factor VIII. Prog Clin Biol Res 1990; 324: 47-56
49. Brettler DB, Forsberg A, Levine PH et al: The use of porcine Factor VIII concentrate (Hyate C) in the treatment of patients with inhibitor antibodies to Factor VIII: a multicenter US experience. Arch Intern Med 1989; 149: 1381-1385
50. Nilsson IM, Sundqvist SB, Freiburghaus C: Extracorporeal protein A-sepharose and specific affinity chromatography for removal of antibodies. In Hoyer LW (ed): Factor VIII Inhibitors, AR Liss, New York, 1984: 225-241
51. Nilsson IM, Berntorp E, Freiburghaus C: Treatment of patients with Factor VIII and IX inhibitors. Thromb Haemost 1993; 70: 56-59
52. Kasper CK and the Haemophilia Study Group: Effect of prothrombin complex concentrates on Factor VIII inhibitor level. Blood 1979; 54: 1358-1368
53. Lusher JM: Controlled clinical trials with prothrombin complex concentrates. In Hoyer LW (ed): Factor VIII Inhibitors, AR Liss, New York, 1984: 277-290
54. Macik BG, Hohneker J, Roberts HR et al: Use of recombinant activated Factor VII for treatment of a retropharyngeal hemorrhage in a hemophilic patient with a high titer inhibitor. Am J Hematol 1989; 32: 232-234
55. Tengborn L, Kjellman B, Elfstrand PO et al: Recombinant Factor VIIa in an infant with haemophilia A and inhibitors. Acta Paediatr Scand 1992; 81: 566-567
56. Rizza CR, Matthews JM: Effect of frequent Factor VIII replacement on the level of Factor VIII antibodies in haemophiliacs. Br J Haematol 1982; 52: 13-24
57. Mariani G, Solinas S, Pasqualetti D et al: Induction of immunotolerance in hemophilia for high titre inhibitor eradication: a long-term follow-up. Thromb Haemost 1989; 62: 835-839
58. Mannucci PM, Gdovin S, Gringeri A et al: Transmission of hepatitis A to patients with hemophilia by Factor VIII concentrates treated with organic solvent and detergent to inactivate viruses. Ann Intern Med 1994; 120: 1-7
59. Gerritzen A, Schneweis KE, Brackmann HH et al: Acute hepatitis A in haemophiliacs. [letter] Lancet 1992; 340: 1231-1232
60. Normann A, Graff J, Gerritzen A et al: Detection of hepatitis A virus RNA in commercially available Factor VIII preparation. [letter] Lancet 1992; 340: 1232-1233
61. Kazazian HH: The molecular basis of hemophilia A and the present status of carrier and antenatal diagnosis of the disease. Thromb Haemost 1993; 70: 60-62
62. Kogan SC, Doherty M, Gitschier J: An improved method of prenatal diagnosis of genetic diseases by analysis of amplified DNA sequences. Application to hemophilia A. N Engl J Med 1987; 317: 985-990
63. Peake I: Registry of DNA polymorphisms within or close to the human Factor VIII and Factor IX genes -- for the Factor VIII/IX Subcommittee of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Thromb Haemost 1992; 67: 277-280
64. Tuddenham EGD, Cooper DN, Gitschier J et al: Haemophilia A: database of nucleotide substitutions, deletions, insertions and rearrangements of the Factor VIII gene. Nucleic Acids Res 1991; 19: 4821-4833
65. Giannelli F, Green PM, High KA et al: Haemophilia B: database of point mutations and short additions and deletions -- fourth edition 1993. Nucleic Acids Res 1993; 21: 3075-3087
66. Lakich D, Kazazian HH Jr, Antonarakis SE et al: Inversions disrupting the Factor VIII gene are a common cause of severe haemophilia A. Nat Genet 1993; 5: 236-241

[Table of Contents]

---

Disclaimer

Options : Traitement prophylactique et correctif à l'aide d'agents hémostatiques et d'appoint : DDAVP (1-diamine-8-D-arginine-vasopressine [acétate de desmopressine]), agents de coagulation recombinants (facteur VIII humain et facteur VIIa humain) ou agents tirés du plasma et traités par inactivation virale (facteur VIII humain de grande ou de très grande pureté ou concentré de facteur VIII humain contenant du facteur de von Willebrand actif, facteur VIII porcin, facteur IX humain très pur, concentré de complexe de prothrombine humaine, concentré de complexe de prothrombine humaine activée) agents antifibrinolytiques d'appoint, thrombine topique et agent de scellement à la fibrine. Il faut aussi tenir compte de l'induction de la tolérance immunitaire des patients chez lesquels des inhibiteurs font leur apparition.

Résultats : Morbidité et qualité de vie liées à l'hémorragie et au traitement.

Preuves : On a examiné des études cliniques et des rapports pertinents publiés de 1974 à 1994. Les auteurs ont procédé à une recherche dans leurs dossiers de réimpressions, dans MEDLINE, dans des citations publiées dans les articles examinés et dans des références fournies par des collègues. Pour la recherche dans MEDLINE, on a utilisé les termes suivants seuls ou combinés : «hemophilia», «von Willebrand's disease», «Factor VIII», «Factor IX», «von Willebrand factor», «diagnosis», «management», «home care», «comprehensive care», «inhibitor», «AIDS», «hepatitis», «life expectancy», «complications», «practice guidelines», «consensus statement» et «controlled trial». L'examen détaillé n'a porté que sur les articles rédigés en anglais, provenant d'Amérique du Nord et d'Europe, qui portaient sur la maladie humaine et sur un aperçu pré-déterminé. On a tenu compte aussi de la disponibilité au Canada des produits de traitement.

Valeurs : On a accordé une valeur élevée à la réduction au minimum de la morbidité et à la maximisation de l'état fonctionnel et de la qualité de vie.

Avantages, préjudices et coûts : Le traitement précoce ou prophylactique à l'aide d'agents hémostatiques appropriés réduit au minimum la morbidité et l'incapacité fonctionnelle et améliore la qualité de vie. La réduction de la mortalité et de la morbidité, ainsi que des coûts qui en découlent, entraînent des gains économiques. Le patient a une meilleure chance de contribuer à la société en occupant un emploi rémunéré et en s'acquittant de rôles sociaux. Les préjudices possibles comprennent l'infection au VIH, l'hépatite B, l'hépatite C et l'apparition d'anticorps inhibiteurs de concentrés de facteur de coagulation. Le risque de transmission virale a été réduit au minimum grâce à la mise en place de procédures d'inactivation virale de concentrés de facteurs de coagulation tirés du plasma et à l'utilisation de concentrés de facteurs de coagulation recombinants et d'autres agents hémostatiques non tirés du plasma.

Recommandations : La DDAVP est le médicament de choix dans le cas des patients atteints d'hémophilie légère ou de la maladie de von Willebrand des types 1 ou 2 (sauf 2B) dont la réaction à la DDAVP lors de tests antérieurs a été adéquate. Les composants sanguins thérapeutiques de choix comprennent les produits recombinants et les produits tirés du plasma et traités par inactivation virale. Au Canada, les produits recommandés sont le facteur VIII recombinant dans le cas de l'hémophilie A, le facteur IX très pur tiré du plasma dans celui de l'hémophilie B et des concentrés de facteur VIII tirés du plasma contenant du facteur de von Willebrand (p. ex., Haemate P) dans celui de la maladie de von Willebrand. Les posologies varient selon des indications précises. Les agents antifibrinolytiques d'appoint, la thrombine topique et les agents de scellement à la fibrine servent au traitement des saignements buccaux ou dentaires et des saignements localisés à des endroits accessibles. Chez les patients qui ont des anticorps inhibiteurs, le facteur VIII porcin ou humain à forte dose est habituellement efficace lorsque le titre de l'inhibiteur est inférieur à 5 unités Bethesda/mL. Chez les patients qui ne réagissent pas ou dont le titre de l'inhibiteur est plus élevé, des agents d'«évitement» (p. ex., concentré de complexe de prothrombine activée et facteur VIIa recombinant) sont utiles. Le traitement à long terme peut comprendre l'induction de la tolérance immunitaire.

Validation : Ces recommandations ont été examinées et approuvées par l'Association canadienne des directeurs des cliniques d'hémophilie (ACDCH) et le Comité consultatif médical et scientifique de la Société Canadienne d'hémophilie. Il n'existe pas d'énoncé consensuel ni de guide de pratique semblable à des fins de comparaison.

---

Commanditaires :