AHCDC clinical practice guidelines

  • CLINICAL PRACTICE GUIDELINES

    Hemophilia and von Willebrand's disease:
    2. Management
    (Edition 2, Update 2 [1999-07-07])


    Association of Hemophilia Clinic Directors of Canada*
    *Members: Drs. Gershon Growe, Jeffrey Davis, Linda Vickars, and John K.M. Wu, Vancouver, BC; Drs. John Akabutu and Bruce Ritchie, Edmonton, Alta.; Drs. Man-Chiu Poon and John W.Y. Wu, Calgary, Alta.; Drs. Robert Card and Kaiser Ali, Saskatoon, Sask.; Drs. Sara J. Israels, Morel Rubinger, Patricia J. McCusker and Kent Stobart, Winnipeg, Man.; Drs. Victor Blanchette, Jerome Teitel and Bernadette Garvey, Toronto, Ont.; Drs. Irwin Walker and Mohan Pai, Hamilton, Ont.; Drs. Martin Inwood*, and Michael Delorme, London, Ont.; Drs. David P. Lillicrap and Mariana Silva, Kingston, Ont.; Drs. Jeanne Drouin and Koon-Hung Luke, Ottawa, Ont.; Dr. Jordan Herst, Thunder Bay, Ont.; Dr. Kulwant Gill, Sudbury, Ont.; Drs. Georges Rivard, Michèle David, Jean St-Louis, and Mason Bond, Montreal, Que.; Drs. François Jobin* and Christine Demers, Quebec, Que.; Dr. Mariette Lepine-Martin, Sherbrooke, Que.; Drs. Sue Robinson and Dorothy Barnard, Halifax, NS; Dr. Sean Dolan, Saint John, NB; Dr. Sheldon Rubin, Moncton, NB; Dr. Elizabeth Ross, Charlottetown, PEI; and Drs. Lawrence Jardine¶ and Marie-France Scully, St. John's, Nfld.
    *retired; ¶resigned as of this update

    Writing Committee Members: Dr. Man-Chiu Poon, Dr. Sara Israels, and Dr. David Lillicrap
    Reprint requests to: Association of Hemophilia Clinic Directors of Canada (AHCDC),     30 Bond Street (70 Bond LL), Toronto, ON  M5B 1W8
    (Fax: 416 864-5251, email:Annie Kaplan <ahcdc @ smh.toronto.on.ca> 
    WEB address: http://www.ahcdc.ca

    Edition 1: Hemophilia and von Willebrand's disease: 2. Management. Canada
    Med Assoc J 1995;153:147-157

    Table of Contents:

    Abstract

    Objective: To present current strategies for the treatment of hemophilia and von Willebrand's disease.

    Options: Prophylactic and corrective therapy with hemostatic and adjunctive agents: desmopressin (1-desamino-8-d-arginine vasopressin [DDAVP]), recombinant coagulation products (human Factors VIII, IX and VIIa) or virally inactivated human plasma-derived products (high- or very-high-purity human Factor VIII or human Factor VIII concentrate containing von Willebrand factor activity, high-purity human Factor IX, human prothrombin-complex concentrate, human activated prothrombin-complex concentrate), porcine plasma-derived factor VIII, 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 for the 1995 edition <1,2>. For this update, the literature search was extended to March 1998. A search was conducted of AHCDC members' 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 particular 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 fulfillment of social roles. Potential harms include allergic reactions, infection with HIV, hepatitis B, hepatitis C, hepatitis A, hepatitis G, and parvovirus B19, Creutzfeldt-Jakob disease (CJD) as well as the development of inhibitor antibodies to clotting-factors. The risk of viral transmission has been minimized through the development of procedures for viral exclusion and inactivation in plasma-derived clotting-factor concentrates and through the use of recombinant coagulation-factor concentrates and other non-plasma-derived hemostatic agents.

    Recommendations: Desmopressin is the drug of choice for patients with mild hemophilia A and type 1 or 2 (except 2B) von Willebrand's disease whose response to desmopressin in previous testing has been found to be adequate. Therapeutic replacement 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 or recombinant 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 non-responsive patients, or in those whose inhibitor titre is higher, "bypassing" agents (e.g., activated prothrombin-complex concentrate and recombinant Factor VIIa) should be used. Long-term management may include immune-tolerance induction. The effectiveness of current recommendations for individual patients needs to be monitored, with changes made to the recommendations as necessary.

    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 former Canadian Blood Agency which until September 28, 1998 funded the provision of all coagulation-factor concentrates for people with congenital bleeding disorders (this function is now provided by the Canadian Blood Services and Héma-Québec), and were developed and endorsed by the AHCDC and the Medical and Scientific Advisory Committee of the Canadian Hemophilia Society.

    Comprehensive care, including home therapy, is the mainstay of treatment for patients with hemophilia and von Willebrand's disease.<1,3-7> In part 1, we focused on the organizational aspects of patient care.<1> In this article, we will outline the blood products and treatments currently available and recommended for use in Canada.

    The development of management recommendations by the Association of Hemophilia Clinic Directors of Canada (AHCDC) was initially requested by the former Canadian Blood Agency which, until September 1998, provided funding for the purchase of all coagulation-factor concentrates for the management of congenital coagulation disorders. A writing committee consisting of the three principal co-authors was established. We developed an outline of the topics to be considered and reviewed relevant clinical studies and reports published from January 1974 to March 1998. The literature search was up to September 1994 for the first edition published in 1995.<1,2> 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. As with the first edition, <1,2> the updated draft was successively critiqued and approved by the five members of the executive committee of the AHCDC, the Medical and Scientific Advisory Committee of the Canadian Hemophilia Society, and individual AHCDC members. The final document received endorsement from the Canadian Hemophilia Society's Medical and Scientific Advisory Committee on March 23, 1998, and approval from the AHCDC membership on May 1, 1998.

    In the literature, there are a few randomized clinical trials that provide evidence at levels I and II <8> regarding the clinical efficacy of agents for the management of hemophilia and von Willebrand's disease. Pertinent ones will be cited. Because the efficacy of hemostatic agents for hemophilia correlates closely with the clotting-factor levels that they induce, clinical trials are usually preceded by pharmacokinetic studies to determine in-vivo half-life and recovery. All very-high-purity and recombinant Factor VIII concentrates used in the treatment of hemophilia A, and all high-purity and recombinant Factor IX concentrates used in the treatment of hemophilia B, have been evaluated in pharmacokinetic studies performed according to the study design and data analysis guidelines established by the Scientific and Standardization Committee of the International Society for Thrombosis and Haemostasis.<9> 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. Double-blind controlled trials have been used to establish the minimum factor VIII dose to treat hemarthroses in hemophilia A <10>, and to establish the usefulness of e-aminocaproic acid therapy for dental extractions in hemophilias A and B.<11> There were also 3 double-blind controlled trials establishing the efficacy of non-activated and activated prothrombin-complex concentrates in the treatment of muscle and joint bleeds in hemophilia A patients with inhibitors.<12-14> The efficacy of Haemate P, a product recommended for the correction of bleeding in von Willebrand's disease, has been compared with that of a number of other Factor VIII concentrates in randomized crossover studies.<15> 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.<16> The development of inhibitors (alloantibodies that inhibit clotting-factor activity) in patients receiving recombinant Factor VIII concentrates <17,18> has been evaluated prospectively (but without randomization) in studies involving previously untransfused patients.

    The present guidelines also represent the collective experience and expert consensus opinion of the members of the AHCDC. They should not be considered to encompass the management of every patient in every situation; exceptions may be dictated by specific clinical circumstances.

    Management of hemophilia A and B

    In general, therapy for hemophilia is given when a bleeding episode arises (demand treatment) or when bleeding is anticipated or likely (prophylactic treatment). Short-term prophylactic treatment is given to patients before they undergo surgical procedures or engage in activities that carry a high risk of provoking a bleed. It may also be given to break the cycle of frequent bleeding into specific joints (target joints) or during rehabilitation from a large bleed, particularly during physiotherapy. In view of the increasing safety of clotting-factor concentrates, long-term prophylactic therapy in the form of Factor VIII infusion three times a week or Factor IX infusion twice a week to prevent hemarthrosis in severely affected patients is gaining acceptance, especially in the treatment of infants and children. It has been shown that increasing in-vivo clotting-factor levels to more than 1% activity at all times (usually accomplished by giving 25 to 40 U/kg of Factor VIII three times a week or 25 to 40 U/kg of Factor IX twice a week) is sufficient to prevent most spontaneous joint bleeds and preserve joint function.<19-23> Dosing based on individual pharmacokinetics has been investigated to optimize dosage schedules and reduce costs.<20> For adults with severe hemophilia already with established arthropathy, the decision to start a prophylaxis program involves balancing the decreased number of bleeds with the inconvenience of the regular injections required.

    Desmopressin Acetate

    Desmopressin acetate (1-desamino-8-d-arginine vasopressin [DDAVP]), a synthetic analog of the natural antidiuretic hormone, arginine vasopressin, is capable of releasing von Willebrand factor into the circulation from biosynthetic stores, thus increasing its plasma level and that of Factor VIII. The intravenous administration of 0.3 µg/kg (up to 20 #181;g in total) of desmopressin causes a 2- to 10-fold (average 3- to 4-fold) rise in plasma levels of Factor VIII and von Willebrand factor.<24-26> Following desmopressin infusion, clotting-factor levels peak at 30 to 60 minutes and have a half-life similar to that of infused exogenous clotting factors. Desmopressin can also be given subcutaneously at the same dosage.<25,27> In Canada, in addition to the usual formulation at 4 µg/mL desmopressin for intravenous use, a formulation at 15 µg/mL suitable for both intravenous and subcutaneous use is available. To limit the volume of subcutaneous injection, a subcutaneous dose of 15 µg may be used in adults if prior testing shows an adequate response. Intranasal preparations (at 150 µg per spray [usual dose one spray in patients weighing <50 kg or 2 sprays, one to each nostril, in patients weighing >50 kg]) ideal for home care and especially useful for the management of menorrhagia <27,28> can be obtained for individual patients by "drop shipment" ordering arrangements with Ferring. Desmopressin for intravenous or subcutaneous injections currently costs about $10 (Cdn) for a 4 µg/mL vial and $35 for the 15 µg/mL vial. The intranasal preparation costs about $386 each vial containing 25 sprays (150 µg per spray).

    Therapeutic use

    Desmopressin is the drug of choice for the treatment of patients with mild hemophilia A (Factor VIII activity more than 5%) or type 1, type 2A or 2N von Willebrand's disease whose response to desmopressin has been found to be adequate in previous testing.<24,26,29,30> Overall, about 80% of patients with von Willebrand's disease will respond to desmopressin. Patients with moderate to severe hemophilia or type 3 von Willebrand's disease will not have an adequate response. The administration of desmopressin to patients with type 2B <31> or platelet-type (pseudo) von Willebrand's disease <32> may be followed by platelet agglutination and, in most instances, thrombocytopenia. Most hematologists would be reluctant to use desmopressin in these patients, although evidence suggests that desmopressin can be clinically efficacious <29,33,34>. Patients with type 2B and platelet-type von Willebrand's disease can be distinguished by their enhanced platelet aggregation response to low-dose ristocetin (0.5 mg/mL).<31,32> This test can be used to exclude these patients from desmopressin testing and therapy. Desmopressin is not effective in the treatment of hemophilia B.

    The response of Factor VIII and von Willebrand factor to desmopressin falls, on average, to approximately 70% of the original increment without further decrease when repeated daily infusions are administered to patients.<35> Patients with von Willebrand's disease tend to respond better to such repeated infusion than patients with hemophilia, and are less likely to become unresponsive. During major surgery or episodes of prolonged bleeding it may be necessary to alternate desmopressin with supplemental coagulation products. Patients with von Willebrand's disease tend to respond better to such repeated infusion than patients with hemophilia, and are less likely to become unresponsive. During major surgery or episodes of prolonged bleeding it may be necessary to alternate desmopressin with supplemental coagulation products. Desmopressin should not be used in a major or life threatening hemorrhage where factor VIII replacement is required.<36>

    Side effects

    The side effects of desmopressin are minor, consisting of facial flushing, headache, nausea, abdominal cramps, tachycardia and, uncommonly, hypertension or hypotension. Rarely, water intoxication with extreme hyponatremia occurs, particularly in patients receiving hypotonic fluids intravenously, and in neonates, infants and elderly people following closely spaced repeated infusions. For these patients and for those with hypertension or renal dysfunction it is particularly important to monitor blood pressure, the serum sodium level and urine output and to avoid giving hyponatremic fluids. Myocardial infarction and stroke from arterial thrombosis have been reported rarely after desmopressin infusion among elderly patients with atherosclerosis.<37,38> Caution should therefore be exercised in the treatment of elderly people with desmopressin.

    Blood components

    Currently, all plasma-derived clotting-factor concentrates except cryoprecipitate undergo viral inactivation procedures. Prospective studies involving previously untransfused patients indicated that when these products are subjected to current virucidal treatments the risk of HIV and hepatitis C virus transmission is substantially reduced.<16,39,40 > Current virucidal procedures include: (a) pasteurization at 60 degrees C for 10 hours, (b) vapour heating at 60 degrees C for 10 hours at 1160 mbar pressure, (c) dry heating at 80 degrees C for 72 hours, (d) solvent-detergent treatment with tri(n-butyl) phosphate and Tween 80 or Triton X-100 or cholate, (e) solvent/detergent treatment plus heating (e.g. dry heating at 80 degrees C for 72 hours or 100 degrees C for 30 minutes, or pasteurization) or nanofiltration, and (f) sodium thiocyanate plus ultrafiltration. Although viral removal and inactivation procedures are highly effective, they cannot offer absolute protection. Therefore, all patients who are expected to receive blood products should be vaccinated against hepatitis B. None of the viral inactivation procedures is expected to inactivate every virus in the concentrate. For example, non-lipid-enveloped viruses such as parvovirus and hepatitis A virus, as well as unknown viruses and prions, such as the agent that causes Creutzfeldt-Jakob disease (CJD), may not be eliminated, and could be transmitted. We recommend vaccination against hepatitis A for patients who have tested negative for IgG antibodies to hepatitis A virus and who are likely to receive plasma-derived coagulation products. At present, no product can be considered unequivocally free from contaminating viruses. Even recombinant clotting-factors could potentially be contaminated by unknown animal viruses in the cell lines or fetal calf serum in which they are initially grown. Human plasma protein fractions are also required for cell cultures for the production of recombinant factor VIII. Currently licensed recombinant factor VIII products also use plasma-derived human albumin as a stabilizer (although human albumin is not used for the licensed recombinant factor IX concentrate and for the B-domainless recombinant factor VIII concentrate now in clinical trials).

    In Canada, coagulation products for the management of inherited bleeding disorders are licensed by the Bureau of Biologicals and Radiopharmaceuticals (BBR), Health Canada. Blood products for all Canadians except those in the Province of Quebec are funded, purchased and distributed by the Canadian Blood Services (CBS). Blood products in Québec are funded, purchased and distributed by Héma Québec. The AHCDC makes requests with regard to the classes of concentrates to be 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, and available from, the Canadian Blood Services and Héma Québec. To obtain products not licensed by the Bureau of Biologicals and Radiopharmaceutics, approval by the Special Access Program of the Bureau of Biologicals and Radiopharmaceutics, Health Canada is required.

    Table 1. Coagulation-factor concentrates used in Canada for the management of hemophilia *
    Factor concentrate Manufacturer Viral inactivation procedure Purity standard Maximum Specific Activity, IU/mg protein BBR licensed Funded by and available through CBS or Héma Québec »
    Factor VIII
    Hemofil M Baxter Solvent detergent very high 2-3000 ¦ yes yes
    Kogenate Bayer no specific step § Recombinant 2-3000 ¦ yes yes
    Recombinate Baxter no specific step § Recombinant 2-3000 ¦ yes no #
    Haemate P Centeon Pasteurization Intermediate 2.3-5 no yes«
    Porcine VIII (Hyate:C) Speywood no specific step High >140 yes yes
    Factor IX (Prothrombin Complex)
    Prothromplex T Immuno Vapor heat Low-Interm no no
    FEIBA Immuno Vapor heat Low-Interm 0.75-2.5 yes yes
    Factor IX (High Purity)
    Alphanine SD/Virus Filtered Alpha Solvent detergent/ nanofiltration High 246±47 no yes
    Immunine Immuno Vapor heat High 100±50 yes yes
    Mononine Centeon Na thiocyanate/
    ultra filtration    		 High >190 yes no #
    BeneFix Genetics Institute no specific step § Recombinant ~260 yes yes
    Factor VIIa
    Niastase Novo Nordisk no specific step Recombinant no yes «
    * Abbreviations: BBR = Bureau of Biologics and Radiopharmaceuticals; CBS = Canadian Blood Services (the CBS funds, purchases and distributes blood products in Canada with the exception that Héma Québec provides these functions to the Province of Québec), NA = not available.
    »/« : »with the exception of those marked by « (Hemate P, Niastase) which are funded by the CBS/Héma Québec but available directly from the manufacturers.
    ¦ Before human albumin is added as a stabilizer. The specific activity in the final formulation containing added human albumin is much less.
    § Specific viral inactivation procedures are not used, but some of the manufacturing or purification steps have virus reduction or removal capability.
    # May be obtained by special application when adverse reactions to equivalent products occur.
    BBR licensure has been applied for.

    Factor VIII concentrates (hemophilia A)

    The following types of concentrate are available for treatment of hemophilia A:
    • Recombinant Factor VIII (rFVIII) concentrate. The clotting factor is produced in cultured hamster cells in the presence of human plasma protein fractions, purified with the use of procedures which include immunoaffinity chromatography on murine monoclonal antibodies, and formulated with human serum albumin as stabilizer.
    • Very-high-purity plasma-derived Factor VIII concentrate purified by immunoaffinity chromatography and 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 develop. Although inhibitors mostly develop in newly treated patients, within the first 50 exposure-days, two outbreaks of inhibitors in previously multitransfused patients attributed to two specific factor VIII concentrates <41-43> have been observed. In these outbreaks, inhibitors developed presumably as an immune response to neoantigens on factor VIII molecules modified during the manufacturing/virus-inactivation process. Recently, there was also some concern that previously untransfused patients receiving rFVIII may be at higher risk of inhibitor development than those receiving the plasma-derived product. Two clinical trials suggest that the cumulative incidence of inhibitors in previously untransfused severe and moderate hemophilia A patients receiving rFVIII was between 25% and 31.5%.<17,18> Many of these inhibitors are of low titre, and some are evanescent. The prevalence of inhibitors in these two studies at 6.5 and 7 study-years was respectively 16.4% and 16.25%.<17,18> The incidence rate of inhibitor development among patients receiving rFVIII may not be higher than that among patients receiving plasma-derived products, and may represent increased detection of transient inhibitors with more frequent prospective monitoring (every 3 months). 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%.<44,45>

  • Recommendation

    In general, rFVIII concentrate, which carries a substantially reduced risk of human viral transmission, is recommended for the management of hemophilia A. The use of very-high-purity Factor VIII concentrates has been reported to delay the decline of CD4+ cell counts in asymptomatic HIV-infected patients when compared with less pure plasma-derived Factor VIII.<46,47> 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 very-high-purity plasma-derived Factor VIII concentrates purified by immunoaffinity chromatography, and not on rFVIII. 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.<48,49>

    As a general recommendation, patients receiving replacement products for the first time should have post-infusion recovery and survival studies performed, with the dosage adjusted accordingly.

    Factor IX concentrates (hemophilia B)

    The following types of concentrate are available:
    • Recombinant factor IX (rFIX) concentrate. The clotting factor is produced in cultured hamster cells in the absence of human proteins, and formulated without the use of human albumin as a stabilizer.
    • 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 significant amount of other vitamin K-dependent clotting factors.

    Side effects

    The potential for allergic reactions, and for viral transmission has been discussed. In a minority (up to 6%) of patients receiving Factor IX therapy, inhibitors may also develop <50> , and, in rare cases associated with gross factor IX gene deletions or derangements, the inhibitor can result in anaphylactic reactions when factor IX is infused.<51> The development of thrombosis and disseminated intravascular coagulation may be associated with the use of prothrombin complex concentrates #60;52> 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).<53,54> 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, crush injuries, extensive intramuscular bleeding, or hepatocellular dysfunction.

    Recommendation

    The use of high-purity plasma-derived Factor IX, or recombinant factor IX, is recommended. The recovery of recombinant factor IX activity following infusion appears to be lower than that for plasma derived factor IX <55,56>, and is especially so in small children <56 >. As a general recommendation, patients receiving replacement products for the first time should have post-infusion recovery and survival studies performed, with the dosage adjusted accordingly. This applies particularly to recombinant factor IX.

    Adjunctive hemostatic agents

    When used properly, the following types of adjunctive agents can promote hemostasis and reduce the amount of blood product required.
    • 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 including prophylaxis for dental extractions <11,57-59> (Table 2 below). A short course (5 days) of antifibrinolytic therapy (Amicar 50-75 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 and menorrhagia. 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, and for epistaxis.
    • 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. The development of antibodies against thrombin, factor V and fibrinogen resulting in bleeding has been reported in patients exposed during surgery to bovine thrombin (a component of both topical thrombin and fibrin sealant).<60-63>

    Treatment of bleeding episodes

    Desmopressin should be used to treat mild bleeding episodes and in preparation for minor surgical procedures among patients with mild hemophilia A (Factor VIII clotting activity more than 5% or 0.05 U/mL - 1 U/mL or 100% activity is the clotting-factor activity present in 1 mL of average normal plasma) who are known through previous testing to have an adequate response. The approach to treatment with clotting-factor concentrates for hemophilia patients is outlined in Table 2, which also indicates the in-vivo levels of clotting-factor activity that should be achieved for various indications. The dosage required to raise the clotting-factor level to a given value depends on (a) the patient's plasma volume (roughly 5% of body weight in kg or 50 mL per kg of body weight), (b) the level to which the clotting factor is to be raised and (c) the in-vivo recovery of the clotting factor in the circulation after infusion (roughly 100% for Factor VIII and 50% for Factor IX). The derived formula is:

    dose (units) = plasma volume (body weight in kg x 50) x desired increment (U/mL) x [100 Ÿ in-vivo clotting factor recovery in %]).

    Thus, to raise the Factor VIII level from 10% activity (0.1 U/mL) to 100% activity (1 U/mL), a 70-kg man whose plasma volume is roughly 3500 mL will need 3150 units (3500 x [1.0 - 0.1]) of Factor VIII. A similar patient with hemophilia B will need 6300 units (3500 x [1.0 - 0.1] x 2) of Factor IX.

    For practical purposes the clotting-factor dose is based on the knowledge that 1 unit of Factor VIII per kg of body weight will raise the in-vivo activity by 2% (0.02 U/mL) and that 1 unit of Factor IX per kg of body weight will raise the in-vivo activity by 1% (0.01 U/mL). Thus, for these two patients, the Factor VIII dosage will be 45 U/kg ([100 - 10] Ÿ 2) and Factor IX dosage 90 U/kg (100 - 10). Some concentrate preparations, such as recombinant factor IX, have a lower in-vivo clotting-factor recovery.<55,56> The dosage must then be adjusted accordingly. Treating physicians must study the product inserts to be familiar with the pharmacokinetic and recovery data characteristic for the products being used, and make dosage adjustment where appropriate.

    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. In the management of musculoskeletal bleeding, such conservative measures as rest, icing, compression and elevation (RICE) should be appropriately used. Follow-up assessments with hemophilia clinic team members including the physiotherapist are also important to ensure that maximum function is restored.

    Delivery of infant with known or suspected hemophilia

    The delivery should be non-traumatic. Vaginal delivery is acceptable but forceps and vacuum extraction must be avoided. <68,69> Fetal scalp sampling and internal fetal scalp electrodes should also be avoided because of the risk of bleeding in the infant.<69> In carriers with very low levels of factor VIII or IX, the possible need for factor replacement for caesarian section should be addressed in the prenatal period.

    Table 2. Management of bleeding episodes in patients with hemophilia A and B using clotting-factor replacement therapy
    Recommended dosage of replacement factor (and desired level of clotting-factor activity ¹ to be achieved)
    Indication factor VIII ²
    for Hemophilia A    		 factor IX ²
    for Hemophilia B
    Mild hemorrhage
    • Early joint or muscle bleed
    • Severe epistaxis
    • Persistent hematuria
    • Gingival or dental bleed unresponsive to e-aminocaproic acid or tranexamic acid
    		 10-15 U/kg (0.2-0.3 U/mL
    or 20-30% activity)    		 20-30 U/kg (0.2-0.3 U/mL
    or 20-30% activity)
    Major hemorrhage
    • Advanced joint or muscle bleed
    • Hematoma of neck, tongue or pharynx
    • Prophylaxis following severe physical trauma without bleeding
    		 20-25 U/kg (0.4-0.5 U/mL
    or 40-50% activity)    		 40-50 U/kg (0.4-0.5 U/mL
    or 40-50% activity)
    Life-threatening hemorrhage ³
    • Intracranial bleed
    • Surgery (except dental)
    • Bleeding from major trauma
    • Gastrointestinal bleeding
      35-50 U/kg (0.7-1.0 U/mL or 70-100% activity)
    		70-100 U/kg § (0.7-1.0 U/mL or 70-100% activity)
    Dental extraction 20-25 U/kg (0.4-0.5 U/mL
    or 40-50%activity)    		 40-50 U/kg (0.2-0.5 U/mL
    or 40-50% activity)
    ¹ 1 U/mL (100% activity) is the clotting-factor activity present in 1 mL of average normal plasma.

    ² clotting factor recovery and half-life assumed as follows. Factor VIII: 1U/kg produces a rise in plasma titer by approximately 0.02 U/mL (2% activity); half-life is 8-12 hr. Factor IX: 1U/kg produces a rise in plasma titer by approximately 0.01 U/mL (1% activity); half-life is 18-24 hr. Some preparations may give a lower recovery, and the dosage must be adjusted accordingly.

    ³ For life-threatening hemorrhage, maintenance treatment with half the initial dose (every 8-12 h for factor VIII, and every 12-24 hr for factor IX) for 5 d to several weeks may be required. Alternatively, recombinant or very-high-purity factor VIII and high purity factor IX can be given by continuous infusion (2 U/kg per hr for factor VIII, 4 U/kg per hr for factor IX, with subsequent dosages adjusted according to the plasma clotting-factor levels) following the initial bolus. <65-68>

    § If prothrombin-complex concentrate is used, 50-60 U/kg (50%-60% activity) at intervals of 12-h or longer should be given.

    For dental extraction, e-amino caproic acid (amicar) 50-75 mg/kg (up to 4 g) every 6 h or tranexamic acid (Cyklokapron), 25 mg/kg every 6-8 h for 5-10 d. should be given in addition to the clotting factor. <12,58-60> For patients with hemophilia B receiving prothrombin-complex concentrates, the systemic use of antifibrinolytic agents may potentiate the thrombogenic effects of prothrombin complex concentrates. Amicar or Cyklokapron mouthwash (e.g. 10 mL of 5% Cyklokapron rinse four times daily for 7-10 d) can also be used for oral or dental bleeding. <58-60> More recent studies suggest that dental extraction can be safely performed with the plasma clotting factor level as low as 10% if both oral and local antifibrinolytic agents are also given for 7 to 10 d. <59>

    Management of von Willebrand's disease

    The fact that approximately 80% of people with von Willebrand's disease respond favourably to desmopressin <24,26> makes this the therapeutic agent of choice for most prophylactic indications and bleeding episodes. In addition, the adjunctive use of tranexamic acid or e -aminocaproic acid and topical thrombin will, in many instances, obviate the need for blood-component infusion.

    For women with von Willebrand's disease, gynecological bleeding can be an additional problem. Physicians should be aware that menorrhagia may be related to an underlying bleeding disorder in addition to gynecological causes. Useful agents in management include desmopressin, antifibrinolytics and oral contraceptives, alone or in combination.

    Blood components

    Cryoprecipitate, the blood component traditionally used in the management of von Willebrand's disease, cannot as yet be virally inactivated and therefore should no longer be used for the treatment of bleeding unless other measures have clearly failed. This problem prompted a randomized crossover study to assess the efficacy of virally inactivated Factor VIII concentrates.<15> The results of this trial indicate that variable success can be expected with Factor VIII concentrates; the most consistent responses, especially with regard to the correction of bleeding time, have so far been documented with Haemate P, manufactured by Centeon as a pasteurized concentrate with an intermediate level of purity.<15,701,71> Trials are underway to assess the efficacy of other factor VIII preparations such as Immunate and Alphanate in von Willebrand's disease. Data are limited at present. The dosage for Factor VIII concentrate is difficult to determine from baseline laboratory results for patients with types 1 and 2 von Willebrand's disease. Following the recommended guidelines for the management of hemophilia A (Table 2) is a reasonable approach.<71> For most indications, the usual dose is 20-40 U/kg every 12-24 hours.

    In rare instances, the use of Factor VIII concentrate fails to stop a bleeding episode. In such cases the use of cryoprecipitate, potentially supplemented by platelet concentrates, should be considered.<72>

    Complications of treatment

    Inhibitor development

    The most challenging complication that can occur as a result of hemostatic therapy is the development of a neutralizing alloantibody or inhibitor to the infused clotting factor. As noted earlier, this occurs in approximately 25% of patients with hemophilia A receiving Factor VIII concentrate <17,18,44,45> and in a very small number (approximately 6%) of patients with hemophilia B.<50> Inhibitors may develop not only in newly treated patients, but also in previously multitransfused patients in response to specific products.<41-43> This underlines the importance of regular monitoring for inhibitors in all treated patients. All patients must have inhibitor assays done shortly before surgery. The management of bleeding in these patients is determined in large part by the in-vitro potency of the inhibitor, a parameter conventionally expressed in Bethesda units, and the severity of bleeding.<73 >

    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.<74> 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.<75,76> In either case, it must be remembered that most patients will subsequently have a marked increase in the titre of their neutralizing antibodies. At the time of this revision, porcine factor VIII was not readily available because of a world wide shortage. Alternatives include prothrombin-complex concentrates and activated prothrombin-complex concentrates (e.g. FEIBA) in doses of 100 U/kg at 12-hour intervals (no more than three to four doses, to minimize the risk of thrombosis).<77,78>

    Patients with an initial inhibitor titre greater than 5 to 10 Bethesda units usually cannot be treated with human clotting factors. Factor VIII ªbypassingº concentrates can be used as first-line agents in the treatment of most bleeding episodes in these patients. Prothrombin-complex concentrates and activated prothrombin-complex concentrates (e.g. FEIBA) can be used.<77,78> Recombinant human Factor VIIa is a new "bypassing" agent effective in these patients.<79,80> High dose porcine factor VIII may also be effective. High doses of human or porcine Factor VIII in conjunction with an antibody-removal protocol, such as the use of extracorporeal immunoadsorption with a staphylococcal protein A column or plasma exchange may be useful in life-threatening bleeding.<81,82>

    In the long-term management of patients with inhibitors, 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.<83-85> Non-responsive patients will require continued management with bypassing concentrates.

    Infectious disease transmission

    With the introduction of recombinant factor concentrates and the development of effective virucidal protocols for plasma-derived concentrates, concern about the potential for human viral disease transmission has lessened substantially. Nevertheless, the catastrophic effects of previously unidentified viruses in these products, the recent reports of hepatitis A transmission through Factor VIII concentrates, <86-88> the inability to inactivate parvovirus by current virus inactivation methods, and the recent large scale recalls relating to the risk of Creutzfeldt-Jakob disease (albeit theoretical) serve to remind us that we must not be complacent about the risk of transmission of infectious agents.

    Additional aspects of management

    Genetic counselling is an essential component of all comprehensive care programs. The past decade has seen a dramatic improvement in our ability to detect carrier states and perform prenatal testing for hemophilia. The introduction of molecular genetic testing has made it possible to provide carrier-state and prenatal diagnostic results with probabilities of greater than 99% to most families with hemophilia A or B. This testing has used linked polymorphism analysis when there is a documented family history of hemophilia.<89-91> More recently, new techniques for the direct detection of the disease-causing mutations in hemophilia A and B have enhanced the effectiveness of genetic testing.<92-94> Genetic testing is not yet available for the most prevalent form of vWD (type 1), but in light of the mild clinical manifestations of von Willebrand's disease, genetic testing is not appropriate except for relatives of patients with the rare type 3 form.

    Validation

    These updated recommendations were approved by all members of the AHCDC on May 1, 1998. They were also reviewed by the Medical and Scientific Advisory Committee of the Canadian Hemophilia Society. This committee, whose members include representatives of hemophilia clinic nurse coordinators, physiotherapists, social workers, dentists and physicians, met on March 23, 1998 and endorsed the recommendations. No similar consensus statements or practice guidelines are available for comparison.

    Priorities for future research

    Research efforts should continue to clarify whether inhibitors develop more commonly in patients treated with rFVIII than in those treated with plasma-derived Factor VIII <17,18,44,45>. 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, <83,84> 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 critical. Research should aim at identifying the factors which predispose some patients to develop inhibitors. 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.<19-23> Clinical studies are now underway in Canada to find the proper dose, and to confirm the efficacy and cost-benefit ratio of this mode of management. Studies are also needed to assess the safety, efficacy and cost-benefit ratio 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 are needed, and research into methods for total elimination of viral contamination is a priority. Such products could include recombinant or plasma-derived concentrates. Until methods for total viral removal/inactivation are available, alternative methods of cell culture and stabilization of recombinant clotting-factor concentrates should be sought to avoid the need for 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. Successful gene therapy would eliminate the need for replacement therapy even though the patient would not necessarily be "cured." Recent studies utilizing recombinant adenovirus and adeno-associated viruses have shown encouraging long-term expression of factor VIII and factor IX transgenes in small laboratory animals.<95-97> However, considerable research is still required before the goal of a cure for hemophilia 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 blood borne diseases. Protective vaccines against HIV and hepatitis C virus should 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.

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