AHCDC clinical practice guidelines

  • CLINICAL PRACTICE GUIDELINES

    Hemophilia and von Willebrand's disease:
    1. Diagnosis, comprehensive care and assessment


    (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: 1 Diagnosis, comprehensive care and assesment. Canad Med Assoc J 1995;153:19-25

    Table of Contents:

    Abstract

    Objective: To present current strategies for the assessment and comprehensive care of patients with hemophilia and von Willebrand's disease.

    Options: Hospital care, home care, single-provider care and multidisciplinary care.

    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 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: Optimal use of treatment procedures and home care offers patients the advantages of minimized disability, improved survival and financial benefit. It is also cost effective. Potential harms include allergic reactions, infection with HIV, hepatitis B, hepatitis C, hepatitis A, hepatitis G, parvovirus B19, and 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: Hemophilia and severe von Willebrand's disease are rare life threatening bleeding disorders with potentially serious complications of the disease and of treatment. These patients should be followed in comprehensive care centres that offer expertise in the diagnosis, assessment and management of bleeding and related complications, and that can meet the educational and counselling needs of patients, family members and health care providers. Eligible patients should be enrolled in a home self-infusion program and be required to maintain records of blood product use. Patients with hemophilia and von Willebrand's disease should wear or carry information identifying the nature of their bleeding disorder and emergency treatment recommendations. They should be vaccinated against hepatitis B and hepatitis A, and attend comprehensive care centres for routine follow-up examinations. Laboratory testing should be carried out as required, and dental and surgical care should be undertaken in consultation with a hematologist. The comprehensive care centres must work closely with family physicians and other health care providers.

    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.

    Hemophilia and von Willebrand's disease are the most common congenital bleeding disorders. The optimal management of patients with these disorders, especially those with severe disease, requires more than the treatment and prevention of acute bleeding. Patients who have repeated episodes of bleeding will need long-term management of joint and muscle damage and other sequelae as well as attention to education, employment and psychosocial needs. An additional concern is that blood products used in the past in the treatment of bleeding disorders have been associated with devastating viral complications such as hepatitis and AIDS. The aim of management should be to prevent disease and treatment-associated morbidity and mortality, and to optimize quality of life. These goals can usually be met through the provision of comprehensive care, including home therapy, with the effective and safer treatments that are now available. Plasma-derived concentrates are now of high purity and are subjected to effective viral attenuation procedures. Recombinant Factors VIII and IX, which are currently thought to provide the greatest degree of safety from viral transmission, are now available. Modern management of these diseases is expensive, but it is cost effective and of considerable benefit when long term outcomes are examined.<3-6>

    The development of diagnosis, assessment and treatment recommendations by the Association of Hemophilia Clinic Directors of Canada (AHCDC), was initially requested by the former Canadian Blood Agency (CBA) which, until September 28, 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 trial that provide evidence at levels I and II as stipulated by Sackett. <7> Pertinent ones will be reviewed in the second article, which outlines the management of hemophilia and von Willebrand's disease. 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.

    In this article, we focus on the diagnosis, comprehensive care and assessment of hemophilia and von Willebrand's disease. In a second article, we will outline the blood products and treatments currently available and recommended for use in Canada.

    Diagnosis

    Hemophilia

    "Hemophilia" refers to X-linked bleeding disorders in which there is a deficiency (activity level of 35% or less) of either Factor VIII (hemophilia A, classic hemophilia) or Factor IX (hemophilia B, Christmas disease). The incidence of hemophilia is about 1 in 5000 males; of those affected, roughly 80% to 85% have hemophilia A and the remainder hemophilia B.<8>

    Coagulation tests for hemophilia show a prolonged activated partial thromboplastin time (APTT), a normal one-stage prothrombin time (PT) and a normal bleeding time. In hemophilia A, Factor VIII activity is decreased or absent, whereas the level of von Willebrand factor (antigen and ristocetin cofactor activity) is normal. In hemophilia B, Factor IX activity is decreased or absent. In patients with mild hemophilia, the APTT may be normal depending on the reagent used, and the appropriate factor assays must be used to confirm/exclude the diagnosis.

    In both hemophilia A and B, there is usually a strong correlation between the level of clotting factor activity and the clinical severity of the disease (Table 1).<9>

    Diagnosis of hemophilia in the male infants of known or suspected carriers should be confirmed soon after birth, particularly if a surgical procedure such as circumcision is contemplated.

    Table 1. Correlation of clotting factor activity and severity of hemophilia <9>
    Clotting factor activity level * (%) Clinical Severity of hemophilia
    <1 Severe: spontaneous musculoskeletal and internal bleeding
    1-5 Moderate: occasional spontaneous musculoskeletal bleeding
    5-35 Mild: delayed-onset bleeding after trauma, surgery, and dental extraction

    *1 U/mL (100% activity) is the clotting-factor activity present in 1 mL of average normal plasma.

    vonWillebrand's disease

    Von Willebrand's disease is typically mild and it generally exhibits an autosomal dominant pattern of inheritance. Several reports have documented the prevalence of von Willebrand's disease in the general population as approximately 1%, <10,11> 11> which makes this the most common inherited coagulopathy.

    The clinical manifestations and laboratory diagnosis of the three main subtypes of von Willebrand's disease are indicated in Table 2. <12> Approximately 85% of confirmed cases are of type 1; most of the remainder are type 2 variants (i.e., type 2A, 2B, 2M, 2N).<13> > The severe type 3 phenotype has a prevalence of one in a million. Patients with mild hemophilia A and type 2N von Willebrand's disease both have low factor VIII activity and normal von Willebrand factor antigen and ristocetin cofactor activity levels.<13,14> These two disorders may be distinguished by their difference in inheritance pattern (X-linked for hemophilia and autosomal for von Willebrand's disease), and by decreased binding of factor VIII to patients' plasma von Willebrand factor in patients with type 2N von Willebrand's disease, but normal binding in patients with mild hemophilia A.<14>

    The laboratory diagnosis of von Willebrand's disease can be problematic. If a patient's clinical history strongly suggests this disorder, testing for abnormalities of the von Willebrand factor/Factor VIII complex should be performed on at least two separate occasions if the initial study results are inconclusive.<15>

    Table 2. Major subtypes of
    von Willebrand's disease <12>
    Subtype Clinical manifestations Laboratory test results *
    Type 1:
    partial quantitative
    deficiency    		 Mild-moderate
    mucocutaneous
    bleeding    		 PTT sometimes prolonged; low factor VIII,
    vWF:Ag and vWF:RiCo levels
    Type 2:
    qualitative defects    		 Mild-moderate
    mucocutaneous
    bleeding    		 ·Type 2A and 2B are similar to Type 1, plus
    evidence of abnormal plasma vWF multimers **

    ·Type 2M normal plasma vWF multimers **,
    but significantly reduced vWF-mediated platelet
    function as measured by the vWF:RiCo test.

    ·Type 2N vWF has abnormal binding to factor VIII.
    Homozygous Type 2N disease can be confused
    with mild hemophilia A with significantly reduced
    factor VIII level, but normal vWF:Ag and vWF:RiCo
    levels and normal vWF multimers **
    Type 3:
    virtually complete
    quantitative
    deficiency    		 Severe mucocutaneous
    and musculoskeletal
    bleeding    		 PTT very prolonged; very low or undetectable
    vWF:Ag and vWF:RiCo levels; very low
    factor VIII level

    * PTT = activated partial thromboplastin time, vWF:Ag = von Willebrand factor antigen (measured
    by an immunoassay), vWF:RiCo = ristocetin cofactor activity (functional assay for von Willebrand
    factor).

     

    ** Multimers are a series of repeating subunits of the vWF protein resolved on gel electrophoresis.
    In normal plasma these multimers range in size from a molecular weight of approximately 600 000
    (2 subunits) to over 20 000 000 in increments of approximately 600 000.

    Bleeding Disorders in Women

    As the inheritance of von Willebrand's disease is autosomal, equal numbers of women and men are affected. However, the clinical manifestations of this typically mild bleeding disorder are often much more prominent in women, in whom menorrhagia is a frequent manifestation. Furthermore, women who are hemophilia carriers may have sufficiently low factor VIII or factor IX levels to have excessive bleeding following trauma or surgery. Rarely, carriers with extreme Lyonization may have factor levels as low as the more typical male patient with hemophilia and similarly severe clinical bleeding problems.

    Comprehensive care

    The aim of comprehensive care is to help patients and their families make decisions affecting their physical, psychologic and social health in the light of the most recent medical knowledge. Given the rarity and complexity of inherited bleeding disorders, it is advisable for all patients to be treated, or at least followed regularly, at a comprehensive care centre that offers expertise in dealing with the wide range of medical problems that these patients may encounter. Smaller centres with few patients cannot develop or maintain this multidisciplinary expertise but can provide routine care in consultation with a comprehensive care centre.<16> The composition of the comprehensive care team reflects the fact that management involves more than the treatment of acute bleeding episodes.

    The comprehensive care team

    The "primary" team should consist of a nurse coordinator, a medical director (preferably a hematologist with an interest and expertise in hemostasis), a physiotherapist and a social worker. <16> This group reviews, regularly, all patients receiving care at the centre and addresses their medical, familial and social concerns. The nurse coordinator, who coordinates the provision of education and care for patients and their families, is usually the first contact for patients with an acute problem or requiring follow-up.

    Arrangements for the involvement of other specialists are made by the primary team as the need arises.<16> The "referral" support team should include specialists in rheumatology, orthopedic surgery, dentistry, clinical genetics, infectious disease, hepatology and gynecology. Specialists in physiatry, psychology and psychiatry should also be available. Care of patients with HIV infection should be supervised by specialized multidisciplinary clinics. Patients with HCV and HBV infections should be managed in conjunction with specialists in liver disease.

    Specialized services, which must be available, are a blood bank with specific expertise in coagulation factor concentrates, and a laboratory capable of performing a full range of tests of hemostasis.

    Involvement of the family

    These lifelong, life-threatening and costly diseases have a significant impact on many aspects of family life. Parents, spouses and other family members are active participants in the patient's care. The diagnosis can produce tremendous anxiety in parents about their children's future and their risks of everyday living. Adolescents who feel their need for independence is in conflict with the need to conform to a care regimen may suffer both anxiety and rebellion. Patients and their families are also anxious about the risks of viral transmission through the blood products they need. Some of this anxiety can be alleviated through proper education of the patient and family about the disease and its management.

    Given the hereditary nature of these bleeding disorders, family members will be concerned about their carrier status and the risk to future children. These concerns can be addressed through genetic counselling for the extended family and, when appropriate, through carrier testing and antenatal diagnosis.<17> The emotional and psychologic stress of living with a severe bleeding disorder or of caring for someone with such a disorder may necessitate psychologic counselling. As a result of HIV, hepatitis C and hepatitis B infections, counselling needs for families have increased drastically.<18> Practice of universal blood precautions reduces the risk of viral transmission to family members. Sexual partners of those infected with HIV and HBV through contaminated blood products are at risk of acquiring HIV or HBV. Present knowledge suggests the concern is less for sexual partners of those infected with HCV.<19>. As for all patients with HIV and HBV infections and their partners, education about safer sexual and other practices to reduce infection transmission must be provided.<20> Susceptible family members of those infected with hepatitis B must be protected by hepatitis B vaccination.

    Assessment

    At diagnosis

    The most important step following diagnosis of an inherited bleeding disorder is the initiation of an education program for the patient and family. Areas that should be addressed include the specific hemostatic defect, signs and symptoms of early hemorrhage, therapy, safety precautions, and appropriate physical activities including advice on "safe" sports, and healthy life style and functioning including not to overprotect the child. Hemophilic patients should be encouraged to exercise regularly to maintain joint flexibility and muscle strength. In addition, the following items require attention:

    • Registration at a comprehensive care centre. Family members should be given an opportunity to meet the team.
    • The patient should be provided with documentation to be carried or worn, identifying the bleeding disorder and indicating appropriate emergency therapy.
    • Patients and parents should be provided with a written record of the specific treatment recommendations.
    • Education about hepatitis in general and initiation of hepatitis B and hepatitis A vaccination series. Given that, at present, blood-derived factor replacement therapy may still transmit hepatitis B <21> and hepatitis A <22,23> viruses, all seronegative patients must be vaccinated, whenever possible, before receiving such products. The standard hepatitis B vaccination schedule consists of three injections: the first two are given 1 month apart, followed by a booster dose at 6 months, while hepatitis A vaccine is given twice, 6 months apart.<24-27> Combination hepatitis B and A vaccines are also available. In hemophilia, Mannucci and associates <24,28> have recommended a more rapid hepatitis B immunization schedule in which the three injections are given at monthly intervals to speed seroconversion. Subcutaneous or intradermal injection in the deltoid region is preferable to intramuscular injection, <29> although intramuscular injection with a small-gauge needle (25 or 26 gauge) followed by the application of adequate local pressure is safe. Intramuscular injections are still preferred for family members not affected with hemophilia.
    • If the patient is to receive most care outside of the comprehensive care centre, the local physician and hospital must be well informed, so that appropriate care will be provided both routinely and in the case of an emergency. The local physician as well as the family must know how to contact the comprehensive care team when questions and emergencies arise.
    • Individuals with hemophilia need to be seen by their family physicians so that incidental health problems can be diagnosed and treated.
    • School staff and fellow students should receive education.

    Home therapy

    Optimal therapy provides the patient with immediate access to treatment for correction of the hemostatic defect at the first sign of hemorrhage. For most patients with severe or moderate hemophilia, this means a home therapy program.<30> Education of patients, their families, school personnel and child care providers, as well as careful supervision by the comprehensive care team have decreased health care costs for hemophilia <6> and improved quality of life as measured by time lost from school or work and the number of days spent in hospital.<3-5> Home therapy can be achieved in most motivated families for children age 4 years or older, and for younger children if indwelling venous access devices are used.

    Preparation for home therapy includes teaching the patient and family when, why, and how to treat bleeding episodes, including the practical aspects of replacement therapy preparation and dosage calculation, sterile technique and venipuncture, and universal blood precaution techniques including proper storage and disposal of used needles and syringes. In most centers, the teaching is carried out by the nurse coordinator.

    The comprehensive care team must assess the family's ability to undertake home therapy. The team should provide ongoing supervision, encouragement and support, and deal with problems or questions as they arise. Reassessment of patient understanding, technique and compliance should be carried out at regular intervals.<31>

    Patients must keep a log of bleeding episodes, recording the dates and sites of bleeding, the dosage and lot numbers of blood products used, and any side effects experienced. These logs must be made available to the comprehensive centres on a regular basis.

    Patients are instructed to contact the comprehensive care centre to report bleeds that do not respond to the standard treatment regimen, allergic reactions, and trauma to critical areas such as the head and neck.

    In the case of young children, the responsibility for home therapy is assumed by the parents or guardians. By their early teens, however, patients should be encouraged to start taking responsibility for their own treatment and taught how to prepare and administer their own replacement therapy.

    Family members who help with home care therapy should be vaccinated against hepatitis B and A if they are seronegative (anti-HBs and IgG anti-HAV negative respectively).

    Routine follow-up

    • Comprehensive re-evaluation of severely and moderately affected patients should be carried out at least once a year for adults and twice a year for children, and more frequently for patients with significant medical problems or frequent bleeding episodes.<16> During each evaluation the patient should be reviewed by the nurse coordinator, the medical director/hematologist, the orthopedic surgeon/rheumatologist/physiatrist or physiotherapist, the social worker and other members of the comprehensive care team when appropriate. The evaluation should include the following:

  • A general examination, with particular attention to the stigmata of liver disease and of viral disease, as well as to weight, growth and development in children.
  • A detailed musculoskeletal examination, with attention to chronic arthropathy and target joints (i.e., joints in which repeated episodes of hemorrhage and resulting inflammation lead to a self-perpetuating cycle of bleeding and progressive damage). Assessment by the orthopedic surgeon/rheumatologist/physiatrist or physiotherapist, should address the management of current problems and provide advice regarding arthritis management including the use of analgesics, appropriate physical activities, regular exercise programs and "safe" sports.<32,33>
  • A review of treatment logs for patients on home therapy to reinforce the recognition and appropriate management of bleeds, to detect manifestations of target joints early so that prophylactic treatment can be introduced, and to determine the need for changes in recommendations. Problems with home management should be discussed and basic management techniques reviewed.
  • · Laboratory assessment, including (a) a complete blood count and platelet count, (b) liver enzyme and function tests (ALT, AST, alkaline phosphatase, albumin and bilirubin), (c) screening for clotting factor inhibitors (allo-antibodies which can develop against the patient's deficient clotting factor following replacement therapy and capable of inhibiting the clotting factor function), (d) viral serologic testing (e.g., for HIV antibody, hepatitis C virus antibody and hepatitis A virus IgG antibody [if the results were previously negative and vaccine was not administered]; hepatitis B surface antibody titre [if this result was previously positive due to vaccination] and hepatitis B surface antigen testing [if the result was previously negative and the patient is not yet vaccinated]) <21,34-36> and (e) radiographs of target joints or those affected by chronic arthropathy <37> if this is expected to modify the treatment approach. (f) Laboratory evaluation relevant to progression of HIV infection (e.g. CD4 cell count, HIV viral load, etc) in affected patients, unless these tests are performed through an HIV clinic.
  • Routine dental evaluation. This is important in promoting preventive dental treatment and encouraging good oral hygiene to avoid dental disease.<38> Attention to good oral health is particularly important for patients before and after total joint arthroplasty to prevent bacteremia and infection of the artificial joint.<39> Hemostasis must be assured during invasive dental procedures. If restorative treatment is required, it should be performed by a dentist familiar with techniques for minimizing hemorrhage. The need for factor replacement will depend on the specific treatment and should be determined in consultation with the medical director/hematologist. The need for antibiotic prophylaxis for invasive dental procedures in hemophilia patients with total joint replacement will depend on whether the patient is immunocompromised or immunosuppressed. <39>
  • Review and counseling of general health, healthy life-style and functioning, psychosocial issues, schooling and/or employment.

     

During a bleeding episode

A quick assessment should be made to identify the site(s) of bleeding. It should be recognized that early treatment is essential for a good response, and in many circumstances, it may be most beneficial to initiate therapy during or even before the assessment. This is particularly important when the bleeding occurs at a site such as the head, neck, chest or abdomen and is therefore potentially life threatening. If a bleeding episode does not appear to be resolving despite reasonable factor replacement therapy, assessment should include measurement of clotting factor activity and screening for an inhibitor if the clotting factor activity is unexpectedly low.

Preoperative assessment

Major surgical procedures require consultation between the surgeon and the hematologist, and should be undertaken only in centres where specific facilities including a coagulation laboratory, blood bank, and expertise in hemophilia care exists. Major surgery can be performed safely in patients without inhibitors when adequate coverage by coagulation factor replacement therapy is provided. The implementation of the following recommendations during planning for major surgery may avert complications.

  • A screen for factor inhibitors must be performed shortly before the surgical date.
  • The patient should avoid using antiplatelet medication before and after surgery.
  • Surgery should be scheduled for early in the week and early in the day to help ensure the availability of laboratory services and consultants.
  • Adequate amounts of the coagulation factor replacement product to be used before and after surgery must be immediately available in the hospital blood bank or pharmacy.
  • Availability of laboratory facilities for frequent and rapid coagulation factor assays must be ensured.

In the case of patients with significant levels of coagulation factor inhibitors, preparation for major surgery is more complicated and good hemostasis more difficult to attain. Decisions regarding surgery for these patients must be made after a careful weighing of the risks; surgery should be undertaken only after consultation with a hematologist experienced in managing patients with inhibitors.<40> Surgery for such patients should only be performed in a centre experienced in the surgical care of inhibitor patients.

Following major surgery, factor levels must be continuously maintained at hemostatic levels throughout the period of high risk.

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

Since the superiority of comprehensive care and home therapy programs was first established some 15 to 20 years ago<3-6>, significant advances have been made in all treatment modalities for patients with hemophilia and von Willebrand's disease. These advances include the development of safer hemostatic products. The cost-effectiveness of current methods of patient assessment, comprehensive care, home care and treatment modalities will, however, need further evaluation in patient outcome research. Such research should measure how well current management processes reduces morbidity, mortality and the need for interventions, and how well they increase the productivity and quality of life. Cost factors that should be considered include direct medical costs as well as indirect medical, economic and socioeconomic costs of the management of complications associated with the disease and with interventions. Longitudinal population analyses can be used to monitor the outcome of comprehensive centre care and home care since randomized studies are no longer possible or ethical.

References

  1. Association of Hemophilia Clinic Directors of Canada. Hemophilia and von Willebrand's disease: 1. Diagnosis, comprehensive care and assessment. Canad Med Assoc J 1995;153:19-25
  2. Association of Hemophilia Clinic Directors of Canada. Hemophilia and von Willebrand's disease: 2. Management. Canad Med Assoc J 1995;153:147-157
  3. 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
  4. Ingram GIC, Dykes SR, Creese AL et al: Home treatment in haemophilia: clinical, social and economic advantages. Clin Lab Haematol 1979; 1: 13-27
  5. Smith PS, Keyes NC, Forman EN: Socioeconomic evaluation of a state-funded comprehensive hemophilia-care program. N Engl J Med 1982; 306: 575-579
  6. 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
  7. Sackett DL: Rules of evidence and clinical recommendations on the use of antithrombotic agents. Chest 1986; 89 (suppl): 2S-3S
  8. Brettler DB, Levine PH: Clinical manifestations and therapy of inherited coagulation factor deficiencies. In Colman RW, Hirsh J, Marder VJ et al (eds): Hemostasis and Thrombosis: Basic Principles and Clinical Practice, 3rd ed, JB Lippincott, Philadelphia, 1994: 169-183
  9. Hoyer LW: Hemophilia A. N Engl J Med 1994; 330: 38-47
  10. Rodeghiero F, Castaman G, Dini E: Epidemiological investigation of the prevalence of von Willebrand's disease. Blood 1987; 69: 454-459
  11. Werner EJ, Broxson EH, Tucker EL et al: Prevalence of von Willebrand disease in children: a multiethnic study. J Pediatr 1993; 123: 893-898
  12. Sadler JE for the Subcommittee on von Willebrand factor of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis: A revised classification of von Willebrand disease. Thromb Haemost 1994; 71: 520-525
  13. Tuddenham EGD: The varieties of von Willebrand's disease. Clin Lab Haematol 1984;6: 307-323
  14. Schneppeheim R, Budde U, Krey S, Drewke E, Bergmann F, Lechler E, Oldenburg J, Schwaab R. Results of a screening for von Willebrand disease type 2N in patients with suspected haemophilia A or von Willebrand disease type 1. Thromb Haemost 1996;76:598-602.
  15. Abilgaard CF, Suzuki Z, Harrison J et al: Serial studies in von Willebrand's disease: variability versus "variants". Blood 1980; 56: 712-716
  16. 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
  17. 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
  18. Levi J, Simon R, Weis H: Family therapy in haemophilia -- a chronic disease model. [abstract] Clin Lab Res 1986; 16: 125
  19. DienstagJL: Sexual and perinatal transmission of hepatitis C. Hepatology 26 (Suppl 1); 1997: 66S-70S
  20. Levine SB, Agle DP: Intimacy, Sexuality, and Hemophilia, National Hemophilia Foundation, New York, 1989
  21. Mannucci PM, Colombo M: Virucidal treatment of clotting factor concentrates. Lancet 1988; 2: 782-785
  22. 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
  23. Centers for Disease Control. Hepatitis A among persons with hemophilia who received clotting factor concentrate -- United States, September-December 1995. MMWR 1996;45:29-32.
  24. Mannucci PM, Gringeri M, Morfini M et al: Immunogenicity of a recombinant hepatitis B vaccine in hemophiliacs. Am J Hematol 1988; 29: 211-214
  25. Centers for Disease Control: Update on hepatitis B prevention. Recommendation of the Immunization Practices Advisory Committee. Ann Intern Med 1987; 107: 353-357
  26. National Advisory Comittee on Immunization. Statement on the prevention of hepatitis A infections. CCDR 1994; 20:133-36, 139-43.
  27. National Advisory Comittee on Immunization. Supplementary statement on hepatitis A prevention. CCDR 1996;22:1-2.
  28. Zanetti AR, Mannucci PM, Tanzi E et al: Hepatitis vaccination of 113 hemophiliacs: lower antibody response in anti-LAV/HTLV-III-positive patients. Am J Hematol 1986;23: 339-345
  29. Desmyster J, Colaert J, Verstraete M et al: Hepatitis B vaccination of haemophiliacs. Scand J Infect Dis 1983; 38 (suppl): 42-45
  30. Jones P: Haemophilia home therapy. Haemostasis 1992; 22: 247-250
  31. Gomperts ED, Sergis-Davenport E: Home therapy programs: the role of the nurse, physician, patient, and family in self-directed care. In Hilgartner MW, Pochedly C (eds): Hemophilia in the Child and Adult, 3rd ed, Raven Press, New York, 1989:173-193
  32. Hill RA, Smith MA: Orthopedic assessment of the hemophilic patient. In Seghatchian MJ, Savidge GF (eds): Factor VIII -- von Willebrand Factor, vol 2, CRC Press, Boca Raton, Fla, 1989: 65-88
  33. Holdredge SA, Cotta S: Physical therapy and rehabilitation in the care of the adult and child with hemophilia. In Hilgartner MW, Pochedly C (eds): Hemophilia in the Child and Adult, 3rd ed, Raven Press, New York, 1989: 236-262
  34. Triger DR, Preston FE: Chronic liver disease in haemophiliacs. Br J Haematol 1990;74: 241-245
  35. Blanchette VS, Vorstman E, Shore A et al: Hepatitis C infection in children with hemophilia A and B. Blood 1991; 78: 285-289
  36. Blanchette, V., Walker, I., Gill, P., Adams, M., Roberts, R., Inwood, M. and the Canadian Hemophilia Clinic Director's Group. Hepatitis C infection in patients with hemophilia: results of a national survey. Transfusion Medicine Review 1994;8:210-217.
  37. Petterson H, Ahlberg A, Nilsson IM: A radiological classification of hemophilic arthropathy. Clin Orthop 1980; 149: 153-159
  38. Evans B: Dental management. In Hilgartner MW, Pochedly C (eds): Hemophilia in the Child and Adult, 3rd ed, Raven Press, New York, 1989: 89-119
  39. American Dental Association, American Academy of Orthopaedic Surgeons. Advisory Statement: Antibiotic prophylaxis for dental patients with total joint replacements. J Am Dental Assoc 1997;128:1004-1007
  40. Kasper CK: Treatment of factor VIII inhibitors. [review] Prog Hemost Thromb 1989; 9:57-86