The Diagnosis, Evaluation and Management of von
Willebrand Disease
Table of Contents
NHLBI von Willebrand Disease Expert Panel
Chair
William L. Nichols, Jr., M.D. (Mayo Clinic, Rochester,
MN)
Members
Mae B. Hultin, M.D. (Stony Brook University, Stony
Brook, NY); Andra H. James, M.D. (Duke University Medical Center, Durham, NC);
Marilyn J. Manco-Johnson, M.D. (The University of Colorado at Denver and Health
Sciences Center, Aurora, CO, and The Children's Hospital of Denver, CO); Robert
R. Montgomery, M.D. (BloodCenter of Wisconsin and Medical College of Wisconsin,
Milwaukee, WI); Thomas L. Ortel, M.D., Ph.D. (Duke University Medical Center,
Durham, NC); Margaret E. Rick, M.D. (National Institutes of Health, Bethesda,
MD); J. Evan Sadler, M.D., Ph.D. (Washington University, St. Louis, MO); Mark
Weinstein, Ph.D. (U.S. Food and Drug Administration, Rockville, MD); Barbara P.
Yawn, M.D., M.Sc. (Olmsted Medical Center and University of Minnesota,
Rochester, MN)
National Institutes of Health Staff
Rebecca Link, Ph.D. (National Heart, Lung, and Blood
Institute; Bethesda, MD); Sue Rogus, R.N., M.S. (National Heart, Lung, and
Blood Institute, Bethesda, MD)
Staff
Ann Horton, M.S.; Margot Raphael; Carol Creech,
M.I.L.S.; Elizabeth Scalia, M.I.L.S.; Heather Banks, M.A., M.A.T.; Patti
Louthian (American Institutes for Research, Silver Spring, MD)
Financial and Other Disclosures
The participants who disclosed potential conflicts
were Dr. Andra H. James (medical advisory panel for ZLB Behring and Bayer; NHF,
MASAC), Dr. Marilyn Manco-Johnson (ZLB Behring Humate-P® Study Steering
Committee and Grant Recipient, Wyeth Speaker, Bayer Advisor and Research Grant
Recipient, Baxter Advisory Committee and Protein C Study Group, Novo Nordisk
Advisory Committee), Dr. Robert Montgomery (Aventis Foundation Grant; GTI,
Inc., VWFpp Assay; ZLB Behring and Bayer Advisory Group; NHF, MASAC), and Dr.
William Nichols (Mayo Special Coagulation Laboratory serves as "central lab"
for Humate-P® study by ZLB Behring). All members submitted financial
disclosure forms.
Introduction
Von Willebrand disease (VWD) is an inherited bleeding
disorder that is caused by deficiency or dysfunction of von Willebrand factor
(VWF), a plasma protein that mediates the initial adhesion of platelets at
sites of vascular injury and also binds and stabilizes blood clotting factor
VIII (FVIII) in the circulation. Therefore, defects in VWF can cause bleeding
by impairing platelet adhesion or by reducing the concentration of FVIII.
VWD is a relatively common cause of bleeding, but the
prevalence varies considerably among studies and depends strongly on the case
definition that is used. VWD prevalence has been estimated in several countries
on the basis of the number of symptomatic patients seen at hemostasis centers,
and the values range from roughly 23 to 110 per million population (0.0023 to
0.01 percent).1
The prevalence of VWD also has been estimated by
screening populations to identify persons with bleeding symptoms, low VWF
levels, and similarly affected family members. This population-based approach
has yielded estimates for VWD prevalence of 0.6 percent,2 0.8 percent,3 and 1.3 percent4—more than two orders of magnitude
higher than the values arrived at by surveys of hemostasis centers.
The discrepancies between the methods for estimating
VWD prevalence illustrate the need for better information concerning the
relationship between VWF levels and bleeding. Many bleeding symptoms are
exacerbated by defects in VWF, but the magnitude of the effect is not known.
For example, approximately 12 percent of women who have menstrual periods have
excessive menstrual bleeding.5
This fraction is much higher among women who have VWD, but it also appears to
be increased for women who have VWF levels at the lower end of the normal
range. Quantitative data on these issues would allow a more informed approach
to the diagnosis and management of VWD and could have significant implications
for medical practice and for public health.
Aside from needs for better information about VWD
prevalence and the relationship of low VWF levels to bleeding symptoms or risk,
there are needs for enhancing knowledge and improving clinical and laboratory
diagnostic tools for VWD. Furthermore, there are needs for better knowledge of
and treatment options for management of VWD and bleeding or bleeding risk. As
documented in this VWD guidelines publication, a relative paucity of published
studies is available to support some of the recommendations which, therefore,
are mainly based on Expert Panel opinion.
Guidelines for VWD diagnosis and management, based on
the evidence from published studies and/or the opinions of experts, have been
published for practitioners in Canada,6 Italy,7 and the United Kingdom,8,9 but not in the United States. The VWD
guidelines from the U.S. Expert Panel are based on review of published evidence
as well as expert opinion. Users of these guidelines should be aware that
individual professional judgment is not abrogated by recommendations in these
guidelines.
These guidelines for diagnosis and management of VWD
were developed for practicing primary care and specialist
cliniciansincluding family physicians, internists,
obstetrician-gynecologists, pediatricians, and nurse-practitioners—as
well as hematologists and laboratory medicine specialists.
History of This Project
During the spring of 2004, the National Heart, Lung,
and Blood Institute (NHLBI) began planning for the development of clinical
practice guidelines for VWD in response to the FY 2004 appropriations
conference committee report (House Report 108-401) recommendation. In that
report, the conferees urged NHLBI to develop a set of treatment guidelines for
VWD and to work with medical associations and experts in the field when
developing such guidelines. In consultation with the American Society of
Hematology (ASH), the Institute convened an Expert Panel on VWD, chaired by Dr.
William Nichols of the Mayo Clinic, Rochester, MN. The Expert Panel members
were selected to provide expertise in basic sciences, clinical and laboratory
diagnosis, evidence-based medicine, and the clinical management of VWD,
including specialists in hematology as well as in family medicine, obstetrics
and gynecology, pediatrics, internal medicine, and laboratory sciences. The
Expert Panel comprised one basic scientist and nine physiciansincluding
one family physician, one obstetrician and gynecologist, and seven
hematologists with expertise in VWD (two were pediatric hematologists). Ad hoc
members of the Panel represented the Division of Blood Diseases and Resources
of the NHLBI. The Panel was coordinated by the Division for the Application of
Research Discoveries (DARD), formerly the Office of Prevention, Education, and
Control of the NHLBI. Panel members disclosed, verbally and in writing, any
financial conflicts. (See financial
and other disclosure summaries.)
Charge to the Panel
Dr. Barbara Alving, then Acting Director of the NHLBI,
gave the charge to the Expert Panel to examine the current science in the area
of VWD and to come to consensus regarding clinical recommendations for
diagnosis, treatment, and management of this common inherited bleeding
disorder. The Panel was also charged to base each recommendation on the current
science and to indicate the strength of the relevant literature for each
recommendation.
The development of this report was entirely funded by
the NHLBI, National Institutes of Health (NIH). Panel members and reviewers
participated as volunteers and were reimbursed only for travel expenses related
to the three in-person Expert Panel meetings.
Panel Assignments
After the Expert Panel finalized a basic outline for
the guidelines, members were assigned to the three sections: (1) Introduction
and Background, (2) Diagnosis and Evaluation, and (3) Management of VWD. Three
members were assigned lead responsibility for a particular section. The section
groups were responsible for developing detailed outlines for the sections,
reviewing the pertinent literature, writing the sections, and drafting
recommendations with the supporting evidence for the full Panel to review.
Literature Searches
Three section outlines, approved by the Expert Panel
chair, were used as the basis for compiling relevant search terms, using the
Medical Subject Headings (MeSH terms) of the MEDLINE database. If appropriate
terms were not available in MeSH, then relevant non-MeSH keywords were used. In
addition to the search terms, inclusion and exclusion criteria were defined
based on feedback from the Panel about specific limits to include in the search
strategies, specifically:
- Date restriction: 19902004
- Language: English
- Study/publication types: randomized-controlled
trial; meta-analysis; controlled clinical trial; epidemiologic studies;
prospective studies; multicenter study; clinical trial; evaluation studies;
practice guideline; review, academic; review, multicase; technical report;
validation studies; review of reported cases; case reports; journal article (to
exclude letters, editorials, news, etc.)
The search strategies were constructed and executed in
the MEDLINE database as well as in the Cochrane Database of Systematic Reviews
to compile a set of citations and abstracts for each section. Initial searches
on specific keyword combinations and date and language limits were further
refined by using the publication type limits to produce results that more
closely matched the section outlines. Once the section results were compiled,
the results were put in priority order by study type as follows:
- Randomized-controlled trial
- Meta-analysis (quantitative summary combining
results of independent studies)
- Controlled clinical trial
- Multicenter study
- Clinical trial (includes all types and phases of
clinical trials)
- Evaluation studies
- Practice guideline (for specific health care
guidelines)
- Epidemiological
- Prospective studies
- Review, academic (comprehensive, critical, or
analytical review)
- Review, multicase (review with epidemiological
applications)
- Technical report
- Validation studies
- Review of reported cases (review of known cases of
a disease)
- Case reports
Upon examination of the yield of the initial
literature search, it was determined that important areas in the section
outlines were not addressed by the citations, possibly due to the date
exclusions. In addition, Panel members identified pertinent references from
their own searches and databases, including landmark references predating the
1990 date restriction, and 2005 and 2006 references (to October 2006).
Therefore, as a followup, additional database searching was done using the same
search strategies from the initial round, but covering dates prior to 1990 and
during 2005 and 2006 to double check for key studies appearing in the
literature outside the limits of the original range of dates. Also, refined
searches in the 19902006 date range were conducted to analyze the
references used by Panel members that had not appeared in the original search
results.
These revised searches helped round out the database
search to provide the most comprehensive approach possible. As a result, the
references used in the guidelines included those retrieved from the two
literature searches combined with the references suggested by the Panel
members. These references inform the guidelines and clinical recommendations,
based on the best available evidence in combination with the Panel's expertise
and consensus.
Clinical RecommendationsGrading and Levels of
Evidence
Recommendations made in this document are based on the
levels of evidence described in Table 1, with a priority
grading system of A, B, or C. Grade A is reserved for recommendations based on
evidence levels Ia and Ib. Grade B is given for recommendations having evidence
levels of IIa, IIb, and III; and Grade C is for recommendations based on
evidence level IV.8 None of the
recommendations merited a Grade of A. Evidence tables are provided at the end
of the document for those recommendations that are graded as B and have two or
more references (see Evidence Tables).
Table 1. Level of Evidence
Level |
Type of Evidence |
Ia |
Evidence obtained from meta-analysis of
randomized-controlled trials |
Ib |
Evidence obtained from at least one
randomized-controlled trial |
IIa |
Evidence obtained from at least one well-designed
controlled study without randomization |
IIb |
Evidence obtained from at least one other type of
well-designed quasi-experimental study |
III |
Evidence obtained from well-designed
non-experimental descriptive studies, such as comparative studies, correlation
studies, and case-control studies |
IV |
Evidence obtained from expert committee reports
or opinions and/or clinical experiences of respected authorities |
Source: Acute pain management: operative or
medical procedures and trauma. (Clinical practice guideline). Publication No.
AHCPR 920032. Rockville, MD: Agency for Health Care Policy and Research,
Public Health Service, U.S. Department of Health and Human Services, February
1992.
External and Internal Review
The NHLBI sought outside review of the guidelines
through a two-fold process. The following Government agencies and professional
organizations were invited to review the draft document and submit comments:
Centers for Disease Control and Prevention, Food and Drug Administration,
American Academy of Family Physicians, American College of Obstetricians and
Gynecologists, American College of Physicians, American Society of Hematology,
American Society of Pediatric Hematology/Oncology, College of American
Pathologists, Hemophilia & Thrombosis Research Society, National Hemophilia
Foundation Medical and Scientific Advisory Committee, and the North American
Specialized Coagulation Laboratory Association. In addition, the guidelines
were posted on the NHLBI Web site for public review and comment during a 30-day
period ending September 22, 2006. Comments from the external review were
compiled and given to the full Panel for review and consensus. Revisions to the
document were then made as appropriate. The final draft, after Panel approval,
was sent through review within the NIH and finally approved for publication by
the NHLBI Director. Back to Top
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