The Diagnosis, Evaluation and Management of von Willebrand Disease

History of the 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 1 basic scientist and 9 physicians-including 1 family physician, 1 obstetrician and gynecologist, and 7 hematologists with expertise in VWD (2 were pediatric hematologists). Ad hoc members of the Panel represented the Division of Blood Diseases and Resources of the NHLBI. The Office of Prevention, Education, and Control (OPEC) of the NHLBI coordinated the Panel. Panel members disclosed, verbally and in writing, any financial conflicts.

Charge to the Panel

Dr. Barbara Alving, 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 most 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.

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: 1990-2004
• 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 pre-dating the 1990 date restriction, and 2005 references as the project continued. 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 to double check for key studies appearing in the literature outside the limits of the original range of dates. Also, refined searches in the 1990-2005 date range were conducted to analyze the references used by Panel members that had not appeared in our 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 Recommendations

Recommendations made in this document are categorized using the schemes in Tables 1 and 2.

Table 1. Grade of Recommendation

Table 2. Level of Evidence