The Diagnosis, Evaluation, and Management of von ...

1 :Layout 1 1/8/08 12:25 PM Page 1. FULL REPORT. The Diagnosis, Evaluation, and Management of von Willebrand Disease NIH Publication No. 08-5832. December 2007. :Layout 1 1/4/08 6:11 PM Page B. :Layout 1 1/4/08 6:11 PM Page A. The Diagnosis, Evaluation, and Management of von Willebrand Disease NIH Publication No. 08-5832. December 2007. :Layout 1 1/4/08 6:11 PM Page B. :Layout 1 1/4/08 6:12 PM Page i NHLBI von Willebrand Disease Expert Panel Chair Staff William L. Nichols, Jr., (Mayo Clinic, Ann Horton, ; Margot Raphael; Carol Creech, Rochester, MN) ; Elizabeth Scalia, ; Heather Banks, , ; Patti Louthian (American Institutes Members for Research, Silver Spring, MD). Mae B. Hultin, (Stony Brook University, Stony Brook, NY); Andra H. James, (Duke University Medical Center, Durham, NC); Marilyn J. Manco- Financial and Other Disclosures Johnson, (The University of Colorado at Denver The participants who disclosed potential conflicts and Health Sciences Center, Aurora, CO, and The were Dr.)

2 Andra H. James (medical advisory panel for Children's Hospital of Denver, CO); Robert R. ZLB Behring and Bayer; NHF, MASAC), Dr. Marilyn Montgomery, (BloodCenter of Wisconsin and Manco-Johnson (ZLB Behring Humate-P Study Medical College of Wisconsin, Milwaukee, WI);. Steering Committee and Grant Recipient, Wyeth Thomas L. Ortel, , (Duke University Speaker, Bayer Advisor and Research Grant Recipient, Medical Center, Durham, NC); Margaret E. Rick, Baxter Advisory Committee and Protein C Study (National Institutes of Health, Bethesda, MD);. Group, Novo Nordisk Advisory Committee), Dr. J. Evan Sadler, , (Washington University, Robert Montgomery (Aventis Foundation Grant;. St. Louis, MO); Mark Weinstein, ( Food GTI, Inc., VWFpp Assay; ZLB Behring and Bayer and Drug Administration, Rockville, MD); Barbara Advisory Group; NHF, MASAC), and Dr. William P. Yawn, , (Olmsted Medical Center and Nichols (Mayo Special Coagulation Laboratory University of Minnesota, Rochester, MN).

3 Serves as central lab for Humate-P study by ZLB. National Institutes of Health Staff Rebecca Link, Behring). All members submitted financial (National Heart, Lung, and Blood Institute; disclosure forms. Bethesda, MD); Sue Rogus, , (National Heart, Lung, and Blood Institute, Bethesda, MD). von Willebrand Disease i :Layout 1 1/4/08 6:12 PM Page ii ii von Willebrand Disease :Layout 1 1/4/08 6:12 PM Page iii Contents List of Tables iv Diagnostic Recommendations 34. I. Evaluation of Bleeding Symptoms and List of Figures v Bleeding Risk by History and Physical Introduction 1 Examination 34. History of This Project 1 II. Evaluation by Laboratory Testing 35. Charge to the Panel 2 III. Making the Diagnosis 35. Panel Assignments 2. Management of VWD 37. Literature Searches 2. Introduction 37. Clinical Recommendations . Therapies To Elevate VWF: Nonreplacement Grading and Levels of Evidence 3.

4 Therapy 37. External and Internal Review 4. DDAVP (Desmopressin: 1-desamino-8- Scientific Overview 5 D-arginine vasopressin) 37. Discovery and Identification of VWD/VWF 5 Therapies To Elevate VWF: Replacement The VWF Protein and Its Functions In Vivo 5 Therapy 42. The Genetics of VWD 9 Other Therapies for VWD 46. Classification of VWD Subtypes 11 Other Issues in Medical Management 46. Type 1 VWD 13 Treatment of AVWS 47. Type 2 VWD 13 Management of Menorrhagia in Women Who Type 3 VWD 15 Have VWD 48. VWD Classification, General Issues 15 Hemorrhagic Ovarian Cysts 49. Type 1 VWD Versus Low VWF: VWF Level as a Pregnancy 49. Risk Factor for Bleeding 15 Miscarriage and Bleeding During Pregnancy 50. Acquired von Willebrand Syndrome 17 Childbirth 50. Prothrombotic Clinical Issues and VWF in Persons Postpartum Hemorrhage 52. Who Do Not Have VWD 18 Management Recommendations 53. IV. Testing Prior to Treatment 53.

5 Diagnosis and Evaluation 19 V. General Management 53. Introduction 19 VI. Treatment of Minor Bleeding and Evaluation of the Patient 19 Prophylaxis for Minor Surgery 53. History, Signs, and Symptoms 19 VII. Treatment of Major Bleeding and Laboratory Diagnosis and Monitoring 24 Prophylaxis for Major Surgery 54. Initial Tests for VWD 26 VIII. Management of Menorrhagia and Other Assays To Measure VWF, Hemorrhagic Ovarian Cysts in Women Define/Diagnose VWD, and Classify Who Have VWD 54. Subtypes 27 IX. Management of Pregnancy and Assays for Detecting VWF Antibody 31 Childbirth in Women Who Have VWD 55. Making the Diagnosis of VWD 31 X. Acquired von Willebrand Syndrome 55. Special Considerations for Laboratory Diagnosis of VWD 32. Summary of the Laboratory Diagnosis of VWD 33. Contents iii :Layout 1 1/4/08 6:12 PM Page iv Contents (continued) List of Tables Opportunities and Needs in VWD Research, Table 1.

6 Level of Evidence 3. Training, and Practice 57 Table 2. Synopsis of VWF Designations Properties, Pathophysiology and Classification of VWD 57 and Assays 6. Diagnosis and Evaluation 58 Table 3. Nomenclature and Abbreviations 7. Management of VWD 58 Table 4. Classification of VWD 12. Gene Therapy of VWD 59 Table 5. Inheritance, Prevalence, and Bleeding Issues Specific to Women 59 Propensity in Patients Who Have VWD 12. Training of Specialists in Hemostasis 59 Table 6. Bleeding and VWF Level in Type 3 VWD. Heterozygotes 16. References 60 Table 7. Common Bleeding Symptoms of Healthy Individuals and Patients Who Have Evidence Tables 83 VWD 21. Evidence Table 1. Recommendation 84 Table 8. Prevalences of Characteristics in Patients Evidence Table 2. Recommendation 85 Who Have Diagnosed Bleeding Disorders Evidence Table 3. Recommendation 87 Versus Healthy Controls 23. Evidence Table 4.

7 Recommendation 90 Table 9. Influence of ABO Blood Groups on Evidence Table 5. Recommendation 91 VWF:Ag 31. Evidence Table 6. Recommendation 92 Table 10. Collection and Handling of Plasma Evidence Table 7. Recommendation 94 Samples for Laboratory Testing 33. Evidence Table 8. Recommendation 96 Table 11. Intravenous DDAVP Effect on Plasma Evidence Table 9. Recommendation 98 Concentrations of FVIII and VWF in Evidence Table 10. Recommendation 100 Normal Persons and Persons Who Have Evidence Table 11. Recommendation 103 VWD 39. Evidence Table 12. Recommendation 107 Table 12. Clinical Results of DDAVP Treatment in Evidence Table 13. Recommendation 111 Patients Who Have VWD 42. Table 13. Efficacy of VWF Replacement Concentrate for Surgery and Major Bleeding Events 44. Table 14. Suggested Durations of VWF Replacement for Different Types of Surgical Procedures 45. Table 15. Initial Dosing Recommendations for VWF.

8 Concentrate Replacement for Prevention or Management of Bleeding 45. Table 16. Effectiveness of Medical Therapy for Menorrhagia in Women Who Have VWD 48. Table 17. Pregnancies in Women Who Have VWD 51. iv von Willebrand Disease :Layout 1 1/4/08 6:12 PM Page v List of Figures Figure 1. VWF and Normal Hemostasis 10. Figure 2. Structure and Domains of VWF 11. Figure 3. Initial Evaluation For VWD or Other Bleeding Disorders 20. Figure 4. Laboratory Assessment For VWD or Other Bleeding Disorders 25. Figure 5. Expected Laboratory Values in VWD 28. Figure 6. Analysis of VWF Multimers 29. Contents v :Layout 1 1/4/08 6:12 PM Page vi vi von Willebrand Disease :Layout 1 1/4/08 6:12 PM Page 1. Introduction Von Willebrand disease (VWD) is an inherited Aside from needs for better information about VWD. bleeding disorder that is caused by deficiency or prevalence and the relationship of low VWF levels dysfunction of von Willebrand factor (VWF), a to bleeding symptoms or risk, there are needs for plasma protein that mediates the initial adhesion of enhancing knowledge and improving clinical and platelets at sites of vascular injury and also binds and laboratory diagnostic tools for VWD.

9 Furthermore, stabilizes blood clotting factor VIII (FVIII) in the there are needs for better knowledge of and treatment circulation. Therefore, defects in VWF can cause options for Management of VWD and bleeding or bleeding by impairing platelet adhesion or by reducing bleeding risk. As documented in this VWD guidelines the concentration of FVIII. publication, a relative paucity of published studies is available to support some of the recommendations VWD is a relatively common cause of bleeding, but which, therefore, are mainly based on Expert Panel the prevalence varies considerably among studies opinion. and depends strongly on the case definition that is used. VWD prevalence has been estimated in several Guidelines for VWD diagnosis and Management , countries on the basis of the number of symptomatic based on the evidence from published studies and/. patients seen at hemostasis centers, and the values or the opinions of experts, have been published for range from roughly 23 to 110 per million population practitioners in Canada,6 Italy,7 and the United ( to percent).

10 1 Kingdom,8,9 but not in the United States. The VWD. guidelines from the Expert Panel are based on The prevalence of VWD also has been estimated review of published evidence as well as expert opin- by screening populations to identify persons with ion. Users of these guidelines should be aware that bleeding symptoms, low VWF levels, and similarly individual professional judgment is not abrogated affected family members. This population-based by recommendations in these guidelines. approach has yielded estimates for VWD prevalence of percent,2 percent,3 and percent4 more These guidelines for diagnosis and Management of than two orders of magnitude higher than the values VWD were developed for practicing primary care arrived at by surveys of hemostasis centers. and specialist clinicians including family physicians, internists, obstetrician-gynecologists, pediatricians, The discrepancies between the methods for and nurse-practitioners as well as hematologists estimating VWD prevalence illustrate the need for and laboratory medicine specialists.