von Willebrand Disease FULL REPORT NIH Publication No. 08-5832 December 2007 The Diagnosis, Evaluation, and Management of cx128620_NIH_Cover.qxp:Layout 1 1/8/08 12:25 PM Page 1 128620_NIH_Text.qxp:Layout 1 1/4/08 6:11 PM Page B von Willebrand Disease The Diagnosis, Evaluation, and Management of NIH Publication No. 08-5832 December 2007 128620_NIH_Text.qxp:Layout 1 1/4/08 6:11 PM Page A 128620_NIH_Text.qxp:Layout 1 1/4/08 6:11 PM Page B NHLBI von Willebrand Disease Expert Panel Chair William L. Nichols, Jr., M.D. (Mayo Clinic, Ro chester, MN) Members Mae B. Hultin, M.D. (Stony Brook University, Stony B rook, 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 w ere 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. i von Willebrand Disease 128620_NIH_Text.qxp:Layout 1 1/4/08 6:12 PM Page i ii von Willebrand Disease 128620_NIH_Text.qxp:Layout 1 1/4/08 6:12 PM Page ii List of Tables iv List of Figures v Introduction 1 History of This Project 1 Charge to the Panel 2 Panel Assignments 2 Literature Searches 2 Clinical Recommendations— Grading and Levels of Evidence 3 External and Internal Review 4 Scientific Overview 5 Discovery and Identification of VWD/VWF 5 The VWF Protein and Its Functions In Vivo 5 The Genetics of VWD 9 Classification of VWD Subtypes 11 Type 1 VWD 13 Type 2 VWD 13 Type 3 VWD 15 VWD Classification, General Issues 15 Type 1 VWD Versus Low VWF: VWF Level as a Risk Factor for Bleeding 15 Acquired von Willebrand Syndrome 17 Prothrombotic Clinical Issues and VWF in Persons Who Do Not Have VWD 18 Diagnosis and Evaluation 19 Introduction 19 E valuation of the Patient 19 History, Signs, and Symptoms 19 Laboratory Diagnosis and Monitoring 24 Initial Tests for VWD 26 Other Assays To Measure VWF, Define/Diagnose VWD, and Classify Subtypes 27 Assays for Detecting VWF Antibody 31 Making the Diagnosis of VWD 31 Special Considerations for Laboratory Diagnosis of VWD 32 Summary of the Laboratory Diagnosis of VWD 33 Diagnostic Recommendations 34 I. Evaluation of Bleeding Symptoms and Bleeding Risk by History and Physical Examination 34 II. Evaluation by Laboratory Testing 35 III. Making the Diagnosis 35 Management of VWD 37 Introduction 37 Ther apies To Elevate VWF: Nonreplacement Therapy 37 DDAVP (Desmopressin: 1-desamino-8- D-arginine vasopressin) 37 Therapies To Elevate VWF: Replacement Therapy 42 Other Therapies for VWD 46 Other Issues in Medical Management 46 Treatment of AVWS 47 Management of Menorrhagia in Women Who Have VWD 48 Hemorrhagic Ovarian Cysts 49 Pregnancy 49 Miscarriage and Bleeding During Pregnancy 50 Childbirth 50 Postpartum Hemorrhage 52 Management Recommendations 53 IV. Testing Prior to Treatment 53 V. General Management 53 VI. Treatment of Minor Bleeding and Prophylaxis for Minor Surgery 53 VII. Treatment of Major Bleeding and Prophylaxis for Major Surgery 54 VIII. Management of Menorrhagia and Hemorrhagic Ovarian Cysts in Women Who Have VWD 54 IX. Management of Pregnancy and Childbirth in Women Who Have VWD 55 X. Acquired von Willebrand Syndrome 55 iii Contents Contents 128620_NIH_Text.qxp:Layout 1 1/4/08 6:12 PM Page iii Contents (continued) Opportunities and Needs in VWD Research, Training, and Practice 57 Pathophysiology and Classification of VWD 57 Diag nosis and Evaluation 58 Management of VWD 58 Gene Therapy of VWD 59 Issues Specific to Women 59 Training of Specialists in Hemostasis 59 References 60 Evidence T ables 83 Evidence Table 1. Recommendation I.B. 84 E vidence Table 2. Recommendation II.B 85 Evidence Table 3. Recommendation II.C.1.a 87 Evidence Table 4. Recommendation II.C.1.d 90 Evidence Table 5. Recommendation II.C.2 91 Evidence Table 6. Recommendation IV.C 92 Evidence Table 7. Recommendation VI.A 94 Evidence Table 8. Recommendation VI.C 96 Evidence Table 9. Recommendation VI.D 98 Evidence Table 10. Recommendation VI.F 100 Evidence Table 11. Recommendation VII.A 103 Evidence Table 12. Recommendation VII.C 107 Evidence Table 13. Recommendation X.B 111 List of Tables Table 1. Level of Evidence 3 Table 2. Synopsis of VWF Designations Properties, and Assays 6 Table 3. Nomenclature and Abbreviations 7 Table 4. Classification of VWD 12 Table 5. Inheritance, Prevalence, and Bleeding P ropensity in Patients Who Have VWD 12 Table 6. Bleeding and VWF Level in Type 3 VWD H eterozygotes 16 Table 7. Common Bleeding Symptoms of Healthy I ndividuals and Patients Who Have VWD 21 Table 8. Prevalences of Characteristics in Patients W ho Have Diagnosed Bleeding Disorders Versus Healthy Controls 23 Table 9. Influence of ABO Blood Groups on VWF:A g 31 Table 10. Collection and Handling of Plasma Samples for Labor atory Testing 33 Table 11. Intravenous DDAVP Effect on Plasma C oncentrations of FVIII and VWF in Normal Persons and Persons Who Have VWD 39 Table 12. Clinical Results of DDAVP Treatment in P atients Who Have VWD 42 Table 13. Efficacy of VWF Replacement Concentrate for S urgery and Major Bleeding Events 44 Table 14. Suggested Durations of VWF Replacement for D ifferent Types of Surgical Procedures 45 Table 15. Initial Dosing Recommendations for VWF Conc entrate Replacement for Prevention or Management of Bleeding 45 Table 16. Effectiveness of Medical Therapy for M enorrhagia in Women Who Have VWD 48 Table 17. Pregnancies in Women Who Have VWD 51 iv von Willebrand Disease 128620_NIH_Text.qxp:Layout 1 1/4/08 6:12 PM Page iv 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 Disor ders 20 Figure 4. Laboratory Assessment For VWD or Other Bleeding Disor ders 25 Figure 5. Expected Laboratory Values in VWD 28 Figure 6. Analysis of VWF Multimers 29 v Contents 128620_NIH_Text.qxp:Layout 1 1/4/08 6:12 PM Page v vi von Willebrand Disease 128620_NIH_Text.qxp:Layout 1 1/4/08 6:12 PM Page vi [...]... Nomenclature and Abbreviations (continued) Designation Definition VWD von Willebrand disease VWF* von Willebrand factor (FVIII carrier protein) VWF:Ac von Willebrand factor activity VWF:Ag* von Willebrand factor antigen VWF:CB* von Willebrand factor collagen-binding activity VWF:FVIIIB* von Willebrand factor: factor VIII binding assay VWF gene von Willebrand factor gene VWF:PB assay von Willebrand factor... assay VWFpp von Willebrand factor propeptide VWF:RCo* von Willebrand factor ristocetin cofactor activity WHO World Health Organization *These abbreviations (for FVIII and VWF and all their properties) are defined in Marder VJ, Mannucci PM, Firkin BG, Hoyer LW, Meyer D Standard nomenclature for factor VIII and von Willebrand factor: a recommendation by the International Committee on Thrombosis and Haemostasis... decreased), the FVIII is often 2–3 times higher than the VWF activity (VWF:RCo).167,168 Therefore, the PTT is often within the normal range If VWF clearance is the cause of low VWF, the FVIII reduction parallels that of VWF, probably because both proteins are cleared together as a complex 26 von Willebrand Disease Initial Tests for VWD Box 3 lists the initial tests commonly used to detect VWD or low VWF These... of laboratory results Evaluation of the Patient History, Signs, and Symptoms The initial clinical assessment of a person who is being evaluated for VWD should focus on a personal history of excessive bleeding throughout the person’s life and any family history of a bleeding disorder The history of bleeding should identify the spontaneity and severity, sites of bleeding, duration of bleeding, type of. .. domains in the protein, and introns often occur at similar positions within the gene segments that encode homologous domains Thus, the structure of the VWF gene reflects the mosaic nature of the protein (Figure 2) A partial, unprocessed VWF pseudogene is located at chromosome 22q11.2.17 This pseudogene spans approximately 25 kb of DNA and corresponds to exons 23–34 and part of the adjacent introns of the. .. platelet adhesion and aggregation and is a carrier for FVIII in plasma See specific VWF assays below von Willebrand factor ristocetin cofactor activity (VWF:RCo) Binding activity of VWF that causes binding of VWF to platelets in the presence of ristocetin with consequent agglutination Ristocetin cofactor activity: quantitates platelet agglutination after addition of ristocetin and VWF von Willebrand factor... review of reported cases; case reports; journal article (to exclude letters, editorials, news, etc.) 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. .. by the presence of clots greater than an inch in diameter and/ or changing a pad or tampon more than hourly, or resulting in anemia or low iron level? Sources: Dean JA, Blanchette VS, Carcao MD, Stain AM, Sparling CR, Siekmann J, Turecek PL, Lillicrap D, Rand ML von Willebrand disease in a pediatric-based population—comparison of type 1 diagnostic criteria and use of the PFA-100® and a von Willebrand. .. chromosome 12 Variant forms of VWF were recognized in the 1970s, and we now recognize that these variations are the result of synthesis of an abnormal protein Gene sequencing identified many of these persons as having a VWF gene mutation The genetic causes of milder forms of low VWF are still under investigation, and these forms may not always be caused by an abnormal VWF gene In addition, there are acquired... 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 . ADAMTS13. 6 von Willebrand Disease Designation von Willebrand factor (VWF) von Willebrand factor ristocetin cofactor activity (VWF:RCo) von Willebrand factor. 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