History

The most common signs of von Willebrand disease (vWD) include nosebleeds and hematomas. Prolonged bleeding from trivial wounds, oral cavity bleeding, and excessive menstrual bleeding are common. Gastrointestinal bleeding rarely occurs. Other manifestations include the following^{[13, 14]}:

Easy bruising - Common but nonspecific
Prolonged bleeding - After minor trauma to skin or mucous membranes
Severe hemorrhage - After major surgery; less common
Delayed bleeding - May occur up to several weeks after surgery
Heavy bleeding - Common after tooth extraction or other oral surgery, such as tonsillectomy and adenoidectomy
Menorrhagia - Common presenting complaint in women
Exacerbation of bleeding symptoms - After ingestion of aspirin
Amelioration of bleeding symptoms with use of oral contraceptives

Pediatric-specific bleeding that may occur in children with vWD include the following^[15]:

Umbilical stump bleeding
Cephalohematoma
Cheek hematoma
Conjunctival bleeding
Post-circumcision bleeding
Post-venipuncture bleeding

Patients with possible vWD should be asked about any family or personal history of bleeding problems. Any use of medications that might affect coagulation should also be elicited.^[13]

Bleeding assessment tools

Bleeding assessment tools (BATs) have been developed to allow clinicians to objectively assess bleeding symptoms in patients with vWD. BAT scores may also help predict bleeding risk in patients with vWD.^{[16, 17]}The International Society on Thrombosis and Haemostasis (ISTH) developed and endorsed a single BAT (ISTH-BAT), to standardize reporting of bleeding symptoms for use in adult and pediatric populations.^{[18, 16]}BATs should always be complemented by coagulation screening tests.^[16]

A practical disadvantage of existing BATs is that they must be administered by a physician or other properly trained health professional. Consequently, Deforest and colleagues have developed and validated a self-administered BAT for vWD. Their Self-BAT generated bleeding scores comparable BS to those of ISTH-BAT and proved reliable and effective screening tool for assessment of a possible bleeding disorder, particularly in women.^[19]

Physical Examination

Physical examination findings are usually normal. However, patients may show physical sequelae, such as bleeding or bruises. The examiner should note the size, location, and distribution of any ecchymoses, hematomas, or petechiae, and should assess for evidence of risks of increased bleeding, such as the following^[13]:

Jaundice or spider angiomata
Splenomegaly
Arthropathy
Joint and skin laxity
Telangiectasia

Differential Diagnoses

Veyradier A, Boisseau P, Fressinaud E, Caron C, Ternisien C, Giraud M, et al. A Laboratory Phenotype/Genotype Correlation of 1167 French Patients From 670 Families With von Willebrand Disease: A New Epidemiologic Picture. Medicine (Baltimore). 2016 Mar. 95 (11):e3038. [QxMD MEDLINE Link]. [Full Text].
Udvardy ML, Szekeres-Csiki K, Hársfalvi J. Novel evaluation method for densitometric curves of von Willebrand factor multimers and a new parameter (M(MW)) to describe the degree of multimersation. Thromb Haemost. 2009 Aug. 102(2):412-7. [QxMD MEDLINE Link].
[Guideline] Laffan MA, Lester W, O'Donnell JS, Will A, Tait RC, Goodeve A, et al. The diagnosis and management of von Willebrand disease: a United Kingdom Haemophilia Centre Doctors Organization guideline approved by the British Committee for Standards in Haematology. Br J Haematol. 2014 Aug 12. [QxMD MEDLINE Link]. [Full Text].
Casonato A, Galletta E, Daidone V. The elusive and heterogeneous pattern of type 2M von Willebrand disease: a diagnostic challenge. Eur J Haematol. 2018 Aug 6. [QxMD MEDLINE Link].
Sutherland MS, Cumming AM, Bowman M, et al. A novel deletion mutation is recurrent in von Willebrand disease types 1 and 3. Blood. 2009 Jul 30. 114(5):1091-8. [QxMD MEDLINE Link].
Odom B, Khourdaji I, Golas V, Zekman R, Rosenberg B. Acquired von Willebrand Disease Secondary to Clear Cell Renal Cell Carcinoma. J Endourol Case Rep. 2018. 4 (1):114-116. [QxMD MEDLINE Link]. [Full Text].
Stuijver DJ, Piantanida E, van Zaane B, Galli L, Romualdi E, Tanda ML, et al. Acquired von Willebrand syndrome in patients with overt hypothyroidism: a prospective cohort study. Haemophilia. 2014 May. 20(3):326-32. [QxMD MEDLINE Link].
Waldow HC, Westhoff-Bleck M, Widera C, Templin C, von Depka M. Acquired von Willebrand syndrome in adult patients with congenital heart disease. Int J Cardiol. 2014 Aug 1. [QxMD MEDLINE Link].
Pelland-Marcotte MC, Humpl T, James PD, Rand ML, Bouskill V, Reyes JT, et al. Idiopathic pulmonary arterial hypertension - a unrecognized cause of high-shear high-flow haemostatic defects (otherwise referred to as acquired von Willebrand syndrome) in children. Br J Haematol. 2018 Aug 23. [QxMD MEDLINE Link].
Cao XY, Li MT, Zhang X, Zhao Y, Zeng XF, Zhang FC, et al. Characteristics of Acquired Inhibitors to Factor VIII and Von Willebrand Factor Secondary to Systemic Lupus Erythematosus: Experiences From a Chinese Tertiary Medical Center. J Clin Rheumatol. 2019 Dec 6. [QxMD MEDLINE Link].
Byams VR, Kouides PA, Kulkarni R, et al. Surveillance of female patients with inherited bleeding disorders in United States Haemophilia Treatment Centres. Haemophilia. 2011 Jul. 17 Suppl 1:6-13. [QxMD MEDLINE Link].
Sanders YV, Giezenaar MA, Laros-van Gorkom BA, Meijer K, van der Bom JG, Cnossen MH, et al. von Willebrand disease and aging: an evolving phenotype. J Thromb Haemost. 2014 Jul. 12(7):1066-75. [QxMD MEDLINE Link].
[Guideline] Nichols WL, Hultin MB, James AH, et al, and the NHLBI von Willebrand Disease Expert Panel. The Diagnosis, Evaluation, and Management of von Willebrand Disease. Bethesda, Md: National Heart, Lung, and Blood Institute. NIH publication no. 08-5832. December 2007. [Full Text].
Rodeghiero F, Castaman G, Tosetto A. How I treat von Willebrand disease. Blood. 2009 Aug 6. 114(6):1158-65. [QxMD MEDLINE Link]. [Full Text].
Sanders YV, Fijnvandraat K, Boender J, Mauser-Bunschoten EP, van der Bom JG, et al. Bleeding spectrum in children with moderate or severe von Willebrand disease: Relevance of pediatric-specific bleeding. Am J Hematol. 2015 Sep 16. [QxMD MEDLINE Link].
Tosetto A. Bleeding Assessment Tools: Limits and Advantages for the Diagnosis and Prognosis of Inherited Bleeding Disorders. Semin Thromb Hemost. 2016 Jul. 42 (5):463-70. [QxMD MEDLINE Link].
Mannucci PM. New therapies for von Willebrand disease. Hematology Am Soc Hematol Educ Program. 2019 Dec 6. 2019 (1):590-595. [QxMD MEDLINE Link].
Rodeghiero F, Tosetto A, Abshire T, Arnold DM, Coller B, James P, et al. ISTH/SSC bleeding assessment tool: a standardized questionnaire and a proposal for a new bleeding score for inherited bleeding disorders. J Thromb Haemost. 2010 Sep. 8 (9):2063-5. [QxMD MEDLINE Link]. [Full Text].
Deforest M, Grabell J, Albert S, Young J, Tuttle A, Hopman WM, et al. Generation and optimization of the self-administered bleeding assessment tool and its validation as a screening test for von Willebrand disease. Haemophilia. 2015 Sep. 21 (5):e384-8. [QxMD MEDLINE Link]. [Full Text].
Castaman G. How I treat von Willebrand disease. Thromb Res. 2020 Dec. 196:618-625. [QxMD MEDLINE Link].
Sharma R, Haberichter SL. New advances in the diagnosis of von Willebrand disease. Hematology Am Soc Hematol Educ Program. 2019 Dec 6. 2019 (1):596-600. [QxMD MEDLINE Link].
Goodeve A. Diagnosing von Willebrand disease: genetic analysis. Hematology Am Soc Hematol Educ Program. 2016 Dec 2. 2016 (1):678-682. [QxMD MEDLINE Link].
Hayward CP, Moffat KA, Graf L. Technological advances in diagnostic testing for von Willebrand disease: new approaches and challenges. Int J Lab Hematol. 2014 Jun. 36(3):334-40. [QxMD MEDLINE Link].
Flood VH, Abshire TC, Christopherson PA, Friedman KD, Cox Gill J, Montgomery RR, et al. Von Willebrand disease in the United States: perspective from the Zimmerman program. Ann Blood. 2018 Jan. 3:[QxMD MEDLINE Link]. [Full Text].
Gill JC, Castaman G, Windyga J, Kouides P, Ragni M, Leebeek FW, et al. Hemostatic efficacy, safety, and pharmacokinetics of a recombinant von Willebrand factor in severe von Willebrand disease. Blood. 2015 Oct 22. 126 (17):2038-46. [QxMD MEDLINE Link]. [Full Text].
O'Donnell JS, Lavin M. Perioperative management of patients with von Willebrand disease. Hematology Am Soc Hematol Educ Program. 2019 Dec 6. 2019 (1):604-609. [QxMD MEDLINE Link].
Franchini M, Targher G, Montagnana M, Lippi G. Antithrombotic prophylaxis in patients with von Willebrand disease undergoing major surgery: when is it necessary?. J Thromb Thrombolysis. 2009 Aug. 28(2):215-9. [QxMD MEDLINE Link].
O'Brien SH, Stanek JR, Kaur D, McCracken K, Vesely SK. Laboratory Monitoring During Pregnancy and Post-Partum Hemorrhage in Women with Von Willebrand Disease. J Thromb Haemost. 2019 Dec 5. [QxMD MEDLINE Link].
Neff AT. Current controversies in the diagnosis and management of von Willebrand disease. Ther Adv Hematol. 2015 Aug. 6 (4):209-16. [QxMD MEDLINE Link].
Di Paola J, Lethagen S, Gill J, et al. Presurgical pharmacokinetic analysis of a von Willebrand factor/factor VIII (VWF/FVIII) concentrate in patients with von Willebrand's disease (VWD) has limited value in dosing for surgery. Haemophilia. 2011 Sep. 17(5):752-8. [QxMD MEDLINE Link].
Mannucci PM. New therapies for von Willebrand disease. Hematology Am Soc Hematol Educ Program. 2019 Dec 6. 2019 (1):590-595. [QxMD MEDLINE Link].
Roberts JC, Flood VH. Laboratory diagnosis of von Willebrand disease. Int J Lab Hematol. 2015 May. 37 Suppl 1:11-7. [QxMD MEDLINE Link].
Sabih A, Babiker HM. Von Willebrand Disease. 2020 Jan. [QxMD MEDLINE Link]. [Full Text].
Baronciani L, Peyvandi F. How we make an accurate diagnosis of von Willebrand disease. Thromb Res. 2020 Dec. 196:579-589. [QxMD MEDLINE Link].

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Author

Eleanor S Pollak, MD Associate Director of Special Coagulation, Associate Professor, Department of Pathology and Laboratory Medicine, Section of Hematology and Coagulation, University of Pennsylvania

Eleanor S Pollak, MD is a member of the following medical societies: American Society of Hematology, College of American Pathologists, National Multiple Sclerosis Society

Disclosure: Nothing to disclose.

Chief Editor

Srikanth Nagalla, MD, MS, FACP Chief of Benign Hematology, Miami Cancer Institute, Baptist Health South Florida; Clinical Professor of Medicine, Florida International University, Herbert Wertheim College of Medicine

Srikanth Nagalla, MD, MS, FACP is a member of the following medical societies: American Society of Hematology, Association of Specialty Professors

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Alexion; Alnylam; Kedrion; Sanofi; Dova; Apellis; Pharmacosmos<br/>Serve(d) as a speaker or a member of a speakers bureau for: Sobi; Sanofi; Rigel.

Acknowledgements

Marcel E Conrad, MD (Retired) Distinguished Professor of Medicine, University of South Alabama

Marcel E Conrad, MD is a member of the following medical societies: Alpha Omega Alpha, American Association for the Advancement of Science, American Association of Blood Banks, American Chemical Society, American College of Physicians, American Physiological Society, American Society for Clinical Investigation, American Society of Hematology, Association of American Physicians, Association of Military Surgeons of the US, International Society of Hematology, Society for Experimental Biology and Medicine, and Southwest Oncology Group

Disclosure: No financial interests None None

Koyamangalath Krishnan, MD, FRCP, FACP Paul Dishner Endowed Chair of Excellence in Medicine, Professor of Medicine and Chief of Hematology-Oncology, Program Director, Hematology-Oncology Fellowship, James H Quillen College of Medicine at East Tennessee State University

Koyamangalath Krishnan, MD, FRCP, FACP is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians-American Society of Internal Medicine, American Society of Hematology, and Royal College of Physicians

Disclosure: Nothing to disclose.

Steven Stein, MD, Assistant Professor, Department of Medicine, Division of Hematology/Oncology, University of Pennsylvania

Steven Stein, MD is a member of the following medical societies: American College of Physicians-American Society of Internal Medicine and American Society of Hematology

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Reference Salary Employment

von Willebrand Disease Clinical Presentation

History

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Physical Examination

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