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ERROR: type should be string, got "https://profreg.medscape.com/px/getpracticeprofile.do?method=getProfessionalProfile&urlCache=aHR0cHM6Ly9lbWVkaWNpbmUubWVkc2NhcGUuY29tL2FydGljbGUvMjA2OTk2LW92ZXJ2aWV3\nDrugs & Diseases > Hematology\nAuthor: Eleanor S Pollak, MD; Chief Editor: Srikanth Nagalla, MBBS, MS, FACP more...\nSections von Willebrand Disease\nEvaluation of vWF Level and Function\nBleeding Time, PT, and aPTT\nWorkup by Type\nTesting for Therapeutic Options\nType I von Willebrand disease\nType 2 von Willebrand disease\nCoagulation Factors\nVasopressin-Related\nVon Willebrand disease (vWD) is a common, inherited, genetically and clinically heterogeneous hemorrhagic disorder caused by a deficiency or dysfunction of the protein termed von Willebrand factor (vWF). Consequently, defective vWF interaction between platelets and the vessel wall impairs primary hemostasis. (See Etiology and Workup.)\nvWF, a large, multimeric glycoprotein, circulates in blood plasma at concentrations of approximately 10 mg/mL. In response to numerous stimuli, vWF is released from storage granules in platelets and endothelial cells. It performs two major roles in hemostasis. First, it mediates the adhesion of platelets to sites of vascular injury. Second, it binds and stabilizes the procoagulant protein factor VIII (FVIII). (See Etiology.)\nvWD is divided into three major categories, as follows:\nType 1 – Partial quantitative vWF deficiency\nType 2 – Qualitative vWF deficiency\nType 3 - Total vWF deficiency\nvWD type 2 is further divided into four variants (2A, 2B, 2N, 2M), based on characteristics of dysfunctional vWF. These categories correspond to distinct molecular mechanisms, with corresponding clinical features and therapeutic recommendations. (See Etiology, Workup, and Treatment.) In a review of 670 French families with von Willebrand Disease, the distribution of VWD types was as follows [1] :\nType 1 – 25%\nType 3 – 8%\nUnknown type – 1%\nThe main treatment options for patients with vWD are desmopressin (DDAVP), recombinant vWF, and vWF/factor VIII (vWF/FVIII) concentrates. In addition, antifibrinolytic drugs (ie, aminocaproic acid, tranexamic acid) can be used orally or intravenously to treat mild mucocutaneous bleeding. See Treatment and Medication.\nFor discussion of vWD in children, see Pediatric Von Willebrand Disease.\nPatients should be instructed about their coagulation disorder and be aware of the conditions in which prophylactic therapy is highly recommended. Patient education information is available online through the following organizations:\nAmerican Society of Hematology\nNational Hemophilia Foundation (includes printable brochure)\nIn the great majority of cases, vWD is an inherited condition. The vWF gene is located near the tip of the short arm of chromosome 12. The gene is composed of 52 exons and spans a total of 180kb of the human genome; therefore, it is similar in size to the FVIII gene. Expression of the vWF gene is restricted to megakaryocytes, endothelial cells, and, possibly, placental syncytiotrophoblasts. A partial, nonfunctional duplication (pseudogene) is present on chromosome 22.\nvWF exists as a series of multimers varying in molecular weight between 0.5-kd (dimer) and 20 million kd (multimer). The building blocks of multimers are dimers, which are held together by disulfide bonds located near the C-terminal end of each subunit. [2]\nvWD type I\nvWD type I causes a mild to moderate quantitative deficiency of vWF (ie, about 20-50% of normal levels). In individuals with vWF levels < 0.3 IU/mL, type I is usually inherited in autosomal dominant fashion; in those with levels > 0.3 IU/mL, mutations show variable penetrance. [3]\nvWD type II\nvWD type II is due to qualitative vWF abnormalities and is subdivided into types IIA, IIB, IIN, and IIM. vWD type IIA, the most common qualitative abnormality of vWF, is associated with selective loss of large and medium-sized multimers. Most cases have autosomal dominant inheritance. [3]\nvWD type IIB characterized by the loss of large multimers occurs through a mechanism distinct from that of type IIA. Observations to date have identified a critical region of vWF involved in the binding of vWF to the platelet receptor glycoprotein Ib (GpIb). Each of the identified single amino acid substitutions is thought to result in a gain of function, leading to spontaneous binding of vWF to platelets.\nNormally, plasma vWF is inert in its interaction towards platelets until it encounters an exposed subendothelial surface. vWF binding to collagen and/or other ligands within the injured vessel wall presumably results in a secondary conformational change, which then facilitates binding to the GpIb receptor.\nIn vWD type IIB, the mutant vWF spontaneously binds to GpIb in the absence of subendothelial contact. The large multimers have the highest affinity for GpIb and are rapidly cleared from the plasma along with the bound platelets, resulting in thrombocytopenia and the characteristic loss of large multimers.\nvWD type IIN, sometimes referred to as vWD Normandy (after the province of origin of one of the first families identified with the disease), is characterized by a defect residing within the patient's plasma vWF that interferes with its ability to bind FVIII. This has important implications in the differential diagnosis of hemophilia. Most patients are compound heterozygotes with a vWF null allele. [3]\nvWD type IIM (for multimer) involves qualitative variants with decreased platelet-dependent function not resulting from absence of high–molecular weight multimers. Type IIM vWD can result from a variety of mutations and is heterogeneous. In a study of 14 patients with vWD type IIM, the consistent findings were significant prolongation in PFA-100 and greatly reduced or absentristocetin-induced platelet aggregation and vWF ristocetin cofactor. [4]\nvWD type III\nPatients with vWD type III, a severe, quantitative deficiency associated with very little or no detectable plasma or platelet vWF, have a profound bleeding disorder. vWD type III appears to result from the inheritance of a mutant vWF gene from both parents. In the most straightforward model, vWD type I would simply represent the heterozygous form of vWD type III; however, inheritance patterns indicate greater complexity.\nvWD type III is much rarer than the predicted frequency of 1 case per 40,000 persons based on this model, instead having a frequency closer to 1 case per 1 million persons. Although few mutations have been identified in families with pure vWD type I, some vWD type I cases have been suggested to be due to a mutant vWF subunit that interferes in a dominant, negative way with the normal allele, accounting for the autosomal dominant inheritance.\nThe discovery of a deletion of vWF (c.221-977_532 + 7059del [p.Asp75_Gly178del]) in 7 of 12 white patients with vWD type III from 6 unrelated families, and its absence in 9 Asian patients, led Sutherland et al to develop a genomic deoxyribonucleic acid (DNA) ̶ based assay for the deletion of vWF exons 4 and 5. [5] This deletion was also found in 12 of 34 vWD type I families and was associated with a specific vWF haplotype, which the investigators noted may indicate a possible founder origin. Additional studies demonstrated the presence of the mutation in other patients with type I vWD and in a family that expressed both type I and type III vWD. [5]\nSutherland et al reported the c.221-977_532 + 7059del mutation as a novel cause of type I and type III vWD and suggested that screening for this mutation in other type I and type III vWD patient populations may clarify its contribution to vWD that arises from quantitative vWF deficiencies. [5]\nAcquired vWD\nAcquired vWD is a rare disorder that results from the development of antibodies to vWF. Acquired vWD may arise from a variety of mechanisms—including lymphoproliferative, cardiovascular, and myeloproliferative diseases [6] —and typically resolves with treatment of the cause. [3]\nFor example, acquired vWD may occur in patients with hypothyroidism; these cases are typically mild to moderate and improve with restoration of euthyroidism. [7] Acquired vWD has also been reported as a cause of postoperative bleeding in patients with congenital heart disease, especially those with complex defects and Eisenmenger syndrome. [8] The narrowed pulmonary vasculature in idiopathic pulmonary arterial hypertension has also been identified as a cause of acquired vWD. [9] Acquired vWD has been reported in patients with active systemic lupus erythematosus. [10]\nClinically significant vWD affects approximately 125 persons per million population, with severe disease affecting approximately 0.5-5 persons per million population. Reports from screenings of unselected individuals indicated a higher prevalence of vWD abnormalities, ie, close to 1% of the population.\nSex- and age-related demographics\nMales and females are affected equally by vWD. However, the phenotype may be more pronounced in females, because of menorrhagia and the greater visibility of bruises. [11]\nIn the great majority of cases, vWD is an inherited condition. Bleeding-related symptoms may occur at a young age, even just after or during birth. Some reports have suggested a decreased bleeding tendency as patients age.\nFor most affected individuals, vWD is a mild, manageable bleeding disorder in which clinically severe hemorrhage manifests only in the face of trauma or invasive procedures. However, significant variability of symptomatology exists among family members.\nIn individuals with vWD types II and III, bleeding episodes may be severe and potentially life threatening. Individuals with type III disease who have correspondingly low FVIII levels may develop arthropathies, as more commonly seen in hemophilia A patients with comparably decreased FVIII levels.\nLevels of vWF normally increase with age. However, Sanders and colleagues found that although vWF levels increased with aging in patients with type I vWD, elderly patients with type I reported no change in their pattern of bleeding did not change. In patients with type II vWD, vWF levels did not increase with aging, and eldelry patients reported significantly more bleeding symptoms. [12]\nVeyradier 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. [Medline]. [Full Text].\nUdvardy 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. [Medline].\n[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. [Medline]. [Full Text].\nCasonato 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. [Medline].\nSutherland 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. [Medline].\nOdom 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. [Medline]. [Full Text].\nStuijver 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. [Medline].\nWaldow 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. [Medline].\nPelland-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. [Medline].\nCao 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. [Medline].\nByams 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. [Medline].\nSanders 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. [Medline].\n[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].\nRodeghiero F, Castaman G, Tosetto A. How I treat von Willebrand disease. Blood. 2009 Aug 6. 114(6):1158-65. [Medline]. [Full Text].\nSanders 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. [Medline].\nTosetto 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. [Medline].\nMannucci PM. New therapies for von Willebrand disease. Hematology Am Soc Hematol Educ Program. 2019 Dec 6. 2019 (1):590-595. [Medline].\nRodeghiero 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. [Medline]. [Full Text].\nDeforest 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. [Medline]. [Full Text].\nSharma 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. [Medline].\nGoodeve A. Diagnosing von Willebrand disease: genetic analysis. Hematology Am Soc Hematol Educ Program. 2016 Dec 2. 2016 (1):678-682. [Medline].\nHayward 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. [Medline].\nFlood 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:[Medline]. [Full Text].\nGill 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. [Medline]. [Full Text].\nO'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. [Medline].\nFranchini 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. [Medline].\nO'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. [Medline].\nNeff AT. Current controversies in the diagnosis and management of von Willebrand disease. Ther Adv Hematol. 2015 Aug. 6 (4):209-16. [Medline].\nDi 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. [Medline].\nRoberts JC, Flood VH. Laboratory diagnosis of von Willebrand disease. Int J Lab Hematol. 2015 May. 37 Suppl 1:11-7. [Medline].\nSabih A, Babiker HM. Von Willebrand Disease. 2020 Jan. [Medline]. [Full Text].\nBaronciani L, Peyvandi F. How we make an accurate diagnosis of von Willebrand disease. Thromb Res. 2020 Dec. 196:579-589. [Medline].\nCastaman G. How I treat von Willebrand disease. Thromb Res. 2020 Dec. 196:618-625. [Medline].\nEleanor S Pollak, MD Associate Director of Special Coagulation, Associate Professor, Department of Pathology and Laboratory Medicine, Section of Hematology and Coagulation, University of Pennsylvania\nEleanor S Pollak, MD is a member of the following medical societies: American Society of Hematology, College of American Pathologists, National Multiple Sclerosis Society\nSrikanth Nagalla, MBBS, MS, FACP Chief of Benign Hematology, Miami Cancer Institute\nSrikanth Nagalla, MBBS, MS, FACP is a member of the following medical societies: American Society of Hematology, Association of Specialty Professors\nDisclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Alexion; Alnylam; Kedrion; Sanofi .\nMarcel E Conrad, MD (Retired) Distinguished Professor of Medicine, University of South Alabama\nMarcel 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\nDisclosure: No financial interests None None\nKoyamangalath 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\nKoyamangalath 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\nSteven Stein, MD, Assistant Professor, Department of Medicine, Division of Hematology/Oncology, University of Pennsylvania\nSteven Stein, MD is a member of the following medical societies: American College of Physicians-American Society of Internal Medicine and American Society of Hematology\nFrancisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference\nDisclosure: Medscape Reference Salary Employment\nencoded search term (von Willebrand Disease) and von Willebrand Disease\nAcquired Hemophilia\nHemophilia C\nImaging in Musculoskeletal Complications of Hemophilia\nFactor IX Deficiency (Hemophilia B)\nFast Five Quiz: Bleeding Disorders\nGene Therapy a Potential 'Game Changer' for Hemophilia B\nMouth Splints Decrease Risk of Post-Dental Extraction Bleeding in Hemophilia\nPractice-Changing Data at This Year's ASH Meeting\nTop News From ASH 2017: Slideshow\nDiseases & Conditions Imaging in Musculoskeletal Complications of Hemophilia\nGene Therapy for Hemophilia: The Latest Updates and Potential Implications for Patient Care 0.5 CME / CE / ABIM MOC Credits\n0.5 CME / CE / ABIM MOC\nGene Therapy for Hemophilia: The Latest Updates and Potential Implications for Patient Care\nDiseases & Conditions Acquired Hemophilia"