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Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014.

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von Willebrand Disease

Synonym: von Willebrand Factor Deficiency

, PhD and , MD, FRCPC.

Author Information
, PhD
Professor and Head, Haemostasis Research Group
Sheffield University Faculty of Medicine, Dentistry & Health
Principal Clinical Scientist, Sheffield Diagnostic Genetics Service
Sheffield Children's NHS Foundation Trust
Sheffield, United Kingdom
, MD, FRCPC
Associate Professor and Hematologist
Queen’s University
Kingston, Ontario, Canada

Initial Posting: ; Last Update: July 24, 2014.

Summary

Disease characteristics. von Willebrand disease (VWD), a congenital bleeding disorder caused by deficient or defective plasma von Willebrand factor (VWF), may only become apparent on hemostatic challenge, and bleeding history may become more apparent with increasing age.

Type 1 VWD (~70% of VWD) typically manifests as mild mucocutaneous bleeding.

Type 2 VWD accounts for approximately 25% of VWD; the subtypes are:

  • Type 2A, which usually manifests as mild to moderate mucocutaneous bleeding;
  • Type 2B, which typically manifests as mild to moderate mucocutaneous bleeding that can include thrombocytopenia that worsens in certain circumstances;
  • Type 2M, which typically manifests as mild-moderate mucocutaneous bleeding;
  • Type 2N, which can manifest as excessive bleeding with surgery and mimics mild hemophilia A.

Type 3 VWD (<5% of VWD) manifests with severe mucocutaneous and musculoskeletal bleeding.

Diagnosis/testing. The diagnosis of VWD typically requires assays of hemostasis factors specific for VWD and/or molecular genetic testing of VWF, the only gene in which pathogenic variants are known to cause VWD. In most cases the diagnosis requires a positive family history.

Management. Treatment of manifestations: Affected individuals benefit from care in a comprehensive bleeding disorders program. Severe bleeding episodes can be prevented or controlled with intravenous infusion of virally inactivated plasma-derived clotting factor concentrates containing both VWF and FVIII; depending on the VWD type, mild bleeding episodes usually respond to intravenous or subcutaneous treatment with desmopressin, a vasopressin analog. Other treatments that can reduce symptoms include fibrinolytic inhibitors and hormones for menorrhagia. Pregnant women with VWD are at increased risk for bleeding complications at or following childbirth.

Prevention of primary manifestations: Prophylactic infusions of VWF/FVIII concentrates in individuals with type 3 VWD.

Prevention of secondary complications: Cautious use of desmopressin (particularly in those age <2 years because of the potential difficulty in restricting fluids in this age group). Vaccination for hepatitis A and B.

Surveillance: Follow up in centers experienced in the management of bleeding disorders. For those with type 3 VWD: periodic evaluations by a physiotherapist to monitor joint mobility.

Agents/circumstances to avoid: Activities involving a high risk of trauma, particularly head injury; medications with effects on platelet function (ASA, clopidogrel, or NSAIDS); circumcision in infant males should only be considered following consultation with a hematologist.

Evaluation of relatives at risk: If the familial pathogenic variant(s) are known, molecular genetic testing for at-risk relatives to allow early diagnosis and treatment, if needed.

Pregnancy management: As VWF levels increase throughout pregnancy, women with baseline VWF and FVIII levels of >30 IU/dL are likely to achieve normal levels by the time of delivery, whereas those with a basal level <20 IU/dL and those with baseline VWF:RCo/VWF:Ag ratio <0.6, are likely to require replacement therapy; desmopressin has been used successfully to cover delivery in women with type 1 VWD; delayed, secondary postpartum bleeding may be a problem.

Therapies under investigation: Recombinant VWF, now in clinical trials, is expected to be available soon for use instead of plasma-derived VWF.

Genetic counseling. Most VWD type 1 and most type 2A, type 2B, and type 2M VWD are inherited in an autosomal dominant (AD) manner. VWD type 2N, type 3 and some type 1 and type 2A are inherited in an autosomal recessive (AR) manner.

  • AD inheritance. Most affected individuals have an affected parent. The proportion of cases caused by de novo mutation is unknown. Each child of an individual with AD VWD has a 50% chance of inheriting the pathogenic variant.
  • AR inheritance. At conception, each sib of an individual with AR VWD has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for family members at risk for AR VWD is possible once the pathogenic variants have been identified in the family.

Prenatal testing, mostly for type 3 VWD, is possible if the pathogenic variant(s) in the family are known or if linkage analysis using intragenic markers is informative.

GeneReview Scope

von Willebrand Disease: Included Disorders
  • Type 1 von Willebrand disease
  • Type 2A von Willebrand disease
  • Type 2B von Willebrand disease
  • Type 2M von Willebrand disease
  • Type 2N von Willebrand disease
  • Type 3 von Willebrand disease

For synonyms and outdated names see Nomenclature.

Diagnosis

Clinical Diagnosis

Von Willebrand disease (VWD) is caused by deficient or defective plasma von Willebrand factor (VWF), a large multimeric glycoprotein that plays a pivotal role in primary hemostasis by mediating platelet hemostatic function and stabilizing blood coagulation factor VIII (FVIII).

The three types of VWD are [Sadler et al 2006]:

  • Type 1, partial quantitative deficiency of essentially normal VWF;
  • Type 2, qualitative deficiency of defective VWF, which is divided into four subtypes depending on VWF function perturbed: 2A, 2B, 2M, 2N;
  • Type 3, complete quantitative deficiency of (virtually absent) VWF;

VWD is suspected in persons with excessive mucocutaneous bleeding including the following:

  • Bruising without recognized trauma
  • Prolonged, recurrent nose bleeds
  • Bleeding from the gums after brushing or flossing teeth or prolonged bleeding following dental cleaning or dental extractions
  • Menorrhagia, particularly if occurring since menarche
  • Prolonged bleeding following surgery, trauma, or childbirth

The utility of standard clinical assessment tools to score occurrence of symptoms and their severity as part of VWD diagnosis is increasingly recognized [Tosetto et al 2006, Bowman et al 2008, Bowman et al 2009, Rodeghiero et al 2010]. These tools can: determine if there is more bleeding than in the general population; justify the diagnosis of a bleeding disorder; quantify the extent of symptoms, indicating situations requiring clinical intervention; and be used to indicate that a bleeding disorder is unlikely [Tosetto et al 2011].

The diagnosis requires assays of hemostasis factors specific for VWD (see Testing) and/or molecular genetic testing of VWF.

In addition, the diagnosis requires (in most cases) a positive family history. Note: In mild type 1 VWD, family history may not be positive because of incomplete penetrance and variable expressivity.

Testing

Screening tests

  • Complete blood count (CBC) may be normal, but could also show a microcytic anemia (if the individual is iron deficient) or a low platelet count (thrombocytopenia), specifically in type 2B VWD.
  • Activated partial thromboplastin time (aPTT) is often normal, but may be prolonged when the factor VIII level is reduced to below 30-40 international units per deciliter (IU/dL), as can be seen in severe type 1 VWD, type 2N VWD, or type 3 VWD. The normal range for factor VIII clotting activity is approximately 50-150 IU/dL.
  • Prothrombin time (PT) is normal in VWD.
  • Other. Although some laboratories may also include a skin bleeding time and platelet function analysis (PFA closure time) in their evaluation of an individual with suspected VWD, these tests lack sensitivity in persons with mild bleeding disorders.

Hemostasis factor assays. The following specific hemostasis factor assays (see Table 1) should be performed even if the screening tests are normal [Budde et al 2006]. Note: Normal ranges are determined by individual laboratory and thus are indicative only.

  • VWF:RCo. Functional VWF assay (also called ristocetin cofactor activity assay); that is, ability of VWF to agglutinate platelets, initiated by the antibiotic ristocetin (normal range ~50-200 IU/dL). Several new VWF activity assays are becoming available, but published comparisons between the VWF:RCo assay and these new tests is insufficient to make any recommendation on their use.
  • VWF:Ag. Quantity of VWF protein (antigen) in the plasma, measured antigenically using enzyme-linked immunosorbant assay (ELISA) or latex immunoassay (LIA) [Castaman et al 2010a] (normal range ~50-200 IU/dL). A reduced ratio (<0.6) of VWF:RCo/VWF:Ag can indicate loss of high molecular-weight (HMW) multimers.
  • Factor VIII:C level. Functional FVIII assay (i.e., activity of FVIII in the coagulation cascade) (normal range~ 50-150 IU/dL)

If abnormalities in the tests above are identified, specialized coagulation laboratories may also perform the following assays to determine the subtype of VWD:

  • VWF multimer analysis. SDS-agarose electrophoresis used to determine the complement of VWF oligomers in the plasma. Normal plasma contains VWF ranging from dimers to multimers comprising more than 40 dimers. Multimers are classified as low (1-5 dimer), intermediate (6-10 dimer), and high (≥10 dimers) molecular weight. HMW multimers are decreased or missing in type 2A and often in 2B VWD; intermediate MW may also be lost in type 2A VWD. Abnormalities in satellite (“triplet”) band patterns can give clues as to pathogenesis and help to classify subtypes of type 2 VWD [Budde et al 2008].
  • Ristocetin-induced platelet agglutination (RIPA). Ability of VWF to agglutinate platelets at 2-3 concentrations of ristocetin. Agglutination at a low concentration (~0.5-0.7 mg/mL) is abnormal and may indicate type 2B or platelet-type pseudo VWD (PT-VWD) caused by pathogenic variants in GPIBA (see Differential Diagnosis), in which enhanced VWF-platelet binding is present.
  • Binding of FVIII by VWF (VWF:FVIIIB). Ability of VWF to bind FVIII. Essential in order to identify type 2N VWD.
  • Collagen binding assay (VWF:CB). Ability of VWF to bind to collagen (a sub-endothelial matrix component). Used to help define functional VWF discordance (i.e., to help distinguish types 1 and 2 VWD) [Flood et al 2013]. Collagen I/III mixture is often used, but isolated deficient binding to collagen VI has recently been recognized [Flood et al 2012]. Normal range is approximately 50-200 IU/dL. A reduced ratio of VWF:CB/VWF:Ag can indicate loss of HMW multimers.

Table 1. Classification of VWD Based on Specific VWF Tests

VWD TypeVWF:RCo 1VWF:Ag 1RCo/AgFVIII:C IU/dL 1Multimer Pattern 2Other
1LowLowEquivalent~1.5x VWF:AgEssentially normal
2ALowLowVWF:RCo < VWF:AgLow or normalAbnormal ↓ HMW
2BLowLowVWF:RCo < VWF:AgLow or normalOften abnormal ↓ HMW↑ RIPA 3 (↓ platelet count)
2MLowLowVWF:RCo << VWF:AgLow or normalNo loss of HMW
2NNormal/lowNormal/lowEquivalent<40Normal in most cases↓ VWF:FVIIIB 4
3AbsentAbsentNA<10Absent

1. Relative to the reference range (approximate values); VWF:RCo (50-200 IU/dL), VWF:Ag (50-200 IU/dL), FVIII:C (50-150 IU/dL)

2. HMW multimers

3. Increased agglutination at low concentrations of ristocetin

4. The ability of VWF to bind and protect FVIII is reduced. VWF and FVIII levels can look exactly like those in males with mild hemophilia A or in symptomatic hemophilia A carrier females.

Molecular Genetic Testing

Gene. VWF is the only gene in which pathogenic variants are known to cause VWD.

Note:

  • The current classification scheme does not restrict VWD to being caused by identifiable pathogenic variants in VWF. Evaluation of the entire VWF coding region fails to identify a VWF pathogenic variant in some cases of “apparent” VWD. A recent study that used Sanger sequence analysis plus dosage analysis identified pathogenic variants in 94% of individuals with type 3 VWD (n=18) and 94% of individuals with type 2 VWD (n= 32), but detected candidate pathogenic variants in only 68% of those diagnosed with type 1 VWD (n= 28) [Yadegari et al 2012]. Mutation detection rates in this study closely reflect those of several other studies. Failure to identify a pathogenic variant in VWF does not exclude a diagnosis of VWD.
  • Platelet-type pseudo VWD (PT-VWD) results from pathogenic variants in GPIBA, but presents phenotypically like type 2B VWD (see Differential Diagnosis).

Clinical testing. Domain structure and exons encoding each VWF domain are shown in Figure 1.

Figure 1

Figure

Figure 1. VWF protein structure [adapted from Zhou et al 2012] and location of VWF mutations by VWD type. Bold horizontal lines indicate the approximate position of exons where mutations are most prevalent; thinner lines indicate exons with mutations (more...)

  • Sequence analysis of the entire coding region and flanking exon/intron junctions of VWF is possible, although it is complicated by gene size, structure, and a partial pseudogene (see Molecular Genetics).
  • Linkage analysis can be useful in type 3 VWD to facilitate prenatal diagnosis if two pathogenic variants cannot be identified in an affected individual. See Table 4 for benign allelic variants of VWF that are useful for linkage analysis.
  • Deletion/duplication analysis of VWF using any of a number of methods that detect copy number changes is possible [Yadegari et al 2011], but the extent of contribution of large deletions or duplications has not been established within VWD patient cohorts and large heterozygous pathogenic variants have likely been previously overlooked. Large deletions currently comprise 7% of pathogenic variant reports in individuals with type 3 VWD in the ISTH-SSC VWF Database. Large in-frame deletions have also been reported in type 1 and type 2 VWD [Sutherland et al 2009, Casari et al 2010] and two duplications of one or two exons have also been reported in conference abstracts [Schneppenheim et al 2011, Boisseau et al 2013].
  • Gene conversion events can affect sequences from the 3’ end of intron 27 into the 5’ end of exon 28. The pathogenic variants can be recognized through two or more sequential sequence variants from the pseudogene sequence (VWFP) replacing those in the coding gene. Conversions of 6-335 bp are most commonly seen and have been reported in VWD types 1, 2B, and 3.

Type 1 VWD. Pathogenic variants have been identified in approximately 60%-65% of individuals with type 1 VWD [Cumming et al 2006, Goodeve et al 2007, James et al 2007a, Yadegari et al 2012].

  • Fully penetrant, dominantly inherited missense mutations are often identified when VWF:Ag and VWF:RCo levels are lower than 25 IU/dL.
  • Incompletely penetrant dominantly inherited missense mutations, such as p.Tyr1584Cys, are identified in approximately 50% of individuals whose VWF:Ag and VWF:RCo levels are 25-50 IU/dL.
  • The extent to which incompletely penetrant VWF pathogenic variants contribute to bleeding phenotype in individuals with VWF levels above 35 IU/dL is not clear and genetic analysis in such cases may not be easy to interpret [Keeney et al 2008].

Because approximately 50% of pathogenic variants in type 1 VWD are located between exons 18 and 28, these exons can be analyzed first. However, the entire gene should be sequenced for comprehensive mutation ascertainment.

Type 2 VWD. Most pathogenic variants seen in types 2A and 2M and all missense mutations in type 2B are located in exon 28; thus, exon 28 should be examined first when any of these three VWD subtypes is suspected.

  • Type 2A (AD) VWD. Pathogenic variants are predominantly located in exon 28, affecting the A2 and (to a lesser extent) the A1 domain. The D3 assembly (exons 22 and 25-27) is also a common location of pathogenic variants (AD) [Schneppenheim et al 2010].
  • Type 2A VWD. Missense mutations have also been reported in exons 11-16 (AR), and 52 (AD & AR), which should be examined subsequently. Additionally, there are case reports of pathogenic variants in several other exons.
  • Type 2A (AR) VWD. Affected individuals are either homozygous for the same missense mutation (often seen in consanguineous families) or compound heterozygous for a missense mutation and a null allele.
  • Type 2B (AD) VWD. Missense mutations are located in exon 28 in or close to the A1 domain [Federici et al 2009].
  • Type 2M (AD) VWD. Pathogenic variants are predominantly located in exon 28. A small group of variants that impair binding to collagen are located in the A3 domain encoded by exons 29-32 [Keeling et al 2012].
  • Type 2N (AR) VWD. Most missense mutations are located in exons 18-20; a much lower proportion has been reported in exons 17 and 24-25 [Mazurier & Hilbert 2005].
    • A proportion of individuals are homozygous for a missense mutation, particularly for p.Arg854Gln, which is present in the heterozygous form in 1% of northern European populations.
    • Most individuals are compound heterozygotes for a missense mutation and a pathogenic variant resulting in a null allele. Less commonly, individuals can be compound heterozygotes for two missense mutations.

Type 3 VWD. Pathogenic variants associated with type 3 VWD are found throughout the entire coding region of VWF (i.e., exons 2-52). Sequence analysis of the entire coding region plus deletion/duplication analysis identifies pathogenic variants in around 90% of type 3 VWD.

  • Twenty percent are missense mutations. Locations include the D1 (exons 3-10) and A1-A2 domains (exon 28) (Figure 1).
  • Eighty percent are null alleles located throughout VWF (see Table A). Null alleles can result from many different types of mutations. Null alleles do not produce a functional protein product because a mutation results in either the complete absence/instability of mRNA or protein or the expression of a non-functional gene product (e.g., a protein that cannot be secreted).
  • Deletion/duplication (dosage) analysis is possible, but the extent of contribution of large deletions or duplications to VWD has not been well established. Large deletions currently comprise 7% of pathogenic variants reported in individuals with type 3 VWD in the ISTH-SSC VWF Database.
  • Linkage analysis can be a useful alternative to mutation analyses in families with type 3 VWD seeking prenatal diagnosis if both pathogenic variants cannot be identified.

Table 2. Summary of Molecular Genetic Testing Used in von Willebrand Disease (VWD)

Gene 1VWD Type(s)Proportion of VWD Attributed to This TypeTest MethodMutations Detected`Proportion of Probands with a Pathogenic Variant Detectable by this Method 2
VWF1~70%Sequence analysis of entire coding and flanking intronic regionsSequence variants 360%-65%
Deletion / duplication analysis 4Partial- and whole-gene deletions/ duplications<5%
Sequence analysis of select exonsSequence variants 3 in exons 18-28~50%
All type 2 forms~25% 5Sequence analysis of selected exonsSequence variants 3~90% 6
2A (AD)
2B
2M
See footnote 2Sequence analysis of select exonsSequence variants 3 in exon 28~70%
2A (AR)See footnote 2Sequence variants 3 in exons 11-16, 22, 25-27 & 52~30% of those with 2A
2NSee footnote 2Sequence variants 3 in exons 18-20~80%
3<5% 7 Sequence analysis of entire coding and flanking intronic regionsSequence variants 3~90%
Deletion / duplication analysis 4Partial- and whole-gene deletions / duplications<10%
All typesNALinkage analysisNANA

AD = autosomal dominant inheritance

AR = autosomal recessive inheritance

NA = not applicable

1. See Table A. Genes and Databases for chromosome locus and protein name. See Molecular Genetics for information on allelic variants.

2. The ability of the test method used to detect a mutation that is present in the indicated gene

3. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

5. Type 2 accounts for approximately 25% of all VWD. The relative frequency of the subtypes is 2A>2M>2N>2B in populations of European origin.

6. Yadegari et al [2012]

7. In populations with frequent consanguineous partnerships, the rate of recessive forms of VWD may be elevated and type 3 VWD comprise a larger proportion of affected individuals.

Test characteristics. Information on test sensitivity and specificity as well as other test characteristics can be found at EuroGentest [Cumming et al 2011 (full text)].

Testing Strategy

To confirm/establish the diagnosis in a proband. In those individuals with type 2 VWD in whom specific VWD hemostasis factor assays can provide a clear diagnosis, molecular genetic testing may not be warranted.

Molecular genetic testing for VWD is usually indicated in the following cases:

  • To establish the VWD subtype in those individuals in whom specific VWD hemostasis factor assays suggest VWD, but in whom genetic analysis may provide a more definitive diagnosis
  • To distinguish between type 2N VWD, mild hemophilia A (males), or a symptomatic carrier of hemophilia A (females), where phenotypic testing remains inconclusive (e.g., VWF:FVIIIB assay is unavailable or inconclusive)
  • To distinguish between type 2B VWD and PT-VWD, as treatment may differ for these two disorders.
  • For families with type 3 VWD requesting prenatal diagnosis
  • To determine inheritance pattern and thus risk to family members, when this is unclear from pedigree analysis

A guideline on VWD genetic testing has been published by the UK Haemophilia Centre Doctors’ Organisation [Keeney et al 2008]

Clinical Description

Natural History

von Willebrand disease (VWD) is a congenital bleeding disorder; however, symptoms may only become apparent on hemostatic challenge and bleeding history may become more apparent with increasing age. Thus, it may take some time before a bleeding history becomes apparent.

Bleeding history also depends on disease severity; type 3 VWD is often apparent early in life, whereas mild type 1 VWD may not be diagnosed until midlife, despite a history of bleeding episodes.

Individuals with VWD primarily manifest excessive mucocutaneous bleeding (bruising, epistaxis, menorrhagia, etc.) and do not tend to experience musculoskeletal bleeding unless the FVIII:C level is lower than 10 IU/dL, as can be seen in type 2N or type 3 VWD.

Type 1 VWD accounts for approximately 70% of all VWD in populations with infrequent consanguineous partnerships. It typically manifests as mild mucocutaneous bleeding; however, symptoms can be more severe when VWF levels are lower than 15 IU/dL. Epistaxis and bruising are common symptoms among children. Menorrhagia is the most common finding in women of reproductive age [James & Lillicrap 2006, Kadir & Chi 2006, Tosetto et al 2006].

Type 2 VWD accounts for approximately 25% of all VWD. The relative frequency of the subtypes is 2A>2M>2N>2B in European populations.

  • Type 2A VWD. Individuals with type 2A VWD usually present with mild to moderate mucocutaneous bleeding.
  • Type 2B VWD. Individuals typically present with mild-moderate mucocutaneous bleeding. Thrombocytopenia may be present. A hallmark of type 2B VWD is a worsening of thrombocytopenia during stressful situations, such as severe infection or during surgery or pregnancy, or if treated with desmopressin.
  • Type 2M VWD. Individuals typically present with mild-moderate mucocutaneous bleeding symptoms, but bleeding episodes can be severe, particularly in the presence of very low or absent VWF:RCo [Castaman et al 2012].
  • Type 2N VWD. Symptoms are essentially the same as those seen in mild hemophilia A and include excessive bleeding at the time of surgery or procedures as both disorders result from reduced FVIII:C.

Type 3 VWD accounts for less than 5% of VWD, apart from in areas where consanguineous partnerships are common. It manifests with severe bleeding including both excessive mucocutaneous bleeding and musculoskeletal bleeding [Metjian et al 2009].

Genotype-Phenotype Correlations

In general, there is an inverse relationship between the VWF level and the severity of bleeding [Tosetto et al 2006]. Bleeding scores (BS) have been documented in several cohort studies and give an indication of the range of bleeding severity associated with different VWD types and with specific pathogenic variants:

Table 3. Bleeding Scores by VWD Type

Patient GroupStudyNumber of PatientsBS MedianBS Range
Type 1Goodeve et al [2007]1509-1-24
Type 2ACastaman et al [2012] 46116-16
Type 2BFederici et al [2009]4054-24
Type 2MCastaman et al [2012] 6174-28
Type 3Solimando et al [2012] 9156-26
Type 3Bowman et al [2013]42133-30

The higher the bleeding score, the greater the bleeding severity

Note: Although the studies above have all used similar bleeding assessment tools, slight variations in the tools and their application may have contributed to differences in bleeding scores.

Type 2N VWD. Missense mutations reduce the ability of VWF to bind and protect FVIII. VWF and FVIII levels can look exactly like those in males with mild hemophilia A or in symptomatic hemophilia A carrier females.

ABO blood group. Blood group contributes approximately 25% of the variance in plasma VWF level; ABO glycosylation of VWF influences its rate of clearance [Jenkins & O'Donnell 2006]. Individuals with non-O blood groups have higher VWF levels than those with O blood group; those with group AB have the highest levels. ABO blood group appears to be an important contributor to penetrance and reduced VWF level in type 1 VWD [Goodeve et al 2007, James et al 2007a], as has been observed with the common pathogenic variant p.Tyr1584Cys [O'Brien et al 2003, Davies et al 2007].

Penetrance

VWD type 1 (AD). Pathogenic variants resulting in plasma VWF levels lower than 25 IU/dL are mostly fully penetrant. Those resulting in higher VWF levels are often incompletely penetrant.

Pathogenic variants causal for other AD types, 2A, 2B, and 2M are often fully penetrant.

Nomenclature

Changes in nomenclature:

  • von Willebrand's disease has been replaced by von Willebrand disease.
  • vWF has been replaced by VWF.
  • vWD has been replaced by VWD.
  • RiCof (ristocetin cofactor activity) has been replaced by VWF:RCo [Mazurier & Rodeghiero 2001]; see ISTH VWF Web site for nomenclature.
  • FVIII RAg (FVIII related antigen) has been replaced by VWF:Ag.
  • Platelet-type pseudo von Willebrand disease (PT-VWD), also called pseudo-VWD, is caused by pathogenic variants in GP1BA and, thus, is not a form of VWD (see Differential Diagnosis).
  • Acquired von Willebrand syndrome (AVWS), previously known as acquired VWD, is the preferred terminology for defects in VWF concentration, structure, or function that are neither inherited nor reflective of pathogenic variants in VWF, but arise as consequences of other medical conditions (see brief discussion of AVWS under Differential Diagnosis).

Prevalence

VWD affects 0.1% to 1% of the population; one in 10,000 seek tertiary care referral.

VWD type 3 affects 0.5 to six per million population, increasing with the rate of consanguinity.

Differential Diagnosis

Two disorders can be difficult to distinguish phenotypically from von Willebrand disease (VWD):

  • Mild hemophilia A, caused by pathogenic variants in F8, resembles type 2N VWD in that reduced levels of FVIII:C (~5-40 IU/dL) and normal-to-borderline-low levels of VWF can be seen in both disorders. The VWF:FVIIIB test, which determines the ability of VWF to bind FVIII, can be used to distinguish between the two disorders [Casonato et al 2007] and a commercial assay is now available [Veyradier et al 2011]; however, its availability may be limited. Alternatively, molecular genetic testing can be used to differentiate the two disorders.

    In families with reduced FVIII:C, an X-linked pattern of inheritance can help identify those with mild hemophilia A. When family history is uninformative, sequence analysis of F8 should be performed first, even in symptomatic females who are simplex cases (i.e., a single occurrence in a family), because an F8 mutation plus skewed X-chromosome inactivation are often responsible for symptoms. In these cases, F8 intrachromosomal inversions should be sought and DNA sequence analysis or mutation scanning of F8 exons 1-26 performed. In females, dosage analysis of F8 can also be used to identify heterozygous partial/complete gene deletions/duplications. Pathogenic variants are detected in more than 50% of cases investigated for “possible 2N VWD or hemophilia A.” When F8 pathogenic variants are absent, screening of VWF exons should follow.
  • PT-VWD (also called pseudo VWD) (OMIM 177820), caused by pathogenic variants in GP1BA, may be difficult to distinguish from type 2B VWD. The two disorders can be distinguished by mixing patient/control plasma and platelets to determine which component is defective [Favaloro et al 2007, Favaloro 2008, Franchini et al 2008]. When pathogenic variants are absent from exon 28 of VWF, pathogenic variants in exon 2 of GP1BA may be identified. To date, missense mutations reported are between GpIbα amino acids Trp246 and Met255 plus a 27-bp in-frame deletion Pro449_Ser457del (1345_1371del27) [Othman et al 2005, Hamilton et al 2011, Woods et al 2014, PT-VWD Registry] (per standard naming conventions of the Human Genome Variation Society; reference sequences NP_000164.4 and NM_000173.4).

    PT-VWD is probably underdiagnosed. Misdiagnosis of the disorder may result in ineffective treatment. VWF concentrate is needed to correct the reduced VWF level, but platelet transfusion may also be required if there is significant thrombocytopenia. The half-life of replaced VWF is reduced as a result of binding to the abnormal GpIbα, necessitating more frequent adminstration of VWF concentrate than in VWD. Molecular genetic testing of GP1BA may identify missense or in-frame mutations in up to 15% of persons diagnosed with 2B VWD [Hamilton et al 2011].

Acquired von Willebrand syndrome (AVWS) is a mild-moderate bleeding disorder that can occur in a variety of conditions [Federici 2006, Nichols et al 2008, Sucker et al 2009, Federici et al 2013] but is not caused by mutation of VWF. It is most often seen in persons over age 40 years with no prior bleeding history. AVWS has diverse pathology and may result from:

  • Lymphoproliferative or plasma cell proliferative disorders, paraproteinemias (monoclonal gammopathy of unknown significance [MGUS]), multiple myeloma, and Waldenstrom macroglobulinemia. Antibodies against VWF have been detected in some of these cases.
  • Autoimmune disorders including systemic lupus erythrematosus (SLE), scleroderma, and antiphospholipid antibody syndrome
  • Shear-induced VWF conformational changes leading to increased VWF proteolysis (e.g., aortic valve stenosis, ventricular septal defect)
  • Markedly increased blood platelet count (e.g., essential thrombocythemia or other myeloproliferative disorders)
  • Removal of VWF from circulation by aberrant binding to tumor cells (e.g., Wilm’s tumor or certain lymphoproliferative disorders)
  • Decreased VWF synthesis (e.g., hypothyroidism)
  • Certain drugs (e.g., valproic acid, ciprofloxacin, griseofulvin, hydroxyethyl starch)

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with von Willebrand disease (VWD), the following evaluations are recommended:

  • A personal and family history of bleeding to help predict severity and tailor treatment. Use of a bleeding assessment tool can facilitate standardized assessment [International Society on Thrombosis and Haemostasis 2011, Tosetto et al 2011].
  • A joint and muscle evaluation for those with type 3 VWD (musculoskeletal bleeding is rare in types 1 and 2 VWD).
  • Screening for hepatitis B and C as well as HIV if the diagnosis is type 3 VWD or if the individual received blood products or plasma-derived clotting factor concentrates before 1985.
  • Baseline serum concentration of iron and ferritin to assess iron stores, as many individuals with VWD (particularly women with menorrhagia) are iron deficient
  • Gynecologic evaluation for women with menorrhagia [Demers et al 2005]
  • Medical genetics consultation

Treatment of Manifestations

See Nichols et al [2008] (full text) and Castaman et al [2013] (full text) for treatment guidelines.

Individuals with VWD benefit from referral to a comprehensive bleeding disorders program for education, treatment, and genetic counseling.

The two main treatments are desmopressin (1-deamino-8-D-arginine vasopressin [DDAVP]) and clotting factor concentrates containing both VWF and FVIII (VWF/FVIII concentrate). Individuals with VWD should receive prompt treatment for severe bleeding episodes.

Desmopressin

Most individuals with type 1 VWD and some with type 2 VWD respond to intravenous or subcutaneous treatment with desmopressin [Castaman et al 2008, Federici 2008, Leissinger et al 2014], which promotes release of stored VWF and raises levels three- to fourfold. Intranasal preparations are also available.

Following VWD diagnosis, a desmopressin challenge is advisable to assess VWF response.

Desmopressin is the treatment of choice for acute bleeding episodes or to cover surgery.

Desmopressin has been used successfully to cover delivery in women with type 1 VWD and also for a proportion of pregnant women with type 2 VWD [Castaman et al 2010b] (see Pregnancy Management).

In persons who do not tolerate desmopressin or who have a poor VWF response, clotting factor concentrate is required.

Desmopressin is contraindicated in individuals with arteriovascular disease and in those over age 70 years for whom VWF/FVIII concentrate is required.

Note: Because desmopressin can cause hyponatremia (which can lead to seizures and coma), fluid intake should be restricted for 24 hours following its administration to minimize this risk.

Intravenous Infusion of VWF/FVIII Clotting Factor Concentrates

In those who are non-responsive to desmopressin (i.e., VWF deficiency is not sufficiently corrected) and for those in whom desmopressin is contraindicated (see Treatment by VWD Type), bleeding episodes can be prevented or controlled with intravenous infusion of virally inactivated plasma-derived clotting factor concentrates containing both VWF and FVIII [Federici 2007]. Such concentrates are prepared from pooled blood donations from many donors. Virus inactivation procedures eliminate potential pathogens.

Indirect Treatments

In addition to treatments that directly increase VWF levels, individuals with VWD often benefit from indirect hemostatic treatments, including:

  • Fibrinolytic inhibitors (i.e., tranexamic acid for treatment or prevention of bleeding episodes);
  • Hormonal treatments (i.e., the combined oral contraceptive pill for the treatment of menorrhagia).

Treatment by VWD Type

Type 1 VWD. Treatments that directly increase VWF levels (e.g., desmopressin or VWF/FVIII clotting factor concentrates) are usually only needed for the treatment or prevention of severe bleeding, as with major trauma or surgery.

Indirect treatment with fibrinolytic inhibitors or hormones is often effective.

Type 2A VWD. Treatment with clotting factor concentrates is usually only required for the treatment or prevention of severe bleeding episodes such as during surgery.

Responsiveness to desmopressin is variable and should be confirmed prior to therapeutic use.

Indirect treatments can be beneficial.

Type 2B VWD. Clotting factor concentrates are usually required to treat severe bleeding or at the time of surgery.

Treatment with desmopressin should be undertaken cautiously as it can precipitate a worsening of any thrombocytopenia. People with certain pathogenic variants associated with mild or atypical 2B VWD, however, do not appear to develop thrombocytopenia when exposed to desmopressin. [Federici et al 2009]

Indirect treatments (i.e., fibrinolytic inhibitors) can be useful.

Type 2M VWD. Because desmopressin response is generally poor, VWF/FVIII concentrate is the treatment of choice.

Type 2N VWD. Desmopressin can be used for minor bleeding, but because the FVIII level will drop rapidly (as FVIII is not protected by VWF), concentrate containing VWF as well as FVIII is required to cover surgical procedures.

Type 3 VWD. Treatment often requires the repeated infusion of VWF/FVIII clotting factor concentrates [Franchini et al 2007].

Desmopressin is not effective in type 3 VWD.

Indirect treatments may also be beneficial.

Pediatric Issues

Special considerations for the care of infants and children with VWD include the following:

  • Infant males should be circumcised only after consultation with a pediatric hemostasis specialist.
  • Desmopressin should be used with caution, particularly in those under age two years, because of the potential difficulty in restricting fluids in this age group.
  • VWF levels are higher in the neonatal period; thus, phenotypic testing for milder forms of VWD should be delayed until later in childhood.

Prevention of Primary Manifestations

Individuals with type 3 VWD are often given prophylactic infusions of VWF/FVIII concentrates to prevent musculoskeletal bleeding and subsequent joint damage.

Prevention of Secondary Complications

Desmopressin should be used with caution, particularly in those under age two years, because of the potential difficulty in restricting fluids in this age group.

Individuals with VWD should be vaccinated for hepatitis A and B [Nichols et al 2008, Castaman et al 2013].

Prevention of chronic joint disease is a concern for individuals with type 3 VWD; however, controversy exists regarding the specific schedule and dosing of prophylactic regimens. An international trial that investigated prophylactic treatment for symptoms including joint bleeding, nosebleeds, and menorrhagia concluded that rates of bleeding within individuals during prophylaxis were significantly lower than levels prior to prophylaxis [Berntorp et al 2010, Abshire et al 2013].

Surveillance

Individuals with milder forms of VWD can benefit from being followed by treatment centers with experience in the management of bleeding disorders.

Individuals with type 3 VWD should be followed in experienced centers and should have periodic evaluations by a physiotherapist to monitor joint mobility.

Agents/Circumstances to Avoid

Activities with a high risk of trauma, particularly head injury, should be avoided.

Medications with effects on platelet function (ASA, clopidogrel, or NSAIDs) should be avoided as they can worsen bleeding symptoms.

Infant males should be circumcised only after consultation with a pediatric hemostasis specialist.

Evaluation of Relatives at Risk

Once the familial pathogenic variant(s) have been identified, at-risk relatives can be readily analyzed for the pathogenic variant(s) to allow early diagnosis and treatment as needed [Keeney et al 2008].

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

VWF levels increase throughout pregnancy with the peak occurring in the third trimester. Nonetheless, pregnant women with VWD are at increased risk for bleeding complications and care should be provided in centers with experience in perinatal management of bleeding disorders [James & Jamison 2007, Varughese & Cohen 2007, James et al 2009].

Women with baseline VWF and FVIII levels of >30 IU/dL are likely to achieve normal levels by the time of delivery, whereas those with a basal level <20 IU/dL and those with baseline VWF:RCo/VWF:Ag ratio <0.6 are likely to require replacement therapy [Castaman et al 2013].

Although deliveries should occur based on obstetric indications, instrumentation should be minimized [Demers et al 2005].

Delayed, secondary postpartum bleeding may be a problem. VWF level rapidly returns to pre-pregnancy level following delivery [Castaman et al 2013].

Therapies Under Investigation

Recombinant VWF is in clinical trials and is expected to be available for patient use in the near future. It may largely replace use of plasma-derived VWF, as has happened for FVIII and FIX recombinant products [Turacek et al 2010, Mannucci et al 2013].

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Most von Willebrand disease (VWD) type 1, most type 2A, type 2B, and type 2M are inherited in an autosomal dominant manner.

VWD type 2N, type 3, and some type 1 and type 2A are inherited in an autosomal recessive manner.

A single case of uniparental disomy has been reported in type 3 VWD. The two copies of the pathogenic variant resulted from maternal uniparental isodisomy [Boisseau et al 2011].

Risk to Family Members – Autosomal Dominant Inheritance

Parents of a proband

  • Most individuals diagnosed with one of the AD types of VWD have an affected parent.
  • A proband with AD VWD may have the disorder as the result of a new gene mutation. The proportion of cases caused by de novo mutation is unknown.
  • If the VWF pathogenic variant causing AD VWD found in the proband cannot be detected in the DNA of either parent, two possible explanations are germline mosaicism in a parent or de novo mutation in the proband. Neither possibility has been sufficiently investigated to comment on relative likelihood of occurrence.
  • The family history of some individuals diagnosed with AD VWD may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the recognition of symptoms, or late significant hemostatic challenges in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless appropriate evaluations (e.g., VWD hemostasis factor assays and/or molecular genetic testing if the proband’s pathogenic variant is known) have been performed on the parents of the proband.

Sibs of a proband

  • The risk to the sibs of the proband depends on the genetic status of the proband’s parents.
  • If a parent of the proband is affected, the risk to the sibs is 50%.
  • The sibs of a proband with clinically unaffected parents are still at increased risk for the disorder because of the possibility of reduced penetrance in a parent.
  • If the VWF variant found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is low, but greater than that of the general population because of the possibility of germline mosaicism.

Offspring of a proband. Each child of an individual with AD VWD has a 50% chance of inheriting the VWF pathogenic variant.

Other family members of a proband. The risk to other family members depends on the status of the proband's parents. If a parent is affected, his or her family members may be at risk.

Risk to Family Members – Autosomal Recessive Inheritance

Parents of a proband

  • The parents of an individual with AR VWD are usually obligate heterozygotes (i.e., carriers of one VWF pathogenic variant).
  • Heterozygotes (carriers) of type 3 VWD are often asymptomatic. However, between 15% and 50% may show some mild bleeding symptoms and may be diagnosed with type 1 VWD [Nichols et al 2008, Bowman et al 2013].
  • Heterozygotes (carriers) of type 2N VWD are often asymptomatic. However, a small proportion may show some mild bleeding symptoms and may be diagnosed with type 1 VWD.

Sibs of a proband

  • When both parents are carriers of a VWF pathogenic variant, each sib of an individual with AR VWD has at conception a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of being unaffected and not a carrier.
  • Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
  • When only one parent is a carrier (in the case of uniparental isodisomy [Boisseau et al 2011]), the risk to sibs of a proband to be affected is unknown, but likely very low (<1%). However, each sib has a 50% chance of being a carrier and a 50% chance of being unaffected and not a carrier.
  • Heterozygotes (carriers) of type 3 VWD are often asymptomatic. However, between 15% and 50% may show some mild bleeding symptoms and may be diagnosed with type 1 VWD [Nichols et al 2008, Bowman et al 2013].

Offspring of a proband. The offspring of an individual with AR VWD are obligate heterozygotes (carriers) for a pathogenic variant in VWF.

Other family members of a proband. Each sib of the proband’s parents is at 50% risk of being a carrier of a VWF pathogenic variant.

Carrier Detection

Carrier testing for at-risk family members is possible once the pathogenic variant(s) have been identified in the family.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Considerations in families with apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has the pathogenic variant or clinical evidence of the disorder, it is likely that the proband has de novo mutation. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the VWF pathogenic variant(s) have been identified in an affected family member, prenatal testing for pregnancies at increased risk (generally for type 3 VWD) may be available from a clinical laboratory that offers either testing for this disease/gene or custom prenatal testing.

Prenatal diagnosis of a treatable condition may be controversial if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider this to be the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the VWF pathogenic variants have been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Medline Plus
  • National Heart, Lung, and Blood Institute (NHLBI)
    PO Box 30105
    Bethesda MD 20824-0105
    Phone: 301-592-8573; 240-629-3255 (TTY)
    Fax: 240-629-3246
    Email: nhlbiinfo@nhlbi.nih.gov
  • National Hemophilia Foundation (NHF)
    116 West 32nd Street
    11th Floor
    New York NY 10001
    Phone: 212-328-3700
    Fax: 212-328-3777
    Email: handi@hemophilia.org
  • National Library of Medicine Genetics Home Reference
  • Canadian Hemophilia Society (CHS)
    400 - 1255 University Street
    Montreal Quebec H3B 3B6
    Canada
    Phone: 800-668-2686 (toll-free); 514-848-0503
    Fax: 514-848-9661
    Email: chs@hemophilia.ca
  • Haemophilia Society
    Petersham House
    57a Hatton Garden
    First Floor
    London EC1N 8JG
    United Kingdom
    Phone: 020 7831 1020; 0800 018 6068 (Toll-free Helpline)
    Fax: 020 7405 4824
    Email: info@haemophilia.org.uk
  • World Federation of Hemophilia
    1425 Rene Levesque Boulevard West
    Suite 1010
    Montreal Quebec H3G 1T7
    Canada
    Phone: 514-875-7944
    Fax: 514-875-8916
    Email: wfh@wfh.org

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. von Willebrand Disease: Genes and Databases

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for von Willebrand Disease (View All in OMIM)

193400VON WILLEBRAND DISEASE, TYPE 1; VWD1
277480VON WILLEBRAND DISEASE, TYPE 3; VWD3
613160VON WILLEBRAND FACTOR; VWF
613554VON WILLEBRAND DISEASE, TYPE 2; VWD2

Gene structure. VWF spans 178 kb of genomic DNA in 52 exons that encode an 8.8-kb mRNA and a 2813-amino acid protein [Sadler 1998]. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Benign allelic variants. Benign variants are extremely common. Currently, more than 500 variants are documented in the exons and closely flanking intronic sequences; benign amino acid substitutions are predicted at 80 residues (Table 4). As ethnic groups that are not of northern European origin are being examined, many additional benign variants are being identified [Bellissimo et al 2012, Johnsen et al 2013, Zhou et al 2014]. In one study, an average of 17 heterozygous benign sequence variants were identified in each individual screened for VWF pathogenic variants [Hashemi Soteh et al 2007]. This large number of benign variants in VWF, along with the large size of the gene and the presence of a partial pseudogene, VWFP (exons 23-34), can make full gene sequencing and data interpretation difficult.

For type 1 von Willebrand disease (VWD), approximately 10% of affected individuals had more than one sequence variant identified; some variants were in cis (on the same allele), whereas others were in trans [Cumming et al 2006, Goodeve et al 2007, James et al 2007a]. Such observations underscore the difficulty of identifying pathogenic versus benign allelic variants. Similarly, sequence variants in the promoter region have been identified, and the pathogenicity of a 13-base pair deletion in a type 1 VWD family has been confirmed [Othman et al 2010].

Benign allelic variants useful for linkage analysis are summarized in Table 4 and include: short tandem repeats in the promoter and intron 40 (rs41402545 and rs36115023) [Vidal et al 2005] and a large number of common single nucleotide variants.

Table 4. Selected VWF Benign Allelic Variants

DNA Nucleotide Change Protein Amino Acid Change VWF Exon/ Intron Reference SNP NumberRestriction Site/ Type of PolymorphismReference Sequences
c.1451A>G 1p.His484ArgExon 13rs1800378Rsa INM_000552​.3
NP_000543​.2
c.1946-19_1946-17dupCTT 1NoneIntron 15rs106222883-bp insertion/deletion
c.2365A>G 1p.Thr789AlaExon 18rs1063856Rsa I
c.2555A>Gp.Gln852ArgExon 20rs216321Nla IV
c.4141A>G 1p.Thr1381AlaExon 28rs216311Hph I
c.4414G>Cp.Asp1472HisExon 28rs1800383RleA I
c.4641C>T 1p.Thr1547ThrExon 28rs216310BstE II
c.6187C>Tp.Pro2063SerExon 36NA
c.6977-542_6977-541ins24NoneIntron 40rs36115023Deletion/ insertion polymorphism
c.6977-715_6977-714ins16NoneIntron 40rs41402545 Deletion/ insertion polymorphism
c.8113G>Ap.Gly2705ArgExon 49rs7962217

Only a small proportion of common non-synonymous variants are listed.

1. Benign variants that may be useful for linkage analysis because they are common in several ethnic groups and/or affect the cleavage site of a well-behaved restriction enzyme

Pathogenic allelic variants. Most cases of VWD result from single nucleotide substitutions (Table 5, Figure 1) [James & Lillicrap 2006]. Qualitative deficiency (type 2 VWD) results from missense mutations in functionally important areas of VWF. Partial quantitative deficiency in type 1 VWD is mostly associated with missense mutations. Severe quantitative deficiency in type 3 VWD mostly results from homozygosity or compound heterozygosity for that result in null alleles, but includes a small proportion of missense mutations. Pathogenic variants are cataloged (see ISTH-SSC VWF Database).

Table 5. Selected VWF Pathogenic Allelic Variants

VWD Type 1DNA Nucleotide Change Protein Amino Acid Change VWF Exon Reference Sequences
1c.3614G>Ap.Arg1205His27NM_000552​.3
NP_000543​.2
1c.4751A>Gp.Tyr1584Cys28
2Ac.4517C>Tp.Ser1506Leu28
2Ac.4789C>Tp.Arg1597Trp28
2Bc.3797C>Tp.Pro1266Leu28
2Bc.3916C>Tp.Arg1306Trp28
2Bc.3946G>Ap.Val1316Met28
2Bc.4022G>Ap.Arg1341Gln28
2Mc.3835G>Ap.Val1279Ile28
2Mc.4273A>Tp.Ile1425Phe28
2Nc.2372C>Tp.Thr791Met18
2Nc.2446C>Tp.Arg816Trp19
2Nc.2561G>Ap.Arg854Gln20
3c.2435delCp.Pro812ArgfsTer3118
3c.4975C>Tp.Arg1659Ter28
3c.7603C>Tp.Arg2535Ter45

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. Examples of the most frequent variants identified in each VWD type are shown. See ISTH-SSC VWF Database for further information on allele variants and frequencies.

Normal gene product. The 2813-amino acid VWF protein comprises a 22-amino acid signal peptide, a 741-amino acid propeptide, and a 2050-amino acid mature protein [Sadler 1998]. The recently revised domain structure of VWF protein [Zhou et al 2012, Valentijn & Eikenboom 2013] is shown in Figure 1. During synthesis, tail-to-tail disulfide-linked dimers are formed through the CK domains, followed by head-to-head VWF oligomers. Disulfide isomerase sites in the propeptide catalyze this process. VWF has two sites of synthesis: endothelial cells and megakaryocytes, the precursors of platelets. VWF secreted from endothelial cells and platelets consists of multimers up to 40 subunits (dimers) in length. The propeptide is cleaved by furin between amino acids 763 and 764 during multimer production and the propeptide (VWFpp) is secreted into the plasma along with VWF. The ratio between VWFpp and mature VWF (VWF:Ag) can be used to estimate relative half-life of mature VWF [Haberichter et al 2008]; the ratio also provides information about pathogenic mechanism [Eikenboom et al 2013].

To render HMW VWF less thrombogenic, it is cleaved by ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 motif) between amino acids 1605 and 1606 following secretion. This multimer proteolysis produces the characteristic “triplet” pattern of satellite bands flanking each main multimer band observed on multimer analysis gels, abnormalities in which can give clues as to VWD subtype [Schneppenheim & Budde 2011].

VWF has two key functions: (1) binding collagen in the sub-endothelium at sites of vascular damage, which initiates repair through platelet recruitment and clot formation plus binding; and (2) protecting FVIII from premature proteolytic degradation and transporting it to sites where fibrin generation is required.

Abnormal gene product. Abnormalities in VWF depend on the type of mutation. The molecular consequences of both the protein and nucleotide abnormality result in different VWD types:

  • Type 1. Missense mutations predominate but may affect VWF through different mechanisms. As molecular genetic testing has been undertaken in type 1 VWD only recently, in many cases pathogenic mechanisms have not yet been ascertained.
    • Missense mutations predominantly in the D3 and A1 domains [Haberichter et al 2008, Millar et al 2008, Eikenboom et al 2013] reduce the residence time of VWF in plasma by many fold. p.Arg1205His, the so-called “Vicenza” variant, is the best characterized and most common of these pathogenic variants. Such pathogenic variants have been referred to as type 1 clearance (1C) [Haberichter et al 2006], although this is not a VWD category that has been recognized by the International Society on Thrombosis and Haemostasis Scientific and Standardisation Committee on VWF (ISTH SSC on VWF) [Sadler et al 2006].
    • Intracellular retention is a common mechanism for type 1 VWD pathogenicity [Eikenboom et al 2009, Eikenboom et al 2013].
    • Haploinsufficiency resulting from a heterozygous null allele results in reduced VWF expression in a small proportion of cases.
  • Type 2A. Missense mutations result in a loss of high and sometimes intermediate molecular-weight multimers through a number of mechanisms which may act together: (1) impaired dimer assembly, (2) impaired multimer assembly, (3) enhanced susceptibility to VWF cleaving protease encoded by ADAMTS13 [Hassenpflug et al 2006], and (4) intracellular retention [Schneppenheim et al 2010]. All result in the loss of HMW forms of VWF with fewer GpIbα binding sites and less effective platelet clot formation.
  • Type 2B. Missense mutations enhance the ability of VWF to bind platelet glycoprotein GpIbα such that binding occurs spontaneously without requiring the normal conformational change in VWF that results from its binding to collagen following subendothelial damage. The platelet-VWF complex is removed from circulation and can result in thrombocytopenia. Higher molecular-weight multimers bind platelets preferentially,and so are lost to a greater extent. VWF binding to platelets can also enhance susceptibility to the VWF cleaving protease (encoded by ADAMTS13), which also contributes to the loss of HMW multimers. Enhanced clearance of VWF from circulation also appears to be a significant contributor to the phenotype [Casonato et al 2010]. Pathogenic variants affecting p.Pro1266Leu and p.Arg1379Cys may only demonstrate enhanced GpIbα binding but no thrombocytopenia or HMW multimer loss [Federici et al 2009, Casonato et al 2010].
  • Type 2M. VWF is poor at binding GpIbα, often as a result of missense mutation in the A1 domain (see Figure 1) altering protein confirmation and rendering the domain incapable of binding GpIbα, but without the loss of HMW multimers seen in type 2A [James et al 2007b]. Alternatively, missense mutations in the A3 domain reduce affinity for subendothelial collagen, with the result that VWF lacks affinity for GpIbα.
  • Type 2N. Affinity of VWF for FVIII is reduced as a result of alteration of key amino acids in the FVIII binding site or of conformational change having an indirect effect on VWF-FVIII binding.
  • Type 3. Both alleles are affected by mutations (null or missense) that result in lack of VWF secretion from the cell. Most individuals with type 3 VWD have two null alleles and therefore produce no significant quantity of VWF. Approximately 20% of alleles have missense mutations often affecting the D1 or A1-A2 domains (see Figure 1). Some may impair VWF multimerization, resulting in intracellular retention and lack of secretion into plasma.

References

Published Guidelines/Consensus Statements

  1. Castaman G, Goodeve A, Eikenboom J; European Group on von Willebrand Disease. Principles of care for the diagnosis and treatment of von Willebrand disease. Available online. 2013. Accessed 7-17-14. [PMC free article: PMC3640108] [PubMed: 23633542]
  2. James AH, Kouides PA, Abdul-Kadir R, Edlund M, Federici AB, Halimeh S, Kamphuisen PW, Konkle BA, Martínez-Perez O, McLintock C, Peyvandi F, Winikoff R. Von Willebrand disease and other bleeding disorders in women: consensus on diagnosis and management from an international expert panel. Available online. 2009. Accessed 7-16-14. [PubMed: 19481722]
  3. Keeney S, Bowen D, Cumming A, Enayat S, Goodeve A, Hill M. The molecular analysis of von Willebrand disease: a guideline from the UK Haemophilia Centre Doctors' Organisation Haemophilia Genetics Laboratory Network. Available online. 2008. Accessed 7-16-14. [PubMed: 18637846]
  4. Nichols WL, Hultin MB, James AH, Manco-Johnson MJ, Montgomery RR, Ortel TL, Rick ME, Sadler JE, Weinstein M, Yawn BP. Von Willebrand disease (VWD): evidence-based diagnosis and management guidelines, the National Heart, Lung, and Blood Institute (NHLBI) Expert Panel report (USA). Available online. 2008. Accessed 7-16-14. [PubMed: 18315614]
  5. NHLBI. The diagnosis, evaluation and management of von Willebrand disease (includes a more detailed version and synopsis of the Nichols et al 2008 guidelines and patient education information). Available online. Accessed 7-16-14.
  6. Sadler JE. Von Willebrand disease. In: Valle D, Beaudet AL, Vogelstein B, Kinzler KW, Antonarakis SE, Ballabio A, Gibson K, Mitchell G, eds. The Online Metabolic and Molecular Bases of Inherited Disease (OMMBID). New York, NY: McGraw-Hill. Chap 174. Available online. 2014. Accessed 7-16-14.

Literature Cited

  1. Abshire TC, Federici AB, Alvárez MT, Bowen J, Carcao MD, Cox Gill J, Key NS, Kouides PA, Kurnik K, Lail AE, Leebeek FW, Makris M, Mannucci PM, Winikoff R, Berntorp E. Prophylaxis in severe forms of von Willebrand's disease: results from the von Willebrand Disease Prophylaxis Network (VWD PN). Haemophilia. 2013;19:76–81. [PubMed: 22823000]
  2. Bellissimo DB, Christopherson PA, Flood VH, Gill JC, Friedman KD, Haberichter SL, Shapiro AD, Abshire TC, Leissinger C, Hoots WK, Lusher JM, Ragni MV, Montgomery RR. VWF mutations and new sequence variations identified in healthy controls are more frequent in the African-American population. Blood. 2012;119:2135–40. [PMC free article: PMC3311248] [PubMed: 22197721]
  3. Berntorp E, de Moerloose P, Ljung RC. The role of prophylaxis in bleeding disorders. Haemophilia. 2010;16:189–93. [PubMed: 20590880]
  4. Boisseau P, Ternisien C, Caron C, Giraud M, Talarmain P, Zawadzki C, Beziau S, Fressinaud E, Goudemand J, Veyradier A. Incidence of large VWF gene deletions and duplications in the French cohort of 1182 patients with von Willebrand disease (VWD). Amsterdam, Netherlands: XXIV Congress of the International Society on Thrombosis and Haemostasis. 2013.
  5. Boisseau P, Giraud M, Ternisien C, Veyradier A, Fressinaud E, Lefrancois A, Bezieau S, Fouassier M. An unexpected transmission of von Willebrand disease type 3: the first case of maternal uniparental disomy 12. Haematologica. 2011;96:1567–8. [PMC free article: PMC3186323] [PubMed: 21750090]
  6. Bowman M, Tuttle A, Notley C, Brown C, Tinlin S, Deforest M, Leggo J, Blanchette VS, Lillicrap D, James P. Association of Hemophilia Clinic Directors of Canada; The genetics of Canadian type 3 von Willebrand disease: further evidence for co-dominant inheritance of mutant alleles. J Thromb Haemost. 2013;11:512–20. [PMC free article: PMC3904644] [PubMed: 23311757]
  7. Bowman M, Mundell G, Grabell J, Hopman WM, Rapson D, Lillicrap D, James P. Generation and validation of the Condensed MCMDM-1VWD Bleeding Questionnaire for von Willebrand disease. J Thromb Haemost. 2008;6:2062–6. [PubMed: 18983516]
  8. Bowman M, Riddel J, Rand ML, Tosetto A, Silva M, James PD. Evaluation of the diagnostic utility for von Willebrand disease of a pediatric bleeding questionnaire. J Thromb Haemost. 2009;7:1418–21. [PubMed: 19496919]
  9. Budde U, Pieconka A, Will K, Schneppenheim R. Laboratory testing for von Willebrand disease: contribution of multimer analysis to diagnosis and classification. Semin Thromb Hemost. 2006;32:514–21. [PubMed: 16862525]
  10. Budde U, Schneppenheim R, Eikenboom J, Goodeve A, Will K, Drewke E, Castaman G, Rodeghiero F, Federici A, Batlle J, Perez A, Meyer D, Mazurier C, Goudemand J, Ingerslev J, Habart D, Vorlova Z, Holmberg L, Lethagen S, Pasi J, Hill F, Peake I. Detailed von Willebrand factor multimer analysis in patients with von Willebrand disease in the European study, molecular and clinical markers for the diagnosis and management of type 1 von Willebrand disease (MCMDM-1VWD). J Thromb Haemost. 2008;6:762–71. [PubMed: 18315556]
  11. Casari C, Pinotti M, Lancellotti S, Adinolfi E, Casonato A, De Cristofaro R, Bernardi F. The dominant-negative von Willebrand factor gene deletion p.P1105_C1926delinsR: molecular mechanism and modulation. Blood. 2010;116:5371–6. [PubMed: 20570857]
  12. Casonato A, Gallinaro L, Cattini MG, Pontara E, Padrini R, Bertomoro A, Daidone V, Pagnan A. Reduced survival of type 2B von Willebrand factor, irrespective of large multimer representation or thrombocytopenia. Haematologica. 2010;95:1366–72. [PMC free article: PMC2913086] [PubMed: 20305138]
  13. Casonato A, Pontara E, Sartorello F, Cattini MG, Perutelli P, Bertomoro A, Gallinaro L, Pagnan A. Identifying carriers of type 2N von Willebrand disease: procedures and significance. Clin Appl Thromb Hemost. 2007;13:194–200. [PubMed: 17456630]
  14. Castaman G, Federici AB, Tosetto A, La Marca S, Stufano F, Mannucci PM, Rodeghiero F. Different bleeding risk in type 2A and 2M von Willebrand disease: a 2-year prospective study in 107 patients. J Thromb Haemost. 2012;10:632–8. [PubMed: 22329792]
  15. Castaman G, Goodeve A, Eikenboom J. Principles of care for the diagnosis and treatment of von Willebrand disease. Haematologica. 2013;98:667–74. [PMC free article: PMC3640108] [PubMed: 23633542]
  16. Castaman G, Lethagen S, Federici AB, Tosetto A, Goodeve A, Budde U, Batlle J, Meyer D, Mazurier C, Fressinaud E, Goudemand J, Eikenboom J, Schneppenheim R, Ingerslev J, Vorlova Z, Habart D, Holmberg L, Pasi J, Hill F, Peake I, Rodeghiero F. Response to desmopressin is influenced by the genotype and phenotype in type 1 Von Willebrand Disease (VWD): results from the European study MCMDM-1VWD. Blood. 2008;111:3531–9. [PubMed: 18230755]
  17. Castaman G, Tosetto A, Cappelletti A, Goodeve A, Federici AB, Batlle J, Meyer D, Goudemand J, Eikenboom JC, Schneppenheim R, Budde U, Ingerslev J, Lethagen S, Hill F, Peake IR, Rodeghiero F. Validation of a rapid test (VWF-LIA) for the quantitative determination of von Willebrand factor antigen in type 1 von Willebrand disease diagnosis within the European multicenter study MCMDM-1VWD. Thromb Res. 2010a;126:227–31. [PubMed: 20650506]
  18. Castaman G, Tosetto A, Rodeghiero F. Pregnancy and delivery in women with von Willebrand's disease and different von Willebrand factor mutations. Haematologica. 2010b;95:963–9. [PMC free article: PMC2878795] [PubMed: 19951969]
  19. Cumming A, Grundy P, Keeney S, Lester W, Enayat S, Guilliatt A, Bowen D, Pasi J, Keeling D, Hill F, Bolton-Maggs PH, Hay C, Collins P. An investigation of the von Willebrand factor genotype in UK patients diagnosed to have type 1 von Willebrand disease. Thromb Haemost. 2006;96:630–41. [PubMed: 17080221]
  20. Cumming AM, Keeney S, Jenkins PV, Nash MJ, O'Donnell JS. Clinical utility gene card for: von Willebrand disease. Eur J Hum Genet. 2011;19(5) [PMC free article: PMC3083611] [PubMed: 21206511]
  21. Davies JA, Collins PW, Hathaway LS, Bowen DJ. Effect of von Willebrand factor Y/C1584 on in vivo protein level and function and interaction with ABO blood group. Blood. 2007;109:2840–6. [PubMed: 17119126]
  22. Demers C, Derzko C, David M, Douglas J. Gynaecological and obstetric management of women with inherited bleeding disorders. J Obstet Gynaecol Can. 2005;27:707–32. [PubMed: 16100628]
  23. Eikenboom J, Federici AB, Dirven RJ, Castaman G, Rodeghiero F, Budde U, Schneppenheim R, Batlle J, Canciani MT, Goudemand J, Peake I, Goodeve A. VWF propeptide and ratios between VWF, VWF propeptide, and FVIII in the characterization of type 1 von Willebrand disease. Blood. 2013;121:2336–9. [PubMed: 23349392]
  24. Eikenboom J, Hilbert L, Ribba AS, Hommais A, Habart D, Messenger S, Al-Buhairan A, Guilliatt A, Lester W, Mazurier C, Meyer D, Fressinaud E, Budde U, Will K, Schneppenheim R, Obser T, Marggraf O, Eckert E, Castaman G, Rodeghiero F, Federici AB, Battle J, Goudemand J, Ingerslev J, Lethagen S, Hill F, Peake I, Goodeve A. Expression of 14 von Willebrand factor mutations identifice in patients with type 1 von Willebrand disease from the MCMDM-1VWD study. J Thromb Haemost. 2009;7:1304–12. [PubMed: 19566550]
  25. Favaloro EJ. Phenotypic identification of platelet-type von Willebrand disease and its discrimination from type 2B von Willebrand disease: a question of 2B or not 2B? A story of nonidentical twins? Or two sides of a multidenominational or multifaceted primary-hemostasis coin? Semin Thromb Hemost. 2008;34:113–27. [PubMed: 18393148]
  26. Favaloro EJ, Patterson D, Denholm A, Mead S, Gilbert A, Collins A, Estell J, George PM, Smith MP. Differential identification of a rare form of platelet-type (pseudo-) von Willebrand disease (VWD) from Type 2B VWD using a simplified ristocetin-induced-platelet-agglutination mixing assay and confirmed by genetic analysis. Br J Haematol. 2007;139:623–6. [PubMed: 17916098]
  27. Federici AB. Acquired von Willebrand syndrome: an underdiagnosed and misdiagnosed bleeding complication in patients with lymphoproliferative and myeloproliferative disorders. Semin Hematol. 2006;43:S48–58. [PubMed: 16427386]
  28. Federici AB. Highly purified VWF/FVIII concentrates in the treatment and prophylaxis of von Willebrand disease: the PRO.WILL Study. Haemophilia. 2007;13 Suppl 5:15–24. [PubMed: 18078393]
  29. Federici AB. The use of desmopressin in von Willebrand disease: the experience of the first 30 years (1977-2007). Haemophilia. 2008;14:5–14. [PubMed: 18173689]
  30. Federici AB, Budde U, Castaman G, Rand JH, Tiede A. Current diagnostic and therapeutic approaches to patients with acquired von Willebrand syndrome: a 2013 update. Semin Thromb Hemost. 2013;39:191–201. [PubMed: 23397553]
  31. Federici AB, Mannucci PM, Castaman G, Baronciani L, Bucciarelli P, Canciani MT, Pecci A, Lenting PJ, De Groot PG. Clinical and molecular predictors of thrombocytopenia and risk of bleeding in patients with von Willebrand disease type 2B: a cohort study of 67 patients. Blood. 2009;113:526–34. [PubMed: 18805962]
  32. Flood VH, Gill JC, Christopherson PA, Bellissimo DB, Friedman KD, Haberichter SL, Lentz SR, Montgomery RR. Critical von Willebrand factor A1 domain residues influence type VI collagen binding. J Thromb Haemost. 2012;10:1417–24. [PMC free article: PMC3809952] [PubMed: 22507569]
  33. Flood VH, Gill JC, Friedman KD, Christopherson PA, Jacobi PM, Hoffmann RG, Montgomery RR, Haberichter SL. Zimmerman Program Investigators; Collagen binding provides a sensitive screen for variant von Willebrand disease. Clin Chem. 2013;59:684–91. [PMC free article: PMC3852672] [PubMed: 23340442]
  34. Franchini M, Montagnana M, Lippi G. Clinical, laboratory and therapeutic aspects of platelet-type von Willebrand disease. Int J Lab Hematol. 2008;30:91–4. [PubMed: 18333841]
  35. Franchini M, Targher G, Lippi G. Prophylaxis in von Willebrand disease. Ann Hematol. 2007;86:699–704. [PubMed: 17634944]
  36. Goodeve A, Eikenboom J, Castaman G, Rodeghiero F, Federici AB, Batlle J, Meyer D, Mazurier C, Goudemand J, Schneppenheim R, Budde U, Ingerslev J, Habart D, Vorlova Z, Holmberg L, Lethagen S, Pasi J, Hill F, Hashemi Soteh M, Baronciani L, Hallden C, Guilliatt A, Lester W, Peake I. Phenotype and genotype of a cohort of families historically diagnosed with type 1 von Willebrand disease in the European study, Molecular and Clinical Markers for the Diagnosis and Management of Type 1 von Willebrand Disease (MCMDM-1VWD). Blood. 2007;109:112–21. [PubMed: 16985174]
  37. Haberichter SL, Balistreri M, Christopherson P, Morateck P, Gavazova S, Bellissimo DB, Manco-Johnson MJ, Gill JC, Montgomery RR. Assay of the von Willebrand factor (VWF) propeptide to identify patients with type 1 von Willebrand disease with decreased VWF survival. Blood. 2006;108:3344–51. [PMC free article: PMC1895439] [PubMed: 16835381]
  38. Haberichter SL, Castaman G, Budde U, Peake I, Goodeve A, Rodeghiero F, Federici AB, Batlle J, Meyer D, Mazurier C, Goudemand J, Eikenboom J, Schneppenheim R, Ingerslev J, Vorlova Z, Habart D, Holmberg L, Lethagen S, Pasi J, Hill FG, Montgomery RR. Identification of type 1 von Willebrand disease patients with reduced von Willebrand factor survival by assay of the VWF propeptide in the European study: molecular and clinical markers for the diagnosis and management of type 1 VWD (MCMDM-1VWD). Blood. 2008;111:4979–85. [PMC free article: PMC2384129] [PubMed: 18344424]
  39. Hamilton A, Ozelo M, Leggo J, Notley C, Brown H, Frontroth JP, Angelillo-Scherrer A, Baghaei F, Enayat SM, Favaloro E, Lillicrap D, Othman M. Frequency of platelet type versus type 2B von Willebrand disease. An international registry-based study. J Thromb Haemost. 2011;105:501–8. [PubMed: 21301777]
  40. Hashemi Soteh M, Peake IR, Marsden L, Anson J, Batlle J, Meyer D, Fressinaud E, Mazurier C, Goudemand J, Eikenboom J, Goodeve A. Mutational analysis of the von Willebrand factor gene in type 1 von Willebrand disease using conformation sensitive gel electrophoresis: a comparison of fluorescent and manual techniques. Haematologica. 2007;92:550–3. [PubMed: 17488667]
  41. Hassenpflug WA, Budde U, Obser T, Angerhaus D, Drewke E, Schneppenheim S, Schneppenheim R. Impact of mutations in the von Willebrand factor A2 domain on ADAMTS13-dependent proteolysis. Blood. 2006;107:2339–45. [PubMed: 16322474]
  42. International Society on Thrombosis and Haemostasis. ISTH Scientific and Standardization Committee Bleeding Assessment Tool. Available online. 2011. Accessed 7-16-14.
  43. James AH, Jamison MG. Bleeding events and other complications during pregnancy and childbirth in women with von Willebrand disease. J Thromb Haemost. 2007;5:1165–9. [PubMed: 17403089]
  44. James AH, Kouides PA, Abdul-Kadir R, Edlund M, Federici AB, Halimeh S, Kamphuisen PW, Konkle BA, Martínez-Perez O, McLintock C, Peyvandi F, Winikoff R (2009) Von Willebrand disease and other bleeding disorders in women: consensus on diagnosis and management from an international expert panel. Am J Obstet Gynecol. 201:12.e1-8. [PubMed: 19481722]
  45. James P, Lillicrap D. Genetic testing for von Willebrand disease: the Canadian experience. Semin Thromb Hemost. 2006;32:546–52. [PubMed: 16862529]
  46. James PD, Notley C, Hegadorn C, Leggo J, Tuttle A, Tinlin S, Brown C, Andrews C, Labelle A, Chirinian Y, O’Brien L, Othman M, Rivard G, Rapson D, Hough C, Lillicrap D. The mutational spectrum of type 1 von Willebrand disease: Results from a Canadian cohort study. Blood. 2007a;109:145–54. [PubMed: 17190853]
  47. James PD, Notley C, Hegadorn C, Poon MC, Walker I, Rapson D, Lillicrap D. Challenges in defining type 2M von Willebrand disease: results from a Canadian cohort study. J Thromb Haemost. 2007b;5:1914–22. [PubMed: 17596142]
  48. Jenkins PV, O’Donnell JS. ABO blood group determines plasma von Willebrand factor levels: a biologic function after all? Transfusion. 2006;46:1836–44. [PubMed: 17002642]
  49. Johnsen JM, Auer PL, Morrison AC, Jiao S, Wei P, Haessler J, Fox K, McGee SR, Smith JD, Carlson CS, Smith N, Boerwinkle E, Kooperberg C, Nickerson DA, Rich SS, Green D, Peters U, Cushman M, Reiner AP. NHLBI Exome Sequencing Project; Common and rare von Willebrand factor (VWF) coding variants, VWF levels, and factor VIII levels in African Americans: the NHLBI Exome Sequencing Project. Blood. 2013;122:590–7. [PMC free article: PMC3724194] [PubMed: 23690449]
  50. Kadir RA, Chi C. Women and von Willebrand disease: controversies in diagnosis and management. Semin Thromb Hemost. 2006;32:605–15. [PubMed: 16977570]
  51. Keeling D, Beavis J, Marr R, Sukhu K, Bignell P. A family with type 2M VWD with normal VWF:RCo but reduced VWF:CB and a M1761K mutation in the A3 domain. Haemophilia. 2012;18(1):e33. [PubMed: 22004444]
  52. Keeney S, Bowen D, Cumming A, Enayat S, Goodeve A, Hill M. The molecular analysis of von Willebrand disease: a guideline from the UK Haemophilia Centre Doctors’ Organisation Haemophilia Genetics Laboratory Network. Haemophilia. 2008;14:1099–111. [PubMed: 18637846]
  53. Leissinger C, Carcao M, Gill JC, Journeycake J, Singleton T, Valentino L. Desmopressin (DDAVP) in the management of patients with congenital bleeding disorders. Haemophilia. 2014;20:158–67. [PubMed: 23937614]
  54. Mannucci PM, Kempton C, Millar C, Romond E, Shapiro A, Birschmann I, Ragni MV, Gill JC, Yee TT, Klamroth R, Wong WY, Chapman M, Engl W, Turecek PL, Suiter TM, Ewenstein BM. Pharmacokinetics and safety of a novel recombinant human von Willebrand factor manufactured with a plasma-free method: a prospective clinical trial. Blood. 2013;122:648–57. [PMC free article: PMC3736194] [PubMed: 23777763]
  55. Mazurier C, Hilbert L. Type 2N von Willebrand disease. Curr Hematol Rep. 2005;4:350–8. [PubMed: 16131435]
  56. Mazurier C, Rodeghiero F. Recommended abbreviations for von Willebrand factor and its activities. Thromb Haemost. 2001;86:712. [PubMed: 11522027]
  57. Metjian AD, Wang C, Sood SL, Cuker A, Peterson SM, Soucie JM, Konkle BA. Bleeding symptoms and laboratory correlation in patients with severe von Willebrand disease. Haemophilia. 2009;15:918–25. [PubMed: 19473418]
  58. Millar CM, Riddell AF, Brown SA, Starke R, Mackie I, Bowen DJ, Jenkins PV, van Mourik JA. Survival of von Willebrand factor released following DDAVP in a type 1 von Willebrand disease cohort: influence of glycosylation, proteolysis and gene mutations. Thromb Haemost. 2008;99:916–24. [PubMed: 18449422]
  59. Nichols WL, Hultin MB, James AH, Manco-Johnson MJ, Montgomery RR, Ortel TL, Rick ME, Sadler JE, Weinstein M, Yawn BP. Von Willebrand disease (VWD): evidence-based diagnosis and management guidelines, the National Heart, Lung, and Blood Institute (NHLBI) Expert Panel report (USA). Haemophilia. 2008;14:171–232. [PubMed: 18315614]
  60. O’Brien LA, James PD, Othman M, Berber E, Cameron C, Notley CR, Hegadorn CA, Sutherland JJ, Hough C, Rivard GE, O’Shaunessey D, Lillicrap D. Founder von Willebrand factor haplotype associated with type 1 von Willebrand disease. Blood. 2003;102:549–57. [PubMed: 12649144]
  61. Othman M, Chirinian Y, Brown C, Notley C, Hickson N, Hampshire D, Buckley S, Waddington S, Parker AL, Baker A, James P, Lillicrap D. Functional characterization of a 13-bp deletion (c.-1522_-1510del13) in the promoter of the von Willebrand factor gene in type 1 von Willebrand disease. Blood. 2010;116:3645–52. [PMC free article: PMC2981484] [PubMed: 20696945]
  62. Othman M, Notley C, Lavender FL, White H, Byrne CD, Lillicrap D, O’Shaughnessy DF. Identification and functional characterization of a novel 27-bp deletion in the macroglycopeptide-coding region of the GPIBA gene resulting in platelet-type von Willebrand disease. Blood. 2005;105:4330–6. [PubMed: 15705799]
  63. Rodeghiero F, Tosetto A, Abshire T, Arnold DM, Coller B, James P, Neunert C, Lillicrap D. ISTH/SSC bleeding assessment tool: a standardized questionnaire and a proposal for a new bleeding score for inherited bleeding disorders. J Thromb Haemost. 2010;8:2063–5. [PubMed: 20626619]
  64. Sadler JE. Biochemistry and genetics of von Willebrand factor. Ann Rev Biochem. 1998;67:395–424. [PubMed: 9759493]
  65. Sadler JE, Budde U, Eikenboom JC, Favaloro EJ, Hill FG, Holmberg L, Ingerslev J, Lee CA, Lillicrap D, Mannucci PM, Mazurier C, Meyer D, Nichols WL, Nishino M, Peake IR, Rodeghiero F, Schneppenheim R, Ruggeri ZM, Srivastava A, Montgomery RR, Federici AB. Update on the pathophysiology and classification of von Willebrand disease: a report of the Subcommittee on von Willebrand Factor. J Thromb Haemost. 2006;4:2103–14. [PubMed: 16889557]
  66. Schneppenheim R, Budde U. von Willebrand factor: the complex molecular genetics of a multidomain and multifunctional protein. J Thromb Haemost. 2011;9:209–15. [PubMed: 21781257]
  67. Schneppenheim R, Ledford-Kraemer M, Lavergne J-M, Marschalek R, Montgomery R, Obser T, Oyen F, Sadler JE, Schneppenheim S, Budde U. Identification of the elusive mutation causing the historical von Willebrand disease type IIC miami. J Thromb Haemost. 2011;9 Suppl 1:P-WE-461.
  68. Schneppenheim R, Michiels JJ, Obser T, Oyen F, Pieconka A, Schneppenheim S, Will K, Zieger B, Budde U. A cluster of mutations in the D3 domain of von Willebrand factor correlates with a distinct subgroup of von Willebrand disease: type 2A/IIE. Blood. 2010;115:4894–901. [PubMed: 20351307]
  69. Solimando M, Baronciani L, La Marca S, Cozzi G, Asselta R, Canciani MT, Federici AB, Peyvandi F. Molecular characterization, recombinant protein expression, and mRNA analysis of type 3 von Willebrand disease: Studies of an Italian cohort of 10 patients. Am J Hematol. 2012;87:870–4. [PubMed: 22674667]
  70. Sucker C, Michiels JJ, Zotz RB. Causes, etiology and diagnosis of acquired von Willebrand disease: a prospective diagnostic workup to establish the most effective therapeutic strategies. Acta Haematol. 2009;121:177–82. [PubMed: 19506364]
  71. Sutherland MS, Cumming AM, Bowman M, Bolton-Maggs PH, Bowen DJ, Collins PW, Hay CR, Will AM, Keeney S. A novel deletion mutation is recurrent in von Willebrand disease types 1 and 3. Blood. 2009;114:1091–8. [PubMed: 19372260]
  72. Tosetto A, Castaman G, Plug I, Rodeghiero F, Eikenboom J. Prospective evaluation of the clinical utility of quantitative bleeding severity assessment in patients referred for hemostatic evaluation. J Thromb Haemost. 2011;9:1143–48. [PubMed: 21435168]
  73. Tosetto A, Rodeghiero F, Castaman G, Goodeve A, Federici AB, Batlle J, Meyer D, Fressinaud E, Mazurier C, Goudemand J, Eikenboom J, Schneppenheim R, Budde U, Ingerslev J, Vorlova Z, Habart D, Holmberg L, Lethagen S, Pasi J, Hill F, Peake I. A quantitative analysis of bleeding symptoms in type 1 von Willebrand disease: results from a multicenter European study (MCMDM-1 VWD). J Thromb Haemost. 2006;4:766–73. [PubMed: 16634745]
  74. Turacek PL, Schrenk G, Rottensteiner H, Varadi K, Bevers E, Lenting P, Ilk N, Sleytr UB, Ehrlich HJ, Shwartz HP. Structure and function of a recombinant von Willebrand factor drug candidate. Semin Thromb Hemost. 2010;36:510–21. [PubMed: 20635317]
  75. Varughese J, Cohen AJ. Experience with epidural anaesthesia in pregnant women with von Willebrand disease. Haemophilia. 2007;13:730–3. [PubMed: 17973849]
  76. Valentijn KM, Eikenboom J. Weibel-Palade bodies: a window to von Willebrand disease. J Thromb Haemost. 2013;11:581–92. [PubMed: 23398618]
  77. Veyradier A, Caron C, Ternisien C, Wolf M, Trossaert M, Fressinaud E, Goudemand J. Validation of the first commercial ELISA for type 2N von Willebrand’s disease diagnosis. Haemophilia. 2011;17:944–51. [PubMed: 21371195]
  78. Vidal F, Julia A, Altisent C, Puig L, Gallardo D. Von Willebrand gene tracking by single-tube automated fluorescent analysis of four short tandem repeat polymorphisms. Thromb Haemost. 2005;93:976–81. [PubMed: 15886817]
  79. Woods AI, Sanchez-Luceros A, Bermejo E, Paiva J, Alberto MF, Grosso SH, Kempfer AC, Lazzari MA. Identification of p.W246L as a novel mutation in the GP1BA gene responsible for platelet-type von Willebrand disease. Semin Thromb Hemost. 2014;40:151–60. [PubMed: 24474090]
  80. Yadegari H, Driesen J, Hass M, Budde U, Pavlova A, Oldenburg J. Large deletions identified in patients with von Willebrand disease using multiple ligation-dependent probe amplification. J Thromb Haemost. 2011;9:1083–6. [PubMed: 21410641]
  81. Yadegari H, Driesen J, Pavlova A, Biswas A, Hertfelder HJ, Oldenburg J. Mutation distribution in the von Willebrand factor gene related to the different von Willebrand disease (VWD) types in a cohort of VWD patients. Thromb Haemost. 2012;108:662–71. [PubMed: 22871923]
  82. Zhou YF, Eng ET, Zhu J, Lu C, Walz T, Springer TA. Sequence and structure relationships within von Willebrand factor. Blood. 2012;120:449–58. [PMC free article: PMC3398765] [PubMed: 22490677]
  83. Zhou Z, Yu F, Buchanan A, Fu F, Campos M, Wu KK, Lloyd E. Possible Race and Gender Divergence in Association of Genetic Variations with Plasma von Willebrand Factor: A Study of ARIC and 1000 Genome Cohorts. PloS One. 2014;9:e84810. [PMC free article: PMC3894939] [PubMed: 24465435]

Suggested Reading

  1. Federici AB, Mannucci PM. Management of inherited von Willebrand disease in 2007. Ann Med. 2007;39:346–58. [PubMed: 17701477]
  2. ISTH-VWF-SSC International Society on Thrombosis and Haemostasis Scientific and Standardization Committee VWF Information Homepage. Available online. Accessed 7-16-14.
  3. James AH. Von Willebrand disease. Obstet Gynecol Surv. 2006;61:136–45. [PubMed: 16433937]

Chapter Notes

Author Notes

Prof. Goodeve’s Web page

Dr. James’s Web page

Acknowledgments

The authors would like to thank Professor David Lillicrap, Kingston, Canada, for critical reading of the review and Dr Mackenzie Bowman, Kingston Canada for preparation of the figure.

Revision History

  • 24 July 2014 (me) Comprehensive update posted live
  • 13 October 2011 (me) Comprehensive update posted live
  • 26 October 2010 (cd) Revision: deletion/duplication analysis available clinically
  • 4 June 2009 (et) Review posted live
  • 4 December 2008 (ag) Original submission
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