Clinical Diagnosis

von Willebrand disease (VWD) is caused by deficient or defective plasma von Willebrand factor (VWF), a large multimeric glycoprotein with 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 can determine if there is more bleeding than in the general population, justifying diagnosis of a bleeding disorder, and can quantify extent of symptoms, indicating situations requiring clinical intervention.

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]. Normal ranges are determined on an individual laboratory basis and so 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)
• 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 2010] (normal range ~50-200 IU/dL)
• 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 three 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 high, intermediate, or low molecular weight. High molecular-weight (HMW) multimers are decreased or missing in types 2A and 2B VWD; intermediate MW may also be lost in type 2A VWD. Abnormalities in satellite (“triplet”) band patterns can give clues about pathogenesis and help to classify subtypes of type 2A 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 mg/mL) is abnormal and may indicate type 2B or platelet type VWD (PT-VWD) caused by mutations 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 in some locations to help define functional VWF discordance (i.e., to help distinguish types 1 and 2 VWD). Normal range is approximately 50-200 IU/dL.

Molecular Genetic Testing

Gene. VWF is the only gene in which mutations are currently known to cause VWD.

Note:

• The current classification scheme does not restrict VWD to being caused by mutations in VWF. Evaluation of the entire VWF gene fails to identify a VWF mutation in some cases of “apparent” VWD. Failure to identify a causative mutation in VWF does not exclude a diagnosis of VWD.
• Platelet-type VWD results from mutations 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

Figure 1. Location of VWF mutations by VWD type. Green horizontal lines indicate the approximate position of exons where mutations are most prevalent; thinner lines indicate exons with mutations of lower frequency. Mutations that result in type 2 VWD (more...)

• Sequence analysis. Sequence analysis of the entire coding region and flanking exon/intron junctions of VWF is possible, although it is technically challenging due to the gene structure (see Molecular Genetics).
• Linkage analysis. Linkage can be useful in type 3 VWD to facilitate prenatal diagnosis if time is insufficient for full sequence analysis, or if two mutations cannot be identified in an affected individual. See Table 3 for normal allelic variants of VWF that are useful for linkage analysis.
• Deletion/duplication analysis. Deletion/duplication analysis of VWF using multiplex ligation-dependent probe amplification (MLPA) is possible [Acquila et al 2009, Cabrera et al 2011], but the extent of contribution of large deletions or duplications has not been established within VWD patient cohorts and large heterozygous mutations have likely been previously overlooked. Large deletions currently comprise 9% of mutation 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].

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

• 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 mutations contribute to bleeding phenotype in individuals with VWF levels of around 50 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 mutations 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 complete mutation ascertainment.

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

• Type 2A (AD) VWD. Most mutations are located in exon 28, affecting predominantly the A2 and, to a lesser extent, the A1 domain.
• Type 2A VWD. Missense mutations have also been reported in exons 11-16 (AR), 22 and 25-27 (AD) [Schneppenheim et al 2010] and 52 (AD & AR), which should be examined subsequently.
• 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. Data are insufficient to generalize about location of mutations other than in exon 28.
• Type 2N (AR) VWD. Most missense mutations are located in exons 18-20 and a much lower proportion have been reported in exons 17 and 24-27 [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 mutation resulting in a null allele. Less commonly, individuals can be compound heterozygotes for two missense mutations.

Type 3 VWD. Mutations 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 identifies mutations in 80%-90% of type 3 VWD.

• Twenty percent are missense mutations located in the D1-D2 (exons 3-11) domains and D4-CK (exons 37-52) domains (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 established. Large deletions currently comprise 9% of mutation reports 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, especially when time is short. If the family structure is sufficient for linkage analysis, results may be obtained more quickly than mutations can be identified in both VWF alleles (see Molecular Genetics).

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

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Gene Symbol	VWD Type(s)	Proportion of VWD Attributed to This Type	Test Method	Mutations Detected	Mutation Detection Frequency by Test Method and VWD Type 1	Test Availability
VWF	1	~70%	Sequence analysis of entire coding and flanking intronic regions	Sequence variants 2	60%-65%	Clinical
			Deletion / duplication analysis 3	Partial- and whole-gene deletions/ duplications	Unknown
			Sequence analysis of select exons	Sequence variants 2 in exons 18-28	~50%
	All type 2 forms	~25% 4	Sequence analysis of selected exons	Sequence variants 2	Unknown
	2A (AD) 2B 2M	See footnote 1	Sequence analysis of select exons	Sequence variants 2 in exon 28	~70%
	2A (AR)	See footnote 1		Sequence variants 2 in exons 11-16, 22, 25-27 & 52	~30% of those with 2A
	2N	See footnote 1		Sequence variants 2 in exons 18-20	~80%
	3	<5%	Sequence analysis of entire coding and flanking intronic regions	Sequence variants 2	~80%
			Deletion / duplication analysis 3	Partial- and whole-gene deletions / duplications	Unknown
	All types	NA	Linkage analysis	NA	NA

3. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or targeted chromosomal microarray analysis (gene/segment-specific) may be used. A full chromosomal microarray analysis that detects deletions/duplications across the genome may also include this gene/segment.

AD = autosomal dominant inheritance

AR = autosomal recessive inheritance

NA = not applicable

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

2. 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.

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

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Information on specific allelic variants may be available in Molecular Genetics (see Table A and/or Pathologic allelic variants).

Testing Strategy

To confirm/establish the diagnosis in a proband. In those individuals with types 2A and 2B 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)
• For families with type 3 VWD requesting prenatal diagnosis

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

Carrier testing for relatives at risk for the autosomal recessive forms of VWD (type 2A and type 2N) requires prior identification of the disease-causing mutations in the family.

Note: Carriers are heterozygotes for these autosomal recessive disorders and are not at risk of developing the disorder, although a small proportion of heterozygotes have mild bleeding symptoms [Castaman et al 2006].

Prenatal diagnosis (PND) and preimplantation genetic diagnosis (PGD) for at-risk pregnancies are generally requested for type 3 VWD only and require prior identification of the disease-causing mutations in the family or of informative linked markers.

Genetically Related (Allelic) Disorders

No other phenotypes are known to be associated with mutations in VWF.

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. 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].

Type 2 VWD accounts for approximately 25% of all VWD. The relative frequency of the subtypes is 2A>2N>2M>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.
• 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. 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].

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 mutation p.Tyr1584Cys [O'Brien et al 2003, Davies et al 2007].

Penetrance

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

Mutations 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].
• FVIII RAg (FVIII related antigen) has been replaced by VWF:Ag.
• Platelet-type von Willebrand disease (PT-VWD), also called pseudo-VWD, is caused by mutations 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 mutations 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 seven per million population, increasing with the rate of consanguinity.

Evaluations Following Initial Diagnosis

To establish the extent of disease 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
• 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), because many individuals with VWD are iron deficient, particularly women with menorrhagia
• Gynecologic evaluation for women with menorrhagia [Demers et al 2005]
• Genetics consultation

Treatment of Manifestations

See Nichols et al [2008] for treatment guidelines (click for full text).

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.

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].

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. This is the subject of an ongoing international trial; prophylactic treatment for joint bleeding, nosebleeds, and menorrhagia is under investigation [Berntorp et al 2010].

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 only be circumcised after consultation with a pediatric hemostasis specialist.

Evaluation of Relatives at Risk

Once familial mutation(s) have been identified, at-risk relatives can be readily analyzed for these mutations 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].

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.

Therapies Under Investigation

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

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

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.

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 mutations is unknown.
• If the mutation 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 a de novo mutation in the proband. Neither possibility has been sufficiently investigated to comment on relative likelihood of occurrence.
• Evaluation of parents of a proband with AD VWD may determine that one is affected but has escaped previous diagnosis because of failure to recognize the symptoms and/or a milder phenotypic presentation. Therefore, an apparently negative family history cannot be confirmed until appropriate evaluations have been performed.

Note: Although most individuals diagnosed with AD VWD have an affected parent, the family history 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.

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 disease-causing mutation found in the proband cannot be detected in the 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 mutation.

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 obligate heterozygotes (i.e., carriers of one mutant allele).
• Heterozygotes (carriers) are generally asymptomatic. However, approximately 10% may show some mild bleeding symptoms.

Sibs of a proband

• At conception, each sib of an individual with AR VWD has 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.
• Heterozygotes (carriers) are generally asymptomatic; approximately 10% may show some mild bleeding symptoms.

Offspring of a proband. The offspring of an individual with AR VWD are obligate heterozygotes (carriers) for a disease-causing mutation in VWF.

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

Carrier Detection

Carrier testing for at-risk family members is possible once the disease-causing mutations 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 an apparent de novo mutation. When neither parent of a proband with an AD condition has the disease-causing mutation or clinical evidence of the disorder, it is likely that the proband has a 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, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the disease-causing mutation(s) have been identified in the family, prenatal diagnosis for pregnancies at increased risk (generally for type 3 VWD) is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation).

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

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 disease-causing mutation(s) have been identified.

Published Guidelines/Consensus Statements

1. 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 10-5-11. [PubMed: 19481722]
2. 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 10-5-11. [PubMed: 18315614]
3. Note: The NHLBI Web site has a more detailed document, a synopsis of these recommendations, and patient education information. Available online. Accessed 10-5-11.
4. 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 10-5-11.
5. Sadler JE. Von Willebrand disease. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Vogelstein B, eds. The Online Metabolic and Molecular Bases of Inherited Disease (OMMBID). New York: McGraw-Hill. Chap 174. Available online. Accessed 10-5-11.

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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 at www​.vwf.group.shef.ac.uk. Accessed 10-4-11.
3. James AH. Von Willebrand disease. Obstet Gynecol Surv. 2006;61:136–45. [PubMed: 16433937]

Author Notes

Dr. Goodeve’s Web page: www.shef.ac.uk/medicine/cardiovascularscience/profiles/goodeve.html

Acknowledgments

The authors would like to thank Professor David Lillicrap, Kingston, Canada, for critical reading of the review.

Revision History

• 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