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)....
DiagnosisClinical 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 VWFType 2, qualitative deficiency of defective VWF, which is divided into four subtypes depending on VWF function perturbed: 2A, 2B, 2M, 2NType 3, complete quantitative deficiency of (virtually absent) VWFVWD is suspected in persons with excessive mucocutaneous bleeding including the following:Bruising without recognized traumaProlonged, recurrent nose bleedsBleeding from the gums after brushing or flossing teeth or prolonged bleeding following dental cleaning or dental extractionsMenorrhagia, particularly if occurring since menarcheProlonged bleeding following surgery, trauma, or childbirthThe 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. TestingScreening 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 assaysThe 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.Table 1. Classification of VWD Based on Specific VWF Tests View in own windowVWD TypeVWF:RCo 1VWF:Ag 1RCo/AgFVIII:C IU/dL 1Multimer Pattern 2Other1LowLowEquivalent~1.5x VWF:AgNormal2ALowLowVWF:RCo < VWF:AgLow or normalAbnormal ↓ HMW2BLowLowVWF:RCo < VWF:AgLow or normalAbnormal ↓ HMW↑RIPA 3 (↓ platelet count)2MLowLowVWF:RCo << VWF:AgLow or normalNormal2NNormal/lowNormal/lowEquivalent<40Normal↓ VWF:FVIIIB 43AbsentAbsentNA<10Absent1. 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 multimers3. Increased agglutination at low concentrations of ristocetin4. 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 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 testingDomain structure and exons encoding each VWF domain are shown in Figure 1. FigureFigure 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)View in own windowGene SymbolVWD Type(s)Proportion of VWD Attributed to This TypeTest MethodMutations DetectedMutation Detection Frequency by Test Method and VWD Type 1Test AvailabilityVWF1~70%Sequence analysis of entire coding and flanking intronic regionsSequence variants 260%-65%ClinicalDeletion / duplication analysis 3Partial- and whole-gene deletions/ duplicationsUnknownSequence analysis of select exonsSequence variants 2 in exons 18-28~50%All type 2 forms~25% 4Sequence analysis of selected exonsSequence variants 2Unknown2A (AD) 2B 2MSee footnote 1Sequence analysis of select exonsSequence variants 2 in exon 28~70% 2A (AR)See footnote 1Sequence variants 2 in exons 11-16, 22, 25-27 & 52~30% of those with 2A2NSee footnote 1Sequence variants 2 in exons 18-20~80%3<5% Sequence analysis of entire coding and flanking intronic regionsSequence variants 2~80% Deletion / duplication analysis 3Partial- and whole-gene deletions / duplicationsUnknownAll typesNALinkage analysisNANA3. 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 inheritanceAR = autosomal recessive inheritanceNA = not applicable1. The ability of the test method used to detect a mutation that is present in the indicated gene2. 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.
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. ...
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].
Two disorders can be difficult to distinguish phenotypically from von Willebrand disease (VWD)....
Differential DiagnosisTwo disorders can be difficult to distinguish phenotypically from von Willebrand disease (VWD).Type 2N VWD and mildhemophilia A (caused by mutations in F8) can be difficult to distinguish because 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, is the best way to distinguish between the two disorders [Casonato et al 2007]; however, its availability may be limited.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 should be undertaken. In females, dosage analysis of F8 using multiplex ligation-dependent probe amplification (MLPA) can also be used to identify heterozygous partial/complete gene deletions/duplications. Mutations are detected in more than 50% of cases investigated for “possible 2N VWD or hemophilia A.” When F8 mutations are absent, screening of VWF exons should follow.Type 2B VWD and PT-VWD (also called pseudo VWD). PT-VWD is caused by mutations in GP1BA. 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 mutations are absent from exon 28 of VWF, mutations in exon 2 of GP1BA may be identified. To date, missense mutations reported are between Gp1bα amino acids p.Gly249 and p.Met255 plus a 27-bp in-frame deletion p.Pro449_Ser457del (c.1345_1371del27) [Othman et al 2005, PT-VWD Registry 2009, Hamilton et al 2011] (per standard naming conventions of the Human Genome Variation Society (www.hgvs.org); reference sequences NP_000164.4 and NM_000173.4). PT-VWD is probably underdiagnosed. Misdiagnosis of PT-VWD 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 GP1b, so VWF concentrate has to be administered more frequently 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] but is not caused by a VWF mutation. 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 valvular 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 , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).Type1 VWDType 2A VWDType 2B VWDType 2M VWDType 2N VWDType 3 VWD
To establish the extent of disease in an individual diagnosed with von Willebrand disease (VWD), the following evaluations are recommended:...
ManagementEvaluations 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 treatmentA 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 1985Baseline serum concentration of iron and ferritin (to assess iron stores), because many individuals with VWD are iron deficient, particularly women with menorrhagiaGynecologic evaluation for women with menorrhagia [Demers et al 2005]Genetics consultationTreatment of ManifestationsSee 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. 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], 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. In persons who are intolerant to desmopressin or 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 ConcentratesIn 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 TreatmentsIn 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 TypeType 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 mutations associated with mild 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. Desmopressin response is almost invariably poor, so 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 IssuesSpecial considerations for the care of infants and children with VWD include the following:Infant males should only be circumcised 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 and so phenotypic testing for milder forms of VWD should be delayed until later in childhood.Prevention of Primary ManifestationsIndividuals with type 3 VWD are often given prophylactic infusions of VWF/FVIII concentrates to prevent musculoskeletal bleeding and subsequent joint damage. Prevention of Secondary ComplicationsDesmopressin 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].SurveillanceIndividuals 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 AvoidActivities 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 RiskOnce 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 ManagementVWF 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 InvestigationRecombinant 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.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation 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 DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDVWF12p13.31von Willebrand factorvon Willebrand Factor Database ISTH-SSC VWF Online DatabaseVWFData 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) View in own window 193400VON WILLEBRAND DISEASE, TYPE 1; VWD1 277480VON WILLEBRAND DISEASE, TYPE 3; VWD3 613160VON WILLEBRAND FACTOR; VWF 613554VON WILLEBRAND DISEASE, TYPE 2; VWD2Normal allelic variants. 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]. Normal variants are extremely common. Currently, approximately 150 normal variants are known in the exons and closely flanking intronic sequences; amino acid substitutions are predicted at over 30 residues (Table 3). As ethnic groups that are not of northern European origin are being examined, many additional normal variants are being identified. In one study, an average of 17 heterozygous normal sequence variants were identified in each individual screened for VWF mutations [Hashemi Soteh et al 2007]. This high degree of polymorphism 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%-15% 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 pathologic versus normal 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]. Normal allelic variants useful for linkage analysis are summarized in Table 3 and include: short tandem repeats in the promoter and intron 40 (rs41402545 and rs36115023) [Vidal et al 2005] that are routinely used for linkage analysis and a large number of common single nucleotide variants. Table 3. Selected VWF Normal Allelic Variants View in own windowDNA Nucleotide Change Protein Amino Acid Change VWF Exon/ Intron Reference SNP NumberRestriction Site/ Type of PolymorphismReference Sequencesc.1451A>G 1p.His484ArgExon 13rs1800378Rsa INM_000552.3 NP_000543.2c.1946-19_1946-17dupCTT 1NoneIntron 15rs106222883-bp insertion/deletionc.2365A>G 1p.Thr789AlaExon 18rs1063856Rsa Ic.2555A>Gp.Gln852ArgExon 20rs216321Nla IVc.4141A>G 1p.Thr1381AlaExon 28rs216311Hph Ic.4414G>Cp.Asp1472HisExon 28rs1800383RleA Ic.4641C>T 1p.Thr1547ThrExon 28rs216310BstE IIc.6187C>Tp.Pro2063SerExon 36NAc.6977-542_6977-541ins24NoneIntron 40rs36115023Deletion/ insertion polymorphismc.6977-715_6977-714ins16NoneIntron 40rs41402545 Deletion/ insertion polymorphismc.8113G>Ap.Gly2705ArgExon 49rs7962217Only a small proportion of common non-synonymous variants are listed.1. Normal variants particularly useful for linkage analysis because they are common in several ethnic groups and/or affect the cleavage site of a well-behaved restriction enzymePathologic allelic variants. Most cases of VWD result from single nucleotide substitutions (Table 4, 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 results from homozygosity or compound heterozygosity for mutations that result in null alleles, including missense mutations that affect dimerization/multimerization domains. Mutations are cataloged (see ISTH-SSC VWF Database).Table 4. Selected VWF Pathologic Allelic Variants View in own windowVWD Type 1DNA Nucleotide Change Protein Amino Acid Change VWF Exon Reference Sequences1c.3614G>Ap.Arg1205His27NM_000552.3 NP_000543.21c.4751A>Gp.Tyr1584Cys282Ac.4517C>Tp.Ser1506Leu282Ac.4789C>Tp.Arg1597Trp282Bc.3797C>Tp.Pro1266Leu282Bc.3916C>Tp.Arg1306Trp282Bc.3946G>Ap.Val1316Met282Bc.4022G>Ap.Arg1341Gln282Mc.3835G>Ap.Val1279Ile 282Mc.4273A>Tp.Ile1425Phe282Nc.2372C>Tp.Thr791Met182Nc.2446C>Tp.Arg816Trp192Nc.2561G>Ap.Arg854Gln203c.2435delCp.Pro812Argfs*31183c.4975C>Tp.Arg1659X283c.7603C>Tp.Arg2535X45See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org).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]. Its domain structure from the amino terminus is S-D1-D2-D’-D3-A1-A2-A3-D4-B1-B2-B3-C1-C2-CK (see Figure 1). During synthesis, tail-to-tail disulphide-linked dimers are formed through the CK domains, followed by head-to-head VWF oligomers. Disulphide 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 763-764 during multimer production and the propeptide (VWFpp) is secreted into the plasma along with VWF. The ratio between mature VWF (VWF:Ag) and VWFpp can be used to estimate relative half-life of mature VWF [Haberichter et al 2008]. 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.VWF has two key functions: binding collagen in the sub-endothelium at sites of vascular damage, which initiates repair through platelet recruitment; and clot formation plus binding and protecting FVIII from premature proteolytic degradation. 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 only been undertaken in type 1 VWD recently, in many cases pathogenic mechanisms have not yet been ascertained. Missense mutations mostly in the D3 domain [Haberichter et al 2008, Millar et al 2008] reduce the residence time of VWF in plasma by up to 15-fold. p.Arg1205His, the so-called “Vicenza” variant, is the best characterized and most common of these mutations. Such mutations 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].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], (4) intracellular retention [Schneppenheim et al 2010]. All result in the loss of HMW forms of VWF with fewer GbIb binding sites and less effective platelet clot formation.Type 2B. Missense mutations enhance the ability of VWF to bind platelet glycoprotein Gp1b such that binding occurs spontaneously without requiring the normal conformational change in VWF resulting 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, 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. Mutations affecting p.Pro1266Leu may only demonstrate enhanced Gp1b binding but no thrombocytopenia or HMW multimer loss [Federici et al 2009]. Type 2M. VWF is poor at binding Gp1b, often as a result of mutation in the A1 domain (see Figure 1) altering protein confirmation, but without the loss of HMW multimers seen in type 2A [James et al 2007b].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 and 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 D4-CK or D1-D2 domains (see Figure 1). These may impair either dimerization or multimerization of VWF, resulting in intracellular retention and lack of VWF secretion into plasma.