Von Willebrand Disease
Summary
Clinical 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.
Recent guidelines on VWD have recommended taking a VWF level of 30 or 40 IU/dL as a cutoff for those diagnosed with the disorder. Individuals with VWF levels greater than 30 IU/dL and lower than 50 IU/dL can be described as having a risk factor for bleeding. This change in guidelines significantly alters the proportion of individuals with each disease type.
Type 1 VWD (~30% of VWD) typically manifests as mild mucocutaneous bleeding.
Type 2 VWD accounts for approximately 60% of VWD. Type 2 subtypes include:
- 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 (<10% of VWD) manifests with severe mucocutaneous and musculoskeletal bleeding.
Diagnosis.
The diagnosis of VWD typically requires characteristic results of assays of hemostasis factors specific for VWD and/or identification of a heterozygous, homozygous, or compound heterozygous pathogenic variant(s) in VWF by molecular genetic testing. In addition, the diagnosis requires (in most cases) a positive family history. In those with a risk factor for bleeding (VWF levels >30 and <50 IU/dL), family history may not be positive because of incomplete penetrance and variable expressivity.
Management.
Treatment of manifestations: Affected individuals benefit from care in a comprehensive bleeding disorders program. The two main treatments are desmopressin (1-deamino-8-D-arginine vasopressin [DDAVP]) and clotting factor concentrates (recombinant and plasma-derived) containing both VWF and FVIII (VWF/FVIII concentrate). Indirect hemostatic treatments that can reduce symptoms include fibrinolytic inhibitors; hormones for menorrhagia are also beneficial. Individuals with VWD should receive prompt treatment for severe bleeding episodes. 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 to prevent musculoskeletal bleeding and subsequent joint damage.
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. Periodic evaluation by a physiotherapist of those with type 3 VWD 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 greater than 30 IU/dL are likely to achieve normal levels by the time of delivery. However, those with a basal level lower than 20 IU/dL and those with baseline VWF:RCo or other VWF activity measurement/VWF:Ag ratio <0.6 are likely to require replacement therapy. Desmopressin has been successfully used to cover delivery in women with type 1 VWD and a proportion of pregnant women with type 2 VWD; delayed, secondary postpartum bleeding may be a problem.
Genetic counseling.
VWD types 2B and 2M are inherited in an autosomal dominant manner. VWD types 1 and 2A are typically inherited in an autosomal dominant manner but may also be inherited in an autosomal recessive manner. VWD types 2N and 3 are inherited in an autosomal recessive manner.
- AD inheritance. Most affected individuals have an affected parent. The proportion of cases caused by de novo pathogenic variants 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 and preimplantation genetic testing are possible if the pathogenic variant(s) in the family are known.
Diagnosis
Several guidelines and testing algorithms have been published [Keeney et al 2008, Nichols et al 2008, Lassila et al 2011, Laffan et al 2014]. See Figures 1 and 2.
Figure 1.
Initial testing algorithm for von Willebrand disease From Nichols et al [2008]. Reprinted with permission of John Wiley and Sons.
Figure 2.
Algorithm for additional testing for von Willebrand disease subtype From Laffan et al [2014]. Reprinted with permission of John Wiley and Sons.
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).
There are three types of VWD [Sadler et al 2006]:
- Type 1. Partial quantitative deficiency of essentially normal VWF
- Type 2. Qualitative deficiency of defective VWF; divided into four subtypes depending on VWF function perturbed: 2A, 2B, 2M, 2N
- Type 3. Complete quantitative deficiency of (virtually absent) VWF
Suggestive Findings
Von Willebrand disease (VWD) should be suspected in individuals with excessive mucocutaneous bleeding including the following:
- Bruising without recognized trauma
- Prolonged, recurrent nosebleeds
- 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
- Gastrointestinal bleeding
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, Rodeghiero et al 2010, Elbatarny et al 2014, Mittal et al 2015]. 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; indicate situations requiring clinical intervention; and be used to indicate that a bleeding disorder is unlikely [Tosetto et al 2011]. Additionally, bleeding severity assessment correlates with the long-term probability of bleeding [Tosetto 2016].
Establishing the Diagnosis
The diagnosis of VWD is established in a proband with excessive mucocutaneous bleeding and characteristic results of assays of hemostasis factors specific for VWD (see Clinical Laboratory Testing and Table 1) and/or identification of a heterozygous, homozygous, or compound heterozygous pathogenic variant(s) in VWF by molecular genetic testing (see Table 2).
In addition, the diagnosis requires (in most cases) a positive family history. Note: In those with a risk factor for bleeding (VWF levels >30 and <50 IU/dL), family history may not be positive because of incomplete penetrance and variable expressivity.
Clinical Laboratory 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 (FVIII:C) level is reduced to below 30-40 IU/dL, as can be seen in severe type 1 VWD, type 2N VWD, or type 3 VWD. The normal range for FVIII:C clotting activity is approximately 50-150 IU/dL.
- Prothrombin time 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 in an individual in whom VWD is suspected [Budde et al 2006]. Note: Normal ranges are determined by the individual laboratory and thus are indicative only.
The International Society on Thrombosis and Haemostasis has recently published new guidance on assays that measure von Willebrand factor activity (VWF:Act) [Bodó et al 2015]. These tests include:
- VWF:RCo. Ristocetin cofactor activity: all assays that use platelets and ristocetin. Ability of VWF to agglutinate platelets, initiated by the antibiotic ristocetin (normal range ~50-200 IU/dL)
- VWF:GPIbR. All assays that are based on the ristocetin-induced binding of VWF to a recombinant WT GPIb fragment
- VWF:GPIbM. All assays that are based on the spontaneous binding of VWF to a gain-of-function variant GPIb fragment
- VWF:Ab. All assays that are based on the binding of a monoclonal antibody (mAb) to a VWF A1 domain epitope
- VWF:Ag. Quantity of VWF protein (antigen) in the plasma, measured antigenically using enzyme-linked immunosorbant assay (ELISA) or by latex immunoassay (LIA) [Castaman et al 2010a] (normal range ~50-200 IU/dL). A reduced ratio (<0.6) of VWF:Act to 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 and molecular weight into gigadaltons. Multimers are classified as low (1-5-dimer), intermediate (6-10-dimer), and high (≥10-dimer) molecular weight. HMW multimers are decreased or missing in type 2A VWD 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 two to three 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 GP1BA (see Differential Diagnosis), in which enhanced VWF-platelet binding is present.
- Binding of FVIII by VWF (VWF:FVIIIB). Ability of VWF to bind FVIII. Useful, but not widely used 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 types IV and 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.
- VWF:GP1BA. Functional tests are used to determine how well VWF binds to GpIbα. Previously, this was assessed using the VWF:RCo assay. Currently, this analysis is undertaken as part of the newer activity assays.
Table 1.
Classification of VWD Based on Specific VWF Tests
| VWD Type | VWF:Act 1 | VWF:Ag 1 | Act/Ag | FVIII:C IU/dL 1 | Multimer Pattern 2 | Other |
|---|---|---|---|---|---|---|
| 1 | Low | Low | Equivalent | ~1.5x VWF:Ag | Essentially normal | |
| 2A | Low | Low | VWF:Act < VWF:Ag | Low or normal | Abnormal ↓ HMW | ↓ VWF:GP1BA binding |
| 2B | Low | Low | VWF:Act < VWF:Ag | Low or normal | Often abnormal ↓ HMW | ↑ RIPA 3 (↓ platelet count) |
| 2M | Low | Low | VWF:Act << VWF:Ag | Low or normal | No loss of HMW | ↓ VWF:GP1BA binding ↓VWF:collagen binding 4 |
| 2N | Normal/low | Normal/low | Equivalent | <40 | Normal in most cases | ↓ VWF:FVIIIB 5 |
| 3 | Absent | Absent | NA | <10 | Absent |
- 1.
Relative to the reference range (approximate values); VWF:Act (50-200 IU/dL), VWF:Ag (50-200 IU/dL), FVIII:C (50-150 IU/dL). VWF activity (VWF:Act) includes VWF:RCo and the newer VWF activity assays in this instance.
- 2.
HMW multimers
- 3.
Increased agglutination at low concentrations of ristocetin
- 4.
Reduction in the ability of VWF to bind to collagen. Types I/III are bound by the A3 domain while types IV and VI are bound by the A1 domain. The latter types are not commonly analyzed.
- 5.
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
Molecular genetic testing approaches can include single-gene testing, use of a multigene panel, and more comprehensive genomic testing:
- Single-gene testing. Sequence analysis of VWF is performed first and followed by gene-targeted deletion/duplication analysis if no pathogenic variant is found.
- A multigene panel that includes VWF and other genes of interest (see Differential Diagnosis) may be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.Note: Analysis of exons 23 to 34 of VWF is complicated by the presence of a partial pseudogene, VWFP1.
- More comprehensive genomic testing (when available) including exome sequencing and genome sequencing may be considered. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene or genes that results in a similar clinical presentation).For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
Table 2.
Molecular Genetic Testing Used in von Willebrand Disease (VWD)
| Gene 1 | VWD Type(s) 2 | Proportion of VWD Attributed to This Type | Method | Proportion of Probands with a Pathogenic Variant 3 Detectable by Method |
|---|---|---|---|---|
| VWF | 1 | ~30% | Sequence analysis 4 | 80% 5 |
| Gene-targeted deletion/duplication analysis 6 | 6% 7 | |||
| All type 2 forms | ~60% | Sequence analysis 4 | ~90% 7 | |
| Gene-targeted deletion/duplication analysis 6 | 0.2% 7 | |||
| 3 | <10% 8 | Sequence analysis 4 | ~90% 7 | |
| Gene-targeted deletion/duplication analysis 6 | 3.7% 7 |
- 1.
See Table A. Genes and Databases for chromosome locus and protein.
- 2.
Recent changes in the von Willebrand factor (VFW) level used for diagnosis have significantly altered the proportion of patients classified with each disease type [Lassila et al 2011, Castaman et al 2013, Laffan et al 2014].
- 3.
See Molecular Genetics for information on allelic variants detected in this gene.
- 4.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
- 5.
Cumming et al [2006], Goodeve et al [2007], James et al [2007a], Yadegari et al [2012], Veyradier et al [2016]
- 6.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
- 7.
Veyradier et al [2016]
- 8.
In populations with frequent consanguineous partnerships, the rate of recessive forms of VWD may be elevated and type 3 VWD comprises a larger proportion of affected individuals.
Clinical Characteristics
Clinical Description
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.
Recent guidelines on VWD have recommended taking von Willebrand factor (VWF) levels of 30 or 40 IU/dL as a cutoff for those diagnosed with the disorder. Individuals with VWF levels greater than 30 IU/dL and lower than 50 IU/dL can be described as having a risk factor for bleeding. This change in guidelines significantly alters the proportion of individuals with each disease type [Lassila et al 2011, Castaman et al 2013, Laffan et al 2014].
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 (e.g., bruising, epistaxis, menorrhagia) 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.
Bleeding score. 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:
Table 3.
Bleeding Scores (BS) Reported in VWD by Type
| Patient Group | Study | # of Patients | BS Median | BS Range |
|---|---|---|---|---|
| Type 1 | Goodeve et al [2007] | 150 | 9 | -1-24 |
| Type 2A | Castaman et al [2012] | 46 | 11 | 6-16 |
| Type 2B | Federici et al [2009] | 40 | 5 | 4-24 |
| Type 2M | Castaman et al [2012] | 61 | 7 | 4-28 |
| Type 3 | Solimando et al [2012] | 9 | 15 | 6-26 |
| Type 3 | Bowman et al [2013] | 42 | 13 | 3-30 |
The higher the bleeding score, the greater the bleeding severity
Note: While the studies reported have all used similar bleeding assessment tools, slight variations in the tools and their application may have contributed to differences in bleeding scores.
Recently established cutoffs for an abnormal BS (≥4 for adult males, ≥6 for adult females, ≥3 for children) can be utilized to objectively assess the affected status of individuals tested using the ISTH-bleeding assessment tool (BAT) in a standard fashion [Elbatarny et al 2014].
BS in adults has also been shown to be a predictor of future bleeding [Federici et al 2014].
Type 1 VWD accounts for approximately 30% of all VWD in populations with infrequent consanguineous partnerships [Batlle et al 2016, Veyradier et al 2016]. 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 [Ragni et al 2016].
Type 2 VWD accounts for approximately 60% of all VWD. The relative frequency of the subtypes is 2A>2M>2N>2B in European populations [Batlle et al 2016, Veyradier et al 2016].
- Type 2A VWD. Individuals with type 2A VWD usually present with mild to moderate mucocutaneous bleeding [Veyradier et al 2016].
- 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 [Federici et al 2009].
- 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, Larsen et al 2013].
- 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 [van Meegeren et al 2015].
Type 3 VWD accounts for up to 10% of VWD (except in areas where consanguineous partnerships are common, where a higher proportion may be found). It manifests with severe bleeding including both excessive mucocutaneous bleeding and musculoskeletal bleeding [Metjian et al 2009, Ahmad et al 2013, Kasatkar et al 2014].
Associated complications
- Gastrointestinal angiodysplasia occurs most commonly in middle-aged/elderly individuals with types 2A and 3 VWD and affects the colon, small intestine, and stomach [Franchini & Mannucci 2014]. Lack of VWF in Weibel-Palade bodies promotes angiogenesis in endothelial cells [Starke et al 2011]. The disorder has also been reported in types 1 and 2B VWD [Hertzberg et al 1999, Siragusa et al 2008].
- Menorrhagia is experienced by a large proportion of women with VWD.
- The development of alloantibodies against VWF is an uncommon but serious complication of VWD treatment. An estimated 5%-10% of individuals with type 3 VWD may experience this complication. Affected individuals present with reduced or absent response to infused VWF concentrates or, in rare cases, with anaphylactic reaction. Individuals who have had multiple transfusions are at highest risk for this complication.
Genotype-Phenotype Correlations
The three phenotypes reflect a partial (type 1 VWD) or complete (type 3 VWD) quantitative deficiency of VWF or qualitative deficits (type 2 VWD) of VWF. See Molecular Genetics, Pathogenic variants for details regarding the genotypes associated with each subtype of VWD.
Individuals with large deletions of VWF are at highest risk for alloantibody development, although some with other null alleles have also been reported to develop this complication [James et al 2013].
Penetrance
Type 1 VWD (AD)
- VWF level. 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.
- 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]. 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.
Other AD types (2A, 2B, and 2M). Pathogenic variants 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 pseudo von Willebrand (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).
See also Mazurier & Rodeghiero [2001] and Bodó et al [2015].
Prevalence
VWD affects 0.1% to 1% of the population; 1:10,000 seek tertiary care referral.
VWD type 3 affects 0.5:1,000,000-6:1,000,000 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. In families with reduced FVIII:C, an X-linked pattern of inheritance can help identify those with mild hemophilia A.The VWF:FVIIIB test, which determines the ability of VWF to bind FVIII, can be used to discriminate between the two disorders [Casonato et al 2007] and a commercial assay is now available [Veyradier et al 2011], although on a limited basis. Alternatively, molecular genetic testing can be used to distinguish the two disorders. Both molecular and phenotypic testing have some fallibilities in interpretation.
- PT-VWD (pseudo VWD) (OMIM 177820), caused by pathogenic variants in GP1BA, may be difficult to distinguish from type 2B VWD; one study identified pathogenic variants in GP1BA in up to 15% of persons diagnosed with 2B VWD [Hamilton et al 2011]. The two disorders can be distinguished by mixing patient/control plasma and platelets to determine which component is defective [Othman et al 2016] or by molecular testing.PT-VWD has been shown to be less severe than type 2B VWD using a bleeding assessment tool [Kaur et al 2014].The two disorders require different treatment. In PT-VWD, 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 administration of VWF concentrate than in VWD.
Acquired von Willebrand syndrome (AVWS) is a mild-moderate bleeding disorder that can occur in a variety of conditions [Sucker et al 2009, Federici et al 2013, Mital 2016] but is not caused by pathogenic variants in VWF. It is most often seen in persons older than age 40 years with no prior bleeding history. AVWS has diverse pathology and a number of possible causes:
- 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)