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Clinical presentation and diagnosis of von Willebrand disease

Clinical presentation and diagnosis of von Willebrand disease
Literature review current through: Sep 2023.
This topic last updated: Jun 16, 2023.

INTRODUCTION — Von Willebrand disease (VWD) is the most common inherited bleeding disorder. Diagnosis can be challenging; some individuals with low von Willebrand factor (VWF) levels may not actually have VWD (or any bleeding disorder), whereas others who have never had a bleeding challenge or never been tested have a significant bleeding risk from VWD that would benefit from evaluation and counseling.

This topic reviews the clinical presentation, diagnosis, and differential diagnosis of VWD.

Separate topic reviews discuss the treatment and pathophysiology of VWD, the diagnosis and treatment of acquired von Willebrand syndrome (AVWS), and a general approach to bleeding disorders.

Treatment of VWD – (See "von Willebrand disease (VWD): Treatment of major bleeding and major surgery" and "von Willebrand disease (VWD): Treatment of minor bleeding, use of DDAVP, and routine preventive care".)

Diagnosis and treatment of AVWS – (See "Acquired von Willebrand syndrome".)

Pathophysiology of VWD – (See "Pathophysiology of von Willebrand disease".)

Approach to evaluating suspected bleeding disorders – (See "Approach to the adult with a suspected bleeding disorder".)

SUMMARY OF VWD TYPES — There are three major types of VWD (table 1) [1,2]:

Type 1 is due to a quantitative reduction in von Willebrand factor (VWF) protein (both concentration and activity are decreased).

Type 2 is due to dysfunctional VWF.

Type 3 is due to absent or severely reduced VWF (a severe quantitative reduction).

Type 2 is divided into four subtypes that reflect the specific VWF function affected; the distribution of VWF multimers is also important for function and may be affected. The type and subtype have potential implications for bleeding risk, diagnostic testing, management, and genetic counseling.

The VWD types and subtypes are summarized in the table (table 1) and briefly below; the known genetic variants associated with each type and mechanisms by which they affect VWF quantity and function are discussed in more detail separately. (See "Pathophysiology of von Willebrand disease".)

Measures of VWF activity are discussed below. (See 'Platelet-dependent VWF activity (VWF:RCo or VWF:GPIbM)' below.)

Type 1 – Type 1 VWD is characterized by reduced levels of VWF and variable degrees of bleeding. Type 1 is the most common type, accounting for approximately 75 percent of individuals with VWD. There is a concordant reduction in VWF activity and antigen, and all multimers are present in decreased amounts. Thus, the ratio of platelet-dependent VWF activity (VWF:RCo or VWF:GPIbM) to VWF antigen (VWF:Ag) is normal (approximately 1:1). (See 'Derived ratios to aid classification' below.)

Guidelines in 2021 recommended the official addition of category type 1C, which is characterized by a concordant reduction in VWF activity and antigen due to rapid clearance of VWD from the circulation [2]. The Vicenza variant is a type 1C variant [3-5]. Treatment may be impacted due to the shorter half-life of VWD [6,7].

Type 2 – Type 2 VWD is characterized by a dysfunctional VWF protein [8]. Different subtypes reflect which protein-protein interactions are affected. In some cases, reduced binding to a physiologic binding partner may be caused by defective multimerization rather than a defect in a specific protein binding domain.

Type 2A – Type 2A VWD involves loss of the platelet binding function of VWF and a reduction in the most functional high molecular weight (HMW) multimers. The loss of HMW multimers may be due to either decreased multimer assembly or to increased proteolysis [9,10]. The ratio of platelet-dependent VWF activity (VWF:RCo or VWF:GPIbM) to VWF:Ag is decreased. This subtype accounts for 10 to 15 percent of VWD cases.

Type 2B – Type 2B VWD involves increased platelet binding by VWF, especially by the HMW multimers, due to a gain-of-function mutation in VWF that enhances binding of VWF to platelet glycoprotein Ib (GPIb). This enhanced binding leads to accelerated clearance or sequestration of platelets and of the bound HMW VWF multimers, in turn causing thrombocytopenia and decreased VWF with abnormal VWF multimer distribution (loss of HMW multimers). The ratio of platelet-dependent VWF activity (VWF:RCo or VWF:GPIbM) to VWF:Ag is decreased. This subtype accounts for approximately 5 percent of VWD cases.

A platelet disease called platelet-type VWD involves enhanced platelet binding by VWF with accelerated platelet clearance and thrombocytopenia, a similar phenotype to type 2B VWD, but in the case of platelet-type VWD, the mutation resides in the platelet GPIb receptor rather than the VWF protein.

Type 2M – Type 2M VWD involves reduced binding of VWF to platelet GPIb (similar to type 2A) or to collagen; these patients have reduced VWF levels. Unlike type 2A, the normal distribution of VWF multimers is preserved. Although the multimer distribution is normal, the ratio of platelet-dependent VWF activity (VWF:RCo or VWF:GPIbM) to VWF:Ag is reduced, differentiating type 2M from type 1 (in those with abnormal collagen binding, testing with VWF:CB is needed). Type 2M is less common than types 2A or 2B.

Type 2N – Type 2N (for Normandy) VWD involves reduced binding of VWF to factor VIII. As a result, the carrier function of VWF for factor VIII is disrupted, leading to low factor VIII levels and a low ratio of factor VIII activity to VWF:Ag. VWF platelet-dependent activity and antigen levels can be normal. Clinical manifestations include mucocutaneous bleeding but are otherwise similar to hemophilia A, with joint and muscle bleeding. Type 2N is uncommon. Homozygosity or double heterozygosity is required for symptomatic type 2N disease.

Type 3 – Type 3 VWD is characterized by absent (or undetectable) levels of VWF. This correlates with severely reduced VWF function and very low factor VIII levels, which contributes to a severe bleeding phenotype. Type 3 is rare.

AVWS – Acquired von Willebrand syndrome (AVWS) is an acquired disorder characterized by low levels of VWF due to reduced production or enhanced removal of VWF from the circulation. It is distinguished from inherited VWD by a lack of prior personal bleeding, a negative family history of VWD, and a nongenetic cause. Often the patient has findings of a disorder associated with AVWS. (See "Acquired von Willebrand syndrome".)

Laboratory findings in the different types of VWD are discussed below. (See 'Additional testing to characterize (classify) the type of VWD' below.)

EPIDEMIOLOGY

Prevalence — VWD is the most common inherited bleeding disorder. In primary care, VWD that causes symptomatic bleeding has a prevalence of approximately 1 in 1000 (0.1 percent) [11,12]

Low von Willebrand factor (VWF) levels affect up to 1 percent of the population as assessed by random laboratory screening [13].

Of individuals diagnosed with VWD, the vast majority have type 1 (75 to 85 percent), followed by type 2A (10 to 15 percent) and type 2B (5 percent). (See 'Summary of VWD types' above.)

Inheritance patterns — All types of VWD are autosomal and thus affect males and females equally [14]. Females experience mucosal bleeding with menses and during the postpartum period and as a result may be diagnosed more commonly than males. (See 'Heavy menstrual bleeding' below.)

Most cases of VWD show autosomal dominant transmission; this includes:

Type 1

Type 2B

Most cases of type 2A

Most cases of type 2M

Autosomal recessive types include:

Type 2N

Type 3

Some cases of type 2A

Some cases of type 2M

VWD types are summarized above (see 'Summary of VWD types' above). The VWF gene and domain structure of the protein are discussed separately. (See "Pathophysiology of von Willebrand disease", section on 'Spectrum of pathogenic variants'.)

CLINICAL FEATURES

Types of bleeding presentations — Bleeding symptoms in VWD occur when plasma von Willebrand factor (VWF) is sufficiently decreased to affect hemostasis or when a qualitative defect in VWF impairs one of its hemostatic functions.

Affected females (adults) are usually symptomatic. Males and children may not have been exposed to sufficient hemostatic challenges to bring them to medical attention.

Many symptomatic individuals with VWD go undiagnosed, and studies have shown that females, in particular, have diagnostic delays of up to 16 years from the onset of bleeding symptoms. Systemic factors, including sexism, contributes to this [15,16].

In patients with mild VWD, use of aspirin, other nonsteroidal antiinflammatory drugs (NSAIDs), or other antiplatelet medications can precipitate bleeding that may not have occurred otherwise (table 2).

Patients with VWD can become symptomatic at any age. A typical history in a patient with mild to moderate disease includes epistaxis lasting longer than 10 minutes in childhood; lifelong easy bruising; heavy menstrual bleeding; and bleeding with (or following) dental extractions, other invasive dental procedures, or other forms of surgery. A typical presentation in a toddler may include oral mucosal bleeding or bleeding with circumcision; intracranial bleeding in infants has also been reported [17].

Although there is significant overlap in the bleeding symptoms experienced between the subtypes, in general, bleeding in type 3 VWD is the most severe, followed by type 2 VWD, followed by type 1 VWD [18]. The following findings (severity and sites of bleeding) are typical:

Type 1 – Variable, from asymptomatic to serious bleeding; mucocutaneous

Type 2A – Usually moderate to severe; mucocutaneous

Type 2B – Usually moderate to severe; mucocutaneous

Type 2M – Variable; usually moderate to severe; mucocutaneous

Type 2N – Variable; usually moderate to severe; mucocutaneous but can include joint and muscle

Type 3 – Severe; mucocutaneous and joint and muscle bleeding; often presents during infancy/childhood (eg, with circumcision)

In summary:

Mild to moderate mucocutaneous bleeding is most common in types 1 and 2. Those without hemostatic challenges (especially adult males and children) may only come to medical attention after a family member is diagnosed with VWD. (See 'Bruising and mucocutaneous bleeding' below and 'Heavy menstrual bleeding' below.)

Severe bleeding is more common with types 2 and 3. In type 3, the combination of reduced factor VIII levels with very low or absent VWF levels can lead to significant bleeding with the eruption of deciduous teeth, with minor trauma as the child begins crawling or walking, or with major or life-threatening hemorrhage at the onset of menstrual periods. (See 'Heavy menstrual bleeding' below and 'Gastrointestinal bleeding and angiodysplasia' below and 'Musculoskeletal bleeding' below.)

Bruising and mucocutaneous bleeding — Bruising and mucocutaneous bleeding are common, including:

Easy bruising

Cutaneous bleeding

Prolonged bleeding from mucosal surfaces (eg, oropharyngeal, gastrointestinal, uterine)

These occur because there the normal initial VWF-dependent binding of platelets to sites of vascular injury is reduced, similar to primary platelet disorders.

These findings are typical in type 1 as well as types 2A, 2B, and 2M. Though mucocutaneous bleeding occurs in type 2N and type 3, type 3 is also characterized by additional muscle and joint bleeding.

In a series of 105 infants and toddlers diagnosed with VWD at age <2 years, 70 percent had a bleeding event [17]. Oral mucous membrane bleeding was the most common site, affecting one-third. Bleeding with circumcision affected 12 percent.

Heavy menstrual bleeding — More than half of females with VWD have heavy menstrual bleeding (as many as 60 to 90 percent in some studies) [19-22]. In one series, 20 percent of participants had undergone hysterectomy to treat severe menstrual bleeding [23].

The converse (the proportion of females with heavy menstrual bleeding diagnosed with VWD) depends on the population studied; systematic reviews report rates of approximately 10 to 15 percent [24,25]. (See "Abnormal uterine bleeding in nonpregnant reproductive-age patients: Terminology, evaluation, and approach to diagnosis" and "Causes of female genital tract bleeding", section on 'Coagulopathy (AUB-C)'.)

Postpartum bleeding — VWF levels generally increase during pregnancy; this can be protective against bleeding prior to and during delivery. However, VWF levels decline precipitously after delivery, and bleeding can occur during the peripartum period, often at or within hours of delivery and later at 5 to 15 days after delivery.

In one series involving 120 individuals with decreased VWF levels, 74 (62 percent) reported postpartum bleeding, and 22 percent required transfusion, critical care, or surgical/radiologic intervention [21]. A case-control study involving 62 deliveries in 33 individuals with VWD found a trend towards an increased incidence of primary postpartum hemorrhage (PPH), with a rate of 19 in those with VWD versus 13 percent in controls (adjusted odds ratio [OR] 1.31; 95% CI 0.48-3.60), and a series of 124 individuals with PPH determined that VWD was present in approximately half, most of whom had type 1 disease [26,27]. (See "Overview of postpartum hemorrhage", section on 'Coagulopathy or other bleeding diathesis' and "von Willebrand disease (VWD): Gynecologic and obstetric considerations", section on 'Obstetric considerations'.)

Gastrointestinal bleeding and angiodysplasia — Bleeding from the gastrointestinal tract can also be seen in VWD, although this is less common than mucocutaneous bleeding.

Often, there may be a contribution of gastrointestinal angiodysplasia, which is common in VWD [28-32]. (See "Pathophysiology of von Willebrand disease".)

Musculoskeletal bleeding — Joint and muscle bleeding are not typical in most patients with VWD.

These types of bleeding are typically only seen with types 2N and 3, which have low factor VIII levels (<10 percent). Low factor VIII occurs because VWF is a carrier protein for factor VIII and prolongs the half-life of factor VIII in the circulation. (See "Pathophysiology of von Willebrand disease", section on 'Stabilization of factor VIII'.)

Factor VIII levels can be reduced if VWF does not bind to factor VIII properly (as in type 2N) or if VWF is markedly reduced or absent (as in type 3) [33-35]. (See 'Summary of VWD types' above.)

In one large study from Iran involving 385 patients with type 3 VWD, 52 percent had muscle bleeding and 37 percent had joint bleeding [36]. Rates of epistaxis and oral bleeding were even higher (77 and 70 percent, respectively).

Abnormalities in the CBC and coagulation tests — Many individuals with VWD have a normal complete blood count (CBC) and normal coagulation studies.

However, the following abnormalities may be seen:

Thrombocytopenia – Individuals with type 2B VWD may have mild thrombocytopenia (platelet count 100,000 to 140,000/microL) due to increased binding between VWF and platelets that increases platelet clearance or sequestration [37]. (See 'Baseline hemostasis assessment' below.)

Thrombocytopenia may worsen in these individuals when VWF levels increase, such as with stress, inflammation, or pregnancy. Administration of desmopressin (DDAVP) also increases VWF levels and can worsen thrombocytopenia in these individuals; this is the rationale for extremely careful use or avoidance of DDAVP in the treatment of patients with type 2B VWD. (See "von Willebrand disease (VWD): Treatment of minor bleeding, use of DDAVP, and routine preventive care", section on 'DDAVP trial'.)

Microcytic anemia – Individuals with heavy menstrual bleeding or gastrointestinal bleeding may develop iron deficiency or iron deficiency anemia, with microcytosis. Ferritin level and/or an iron studies panel should be obtained to assess for iron deficiency if significant bleeding or microcytosis is present. (See "Microcytosis/Microcytic anemia", section on 'Approach to the evaluation'.)

Prolonged aPTT – The activated partial thromboplastin time (aPTT) may be prolonged if the factor VIII level is significantly reduced. The factor VIII level below which the aPTT becomes prolonged depends on the sensitivity reagents and instrument used for the assay.

Changes with aging and pregnancy — VWF levels increase with age, by approximately 0.8 percentage points per year (approximately 8 percentage points per decade) [8]. An individual with a VWF level of 30 to 50 international units [IU]/mL and a bleeding history as a young adult who is retested years later may no longer have a VWF level below the threshold for diagnosis. Whether the increase in VWF levels in type 1 patients results in decreased bleeding symptoms is not established. Re-evaluation may be warranted if VWF levels increase into the normal range, but the diagnosis is not revised [38].

In a 2017 study that followed 26 individuals with type 1 VWD or low VWF for over 10 years, 28 percent had normalized VWF levels by the end of the study [39]. The age-related increase in VWF levels may apply only to individuals with type 1 VWD and not to those with type 2 [40,41].

Estrogen stimulates VWF production; thus, VWF levels are higher with estrogen therapy and during pregnancy, and the bleeding risk may decrease prior to delivery. VWF levels increase by approximately three- to fivefold by the end of the third trimester. (See "Pathophysiology of von Willebrand disease", section on 'VWF protein'.)

Initial testing for the diagnosis of VWD is not ideally done during pregnancy; if an individual with suspected VWD has a borderline or normal level during pregnancy, it is appropriate to retest six weeks or more after delivery.

EVALUATION

Indications for evaluation — VWD should be considered in individuals with one or more of the following:

Increased history of bleeding, especially mucocutaneous bleeding, abnormal bruising, nosebleeds, or abnormal uterine bleeding. (See 'Personal bleeding history and bleeding assessment tool (BAT)' below.)

Positive family history of VWD or of a bleeding phenotype suggestive of VWD. (See 'Family history and transmission pattern' below.)

Mild thrombocytopenia or mildly prolonged activated partial thromboplastin time (aPTT) without an explanation. (See "Approach to the adult with a suspected bleeding disorder".)

Apparent hemophilia A (low factor VIII in the absence of a factor VIII inhibitor). (See 'Differential diagnosis' below.)

In general, the likelihood of VWD is higher in individuals with a significant personal and/or family history of bleeding (or a confirmed diagnosis of VWD in a family member) [42,43].

The role of screening for VWD in asymptomatic individuals is controversial; however, testing is often appropriate in someone with a clear family history. If the patient has not experienced a hemostatic challenge, the decision to test may depend on the patient's personal activities. As an example, we would be more likely to screen an individual prior to invasive procedures or in someone who participates in sports that are associated with an increased risk of injury, or if a parent/caregiver or patient has specific concerns about a bleeding disorder in a kindred.

Personal bleeding history and bleeding assessment tool (BAT) — An accurate bleeding history is essential to the evaluation of any suspected bleeding disorder, including VWD. (See "Approach to the adult with a suspected bleeding disorder", section on 'Patient history'.)

The bleeding history should address spontaneous bleeding and should specifically ask about bleeding challenges such as invasive dental procedures, tonsillectomy, circumcision, other surgical procedures (particularly involving mucous membranes), and menstrual and peripartum bleeding. The value of the history depends on the skill of the questioner and on the follow-up questions they use to evaluate the significance of the answers provided.

Details of the bleeding history can be documented using bleeding an assessment tool (BAT), which helps to quantify the severity, duration, and sites of bleeding, and whether treatment was needed. Guidelines from 2021 recommend using a BAT as the initial screening test for low-risk individuals seen in primary care, as a means of determining which individuals need VWD-specific laboratory testing [2]. However, for individuals with a high risk of VWD, such as a first-degree relative with VWD, laboratory testing should be done regardless of bleeding history. In these patients, the BAT may be helpful in assessing the severity of bleeding and in guiding therapy.

Some BATs have been validated in clinical practice, especially for females, and the International Society of Thrombosis and Haemostasis (ISTH) has created and validated the ISTH-BAT, which can be found online at the ISTH reference tools page [44,45]. A 2021 meta-analysis of BATs found the overall sensitivity for identifying VWD to be 75 percent (95% CI, 66 to 83 percent) and the overall specificity to be 54 percent (95% CI, 29 to 77 percent) [46]. Performance characteristics of several BATs are presented in the analysis. (See "Approach to the adult with a suspected bleeding disorder", section on 'Bleeding score'.)

A self-administered BAT (Self-BAT) for adults has also been used, and an online version has proven useful, especially in females [47,48]. Larger studies in individuals with and without VWD will be helpful in assessing the effectiveness of the self-administered tests. A separate pediatric BAT called the pediatric bleeding questionnaire (PBQ) and a self-administered pediatric version have also been designed, and both have been validated for clinical use [47,49,50].

We encourage the use of the ISTH-BAT or Self-BAT in individuals with suspected VWD because it provides an objective, quantitative picture of the bleeding history. The ISTH-BAT needs to be administered by a trained health care worker. In an analysis of data from 1040 adults and 328 children, the normal ranges were determined to be 0 to 3 for adult males, 0 to 5 for adult females, and 0 to 2 for children [44].

Other important aspects of the personal bleeding history include:

Use of medications that may increase bleeding risk (table 2)

Family history of bleeding symptoms (see 'Family history and transmission pattern' below)

Medical conditions that could increase bleeding risk (see "Approach to the adult with a suspected bleeding disorder", section on 'Underlying medical conditions')

Medical conditions associated with acquired von Willebrand syndrome (see "Acquired von Willebrand syndrome", section on 'Associated diseases')

The physical examination should include a search for ecchymoses and hematomas, documenting their size and location, and evidence for current or recent mucosal bleeding. A negative physical examination is common in patients.

Family history and transmission pattern — Family history is important in the evaluation for VWD. A positive family history is especially important for individuals who have not experienced a major bleeding challenge, since significant bleeding in a family member suggests the possibility of a serious bleeding disorder. In contrast, a negative family history cannot be used to eliminate the possibility of VWD because of the issues of missed/delayed diagnosis as well as incomplete penetrance and variable expressivity that affect type 1 VWD families.

The transmission pattern may be helpful in evaluating the likelihood of VWD (autosomal) rather than hemophilia A or B (X-linked). The transmission pattern (autosomal dominant versus recessive) may be helpful in suggesting the VWD subtype. (See 'Inheritance patterns' above.)

It is also very useful to have laboratory data on family members, including von Willebrand factor (VWF) levels and function, as well as specialized testing for the type of VWD and testing for other bleeding disorders. (See 'VWD screening tests' below and 'Additional testing to characterize (classify) the type of VWD' below.)

Recommendations for referral to a specialist — It is appropriate to refer patients to a hematologist with expertise in VWD for either of the following:

When the personal bleeding history is abnormal or testing is borderline or difficult to obtain or interpret for diagnosis.

When the family history is positive.

When management requires clinical expertise, treatments, and timely testing beyond the ability of the local facility or clinicians.

LABORATORY TESTING

Baseline hemostasis assessment — Most patients will have a complete blood count (CBC) with platelet count and coagulation studies during the initial evaluation for excessive bleeding or bruising.

Individuals with VWD can have a normal CBC and a normal platelet count. An exception is individuals with type 2B VWD, some of whom will have mild thrombocytopenia at baseline (platelet count 100,000 to 140,000/microL) [37]. Those with significant bleeding may have microcytic anemia.

Individuals with VWD may have a normal or prolonged activated partial thromboplastin time (aPTT), depending on the degree of reduction in factor VIII activity. The prothrombin time (PT) is normal. (See 'Abnormalities in the CBC and coagulation tests' above.)

VWD screening tests — For initial testing for VWD, three screening tests that assess the quantity and function of von Willebrand factor (VWF) are recommended by guidelines jointly published by the American Society of Hematology (ASH), International Society on Thrombosis and Haemostasis (ISTH), National Hemophilia Foundation (NHF), and World Federation of Hemophilia (WFH) [1,2,51]; these three tests usually establish whether the patient has VWD (algorithm 1).

VWF antigen (VWF:Ag) – Quantitative measurement of VWF protein level (see 'VWF antigen' below)

Platelet-dependent VWF activity (see 'Platelet-dependent VWF activity (VWF:RCo or VWF:GPIbM)' below)

Factor VIII activity (see 'Factor VIII activity' below)

These tests are performed on plasma, when the individual is at their baseline (not acutely ill; not pregnant). Interpretation is summarized in the table (table 3) and discussed below.

VWF antigen — Plasma von Willebrand factor antigen (VWF:Ag) measures the quantity of VWF protein in the plasma. Testing methods have evolved over time, and most testing is now done using an enzyme-linked immunosorbent assay (ELISA)-based method on microtiter plates or by other automated methods using latex beads coated with antibodies to VWF and patient plasma as the source of VWF [52,53]. The latter use a turbidimetric endpoint. Results of the latex bead assay compare favorably with the ELISA in most but not all instances. A potential problem is that rheumatoid factors can falsely elevate the VWF latex assay [54].

A VWF:Ag level <30 percent (<30 international units [IU]/dL) is consistent with VWD. Levels between 30 and 50 percent in a patient with a positive bleeding history also indicate VWD. Levels >50 percent are considered normal.

Platelet-dependent VWF activity (VWF:RCo or VWF:GPIbM) — VWF functional assays assess the ability of VWF to bind to its normal binding partners, platelet glycoprotein Ib (GPIb), collagen, and factor VIII (figure 1). The results of these tests are commonly referred to as "VWF activity." Unfortunately, confusion may result because some of the specific tests for measuring VWF binding to recombinant GPIb are themselves commercially labeled as "VWF activity."

Platelet (GPIb) binding – VWF binding to platelet receptor GPIb allows VWF to recruit platelets to a site of vascular injury; it can be assayed by several methods:

VWF:RCo (ristocetin cofactor) – VWF:RCo is an assay that measures the ability of VWF to bind to platelet membrane receptor GPIb. It takes advantage of the ability of ristocetin (an antibiotic that is no longer in clinical use because it causes platelet agglutination) to bind to VWF and platelets and enhance their interaction [55-58]. In the VWF:RCo assay, ristocetin is added to patient plasma along with washed or formalin-fixed platelets, and the amount of functional VWF in the plasma that causes platelet agglutination is quantified using platelet aggregometry or a manual (tilt tube) method [59,60]. Using fixed platelets avoids the need to use fresh platelets for each assay and avoids the secondary aggregation reaction that occurs with fresh platelets [61].

This test is limited by a high coefficient of variation and low reproducibility. A low value can be the result of VWF variants that affect ristocetin binding but do not affect VWF function or cause bleeding (ie, D1472, which is common in patients of African descent). As a result, the 2021 VWD Diagnosis Guideline suggests the use of the newer assays listed below (such as VWF:GPIbR or VWF:GPIbM) to measure platelet-dependent VWF function [2,62,63].

VWF:RCo is different from ristocetin-induced platelet aggregation (RIPA); the RIPA tests aggregation of the patient's platelets in the patient's plasma (platelet-rich plasma) at low concentrations of ristocetin, and it does not measure VWF activity. Increased RIPA is seen in type 2B VWD. (See 'Ristocetin-induced platelet aggregation (RIPA)' below.)

VWF:GPIbR – VWF:GPIbR measures the ability of the patient's VWF to bind to a recombinant platelet GPIb receptor attached to a solid phase such as latex beads (in the place of platelets that contain membrane GPIb). Ristocetin is added to enhance binding, as done in the VWF:RCo assay. VWF:GPIbR is more sensitive than VWF:RCo and is automated [64,65].

VWF:GPIbM – VWF:GPIbM measures the ability of the patient's VWF to bind to a recombinant mutated GPIb receptor attached to latex beads. Ristocetin is not needed due to the gain-of-function mutation in the recombinant GPIb reagent. The test is more sensitive than VWF:RCo and is automated [64].

VWF activity of <30 percent (<0.30 international units [IU]/mL) confirms the diagnosis of VWD, regardless of bleeding history; VWF activity <50 percent (<0.50 IU/mL) confirms the diagnosis of VWD in someone with a positive bleeding history [2].

Though the VWF:RCo assay has been the "gold standard" for the platelet binding activity of VWF, the automated tests listed above are generally more reproducible and are more sensitive in the lower range; they are becoming widely used [64,66]. When compared with the VWF:RCo, the VWF:GPIbR, and VWF:GPIbM function well in most instances and are more sensitive below 10 IU/dL; however, a few VWF variants have not been identified correctly [64,65,67].

The VWF:Ab assay may be available but is not recommended [51,64].

Flow cytometry has also been used to measure VWF-platelet binding, but it is not widely available.

VWF:CB (collagen binding) – Another functional assay evaluates the ability of the patient's VWF to bind to collagen. VWF binding to collagen allows VWF to be localized to the subendothelial matrix, bringing bound platelets to the site of vascular injury. Assays for collagen binding are performed using ELISA plates coated with collagen (typically collagen types I and III) [68,69]. Collagen binding assays are not used as frequently as platelet binding assays in the United States, but some laboratories are using it, and it measures a different function of VWF from the other VWF:Act assays [68,69]. Decreased collagen binding is also used by some laboratories as a surrogate test for decreased high molecular weight (HMW) multimers of VWF, but this has not been favored in the United States [70]. The 2021 VWD Diagnosis Guideline suggests the use of either the VWF:CB or VWF multimers [2].

Standards for reagents – The VWF reagents used in VWF activity assays should always be related to the World Health Organization (WHO) standard for VWF, and the results should be reported in IU/dL or IU/mL, where 100 percent equals 100 IU/dL or 1 IU/mL.

As noted below, a VWF functional test showing activity <30 percent (<30 IU/dL) is consistent with VWD. (See 'Clinical considerations and evolution of guidelines' below.)

As in individuals with a VWF:Ag <30 IU/dL or in a patient with a bleeding history and activity of 30 to 50 IU/dL, further testing should be done to categorize the type of VWD. (See 'Additional testing to characterize (classify) the type of VWD' below.)

Factor VIII activity — Decreased factor VIII activity may indicate reduced or dysfunctional VWF, as VWF acts as a carrier for factor VIII that protects it from proteolysis, increasing its plasma half-life. Significant reduction in VWF can lead to a decrease in factor VIII sufficient to prolong the aPTT. The level below which this occurs is highly dependent on the reagents and instruments used at each institution.

Factor VIII activity is in the low normal range in many cases of mild VWD or only moderately decreased in type 1 and types 2A, 2B, and 2M.

Factor VIII activity is low in type 2N VWD (impaired binding of VWF to factor VIII; factor VIII activity 5 to 15 percent) and in type 3 VWD (absent VWF; factor VIII activity 1 to 10 percent) [1,35,71].

In cases with low factor VIII activity, it is important to distinguish VWD from mild hemophilia. This is done using tests for VWF binding to normal factor VIII and/or by genetic analysis of the VWF binding site for factor VIII. (See 'Differential diagnosis' below.)

If the levels are discordant with the clinical picture (eg, if there is a high index of suspicion for VWD in the face of normal or equivocal initial results), testing should be repeated when the patient is at baseline. It is also appropriate to refer the patient to a hematologist with expertise in VWD in this setting.

Diagnostic testing is not recommended when the individual has any acute illness, pregnancy, other physiologic stress, or other estrogen exposure. (See 'Repeat testing in individuals with borderline or discordant clinical and laboratory findings' below.)

Other screening tests — The following tests are sometimes used in initial screening:

Platelet function analyzer (PFA) assay – The PFA-100 assesses platelet plug formation in citrated whole blood exposed to shear stress [72]. The plug forms on a membrane with a central aperture that is coated with collagen and another platelet agonist, either ADP or epinephrine. The time to closure of the aperture as the platelet plug forms is measured. The closure time is dependent upon both VWF and intrinsic platelet function.

This instrument has been used to screen for VWD due to its high sensitivity [73-75]. However, it lacks specificity, leading many to question its role in screening; the PFA-100 is not included in the recommended diagnostic assays by VWF guidelines [1,2,76]. (See "Platelet function testing", section on 'PFA-100'.)

Bleeding time (BT) – The BT is an in vivo measure of the interaction of platelets with the blood vessel wall. It is performed by making a small, standardized cut on the skin and determining the time for bleeding to stop. The BT is no longer routinely used because it is time consuming, highly operator dependent, and does not correlate well with bleeding risk or with any specific assay of VWF function [77,78]. The BT may be abnormal in some individuals with VWD, but a normal BT does not eliminate the possibility of VWD.

Repeat testing in individuals with borderline or discordant clinical and laboratory findings — A number of things affect VWF levels. Thus, in patients who are deemed likely to have a bleeding disorder (especially if they have a positive personal or family history and borderline laboratory results), repeat diagnostic testing should be undertaken, reducing the stress-related elevation of VWF [79].

Conditions that can affect VWF levels include the following:

VWF and factor VIII are acute phase reactants, and their levels can increase two to five times over baseline during exercise, adrenergic stimulation (stress), and inflammatory processes [80-85]. (See "Acute phase reactants".)

VWF levels increase with estrogen exposure (eg, estrogen-containing oral contraceptives, menopausal hormone therapy). Pregnancy is associated with a two- to fivefold increase in VWF levels [80]. (See 'Changes with aging and pregnancy' above.)

VWF levels decrease in hypothyroidism. (See "Clinical manifestations of hypothyroidism", section on 'Hematologic' and "Acquired von Willebrand syndrome", section on 'Hypothyroidism'.)

VWF levels can be affected by age, ethnicity, ABO blood type, and genes unrelated to VWF [86].

The mechanisms of these effects are discussed separately. (See "Pathophysiology of von Willebrand disease", section on 'Clearance and control of plasma VWF levels'.)

Additional testing to characterize (classify) the type of VWD — If one of the VWF:Ag or platelet-dependent VWF activity tests is <30 percent, or <50 percent in a patient with a bleeding history, indicating a diagnosis of VWD, additional assays should be completed to determine the type of VWD (table 3). Use of this testing to classify the type of VWD is illustrated in the algorithm (algorithm 2).

Derived ratios to aid classification

Platelet-dependent VWF activity to VWF antigen – Laboratories make use of the ratio of platelet-dependent VWF activity to VWF:Ag as a means of helping to identify patients with type 2 VWD (dysfunctional VWF; qualitative defect). (See 'Platelet-dependent VWF activity (VWF:RCo or VWF:GPIbM)' above.)

The following cutoffs are recommended by the 2021 guideline [2]:

Ratio >0.7 – Individuals with type 1 VWD generally have good concordance between VWF activity and protein levels, leading to a ratio of platelet-dependent VWF activity to VWF:Ag close to 1.0. A ratio >0.7 is generally considered concordant and consistent with type 1 VWD. The ratio is also close to 1.0 in individuals with normal VWF levels.

Ratio <0.7 – Types 2A, 2B, and 2M VWD all have decreased platelet-dependent VWF activity or VWF:CB out of proportion to the reduction of VWF protein in the circulation; thus, a low ratio of platelet-dependent VWF activity to VWF:Ag may be used to predict these type 2 patients. A ratio of <0.7 is considered discordant, consistent with type 2 VWD.

The ratio is not applicable to rare type 3 VWD patients who have extremely low or undetectable platelet-dependent VWF activity and VWF:Ag.

A meta-analysis from 2022 showed that a ratio of platelet-dependent VWF activity to VWF:Ag of <0.7 has moderate sensitivity and very low specificity for the diagnosis of type 2 VWD [38]. The same analysis found that a ratio of <0.7 was superior to ratios of <0.6 or <0.5, though these results are based on fewer patients.

There is an increased frequency of the D1472H VWF polymorphism in some African Americans, which leads to slightly lower measured VWF:RCo levels even though the actual platelet-dependent VWF function is normal [62]. This is a limitation of the VWF:RCo assay and may result in some individuals with type 1 VWD being erroneously classified as having type 2M.

Distinction among the subtypes of types 2A, 2B, and 2M VWD is made using results of VWF multimer analysis (or VWF:CB) and ristocetin-induced platelet aggregation (RIPA).

Factor VIII activity to VWF antigen – The ratio of factor VIII activity to VWF:Ag is low in type 2N VWD and is helpful in directing the evaluation to a VWF:factor VIII (VWF:FVIIIB) binding assay. (See 'VWF binding to factor VIII (VWF:FVIIIB)' below.)

VWF multimer analysis — We perform VWF multimer analysis in newly diagnosed patients with VWD. The VWF multimer assay is a qualitative visual assessment of the size spectrum and the banding pattern of VWF multimers that can be seen on gel electrophoresis (picture 1) [87].

Patient plasma is used to provide the source of VWF for analysis; patient platelets can also be examined, although this is not widely available. The proteins are separated by agarose gel electrophoresis, and multimers of different sizes are detected using anti-VWF reagents after transfer to a membrane (eg, Western blotting with chemiluminescence detection) [88].

Multimer distribution is assessed visually and can be quantified using densitometry of the bands. Often, the clinician will be provided only with the interpretation (without the actual gel image).

VWF multimer analysis is used to identify variants of type 2 VWD that lack the largest multimers (types 2A and 2B; in lanes 3 and 4 of the gel image (picture 1)), or those that have unusually large multimers or other qualitatively abnormal "bands" that indicate an abnormal VWF structure (table 1).

Ristocetin-induced platelet aggregation (RIPA) — The RIPA assay can be performed in all newly diagnosed patients with established VWD and abnormal ratios of platelet-dependent VWF activity to VWF:Ag. RIPA measures the affinity with which VWF binds to the platelet receptor GPIb. The end-point of this assay is platelet aggregation, using the patient's platelet-rich plasma (PRP) as a source of VWF and platelets and low concentrations of ristocetin.

The RIPA test is different from the ristocetin cofactor activity (VWF:RCo) described above (see 'Platelet-dependent VWF activity (VWF:RCo or VWF:GPIbM)' above), because RIPA evaluates binding of VWF to platelets using suboptimal concentrations of ristocetin and patient PRP, and it does not quantitate VWF.

The RIPA test is performed by placing the patient's PRP in a series of test tubes and sequentially adding lower concentrations of ristocetin to each tube, using a range of concentrations from 0.4 to 1.2 mg/mL. The presence or absence of platelet aggregation is noted at each concentration of ristocetin. PRP from patients with normal VWF does not aggregate at concentrations of ristocetin that are lower than approximately 0.6 to 0.8 mg/mL, but PRP from patients with type 2B VWD will usually aggregate at concentrations of ristocetin of 0.4 to 0.5 mg/mL.

The RIPA test is most useful for identifying enhanced VWF binding to platelets due to a gain-of-function mutation that is characteristic of type 2B VWD, in which the RIPA is increased. (See 'Summary of VWD types' above.)

RIPA increased – Consistent with type 2B VWD.

RIPA decreased – Consistent with types 1 (if severe), 2A, 2M, and 3.

RIPA normal – Consistent with mild types 1, 2A, 2M, and type 2N.

The 2021 VWD guideline suggests targeted genetic testing over the RIPA to determine if a patient has type 2B VWD [2]. Both the RIPA test and genetic testing are sensitive for distinguishing type 2B.

In addition to type 2B VWD, the RIPA test can also be abnormal in some primary disorders of platelet function:

Platelet-type VWD – In platelet-type VWD, RIPA is increased similarly to type 2B VWD. However, the increase is caused by a gain-of-function mutation in the patient's platelet GPIb rather than a variant in VWF [37,89,90].

Bernard-Soulier syndrome (BSS) – In BSS, RIPA is absent (table 4). BSS platelets are dysfunctional due to a pathogenic variant in GPIb that reduces its function and/or abundance on the platelet surface [91]. These individuals have thrombocytopenia with giant platelets and a bleeding phenotype that is greater than expected based on their platelet count. (See "Inherited platelet function disorders (IPFDs)", section on 'Bernard-Soulier syndrome'.)

Distinction of these conditions from VWD is discussed below. (See 'Differential diagnosis' below.)

VWF binding to factor VIII (VWF:FVIIIB) — Abnormal binding of VWF to factor VIII specifies VWD type 2N. This can be determined by genetic testing and/or a binding assay. VWF mutations in the binding site for factor VIII cause decreased binding of VWF to factor VIII and lead to low levels of factor VIII and low ratios of FVIII:VWF:Ag.

The binding assay is usually performed in an ELISA format, using the patient's plasma VWF to coat the wells and recombinant factor VIII as the added binding protein. The ability of the patient's plasma VWF to bind factor VIII is compared with that of a normal plasma pool [35].

Genetic testing can also be diagnostic for type 2N, and the 2021 guideline points out that it can provide information beyond the diagnosis with regard to the inheritance (eg, homozygous versus doubly heterozygous) for genetic counseling [2]. If genetic testing is negative, however, the VWF:FVIIIB should definitely be obtained.

Response to DDAVP — The response to a desmopressin (DDAVP) trial may reveal or confirm a diagnosis of type 1C or type 2N when the four-hour post-DDAVP VWF level falls by >30 percent over peak, or if the rise in factor VIII activity after DDAVP is short-lived. The results can also be used to guide management. (See "von Willebrand disease (VWD): Treatment of minor bleeding, use of DDAVP, and routine preventive care", section on 'DDAVP trial'.)

Specialized tests for VWD

VWF propeptide (VWF:pp) — The VWF:pp is a protein sequence that is part of VWF when it is initially synthesized; it is cleaved during the release of VWF into the circulation, and it circulates independently with its own half-life. As such, it is a marker for the amount of newly synthesized and released VWF [92-94]. When VWF has a short half-life (as in rapid clearance of VWF due to any cause), the ratio of VWF:pp to VWF:Ag is elevated (ratio >3). This assay has been used as a surrogate measurement for a shortened VWF half-life, and the VWF:pp to VWF:Ag ratio can be helpful in the diagnosis and follow-up of acquired von Willebrand syndrome [95]. (See "Acquired von Willebrand syndrome".)

The 2021 guideline suggests that VWF:pp not be used for the diagnosis of VWD type 1C, since a DDAVP trial is important for management and yields similar information about half-life [2].

Genetic testing — Genetic testing is not required for the diagnosis of VWD, but it may be useful in selected settings [67,96].

It can be useful in the following settings:

Diagnosis or confirmation of type 2N

Distinguishing type 2N from mild hemophilia A in males

Distinguishing type 2N from hemophilia A carrier status in female carriers of hemophilia A

Diagnosis or confirmation of type 2M

Diagnosis or confirmation of type 2B

Distinguishing type 2B from platelet-type VWD

Diagnosis or confirmation of type 2A

Prenatal testing for type 3 VWD

Further details of the VWF gene structure and mechanisms by which different mutations affect VWF function are discussed separately. (See "Pathophysiology of von Willebrand disease".)

The VWF gene is very large and has not been completely characterized [97]. Some variants that were previously classified as disease causing (eg, M740I) were subsequently determined to be common in the general population, for example, in African Americans [67,97]. New mutations in mRNA processing are being studied and some may be causal [98]. Importantly, as noted above, a significant portion of individuals with type 1 VWD (as many as one-third) do not have an apparent VWF mutation, suggesting that variants in other genes that control VWF levels or that control other proteins important in hemostasis may be responsible. Caution should be used in interpreting results of genetic testing that reveals new mutations; these may be normal variants.

Assays under development — A number of groups are working to develop assays that provide diagnostic information using platforms that can be automated or that can test the multiple physiologic roles of VWF in the same setting. As examples:

ELISA assay for classification – An assay has been reported that uses enzyme-linked immunosorbent assay (ELISA) plate technology for discriminating between VWD types 1 and 2, including assignment of each type 2 [99]. The multi-well format and computer-based statistical analysis allow testing of patient plasma across multiple reagents including GPIbM, GPIb plus ristocetin, collagen, and factor VIII. In a sample of 160 previously diagnosed patients with VWD, the accuracy was greater than 88 percent. Larger studies using this approach are needed.

Assays using flow (shear stress) – Several assays have been published that incorporate shear stress into the assay as a means of promoting VWF binding to platelet GPIb [100,101]. Shear stress is the physiologic stimulus for VWF-platelet binding; high shear stress causes unfolding of the VWF molecule to expose GPIb binding sites in vivo. In contrast, ristocetin binding is based on a non-physiologic means of activating the binding reaction. Shear-based assays have not been adopted on a large scale.

We do not use testing such as thromboelastography (TEG) because the results may be non-specific, and there appears to be significant overlap between individuals with type 1 VWD and unaffected individuals.

INTERPRETATION AND DIAGNOSIS

Clinical considerations and evolution of guidelines — The diagnosis of VWD is a clinical and laboratory diagnosis that incorporates the personal bleeding history, family history, and results of laboratory testing (algorithm 1).

There are no confirmatory genetic tests available for the diagnosis of most cases of type 1 VWD, which comprise the vast majority of VWD cases [102]. It is uncommon that the diagnosis of VWD would be made in an individual with a negative personal and family history of bleeding.

The results of laboratory testing are a continuum, and the diagnostic cutoffs for platelet-dependent von Willebrand factor (VWF) activity and antigen (VWF:Ag) levels for the diagnosis of VWD are controversial.

Guidelines in 2008 set the levels for a definitive diagnosis as <30 international units [IU]/dL and created a category of "low VWF" for individuals with levels of 30 to 50 IU/dL (this category of patients may have VWD, an undiagnosed platelet disorder, another unrecognized bleeding disorder, or no disease) [1]. This change in diagnostic limits also took into account the observations that VWF levels are affected by several common physiologic conditions and by variants of certain genes such as ABO, STXBP5, or CLEC4M, which can alter VWF levels [86]. There was, however, a danger that true VWF patients with VWF levels of 30 to 50 IU/dL would be missed and not be diagnosed as having VWD.

A 2021 guideline from the American Society of Hematology (ASH), International Society on Thrombosis and Haemostasis (ISTH), National Hemophilia Foundation (NHF), and World Federation of Hemophilia set the cutoff level for diagnosing VWD at <30 IU/dL (<0.3 IU/mL; <30 percent) regardless of bleeding [2].

It also recommended that patients with a history of bleeding and VWF levels of 30 to 50 IU/dL (or levels between 30 and the lower limit of normal range in the local laboratory) be given the diagnosis of VWD. This definition errs on the side of not missing a diagnosis of VWD and access to further health care; it applies mainly to VWD type 1, since other testing would confirm the diagnosis in type 2 VWD, and type 3 VWD would have very low levels of VWF. Individuals with VWF values in the range of 30 to 50 IU/dL who do not have bleeding would not be designated as having VWD. Exceptions to this may include individuals (often, children) who have not had bleeding challenges).

Diagnosis — Diagnosis is as follows:

VWF <30 percent – Individuals with platelet-dependent VWF activity (VWF:RCo or VWF:GPIbR) or VWF:Ag <30 IU/dL (<30 percent) are diagnosed with VWD regardless of bleeding history. Tests to determine the type of VWD are appropriate since the type has implications for bleeding risk and management. (See 'Additional testing to characterize (classify) the type of VWD' above.)

VWF 30 to 50 percent (or the lower limit of normal range in the local laboratory), and positive personal bleeding history – Individuals with a positive personal history of bleeding and platelet-dependent VWF activity or VWF:Ag of 30 to 50 percent are given the diagnosis of VWD (providing the VWF levels are not spuriously elevated due to stress, inflammation, or other stimuli that increase VWF). These individuals usually have had repeat testing with plans for careful and non-stressful baseline testing. (See 'Repeat testing in individuals with borderline or discordant clinical and laboratory findings' above.)

VWF levels of 30 to 50 percent and negative personal bleeding history – Individuals with a negative personal bleeding history (providing they have had bleeding challenges) and platelet-dependent VWF activity or VWF:Ag of ≥30 to 50 percent are not diagnosed with VWD.

Other contributing factors:

VWF levels tend to be lower in individuals with type O blood (approximately 25 to 30 percent lower than in individuals with type A, B, or AB) [103-105]. Approximately 80 percent of individuals in the United States with levels of 30 to 50 IU/dL have blood type O [1]. This is significantly higher than the overall prevalence of type O in the United States population. (See "Pathophysiology of von Willebrand disease", section on 'Clearance and control of plasma VWF levels'.)

VWF levels tend to be lower in White individuals than in many African American individuals or individuals of African ancestry, although there is substantial overlap. In a series of 310 participants in an unrelated study in South Africa, VWF:Ag was 102 IU/dL in White South Africans, 118 IU/dL in Zulu Africans, and 105 IU/dL in individuals from the Durban region of South Africa, with predominantly Indian ancestry [106].

A meta-analysis of 21 studies concluded that platelet-dependent VWF activity and VWF:Ag levels <0.3 IU/dL (<30 percent) are reasonable for diagnosing VWD, as are levels of 0.30 to 0.5 IU/dL (30 to 50 percent) in individuals with a personal history of bleeding, although certainty is very low [38]. The analysis also showed that pathogenic variants in the VWF gene are more likely to be found when VWF levels are <0.3 IU/dL (pathogenic variants found in 75 to 82 percent) than with VWF levels of 0.3 to 0.5 IU/dL (pathogenic variants found in 44 to 60 percent).

Considering the VWF levels across the general population, there are many more people with VWF levels of 30 to 50 IU/dL who do not have bleeding symptoms than those who have bleeding symptoms. It is possible that these lower VWF levels contribute partly to any bleeding these patients may have and that additional factors besides low VWF also contribute [107].

If an individual has a VWF level of 30 to 50 percent and the bleeding history is uncertain, it is appropriate to refer such individuals to a VWD specialist who can evaluate the bleeding history, perform additional testing to detect rare VWD subtypes, and perform other coagulation and platelet testing in patients with apparently normal initial testing. (See 'Repeat testing in individuals with borderline or discordant clinical and laboratory findings' above and 'Additional testing to characterize (classify) the type of VWD' above.)

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of VWD includes inherited and acquired bleeding disorders, as well as the possibility that an individual does not have a bleeding disorder.

Mild hemophilia A — Like hemophilia A (factor VIII deficiency), VWD types 2N and 3 usually have significantly low factor VIII levels and can share similar symptoms. Points of differentiation and tests to distinguish these conditions include:

Severity of bleeding – In hemophilia A, bleeding can be severe and presents early in life, but bleeding may be mild and may present at an older age. In VWD type 2N, bleeding is variable but may be severe. In VWD type 3, bleeding is usually severe.

Type of bleeding – In hemophilia A, bleeding occurs in joints and muscles. In VWD type 2N, bleeding can be mucocutaneous but also into joints and muscles. In VWD type 3, bleeding occurs in both mucocutaneous sites and joints and muscles.

Inheritance and sex distribution – Hemophilia A is X-linked recessive; males are generally more severely affected (female carriers [heterozygotes] may be affected). VWD types 2N and 3 are autosomal; males and females are equally affected.

Laboratory testing – In hemophilia A, platelet-dependent von Willebrand factor (VWF) activity, VWF antigen (VWF:Ag), and factor VIII binding are normal. In VWD type 2N, platelet-dependent VWF activity and VWF:Ag can be normal, but binding of the patient's VWF to factor VIII is low. In VWD type 3, platelet-dependent VWF activity and VWF:Ag are undetectable or extremely low. (See "Clinical manifestations and diagnosis of hemophilia".)

Inherited platelet disorders — There are several inherited platelet disorders that may present with similar bleeding patterns as VWD (eg, mucosal or skin bleeding). In addition, there are two inherited platelet disorders that produce abnormal results on the ristocetin-induced platelet aggregation (RIPA) test. (See 'Ristocetin-induced platelet aggregation (RIPA)' above.)

Bernard-Soulier syndrome (BSS) – BSS is characterized by thrombocytopenia and giant platelets; it is due to a mutation that causes a low concentration of glycoprotein Ib (GPIb) in platelets. Like moderate to severe VWD types 1, 2A, 2M, and 3, BSS is associated with reduced RIPA. Unlike VWD, in BSS the VWF:Ag and platelet-dependent VWF activity are normal.

Platelet-type (pseudo) VWD – Platelet-type VWD has a very similar phenotype to type 2B VWD; it is due to a gain-of-function mutation in platelet GPIb that enhances VWF binding to platelets, leading to increased platelet clearance and thrombocytopenia. Like type 2B VWD, platelet-type VWD is associated with increased RIPA. Unlike VWD, platelet-type VWD has normal VWF multimers and normal VWF genotype. These and other inherited platelet disorders are discussed separately. (See "Inherited platelet function disorders (IPFDs)" and "Approach to the child with bleeding symptoms".)

Acquired von Willebrand syndrome (AVWS) — AVWS refers to acquired deficiency or dysfunction of VWF, which is usually associated with various medical conditions that lead to immune or proteolytic destruction of VWF or to decreased VWF production. Examples include:

Lymphoproliferative or myeloproliferative disorders

Autoimmune disorders

Cardiovascular disease

Extracorporeal circulation that increases shear stress

Hypothyroidism

Certain medications

Like inherited VWD, AVWS presents with symptoms and laboratory results compatible with VWD. However, it generally presents later in life without a previous personal or family bleeding history, and it usually can be differentiated by finding an associated disease and often by measuring the ratio of VWF propeptide to VWF:Ag. (See 'VWF propeptide (VWF:pp)' above and "Acquired von Willebrand syndrome".)

SCREENING FAMILY MEMBERS — For first-degree relatives who are symptomatic, the evaluation is similar to that discussed above, with the exception that additional laboratory testing can be more focused if the propositus has a known VWF genotype.

For asymptomatic first-degree relatives, the decision to test for VWD may be based on the severity of VWD in family members, the likelihood of bleeding challenges (eg, planned surgeries, high-impact sports), and the patient's desire for testing.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: von Willebrand disease".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topics (see "Patient education: von Willebrand disease (The Basics)")

Beyond the Basics topics (see "Patient education: von Willebrand disease (Beyond the Basics)")

PATIENT PERSPECTIVE TOPIC — Patient perspectives are provided for selected disorders to help clinicians better understand the patient experience and patient concerns. These narratives may offer insights into patient values and preferences not included in other UpToDate topics. (See "Patient perspective: von Willebrand disease".)

SUMMARY AND RECOMMENDATIONS

Classification – Von Willebrand disease (VWD) is the most common inherited bleeding disorder. Symptomatic disease affects 1 in 1000 people. There are three types (table 1). (See 'Epidemiology' above and 'Summary of VWD types' above.)

Type 1 (reduced von Willebrand factor [VWF]) is the most common

Type 2 (dysfunctional VWF), includes four subtypes

Type 3 (absent/undetectable VWF) is rare

Transmission is usually autosomal dominant. Types 2N, 3 and some 2A and 2M are autosomal recessive.

Acquired von Willebrand syndrome (AVWS) is due to conditions that decrease VWF production or increase removal. (See "Acquired von Willebrand syndrome".)

Presentation – Bruising, mucocutaneous bleeding, heavy menstrual bleeding, and postpartum bleeding are common. Gastrointestinal bleeding is less common; gastrointestinal angiodysplasia may contribute. Joint and muscle bleeding are not typical but can be seen with types 2N and 3. Some individuals have a normal complete blood count (CBC); many have normal coagulation studies. Some have a prolonged activated partial thromboplastin time (aPTT) due to low factor VIII. Some have thrombocytopenia (type 2B) or microcytic anemia (from iron deficiency). VWF levels increase with aging, inflammation, and estrogen. (See 'Clinical features' above.)

Evaluation – VWD should be considered in individuals with bleeding (especially mucocutaneous), positive family history, mild thrombocytopenia, unexplained prolonged aPTT, or apparent hemophilia A. Accurate bleeding history is essential; a bleeding assessment tool (BAT) provides an objective picture. (See 'Evaluation' above.)

Diagnosis – Initial testing includes CBC, platelet count, and coagulation studies. Screening tests for VWD include VWF antigen (VWF:Ag), platelet-dependent VWF activity (VWF:RCo or VWF:GPIbM), and factor VIII activity (algorithm 1).

Platelet-dependent VWF activity or VWF:Ag <30 percent confirms VWD. VWF is an acute phase reactant; individuals with VWF:Ag or platelet-dependent VWF activity of 30 to 50 percent should be retested. VWF level 30 to 50 percent in an individual with a bleeding history qualifies as VWD; with a negative bleeding history (provided bleeding challenges have occurred) it does not. (See 'Laboratory testing' above and 'Interpretation and diagnosis' above.)

Type – After diagnosis, specialized assays are used to determine the type (table 3). The ratio of platelet-dependent VWF activity to VWF:Ag helps distinguish type 1 from type 2 (algorithm 2). VWF multimer analysis and ristocetin-induced platelet aggregation (RIPA) are also helpful. Concordant reduction of platelet-dependent VWF activity and VWF:Ag is consistent with type 1; discordant results suggest type 2A, 2B, or 2M; and absent/undetectable VWF suggests type 3. Low factor VIII activity and low factor VIII activity to VWF:Ag ratio suggests type 2N. Genetic testing is not helpful in most cases of type 1 but can be very helpful in certain type 2 and 3 patients. (See 'Additional testing to characterize (classify) the type of VWD' above.)

Differential diagnosis – The differential diagnosis includes mild hemophilia, hereditary platelet disorders, and AVWS. (See 'Differential diagnosis' above and "Approach to the child with bleeding symptoms" and "Approach to the adult with a suspected bleeding disorder".)

Treatment – Separate topics discuss pathophysiology and treatment of VWD. (See "Pathophysiology of von Willebrand disease" and "von Willebrand disease (VWD): Treatment of major bleeding and major surgery" and "von Willebrand disease (VWD): Treatment of minor bleeding, use of DDAVP, and routine preventive care".)

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Topic 1307 Version 50.0

References

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