Approach

The diagnostic work-up for von Willebrand disease (VWD) includes:

  • History and physical examination

  • Assessment of bleeding symptoms (including use of bleeding assessment tools [BATs])

  • Laboratory tests (including blood tests to assess von Willebrand factor [VWF] level, binding activity, and multimer structure)

  • Genetic tests (to confirm VWD subtype)

History

Patients with VWD commonly have a history of abnormal bleeding, including:[8][9]​​​

  • Easy and excessive bruising

  • Excessive or prolonged bleeding from trauma or minor wounds

  • Excessive mucosal bleeding (e.g., epistaxis, gum bleeding)

  • Heavy menstrual bleeding (HMB)

  • Postpartum haemorrhage

  • Excessive bleeding after invasive surgical procedures, particularly in those with severe disease (type 2 and type 3 VWD) and if procedures involve the mucous membrane (e.g., tonsillectomy, dental extraction). Some patients may need to return to hospital to control rebleeding.

Patients may have haematuria or central nervous system bleeding, but these are less common.[7][9][10]​​[11]

Bleeding symptoms are usually more severe in people with type 2 and 3 VWD than type 1 VWD, and may begin at an earlier age.[8][9]​​ ​Serious bleeding symptoms that mimic mild haemophilia A (e.g., joint bleeding [haemarthrosis] and gastrointestinal bleeding) occur more commonly in type 2 and 3 VWD than type 1 VWD.[8][9]​​[12]

Bleeding in infancy is rare, although young children may bruise more easily and have problems with epistaxis, the latter being especially common in boys.[42] Girls with VWD may have HMB from the onset of menarche.

Patients with HMB, chronic epistaxis, persistent haematuria, or gastrointestinal bleeding may give histories compatible with anaemia due to ongoing blood loss and iron deficiency.

Patients with VWD may have a history of requiring repeat blood transfusion for post-operative bleeding or significant anaemia.

Family history of VWD and bleeding

Patients with type 1 VWD may have a family history of VWD or bleeding symptoms that exhibit an autosomal dominant inheritance pattern. However, a family history is not always present because some cases of type 1 VWD are not linked to inherited mutations in the VWF gene, particularly people with milder disease. Furthermore, inheritance of type 1 VWD is often complicated by incomplete penetrance and variable expressivity.[40][41]

Patients with type 2A, 2B, and 2M VWD generally have a family history of VWD or bleeding symptoms that is clearly autosomal dominant. Most mutations associated with type 2 VWD are fully penetrant.[40][41]

Patients with type 2N or type 3 VWD may or may not have a family history of VWD or bleeding symptoms due to its autosomal recessive inheritance pattern. Family members who are heterozygotes (i.e., carriers) for type 2N or type 3 VWD are usually asymptomatic and may be undiagnosed.

Physical examination

Physical examination may be normal. There may be signs of anaemia (e.g., pale conjunctiva).

Bruises are a non-specific finding, but very large bruises or bruising found on the trunk or other areas not normally exposed to injury may be more significant.

Evidence of joint bleeding (e.g., swelling) is rare and usually only occurs in patients with severe disease and markedly decreased FVIII levels (e.g., type 3 VWD).[8][9]​​[12]

Assessment of bleeding symptoms

The following validated BATs can be used to assess severity of bleeding symptoms, and guide referral and diagnosis:[15][43][44][45][46]

  • MCMDM-1 VWD (Molecular and Clinical Markers for the Diagnosis and Management of Type 1 VWD) bleeding questionnaire

  • Self-BAT (self-administered bleeding assessment tool)

  • ISTH/SSC BAT (International Society on Thrombosis and Haemostasis/Standardization and Scientific Committee bleeding assessment tool)

  • PBQ (paediatric bleeding questionnaire)

Guidelines recommend using a BAT as initial screening to guide referral for specific blood tests for VWD in patients with a low probability of VWD (e.g., those seen in primary care).[15]

Guidelines recommend against using a BAT to make referral decisions in patients with an intermediate probability of VWD (e.g., those typically seen by a haematologist because of an abnormal personal bleeding history or abnormal initial laboratory tests e.g., prolonged activated partial thromboplastin time [aPTT]) or a high probability of VWD (e.g., those seen by a haematologist because of an affected first-degree relative).[15]

Initial laboratory tests

Initial laboratory screening tests for patients with symptoms of a bleeding disorder include:[15]

  • Full blood count (FBC)

  • Prothrombin time (PT)

  • Activated partial thromboplastin time (aPTT)

  • Fibrinogen (optional)

  • Thrombin time (optional)

CBC may be normal in VWD, or may show anaemia (due to ongoing blood loss and iron deficiency) or thrombocytopenia (e.g., in type 2B VWD or platelet type [pseudo]-VWD).[15][32]​​​ An abnormal blood count (e.g., elevated platelet count) may indicate acquired von Willebrand syndrome (AVWS) associated with a myeloproliferative neoplasm (e.g., essential thrombocythemia).

PT is normal in VWD. Activated PTT is often normal in VWD, but may be prolonged in patients with reduced FVIII levels (e.g., in type 2N or type 3 VWD).[32]

Do not use the bleeding time test (historically a screening test for platelet-dependent haemostasis) to guide patient care; it is neither sensitive nor specific enough to be useful in the diagnosis of VWD​.[47][48]

A platelet function analyser (e.g., PFA-100) can be used to screen for VWD (particularly more severe types), but it is not thought to be sensitive and specific enough to be widely recommended for the diagnosis of VWD.[48][36]​​​ A specific diagnosis does not follow directly from an abnormal screening result; therefore, further testing is needed.

Specific blood tests for VWD

The following blood tests should be performed initially to screen for VWD:[15]

  • VWF antigen assay (VWF:Ag)

  • VWF platelet-binding activity assays, including

    • VWF binding to mutant glycoprotein Ibɑ (VWF:GPIbM)

    • VWF binding to recombinant glycoprotein Ibɑ (VWF:GPIbR)

    • VWF ristocetin cofactor activity (VWF:RCo)

  • FVIII coagulant activity assay (FVIII:C)

Use of VWF:GPIbM or VWF:GPIbR to assess VWF platelet-binding activity is recommended over VWF:RCo.[15] These newer assays have lower variability and higher reproducibility, and are not affected by the VWF D1472H polymorphism (a benign VWF gene variant that impairs binding of VWF to ristocetin and can lead to a false diagnosis).[49][50]​​

Additional tests can be used to help establish a diagnosis and confirm the specific subtype of VWD; these include:[15] 

  • VWF multimer analysis

  • VWF collagen binding assay (VWF:CB)

  • Genetic testing (for type 2B or 2N VWD variants)

  • Low-dose ristocetin-induced platelet agglutination (RIPA)

  • WF FVIII binding assay (VWF:FVIIIB)

  • VWF propeptide assay (VWFpp/VWF:Ag)

Diagnostic tests for VWD should be repeated to avoid misdiagnosis.[36] If the patient history or BAT (if used for initial screening) indicates an abnormality of haemostasis but initial blood tests for VWD are normal, then further investigations for platelet, coagulation, and blood vessel wall abnormalities should be pursued. 

VWF is an acute phase reactant and may be elevated in patients who are pregnant or receiving exogenous oestrogen therapy. Diagnostic testing for VWD in these patients may lead to inaccurate results and require repeating. Testing should be avoided during pregnancy or while the patient is receiving exogenous oestrogen therapy.[36][51]

Diagnosing type 1 VWD

Type 1 VWD is characterised by partial quantitative deficiency of normal functioning VWF.[15][20]​ VWF antigen level (VWF:Ag) and VWF platelet-binding activity (e.g., VWF:GP1bM, VWF:GPIbR) are reduced proportionally in type 1 VWD.

A diagnosis of type 1 VWD is confirmed if:[15]

  • VWF:Ag and/or VWF platelet-binding activity is <0.30 IU/mL regardless of bleeding (or 0.30 to <0.50 IU/mL for patients with abnormal bleeding), and

  • VWF platelet-binding activity/VWF:Ag ratio is normal (i.e., >0.7).

If type 1C VWD is suspected, VWF levels are checked at 1 and 4 hours following a desmopressin infusion.[15][50] VWF levels are expected to be decreased at 4 hours due to increased clearance. The 2021 ASH ISTH NHF WFH (American Society of Hematology, International Society on Thrombosis and Haemostasis, National Hemophilia Foundation, and World Federation of Hemophilia) guideline recommends using a desmopressin trial over the VWF propeptide assay (VWFpp/VWF:Ag) to confirm increased clearance of VWF, but acknowledges that the VWFpp/VWF:Ag ratio may be helpful for patients who cannot safely undergo a desmopressin trial (e.g., very young or very old patients).[15] Observational studies suggest that a substantial increase in the VWFpp/VWF:Ag ratio is predictive of a significantly decreased VWF half-life, but the certainty of evidence was judged to be very low in one systematic review.[50]

See Diagnostic algorithm.

Diagnosing type 2A, 2B, or 2M VWD

Type 2A, 2B, and 2M VWD subtypes are characterised by qualitative defects of VWF resulting in abnormal platelet adhesion/aggregation.

A diagnosis of type 2A, 2B, or 2M VWD is suspected if:[15]

  • VWF:Ag and/or VWF platelet-binding activity is <0.30 IU/mL regardless of bleeding (or 0.30 to <0.50 IU/mL for patients with abnormal bleeding), and

  • VWF platelet-binding activity/VWF:Ag ratio is abnormal (i.e., <0.7).

Additional blood tests (including VWF multimer analysis, VWF:CB, RIPA, and genetic testing) are required to confirm the specific subtype of type 2 VWD.[15] A normal VWF multimer analysis or normal VWF:CB/VWF:Ag ratio confirms a diagnosis of type 2M VWD. An abnormal VWF multimer analysis or abnormal (reduced) VWF:CB/VWF:Ag ratio suggests type 2A or 2B VWD; these two subtypes can be differentiated using genetic testing (to identify type 2B VWD variants).[15][36]

Genetic testing and low-dose RIPA mixing studies (combining normal donor plasma with patient platelets, and combining normal platelets with patient plasma) can be used to differentiate type 2B VWD and platelet type (pseudo)-VWD.[36]

See Diagnostic algorithm.

Diagnosing type 2N VWD

Type 2N VWD is characterised by decreased binding affinity of VWF for FVIII. In these patients, FVIII:C level is low relative to VWF:Ag level (similar to patients with mild haemophilia A).[15][36][52]

It is important to differentiate type 2N VWD and haemophilia A because these conditions are managed differently.

Additional tests required to establish a diagnosis of type 2N VWD include VWF:FVIIIB and genetic testing (for type 2N variants).[15]

A diagnosis of type 2N VWD is confirmed in those with low FVIII:C levels if:[15]

  • VWF:FVIIIB is abnormal (i.e., reduced VWF:FVIIIB/VWF:Ag ratio) and genetic testing is positive for type 2N variants; or

  • genetic testing alone is positive for type 2N variants.

A diagnosis of type 2N VWD can be ruled out if genetic testing is negative for type 2N variants, or if VWF:FVIIIB is normal (i.e., normal VWF:FVIIIB/VWF:Ag ratio).

See Diagnostic algorithm.

Diagnosing type 3 VWD

Type 3 VWD is characterised by a complete or near absence of VWF, which results in very low FVIII levels.[15][39]

A diagnosis of type 3 VWD can be made if VWF:Ag is undetectable (<0.01 IU/mL).[36]

Diagnostic algorithm

[Figure caption and citation for the preceding image starts]: Diagnosis algorithm for VWDJames PD et al. Blood Adv 2021; 5(1): 280-300; used with permission [Citation ends].com.bmj.content.model.Caption@5898bc5d

Diagnostic algorithm for von Willebrand disease. *If BS is normal/negative, VWD may be ruled out in patients with a low probability of VWD (e.g., those seen in the primary care setting); patients with an intermediate or high probability of VWD (e.g., those typically seen by a haematologist because of an abnormal personal bleeding history, abnormal initial laboratory tests, or an affected first-degree relative) should be referred for specific blood tests for VWD even if BS is normal. aPTT: activated partial thromboplastin time; BS: bleeding assessment tool (BAT) score; FBC: full blood count; FVIII: factor VIII; FVIII:C: FVIII coagulant activity assay; PT: prothrombin time; RIPA: low-dose ristocetin-induced platelet agglutination; TT: thrombin time; VWD: von Willebrand disease; VWF: von Willebrand factor (levels in IU/mL); VWF:Ag: VWF antigen assay; VWF:CB: VWF collagen binding assay; VWF:FVIIIB: VWF FVIII binding assay; VWF:RCo: ristocetin cofactor activity assay. Adapted (with permission) from: ASH ISTH NHF WFH (American Society of Hematology, International Society on Thrombosis and Haemostasis, National Hemophilia Foundation, and World Federation of Hemophilia) 2021 guidelines on the diagnosis of von Willebrand disease.[15]

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