Von Willebrand Disease | vWD

Introduction

Von Willebrand disease (vWD) is the most common inherited bleeding disorder, with an estimated prevalence of 0.6-1.3%.¹ It leads to reduced levels and/or function of Von Willebrand factor (vWF), a protein that helps with blood clotting.¹

It is inherited in an autosomal pattern, and affects males and females equally, but females are more likely to be diagnosed due to bleeding stressors such as menstruation and childbirth.² 

Aetiology

vWD is typically caused by a mutation in the vWF gene on chromosome 12, leading to reduced vWF activity.¹ In normal haemostasis, vWF helps to form the platelet plug by facilitating platelet adhesion to exposed subendothelium in blood vessels.³ It also acts as a cofactor for factor VIII, protecting it from rapid degradation.³

Patients with vWD have reduced activity of vWF, leading to problems with platelet aggregation and haemostasis as factor VIII is degraded more rapidly in the body. This causes people to present with symptoms associated with platelet dysfunction, such as excessive bleeding from mucous membranes.¹

Several other factors are also thought to play a role in the levels of vWF, including age, blood type, thyroid status, inflammation, stress, and hormone levels. The age at which symptoms become significant can vary widely, and some patients with mild disease may not receive a diagnosis. However, those with more severe forms of the disease may present as early as the first year of life.⁴ 

Rarely, patients can develop an acquired form of vWD. This is generally associated with haematological disorders such as multiple myeloma, monoclonal gammopathy of undetermined significance (MGUS) or Waldenström’s macroglobulinaemia.³

Risk factors

Risk factors for developing vWD include:

• Family history of vWD
• Consanguineous relationships
• Lymphoproliferative disorders
• Hypothyroidism ³

Clinical features

History

Symptoms will vary depending on the severity of the disease, but may include:

Patients with type 1 vWD (the most common subtype) will typically present with excessive bleeding following minor injuries, epistaxis or gum bleeding after dental procedures.^{3, 5-6}

Those with more severe subtypes, such as type 2 or 3 vWD, may present with more severe bleeding symptoms, such as intra-articular bleeding or muscle haematomas.³

Life-threatening events such as gastrointestinal or intracranial bleeds are rare but have been reported.⁷

Clinical examination

Unless a patient is actively bleeding, clinical examination may be normal. The most common finding on examination will be bruising, including in areas that are not commonly injured (e.g. the trunk).³

Otherwise, there may be signs of anaemia such as pallor or pale conjunctiva.

Differential diagnosis

Differential diagnoses to consider include:

• Haemophilia A: bleeding symptoms may be similar, but vWD is more associated with mucosal bleeding. Haemophilia A is also inherited in an X-linked pattern, so will generally affect a greater proportion of males in a family than vWD, which is inherited in an autosomal pattern.
• Other inherited disorders of platelet function (e.g. Bernard-Soulier syndrome): these other platelet disorders are typically much rarer than vWD and would be differentiated with diagnostic investigations ³

Investigations

Bedside investigations

Bedside investigations that are useful in suspected bleeding disorders include:

• Bleeding time: this involves counting the time taken for any bleeding to stop and is prolonged in vWD. It is less commonly used due to its limited specificity and sensitivity.³

Laboratory investigations

Laboratory investigations to consider include:

• Full blood count (FBC): to exclude thrombocytopaenia as the cause of mucocutaneous bleeding. Microcytic, hypochromic anaemia may be present in chronic bleeding. Moderate thrombocytopaenia may be present in type 2B vWD.
• Prothrombin time (PT): normal in vWD
• Activated partial thromboplastin time (APTT): may be normal or prolonged depending on factor VIII activity levels
• Platelet function analyser (PFA-100): a more sensitive tool to evaluate bleeding time, which may be normal in mild platelet function defects
• vWF antigen (vWF: Ag): quantitative measurement of vWF plasma protein level. Due to the variability of vWF levels in individuals, at least two samples should be taken on separate occasions to establish a definitive diagnosis.
• Factor VIII activity (FVIII:C): can be normal or reduced. Low levels are associated with a more severe form of the disease, such as type 2N and 3 vWD. Haemophilia A should be ruled out in cases of factor VIII deficiency.
• Platelet-dependent vWF activity: specialised tests to evaluate the functional activity of vWF ^{3, 8}

If a diagnosis of vWD is confirmed, then further tests can be carried out to determine the subtype, but these are beyond the scope of this article.

Diagnosis

The diagnosis of vWD is determined by:

1. Personal history of excessive mucocutaneous bleeding

2. Positive family history of bleeding

3. Laboratory evaluation consistent with quantitative and/or qualitative abnormalities in vWF, factor VIII or both ⁸

A validated bleeding assessment tool is useful for providing an objective evaluation of bleeding symptoms and determining the likelihood of an underlying bleeding disorder, such as the ISTH/SSC bleeding assessment tool.^8-9

Classification

In clinical practice, vWD is classified based on the characteristics of the vWF protein rather than the detection of specific vWF mutations.¹⁰

Table 1. Classification of Von Willebrand disease subtypes.^10-11

Management

The treatment approach for patients with vWD should be individualised based on the subtype, severity, and clinical context. The focus is primarily on restoring levels of vWF and factor VIII in active bleeding and planning appropriate prophylactic measures prior to invasive procedures.³

Prophylactic therapy

This is rarely required except in patients with recurrent or severe bleeding episodes or individuals with type 3 vWD who suffer from serious spontaneous bleeding.⁸

Regular infusions of vWF-containing concentrates have been shown to decrease the frequency of bleeding episodes significantly. They may help prevent arthropathy, especially when initiated early in young children experiencing haemarthrosis.¹²

Mild to moderate bleeding

Management options in mild to moderate bleeding include:

• Desmopressin: a synthetic analogue of vasopressin and is considered first-line therapy in the majority of patients with vWD. It works by stimulating the release of endogenous vWF and factor VIII from endothelial stores. A test dose is required to assess individual responsiveness prior to administration. It is available in intravenous, subcutaneous and intranasal forms.
• vWF-containing concentrates: indicated in those with persistent bleeding despite desmopressin or those with contraindications to its use.
• Antifibrinolytic therapy (e.g. tranexamic acid): often used as an adjunct therapy to desmopressin or vWF concentrates and can be administered orally or intravenously, depending on the clinical context. Topical formulations are commonly used for managing nasal or oral bleeding.^{2-3, 8}

Major bleeding

Management options in major bleeding include:

• vWF-containing concentrates: first line in cases of serious bleeding
• Platelet transfusions or cryoprecipitate: may be used as adjunctive therapy in cases where bleeding persists despite optimal vWF and FVIII levels ³

Complications

Most complications of vWD are those associated with platelet dysfunction and repeated episodes of bleeding, such as:

In rare cases, patients with type 3 vWD, or those repeatedly receiving vWF-containing concentrates may develop antibodies to vWF, which can lead to anaphylactic reactions on further exposure to exogenous vWF.³

Reviewer

Dr Azizan Bin Sharif

Consultant Haematologist

Editor

Dr Jess Speller

References

1. Elaine MK, Catherine NO and Jeanine MW. Rodak’s Haematology: Clinical Principles and Applications. 2020.
2. Atiq F, Saes JL, Punt MC, et al. Major differences in clinical presentation, diagnosis and management of men and women with autosomal inherited bleeding disorders. eClinical Medicine. 2021. Available from: [LINK].
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9. Rodeghiero F, Tosetto A, Abshire T, et al. ISTH/SSC bleeding assessment tool: a standardized questionnaire and a proposal for a new bleeding score for inherited bleeding disorders. Journal of Thrombosis and Haemostasis. 2010. Available from: [LINK].
10. Sadler JE, Budde U, Eikenboom JCJ, et al. Update on the pathophysiology and classification of von Willebrand disease: a report of the Subcommittee on von Willebrand Factor. Journal of Thrombosis and Haemostasis. 2006. Available from: [LINK].
11. Nichols WL, Hultin MB, James AH, et al. von Willebrand disease (VWD): evidence-based diagnosis and management guidelines, the National Heart, Lung, and Blood Institute (NHLBI) Expert Panel report (USA). Haemophilia. 2008. Available from: [LINK].
12. Berntorp E, de Moerloose P, Ljung RCR. The role of prophylaxis in bleeding disorders. Haemophilia. 2010. Available from: [LINK].