Von Willebrand disease

Definition

Von Willebrand disease (VWD) is the most common inherited bleeding disorder. It is caused by a quantitative deficiency or a functional defect of von Willebrand factor (VWF). VWF mediates platelet adhesion to the injured vessel wall and carries and stabilises factor VIII in plasma. The bleeding tendency is usually mild and mainly affects the skin and mucous membranes.

A separate entity is the rare acquired von Willebrand syndrome, for example in lymphoproliferative, myeloproliferative (particularly essential thrombocythemia) and autoimmune disorders.

Classification

• Type 1 (about 60–70 %): quantitative deficiency with normal structure, usually autosomal dominant; VWF antigen, VWF activity and factor VIII reduced proportionally
• Type 2 (about 20–30 %): qualitative defect, usually autosomal dominant; activity is reduced more than antigen
• Type 2A: reduced platelet binding, loss of large multimers
• Type 2B: increased binding of large multimers to platelets with accelerated clearance of both – often with thrombocytopenia
• Type 2M: reduced platelet binding with a preserved multimer pattern
• Type 2N: impaired binding of factor VIII with markedly reduced factor VIII, resembling mild hemophilia A
• Type 3 (about 5–10 %): autosomal recessive, VWF virtually undetectable, factor VIII markedly reduced

Occurrence & epidemiology

Figures vary widely because it is difficult to separate low-normal VWF from definite disease. For type 1, 0.1–1 % of the population is cited; type 3 is very rare at 0.1–5.3 per million and more frequent with consanguinity. The disease is diagnosed more often in women, although both sexes are expected to be affected about equally. People with blood group O have VWF levels 25–30 % lower and are over-represented among those affected.

Aetiopathogenesis

VWF is produced by vascular endothelium and released as multimers of varying size. Via the glycoprotein Ib receptor it links platelets to subendothelial collagen; large multimers are the most effective. If VWF is missing or dysfunctional, primary platelet plug formation (platelet adhesion) is impaired. Because VWF protects factor VIII from degradation, factor VIII is additionally reduced in type 2N and type 3 – and to a lesser extent in type 1.

VWF levels rise temporarily with stress, exercise, pregnancy, inflammation and infection and with increasing age. VWF deficiency also predisposes to angiodysplasia of the gastrointestinal tract.

Clinical features

Mucocutaneous bleeding and bleeding in risk situations are typical; the extent varies between patients, within a family and over a lifetime.

• nosebleeds, gum bleeding, bleeding after dental extractions
• easy bruising, prolonged bleeding from small cuts
• heavy menstrual bleeding, bleeding after childbirth and after surgery (e.g. tonsillectomy)
• gastrointestinal bleeding, including from angiodysplasia
• petechiae and purpura are rare
• Type 2 usually more severely affected than type 1, type 3 with spontaneous hematomas, joint bleeds up to arthropathy and life-threatening bleeding after surgery; intracerebral hemorrhage in 0.1–0.5 %, most frequently in type 3

Diagnosis

• Structured bleeding history using a validated questionnaire (ISTH bleeding assessment tool) and family history
• Global tests: platelet count and INR normal, aPTT usually normal (prolonged in type 3 and type 2N due to factor VIII deficiency); therefore unsuitable for exclusion. Thrombocytopenia sometimes in type 2B
• Specific tests: VWF antigen, platelet-dependent VWF activity (e.g. ristocetin cofactor activity or GPIb binding) and factor VIII activity, plus PFA closure time
• Type 1: antigen, activity and factor VIII reduced proportionally; the degree of reduction determines the bleeding tendency
• Pointer to type 2: ratio of VWF activity to VWF antigen below 0.7
• Multimer analysis (gel electrophoresis) and collagen-binding activity to distinguish 2A, 2B and 2M; ristocetin-induced platelet agglutination with low ristocetin concentration in type 2B; factor VIII binding assay in type 2N
• Pitfalls: pregnancy, inflammation, stress and age raise VWF and can mask type 1 disease; repeat testing is often necessary. VWF is physiologically lower with blood group O.
• Molecular genetics in selected cases

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Further reading (open access)

1. Onkopedia-Leitlinie (DGHO): von Willebrand Erkrankung
2. MSD Manual Professional: Von Willebrand Disease

Cross-references