This is the commonest hereditary coagulopathy in humans. It can be congenital or acquired. It was described in 1926 by Erik von Willebrand in inhabitants of the Aland Islands in the Sea of Bothnia between Sweden and Finland. It was called pseudohemophilia but later became known as vascular haemophilia.

Pathophysiology

Von Willebrand's disease (vWD) results from the deficiency or abnormal function of von Willebrand factor (vWF). vWF is a multimeric glycoprotein encoded for by gene map locus 12p13.¹ It is made in the endothelium and stored in Weibel-Palade bodies. It has two main functions:

1. Assists in platelet plug formation by attracting circulating platelets to the site of damage
2. Binds to coagulation factor VIII preventing its clearance from the plasma

Epidemiology

• Prevalence as high as 1-2% in the general population on unselected screening
• Worldwide incidence is around 125 per million with between 0.5 and 5 per million being severely affected
• Most patients have mild disease
• Commoner in females
• More severe with blood type O

Presentation

This varies according to the extent of the deficiency

• Bleeding tendency from mucosa, e.g. epistaxis, menorrhagia (consider in women with no other obvious cause)
• Spontaneous bleeding, e.g. internal or joint bleeding (only in severest of cases)
• Blood clots during childbirth (rare)
• Death may occur

Causes

1. Hereditary - 3 types (see below)
2. Acquired - also called pseudo-von Willebrand's disease or platelet-type; causes include:²

• Auto-antibody formation which binds vWF and results in rapid clearance of it from the circulation
• Aortic stenosis - rarely can develop Heyde's syndrome, resulting in vWD and predisposition to gastrointestinal bleeding
• Others - Wilms' tumour, hypothyroidism

Classification of hereditary types

Subtypes of type 2

Type 2A

• Abnormal synthesis or proteolysis of vWF multimers
• Leads to small multimers in circulation; factor VIII still binds as normal

Type 2B

• Spontaneous binding of platelets with rapid clearance of platelets and large vWF multimers
• Mild thrombocytopaenia
• Factor VIII binding normal or low normal
• Desmopressin will not help as leads to unwanted platelet aggregation

Type 2M

• Low or absent binding to receptor on platelets
• Factor VIII binds as normal

Type 2N

• Autosomal recessive rather than X-linked
• Show incomplete response to haemophilia A treatment
• Factor VIII levels reduced to around 5% as vWF has a reduced affinity for factor VIII

Investigations

The severity of vWD varies and many patients will never be diagnosed as their disorder may never come to light. In practice - both primary and secondary, the patients with more severe forms of the disorder will present with abnormal bleeding. Following this basic blood tests including FBC, clotting screen and liver function should be performed and patients should be referred for a specialist opinion and other more specialised investigations such as, plasma levels of vWf. The haematologist will also be able to test for other bleeding disorders which will form part of the differential diagnosis.

• Bloods including full blood count, fibrinogen level, platelet count, clotting screen, factor IX levels
• Plasma levels of vWF - keep in mind that deficiency can be qualitative or quantitative
  • Quantitative deficiency - detected by vWF antigen assay
  • Qualitative deficiency - detected by a number of methods including glycoprotein binding assay, ristocetin cofactor activity, ristocetin induced platelet agglutination³
• Factor VIII measurement - factor VIII binds to vWF which in turn prevents the rapid breakdown of factor VIII; thus a deficiency of vWF can also lead to deficiency of factor VIII
• In type 2 vWF - factor VIII levels are normal; studies of platelet aggregation with subendothelium are necessary

Oestrogens, vasopressin and growth hormone all elevate levels.

Pregnancy and von Willebrand's disease

In pregnancy the levels of vWF increase, even in type III and there is usually no problem with labour and delivery but there may be problems in the first week or two postpartum.

Management

• No regular therapy required.⁴
• Educate patients as to bleeding risk which depends upon level and type of deficiency.
• In some mild cases desmopressin can be given which will enhance vWF and factor VIII levels by inducing its release from storage in the endothelial cells.
• Desmopressin is first-line in type I vWD; in all other types factor VIII - vWF concentrates are first-line. If the response to the first-line agents is poor, then the other can be tried as an alternative (not in type 3).⁵
• Desmopressin is ineffective in type 3 as there are no vWF levels to boost.
• For major procedures prophylactic factor VIII complexed to vWF can be used. This can be found in fresh frozen plasma; however, the amount required may be associated with volume overload. Cryoprecipitate can also be used and only 8-12 bags are required.
• Patients who have alloantibodies to vWF will require recombinant factor VIII.⁵

More therapies

• Humate-P (novel) - contains antihaemophilic factor
• Antifibrinolytic antibodies, e.g. aminocaproic acid or traxenamic acid may also help