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This is the most common 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.
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 12p13.31.It is made in the endothelium and stored in Weibel-Palade bodies. It has two main functions:
- It assists in platelet plug formation by attracting circulating platelets to the site of damage.
- It binds to coagulation factor VIII preventing its clearance from the plasma.
- Prevalence is 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.
- It is more common in females.
- It is more severe with blood type O.
This varies according to the extent of the deficiency:
- Bleeding tendency from mucosa - eg, epistaxis, menorrhagia (consider in women with no other obvious cause).
- Spontaneous bleeding - eg, internal or joint bleeding (only in the most severe of cases).
- Blood clots during childbirth (rare).
- Death may occur.
- Hereditary - three types (see below).
- Acquired - also called pseudo-von Willebrand's disease or platelet-type; it is frequently found in lymphoproliferative or myeloproliferative disorders and can also be associated with solid tumours, immunological and cardiovascular disorders, and various other conditions - eg, aortic stenosis, Wilms' tumour, hypothyroidism.
Classification of hereditary types
Types of hereditary von Willebrand's disease (vWD)
Type of vWD
Epidemiology - percentage of all cases
Quantitative or qualitative defect
|60-80%||Quantitative defect (19-45% of enzyme level present)|
|20-30%||Qualitative defect - multimers abnormal or subgroups absent|
|Rare - the most severe form; 1-5% of cases||Quantitative - levels very low or undetectable|
|Rare - fewer than 70 cases described||Functional mutations of vWF receptor on platelet|
Subtypes of type 2
- Abnormal synthesis or proteolysis of vWF multimers.
- Leads to small multimers in circulation; factor VIII still binds as normal.
- Spontaneous binding of platelets with rapid clearance of platelets and large vWF multimers.
- Mild thrombocytopenia.
- Factor VIII binding normal or low normal.
- Desmopressin will not help, as it leads to unwanted platelet aggregation.
- Low or absent binding to receptor on platelets.
- Factor VIII binds as normal.
- Autosomal recessive rather than X-linked.
- Shows incomplete response to haemophilia A treatment.
- Factor VIII levels reduced to around 5%, as vWF has a reduced affinity for factor VIII.
See also separate Bleeding Disorders article.
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 FBC, fibrinogen level, platelet count, clotting screen, factor IX levels. The platelet count and morphology are normal.
- Plasma levels of vWF - keep in mind that deficiency can be quantitative or qualitative:
- 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 agglutination.
- 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 sub-endothelium are necessary.
- Oestrogens, vasopressin and growth hormone all elevate levels.
Pregnancy and von Willebrand's disease
During pregnancy the level of vWF increases in most women with types 1 and 2 vWD and labour and delivery usually proceed normally. However, patients with type 2B disease may experience haemorrhagic problems. Women with vWD whose vWF does not rise to normal levels during pregnancy need specialist assessment and multidisciplinary team management.
- Educate patients as to the bleeding risk. Provide advice regarding drugs that must be avoided such as non-steroidal anti-inflammatory drugs and antiplatelet drugs.
- Minor bleeding problems, such as bruising or a brief nosebleed, may not require any specific treatment.
- Treatments to achieve homeostasis in vWD are tranexamic acid and desmopressin or concentrates containing either high-purity vWF alone or intermediate-purity concentrates containing factor VIII-vWF.
- Tranexamic acid is an antifibrinolytic agent. It can be used topically, as a mouthwash, orally or intravenously, as a treatment for minor bleeding or given before surgery, either on its own or as an adjunct to desmopressin or concentrates.
- In women with menorrhagia, combined oral contraceptives or progesterone-containing intrauterine systems often provide significant clinical benefit
- Desmopressin (DDAVP®) works by temporarily increasing factor VIII and vWF levels by releasing endothelial stores. It is given intranasally or parentally.It can be used to treat bleeding complications or prophylactically before surgery. It's ineffective in type 3 vWD as there are no vWF levels to boost. It is not recommended for type 2B vWD as a transient thrombocytopenia may occur and the therapeutic response is usually poor.
- Since individual response to desmopressin is unpredictable, all vWD patients should undergo a therapeutic trial of administration to assess their response.
- Platelet transfusions may be helpful in some patients with disease refractory to other therapies.
- For prophylaxis in major surgery or for treatment of serious bleeding episodes, vWF-containing factor VIII concentrates are the treatment of choice.
- Patients with type 3 vWD and haemarthroses, severe epistaxis, menorrhagia and other bleeding risk factors require regular prophylaxis with vWF concentrates (given 2-3 times per week).
- Patients who have alloantibodies to vWF will require recombinant factor VIII.
After the diagnosis of vWD has been made, testing should be offered to first-degree relatives (with or without a positive bleeding history).
Further reading and references
Von Willebrand's disease; The Haemophilia Society
Berntorp E, Peake I, Budde U, et al; von Willebrand's disease: a report from a meeting in the Aland islands. Haemophilia. 2012 Sep18 Suppl 6:1-13. doi: 10.1111/j.1365-2516.2012.02925.x.
Von Willebrand Disease, Type 1, VWD1; Online Mendelian Inheritance in Man (OMIM)
Federici AB; Acquired von Willebrand syndrome: an underdiagnosed and misdiagnosed bleeding complication in patients with lymphoproliferative and myeloproliferative disorders. Semin Hematol. 2006 Jan43(1 Suppl 1):S48-58.
Guidelines for the laboratory investigation of heritable disorders of platelet function; British Committee for Standards in Haematology (2011)
Chalmers EA; Neonatal coagulation problems. Arch Dis Child Fetal Neonatal Ed. 2004 Nov89(6):F475-8.
The diagnosis and management of von Willebrand disease; United Kingdom Haemophilia Centre Doctors Organization guideline approved by the British Committee for Standards in Haematology (2014)
British National Formulary (BNF); NICE Evidence Services (UK access only)
Von Willebrand Disease: an introduction for the primary care physician; World Federation of Hemophilia, 2009
Mannucci PM; Treatment of von Willebrand's Disease. N Engl J Med. 2004 Aug 12351(7):683-94.
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