Von Willebrand disease

• Von Willebrand disease (VWD) is the commonest inherited bleeding disorder in humans: about 1% of people carry a low von Willebrand factor level, and clinically significant disease affects roughly 125 people per million. ^[1]
• The problem is a shortage or fault in von Willebrand factor (VWF), a multimeric plasma protein made by endothelial cells and megakaryocytes. It has two jobs: it sticks platelets to injured vessel walls, and it carries factor VIII in the blood. ^[1][2]
• Bleeding is usually mucocutaneous: nosebleeds, bruising, gum bleeding, heavy periods, prolonged bleeding after dental work, cuts, childbirth or surgery. Severe type 3 disease can also bleed into joints and muscles like haemophilia. ^[2][3]
• The diagnosis rests on measuring VWF antigen, a platelet-dependent VWF activity assay and factor VIII activity, ideally when the patient is well and not bleeding, because VWF is an acute-phase reactant. ^[2]
• Treatment matches the type: desmopressin for many type 1 patients, VWF-containing concentrates for type 3 and severe disease, plus tranexamic acid, hormonal therapy for heavy periods, and a great deal of anticipatory care around procedures and pregnancy. ^[3]

By the end of this page you should be able to:

1. Explain the two haemostatic jobs of VWF and predict the bleeding pattern when each fails.
2. Classify VWD into types 1, 2A, 2B, 2M, 2N and 3, and state the inheritance and the laboratory finding that separates each.
3. Take a sensible first bleeding history and know which initial laboratory tests to order, including when an aPTT may be prolonged.
4. Interpret VWF:Ag, VWF activity and the activity-to-antigen ratio, and outline how type 2 subtypes are confirmed.
5. Write a safe treatment plan for a nosebleed, heavy periods, dental work, major surgery and pregnancy, including the doses of desmopressin and tranexamic acid.
6. Recognise acquired von Willebrand syndrome and know which dangerous tests and habits to avoid in VWD.

The VWF gene sits on the long arm of chromosome 12 and has 52 exons encoding 2813 amino acids. ^[2] Its product is made in endothelial cells and megakaryocytes, stored in Weibel-Palade bodies and platelet alpha granules, and released into plasma as multimers of widely varying size. ^[1] This variability is not academic: the largest multimers are the most haemostatically active, and their loss (type 2A/2B) causes a particularly troublesome bleeding pattern.

When a vessel is injured, subendothelial collagen is exposed. VWF binds that collagen, changes shape under shear stress, and captures circulating platelets through the platelet receptor glycoprotein Ib (GPIb). This is primary haemostasis, and it is why VWD bleeding is mucocutaneous: the small vessels of the nose, gums, skin, uterus and gut are the places where platelets must plug gaps quickly. ^[1][2]

VWF also binds factor VIII (FVIII) in plasma. This protects FVIII from degradation and delivers it to the site of injury. Without VWF, FVIII falls, and the common pathway of coagulation slows down. In severe disease (type 3) this produces deep bleeding, haemarthroses and muscle haematomas resembling haemophilia. ^[1][2]

VWF is an acute-phase reactant and rises with stress, trauma, infection, pregnancy and exercise. Levels also vary mildly with ABO blood group (lowest in group O). A patient tested while unwell or pregnant can have a "normal" level, which is why a suspected case must be re-tested when well, and sometimes tested more than once. ^[1][2]

VWD is classified by how much VWF is present (quantitative types 1 and 3) and by how well it works (qualitative type 2). Type 2 has four subtypes. ^[2][3]

The old distinction "mild, moderate, severe type 1" is now framed by numbers: VWF below 0.30 IU/mL confirms VWD even without a bleeding history, and VWF below 0.50 IU/mL with an abnormal bleeding history also confirms it. ^[2] Levels between 0.30 and 0.50 IU/mL are usually called "low VWF" rather than VWD, and these patients are treated when they face high-bleeding-risk situations. ^[1]

VWD affects roughly 1% of the unselected population, but clinically significant disease is far less common: about 125 people per million, with severe disease in up to five per million. ^[1] Men and women are affected equally, but women come to medical attention more often because of gynaecological and obstetric bleeding. ^[1][2] At primary-care level about one in 1000 people need medical attention for bleeding from VWD. ^[2] Acquired VWD (see below) makes up an unknown fraction of all cases, estimated at 1 to 5%, and is more frequent in malignancy and in high-flow cardiac states. ^[1]

Inherited VWD is autosomal dominant for types 1, 2A, 2B and 2M, and autosomal recessive for types 2N and 3. ^[1] Type 1 shows incomplete penetrance of about 60%, so a normal parent can still carry the gene and a mildly affected relative can be missed. ^[1] The VWF gene is highly polymorphic, which is part of why "low VWF" is common and why normal ranges are wide. ^[1]

There is no modifiable risk factor for inherited disease. VWF levels can still vary (and type 2B patients may worsen) because of assay error, blood group, stress, or acquired conditions. The questions that predict VWD best in practice are still the patient's own bleeding history plus a family history, with a validated bleeding assessment tool used as a screening test in low-probability patients. ^[2]

The hallmark is mucocutaneous bleeding: ^[2][3]

• Epistaxis that is frequent, prolonged, or hard to stop.
• Heavy menstrual bleeding: periods lasting longer than usual, flooding, clots, or anaemia.
• Easy bruising and prolonged bleeding from minor cuts.
• Gingival bleeding, especially after brushing or dental work.
• Prolonged bleeding after surgery, dental extraction, circumcision, or childbirth.
• Gastrointestinal bleeding, sometimes recurrent, especially in type 3 and older patients.
• In type 3: joint and muscle bleeding, haematuria, and prolonged post-traumatic bleeding after trivial injury.

Women often present late. Repeated heavy periods normalised as "just heavy" can cause years of iron deficiency before anyone measures a VWF level. ^[3]

Examination is often normal. Look for bruising or haematomas, signs of anaemia (pallor, tachycardia), a murmur suggesting aortic stenosis in acquired disease, and joint changes if recurrent haemarthroses have occurred.

VWF and FVIII rise in most women with types 1 and 2 VWD during pregnancy, so labour and delivery are usually uneventful. ^[1] Patients with type 2B disease, whose platelet binding is already exaggerated, can instead develop thrombocytopenia as the VWF level rises, and need haematology-led plans in advance. ^[1][3] Third-trimester VWF and FVIII levels should be checked so that analgesia and delivery can be planned. ^[3]

Two questions arise. First, is this VWD or another bleeding disorder? Second, when a low VWF level is found, is it inherited or acquired?

In a patient with a suggestive bleeding history:

• Full blood count: platelets are usually normal; anaemia if heavy bleeding. Type 2B may have thrombocytopenia. ^[1][3]
• aPTT and PT: PT is normal. The aPTT may be prolonged, because low VWF allows FVIII to fall, and it is more often prolonged in type 2N and type 3. ^[1]
• VWF:Ag, a platelet-dependent VWF activity assay (VWF:GPIbM or VWF:GPIbR; older labs still use VWF:RCo), and FVIII:C. ^[2]

The ASH 2021 guideline suggests that newer platelet-binding assays (VWF:GPIbM, VWF:GPIbR) be used in preference to the ristocetin cofactor assay (VWF:RCo) where available. ^[2] In any event, the blood must be handled correctly: ristocetin-dependent assays are sensitive to collection and transport, and an abnormal result should be repeated. ^[2]

• A ristocetin cofactor activity above 50 IU/dL is normal; below 30 IU/dL is diagnostic of VWD. ^[1]
• VWF below 0.30 IU/mL confirms VWD regardless of bleeding; below 0.50 IU/mL with abnormal bleeding also confirms it. ^[2] (Note that 0.30 IU/mL equals 30 IU/dL, the same cut-off from the other convention.)
• The platelet-dependent activity to antigen ratio separates qualitative from quantitative disease: a ratio below 0.7 points to type 2A, 2B or 2M. ^[2]
• ABO-specific reference ranges are not required. ^[2]

• Type 2 subtypes in doubt (2A vs 2B vs 2M): VWF multimer analysis or VWF collagen binding (VWF:CB) to antigen ratio. ^[2]
• Type 2B suspected: targeted genetic testing in preference to low-dose ristocetin-induced platelet agglutination. ^[2]
• Type 2N suspected: VWF:FVIII binding assay or targeted genetics. ^[2]
• Type 1C suspected: a desmopressin trial with levels at 1 and 4 hours rather than a VWF propeptide ratio. ^[2]
• Repeat testing should be done when the patient is well, off acute illness, and ideally not during pregnancy, because VWF is an acute-phase reactant. ^[1][2]

For patients with low pre-test probability (typical primary care), a validated bleeding assessment tool (BAT) is recommended as the initial screen to decide who needs specific blood testing. ^[2] In patients referred to haematology with intermediate or high probability (abnormal bleeding history, prolonged aPTT, or an affected first-degree relative), the panel suggests against relying on a BAT alone to decide whether to test. ^[2]

Treatment is individualised by type, bleeding phenotype and the specific situation (a nosebleed at home versus major surgery). The two pillars are raising VWF (desmopressin or VWF-containing concentrate) and stabilising clots (tranexamic acid), with hormonal therapy for menstrual bleeding and iron replacement throughout. ^[3]

Desmopressin releases stored VWF and FVIII from endothelial cells and is the first treatment to try in type 1 VWD. ^[1][3][4]

• Dose: 0.3 micrograms (mcg) per kilogram of actual body weight (maximum 20 mcg), given by intravenous infusion over 15 to 30 minutes. If used pre-operatively, give it shortly before the procedure, as the product label advises. ^[4]
• Repetition: if used for spontaneous or traumatic bleeding, doses may be repeated after 8 to 12 hours and then once daily as needed, guided by VWF and FVIII levels. ^[4]
• Tachyphylaxis develops with repeated dosing, so desmopressin suits minor or short-lived problems rather than prolonged treatment. ^[1]
• A trial at diagnosis is recommended for patients with type 1 VWD and a baseline VWF below 0.30 IU/mL, i.e. measure VWF and FVIII at 1 and 4 hours after a dose; a successful response reaches at least 30 IU/dL, ideally 50 IU/dL. ^[1][3]
• Patients with type 1 VWD and baseline VWF at or above 0.30 IU/mL are usually presumed responsive. ^[3]

Desmopressin is contraindicated or ineffective in (do not use): ^[3][4]

• Type 3 VWD (no releasable stores).
• Type 2B VWD (worsens platelet binding and thrombocytopenia; risk of thrombosis).
• Many type 2 patients (2A, 2M, 2N respond variably and often need concentrates).
• Active cardiovascular or cerebrovascular disease, and patients with seizure disorders.
• Children under 2 years.
• Type 1C VWD before surgery.
• Concomitant free-water overload; patients need normal saline if IV fluids are given and restricted oral intake, because hyponatraemia is a real risk. ^[3]

Monitor blood pressure and sodium during use. ^[1][4]

These are needed for type 3 disease, severe type 1 or 2 variants that fail desmopressin, and major bleeding or surgery. ^[1][3] They are plasma-derived or recombinant products carrying VWF (usually with FVIII). Dosing is set by the haematology service by body weight, target level and pharmacokinetic response; no fixed dose is given in the guidelines. ^[3]

Tranexamic acid stabilises clots by inhibiting fibrinolysis and helps mucosal bleeding.

• Oral dose (postpartum/chronic): 25 mg/kg (typically 1000 to 1300 mg) three times a day for 10 to 14 days, or longer if bleeding remains heavy. ^[3]
• It can be given orally or intravenously, and local measures (tranexamic-acid mouthwash, gelatin sponges, fibrin glue) help dental procedures. ^[3]
• Do not use it in gross haematuria: clots can obstruct the ureter or urethra. ^[1]

This is the commonest practical problem in VWD. The ASH 2021 guideline suggests either hormonal therapy (combined hormonal contraception or a levonorgestrel-releasing intrauterine system) or tranexamic acid for women who do not want to conceive, and tranexamic acid for women who do. ^[3] Desmopressin is generally inferior here and is excluded in type 3 and type 2B disease. ^[3] In addition, women with known bleeding disorders and heavy periods should have a standard gynaecological assessment to exclude fibroids and polyps, particularly if first-line treatment fails, and should be checked and treated for iron deficiency. ^[3]

• For major surgery, aim for both FVIII and VWF activity at or above 0.50 IU/mL for at least 3 days after the operation. ^[3]
• For minor procedures, raising VWF to at least 0.50 IU/mL with desmopressin or concentrate is combined with tranexamic acid. Tranexamic acid alone is acceptable for type 1 VWD with baseline activity above 0.30 IU/mL and a mild bleeding phenotype undergoing minor mucosal procedures. ^[3]
• Dental work benefits from local haemostatic measures. ^[3]
• Patients at higher thrombotic risk should avoid prolonged simultaneous high VWF, high FVIII (above 1.50 IU/mL) and prolonged tranexamic acid. ^[3]

Where it is deemed suitable, target a VWF activity of 0.50 to 1.50 IU/mL rather than above 1.50 IU/mL; keep VWF above 0.50 IU/mL while the epidural is in place and for at least 6 hours after removal. ^[3] The decision is multidisciplinary (anaesthetics, haematology, obstetrics) and made well before delivery. ^[3]

Tranexamic acid is suggested during the postpartum period in type 1 VWD and low VWD (and it may also help in types 2 and 3). ^[3] Reassess thrombotic and bleeding risk after delivery. ^[3]

If VWD patients need antiplatelet or anticoagulant therapy (for example after a myocardial infarction or for atrial fibrillation), the panel suggests giving the indicated treatment rather than withholding it, with individualised risk-benefit assessment by a multidisciplinary team; severe-phenotype patients may need VWF concentrate prophylaxis during it. ^[3] Desmopressin is generally contraindicated in cardiovascular disease. ^[3]

For patients with VWD and history of severe, frequent bleeding, long-term prophylaxis with VWF concentrate is suggested over on-demand therapy. ^[3] Bleeding symptoms and the need for prophylaxis should be reassessed periodically. ^[3]

Most childhood VWD is type 1 inherited; type 2B may present with thrombocytopenia. Desmopressin is not used under 2 years. ^[3][4]

Most women with types 1 and 2 do well because VWF rises; type 2B can get worse; third-trimester levels guide planning; postpartum tranexamic acid is suggested. ^[1][3]

Type 3 disease is the main source of serious morbidity: severe bleeding, joint damage, alloantibody formation in 10 to 15%, and treatment complexity. ^[1][3]

Acquired von Willebrand syndrome (AVWS) is not inherited: a previously normal person develops VWF deficiency, usually from an underlying disorder. It accounts for an estimated 1 to 5% of all VWD and clusters in two settings. ^[1]

• High-shear or high-flow states: aortic stenosis (Heyde syndrome), ventricular septal defect, ventricular assist devices, ECMO, prosthetic valves. Large VWF multimers are literally sheared apart. ^[1]
• Malignancy and plasma-cell/lymphoid disorders: Wilms' tumour, lung, gastric and other solid tumours, MGUS, multiple myeloma, CLL, hairy-cell leukaemia, lymphoma, myeloproliferative neoplasms. Mechanisms include adsorption of VWF onto tumour cells, immune-complex clearance and proteolysis. ^[1]
• Autoimmune disease: systemic lupus erythematosus, other autoimmune disorders. ^[1]
• Drug effects and hypothyroidism. ^[1]

AVWS can account for up to 20% of VWD in malignancy and is nearly universal in some high-flow states such as ECMO and metallic valves. ^[1] Clinically it presents as new bleeding in an older patient without a family history, often with an abnormal laboratory pattern resembling type 2A. Management is to treat the underlying condition, give a desmopressin trial, and use VWF concentrate if needed. ^[1][3]

• Alloantibody formation to VWF in 10 to 15% of type 3 patients, with risk of severe reactions to VWF-containing products. ^[1]
• Iron deficiency and anaemia from chronic mucosal bleeding, especially heavy periods. ^[3]
• Joint and muscle damage in type 3 from recurrent bleeds. ^[1]
• Thrombosis risk from concentrates, desmopressin and tranexamic acid in the wrong patient. ^[1][3]
• Hyponatraemia with desmopressin and free-water intake. ^[3][4]

Most VWD is mild and manageable. Clinically significant bleeding usually occurs with trauma or invasive procedures, and life expectancy is normal. ^[1] Severe disease, alloantibody formation and AVWS are the situations that change the outlook and need specialist centres.

• Diagnosis is mostly clinical. A bleeding history plus affected relatives carries a lot of information. Where laboratory capacity is limited, a prolonged aPTT with a normal PT and normal platelets already points strongly towards a coagulation-factor problem such as VWD. ^[1]
• Repeat and re-test. Levels that are "normal" during illness or pregnancy may be low when the patient is well. Testing twice is cheap relative to missing the diagnosis. ^[1][2]
• Blood group O is associated with the lowest VWF levels; keep this in mind when interpreting borderline results in populations with high group O prevalence. ^[1]
• Desmopressin, tranexamic acid and combined oral contraceptives are inexpensive and widely available; desmopressin and tranexamic acid handle most type 1 and many minor-procedure scenarios. ^[1][3][4]
• Iron replacement and avoidance of NSAIDs/antiplatelet drugs (unless specifically indicated) prevent the common long-term harm of untreated heavy periods. ^[3]
• Refer early for severe, type 2B (thrombocytopenia), type 3 and AVWS patients, who need VWF concentrates, blood-bank and surgical-clinic support that district hospitals may not have. ^[3]
• In AVWS, treat the underlying condition (such as aortic stenosis) rather than indefinitely replacing VWF. ^[1]

Plain-text related topics (not yet linked in-text): Haemophilia A; platelet function disorders; immune thrombocytopenia; iron deficiency anaemia and heavy menstrual bleeding; oral anticoagulant management; coagulation screening tests (aPTT); postpartum haemorrhage.

• VWD is the commonest inherited cause of bleeding; its problem is a shortage or fault in VWF, which both sticks platelets to injured vessels and carries factor VIII.
• Bleeding is mucocutaneous: epistaxis, bruising, gum bleeding, heavy periods, prolonged surgical and dental bleeding. Type 3 disease also bleeds into joints and muscles.
• Type 1 is partial quantitative loss (autosomal dominant, penetrance about 60%); type 3 is near-absent VWF (autosomal recessive); type 2 subtypes are qualitative and differ in multimer pattern, platelet binding (2A, 2B, 2M) or FVIII binding (2N).
• VWF below 0.30 IU/mL confirms VWD regardless of bleeding; below 0.50 IU/mL with abnormal bleeding also confirms it. Levels between 0.30 and 0.50 IU/mL are "low VWF."
• Platelet-dependent VWF activity below 30 IU/dL is diagnostic; above 50 IU/dL is normal. A ratio of activity to antigen below 0.7 suggests type 2A, 2B or 2M.
• Test when the patient is well and not bleeding, and repeat if needed, because VWF is an acute-phase reactant and varies with ABO blood group.
• The aPTT can be prolonged because FVIII is low; PT and platelet count are usually normal (except type 2B thrombocytopenia).
• Classify type 2 with multimer analysis or collagen binding, targeted genetics for 2B, FVIII-binding assay for 2N, and a desmopressin trial for 1C.
• Desmopressin 0.3 mcg/kg (max 20 mcg) IV over 15 to 30 minutes is first-line for many type 1 patients; it is contraindicated in type 3, type 2B, cardiovascular disease, seizure, under 2 years, and type 1C before surgery. ^[3]
• Tranexamic acid: 25 mg/kg (typically 1000 to 1300 mg) orally three times daily for 10 to 14 days; useful for mucosal bleeding; avoid in gross haematuria. ^[3]
• For heavy periods use hormonal therapy or tranexamic acid; tranexamic acid alone for those wanting to conceive; check and treat iron deficiency.
• Major surgery target: FVIII and VWF activity at or above 0.50 IU/mL for at least 3 days; keep above 0.50 IU/mL while an epidural is in place and for 6 hours after. ^[3]
• Acquired VWD should be suspected with new bleeding in an older patient; treat the underlying cause (including aortic stenosis and malignancy).
• Most VWD is mild and manageable; severe disease, AVWS and alloantibody formation need specialist care.