Von Willebrand disease

01OverviewDefinition, clinical context and the essential points that orientate the chapter.

Von Willebrand factor supports platelet adhesion at damaged vessels and carries factor VIII. VWD therefore sits between a platelet disorder and a coagulation-factor deficiency. The most typical phenotype is mucocutaneous bleeding: recurrent nosebleeds, gum bleeding, easy bruising, heavy menstrual bleeding, postpartum haemorrhage and disproportionate bleeding after dental or surgical procedures. Severe type 3 disease can also cause joint and muscle bleeding because factor VIII becomes very low.

Classification changes treatment. Type 1 is a partial quantitative deficiency; type 3 is near-complete absence. Type 2 is qualitative: 2A loses effective multimers, 2B has increased platelet binding with possible thrombocytopenia, 2M has reduced function without the classic multimer loss, and 2N fails to bind factor VIII. Low VWF between normal and diagnostic ranges may still be clinically relevant, but the label must integrate bleeding phenotype, repeat levels and family context rather than one number.

Initial laboratory testing combines VWF antigen, a platelet-dependent VWF activity assay and factor VIII. Activity disproportionately below antigen suggests a qualitative defect. Results change with stress, age, pregnancy, inflammation, thyroid state and ABO group; repeat sampling when well is often essential. Specialist tests establish subtype and distinguish type 2N from haemophilia A or type 2B from platelet-type VWD. Genetic testing is selective, especially when it clarifies inheritance or prenatal options.

Treatment is event and phenotype specific. Local measures and tranexamic acid may be enough for minor mucosal bleeding. Desmopressin releases endogenous VWF, so it works only if adequate functional stores exist; response should be measured in advance when possible. VWF-containing concentrate is used for severe disease, major bleeding and procedures when desmopressin is unsuitable or insufficient. Major surgery needs both early haemostasis and postoperative trough monitoring because endogenous and infused FVIII can accumulate.

Key points

VWD is the commonest inherited bleeding disorder and usually causes epistaxis, easy bruising, heavy menstrual bleeding and immediate or delayed procedural haemorrhage.
A normal PT and often normal APTT do not exclude VWD; begin with a standardised bleeding history, FBC and ferritin, VWF antigen, platelet-dependent VWF activity and factor VIII.
Confirm a borderline result with repeat baseline testing because acute stress, bleeding, pregnancy, oestrogen and inflammation can temporarily raise VWF and mask deficiency.
Subtype is clinically important: compare activity with antigen, assess FVIII and use multimer, collagen-binding, low-dose ristocetin or genetic testing through a specialist laboratory when indicated.
Preferred treatment for a responsive mild type 1 phenotype is often desmopressin after a documented test dose; it is ineffective in type 3 and may be unsafe in type 2B.
For major bleeding, major surgery, childbirth or non-responsive disease, use a VWF-containing concentrate with product-specific dosing and VWF and FVIII targets from the haemophilia centre.
Tranexamic acid is valuable for dental, nasal, oral and menstrual bleeding and is commonly combined with desmopressin or concentrate, but requires renal adjustment and site-specific cautions.
Every patient should have a written bleeding plan, haemophilia-centre contact, medicine and procedure advice, and coordinated menstrual, pregnancy and postpartum planning.

02AetiologyUnderlying causes, associations and risk factors, with why each one matters.

Quantitative inherited deficiency

Type 1 usually causes partial VWF deficiency and type 3 causes near-complete deficiency; inheritance is often dominant in type 1 and recessive in type 3.

Qualitative VWF variants

Type 2A, 2B, 2M and 2N variants impair multimer assembly, platelet binding or factor VIII binding despite a measurable antigen level.

Acquired VWF loss

Cardiac shear, monoclonal proteins, hypothyroidism and myeloproliferative disease can produce an acquired syndrome without a lifelong or family bleeding pattern.

03PathophysiologyThe causal sequence from the underlying abnormality to symptoms and harm.

1
Impaired platelet adhesion
VWF bridges exposed subendothelium to platelet glycoprotein Ib under shear, so deficiency produces mucosal and immediate procedural bleeding.
2
Reduced factor VIII survival
VWF protects factor VIII from clearance; severe quantitative loss or type 2N binding failure can lower FVIII and create a haemophilia-like laboratory pattern.
3
Multimer-dependent function
High-molecular-weight multimers are most effective in primary haemostasis; their selective loss explains low activity relative to antigen in several type 2 disorders.
4
Physiological variation
Stress, exercise, inflammation, oestrogen and pregnancy raise VWF, while blood group O is associated with lower levels, complicating a single borderline result.

04Clinical features and red flagsSymptoms, examination findings, patterns of presentation and time-critical warnings.

Mucosal bleeding

Recurrent epistaxis, gingival bleeding, prolonged bleeding from small cuts and easy bruising are more typical than spontaneous haemarthrosis.

Heavy menstrual bleeding

Flooding, clots, double protection, iron deficiency or impaired daily activity should prompt a structured bleeding and gynaecological history.

Procedural challenge

Dental extraction, tonsillectomy, childbirth or surgery may reveal bleeding that was not apparent during ordinary daily life.

Severe phenotype

Type 3 disease can produce muscle, joint and deep postoperative bleeding because FVIII is profoundly reduced as well as VWF absent.

Acquired pattern

New bleeding in later life without affected relatives suggests an associated cardiac, endocrine, clonal or autoimmune mechanism.

Red flags requiring action

Head injury, new severe headache, neurological deficit or reduced consciousness in a person with severe VWD requires urgent imaging and haemostatic treatment before deterioration.
Persistent postpartum bleeding can recur after initially adequate haemostasis as pregnancy-elevated VWF falls; obstetric and haemophilia teams must coordinate prevention and follow-up.
Type 2B disease or platelet-type VWD may develop or worsen thrombocytopenia with desmopressin, so subtype and prior trial response must be checked before use.

05InvestigationsWhat to request, why it matters and how to interpret it.

Investigation order

Read from the initial assessment onwards. Tests may run in parallel in urgent care; first-line, preferred, confirmatory, definitive and gold-standard labels appear only when the chapter explicitly states them.

01
First-line: bleeding assessment, FBC and ferritinFirst stepFirst line
Why
Establish phenotype, inherited pattern and consequences before interpreting VWF numbers.
Interpretation and limitations
Use a validated bleeding-assessment approach where available and document haemostatic challenges. Anaemia or low ferritin demonstrates cumulative loss and needs treatment.
02
First-line: VWF antigen, VWF activity and FVIIIFirst line
Why
Measure VWF quantity, platelet-dependent function and carrier effect on factor VIII.
Interpretation and limitations
Low antigen and activity support quantitative deficiency; disproportionately low activity suggests type 2. Repeat when clinically baseline because stress can falsely reassure.
03
Baseline PT and APTT
Why
Identify an alternative or additional coagulation disorder and recognise severe FVIII reduction.
Interpretation and limitations
PT is usually normal and APTT may be normal in mild VWD. A prolonged APTT requires mixing and factor assessment but does not define subtype.
04
Confirmatory specialist phenotypingConfirmatory
Why
Classify type 2 disease and distinguish phenocopies that alter treatment.
Interpretation and limitations
Multimer distribution, collagen binding, ristocetin-induced platelet aggregation, VWF-FVIII binding and platelet studies are selected by the haemostasis laboratory, not ordered as an indiscriminate panel.
05
Desmopressin response trial
Why
Establish whether an adequate and sustained VWF and FVIII rise can cover future minor bleeding or procedures.
Interpretation and limitations
Measure pre-dose and defined post-dose levels, often including a later sample to detect rapid clearance. Record dose, route, peak, duration and adverse effects in the care plan.

06Differential diagnosisRealistic alternatives and the features that help distinguish them.

Platelet dysfunction

Aspirin, P2Y12 inhibitors, uraemia and inherited platelet disorders cause similar mucocutaneous bleeding; medicine history and specialised assays distinguish them.

Mild haemophilia

Isolated low factor VIII with deep or delayed bleeding may be haemophilia A, but type 2N VWD can closely mimic it and affects family counselling.

Connective-tissue bleeding

Hypermobile tissue, corticosteroid exposure and vascular fragility can produce easy bruising with repeatedly normal haemostasis studies.

Acquired von Willebrand syndrome

Late-onset bleeding without family history, particularly with aortic stenosis, monoclonal gammopathy or extreme thrombocytosis, suggests secondary VWF loss.

07ManagementImmediate care, first-line treatment, alternatives and escalation.

01Suspected inherited VWDCombine phenotype with baseline testsFirst stepMucocutaneous or procedural bleeding, heavy periods or a compatible family history raises suspicion.

1Document bleeding across dental, surgical, menstrual and obstetric challenges and construct a three-generation family history where possible.
2Send FBC, ferritin, PT, APTT, VWF antigen, platelet-dependent activity and FVIII when the patient is clinically well if feasible.
3DefinitiveRepeat borderline or discordant results and refer to a haemophilia centre for subtype testing before definitive treatment decisions.

02Minor mucosal eventUse local and antifibrinolytic controlBleeding is limited to a compressible oral, nasal or menstrual site without major physiological compromise.

1Apply sustained local pressure or procedure-specific haemostasis and assess anaemia, ongoing loss and need for ENT, dental or gynaecology input.
2Use renal-adjusted tranexamic acid when appropriate and add documented responsive desmopressin if the event or procedure needs more coverage.
3EscalationEscalate persistent bleeding to the haemophilia centre for VWF concentrate rather than repeating desmopressin without sodium and response review.

03Major bleed or surgeryReplace VWF and monitor FVIIIBleeding threatens life or organ function, or a major operation requires sustained haemostatic levels.

1Contact the haemophilia centre immediately and give the patient's product-specific VWF-containing concentrate plan while securing anatomical haemostasis.
2Measure VWF activity, FVIII, haemoglobin and clinical response at protocol-defined intervals and account for ongoing blood loss and concentrate recovery.
3Continue postoperative trough-directed treatment for the planned healing period while preventing excessive FVIII accumulation and thrombosis.

04Pregnancy pathwayPlan delivery and postpartum fallA patient with VWD is pregnant, considering neuraxial anaesthesia or approaching delivery.

1Review subtype and previous bleeding early and measure VWF activity and FVIII in the third trimester through obstetric-haematology care.
2Agree delivery, neuraxial and haemostatic thresholds, product access, neonatal precautions and avoidance of traumatic fetal monitoring when inheritance risk is relevant.
3Continue postpartum surveillance and antifibrinolytic or replacement cover as planned because VWF falls after birth and secondary haemorrhage can occur.

Key medicines and prescribing safety3 treatments · regimens, roles and cautions

Releases stored endogenous VWF and FVIII for selected type 1 and some type 2 patients with minor bleeding or procedures.

Desmopressin

For a documented responsive phenotype, give 0.3 micrograms/kg intravenously diluted and infused over 20–30 minutes before the haemostatic challenge; repeat only under the haemophilia plan because response wanes and water retention accumulates.

Test response when possible. Avoid in type 3 and generally type 2B, and use caution in cardiovascular disease. Restrict hypotonic fluid and monitor sodium; children, older adults and repeated doses have greater hyponatraemia risk.

Prevents premature fibrin breakdown at mucosal sites and supplements desmopressin or VWF concentrate.

Tranexamic acid

Use 1 g orally three times daily for adult oral, nasal, dental or menstrual bleeding for the shortest effective course, or the exact intravenous or topical regimen in the specialist procedure plan; reduce in renal impairment.

Review active thrombosis and upper urinary-tract bleeding, where clot obstruction is a concern. Accumulation in severe kidney impairment increases toxicity, and it does not replace factor support for major haemorrhage.

Replaces functional VWF, with or without factor VIII, when endogenous release is absent, unsafe or insufficient.

VWF-containing concentrate

For major bleeding or surgery, use the named product and haemophilia-centre protocol, commonly an initial 40–60 IU VWF activity/kg intravenously followed by trough-directed doses every 8–24 hours for the required healing period.

Products differ in VWF activity, FVIII content and licensed dosing, so units are not interchangeable. Monitor VWF and FVIII recovery, thrombosis, hypersensitivity and rare inhibitors; pregnancy and surgery require explicit targets.

08ComplicationsImportant consequences, why they occur and why they matter clinically.

Iron-deficiency anaemia

Heavy menstrual, nasal and gastrointestinal bleeding may cause substantial iron depletion even when individual episodes seem minor.

Procedural haemorrhage

Dental work, tonsil surgery, childbirth and major operations can expose inadequate VWF-dependent platelet adhesion and low factor VIII.

Angiodysplasia bleeding

Recurrent gastrointestinal bleeding from angiodysplasia is particularly associated with loss of high-molecular-weight multimers and may be difficult to control.

Treatment toxicity

Desmopressin can cause dilutional hyponatraemia and thrombocytopenia in type 2B; concentrate exposure rarely produces thrombosis or inhibitors.

09Monitoring and follow-upTreatment response, safety checks and longer-term review.

Maintain a haemophilia-centre record of subtype, baseline VWF and FVIII, desmopressin response, concentrate product, allergies and emergency contacts.
Check haemoglobin and ferritin in recurrent nasal, menstrual or gastrointestinal bleeding and confirm iron repletion rather than treating fatigue empirically.
After desmopressin, monitor fluid balance and sodium and record measured haemostatic response; do not infer future efficacy from clinical impression alone.
During replacement for major surgery, measure VWF activity and FVIII troughs using the product-specific plan and review VTE prophylaxis as haemostasis normalises.
Reassess bleeding and VWF levels at life transitions including adolescence, pregnancy, menopause, major illness and before procedures, because phenotype and measured levels change.

10Special situationsVariants, exceptions and circumstances that change the usual approach.

Normal APTT is common

Mild VWF deficiency may leave FVIII high enough for a normal routine screen, so dedicated VWF testing follows the bleeding history.

Activity-to-antigen relationship matters

A low function result out of proportion to antigen is the clue to qualitative type 2 disease and prompts specialist classification.

Stress can conceal deficiency

Acute bleeding, inflammation and anxiety elevate VWF, making a later well-state repeat important when initial suspicion remains strong.

Type 2B changes treatment

Enhanced platelet binding can produce thrombocytopenia, and desmopressin may aggravate the mechanism rather than provide safe haemostasis.

Postpartum risk returns

Pregnancy raises VWF in many patients, but the level falls after delivery when secondary postpartum haemorrhage remains possible.

11Common pitfallsFrequent interpretation and management errors.

01
Excluding VWD because PT and APTT are normal.
02
Diagnosing or dismissing disease from one borderline VWF value.
03
Using desmopressin without knowing subtype or response.
04
Repeating desmopressin without fluid and sodium precautions.
05
Treating heavy periods without checking ferritin and gynaecological causes.
06
Planning delivery without postpartum haemostatic cover.