Von Willebrand disease (VWD)

Von Willebrand disease (VWD)

• VWD is the most prevalent inherited bleeding disorder and arises from either a quantitative or qualitative deficiency of von Willebrand factor (VWF).
• VWF is a large multimeric glycoprotein crucial to primary haemostasis and the stability of coagulation factor VIII.

Functional Roles of von Willebrand Factor

Platelet adhesion

• VWF mediates the adhesion of platelets to exposed subendothelial collagen at sites of vascular injury.
• It binds platelet glycoprotein Ib (GPIb), facilitating initial platelet tethering.

Platelet aggregation

• VWF promotes platelet-to-platelet interaction, especially under high shear stress conditions.

Stabilisation of factor VIII

• VWF binds to and stabilises factor VIII in the circulation, protecting it from proteolytic degradation.
• A deficiency or functional defect in VWF leads to a secondary reduction in factor VIII levels.

Classification

Type 1 VWD

• Partial quantitative deficiency of functionally normal VWF.
• It is the most common form, accounting for approximately 75% of cases.
• Inheritance is typically autosomal dominant.

Type 2 VWD

• Qualitative defects in VWF, further divided into subtypes based on specific functional impairments:

Type 2A

• Loss of high-molecular-weight multimers resulting in defective platelet adhesion.

Type 2B

• Increased affinity for platelet GPIb, leading to enhanced platelet binding, removal of platelets, and mild thrombocytopenia.

Type 2M

• Decreased platelet-dependent function without multimer deficiency.

Type 2N (Normandy variant)

• Decreased binding affinity of VWF to factor VIII, resulting in low factor VIII levels and clinical similarity to mild haemophilia A.

Type 3 VWD

• Virtually complete deficiency of VWF, leading to absent VWF and very low factor VIII levels.
• It is the most severe form and is inherited in an autosomal recessive pattern.

Acquired von Willebrand Syndrome (AVWS)

• While not a genetic disorder, AVWS mimics inherited VWD in terms of clinical presentation/
• Arises due to underlying conditions such as lymphoproliferative disorders, cardiovascular abnormalities, autoimmune diseases, or hypothyroidism.
• Characterised by either reduced synthesis or increased clearance of VWF, often mediated by autoantibodies or mechanical destruction of the protein.

 Genetic and Molecular Foundations

• VWD is primarily an inherited bleeding disorder caused by mutations in the VWF gene.
• The VWF gene is located on chromosome 12p13.3, comprising:
  • 52 exons over approximately 180 kilobases.
  • A pseudogene on chromosome 22, non-functional but structurally similar.
• VWF is synthesised by:
  • Endothelial cells lining blood vessels.
  • Megakaryocytes, the precursors of platelets.
  • Possibly placental syncytiotrophoblasts during gestation.
• Post-translational modification results in multimer formation:
  • Monomers → dimers (via C-terminal disulphide bonds) → multimers (via N-terminal bonds).
  • Multimers range from 0.5 kDa to over 20 million kDa in mass.
  • Larger multimers are most active in haemostasis.

Inheritance Patterns and Modifiers of Expression

• VWD displays:
  • Autosomal dominant inheritance in most type 1 and type 2 forms.
  • Autosomal recessive inheritance in type 3 and type 2N variants.
• Phenotypic expression is influenced by:
  • ABO blood group: Type O associated with 25–30% lower VWF levels.
  • Age: VWF levels naturally increase with ageing.
  • Hormonal fluctuations: Oestrogen enhances VWF synthesis (e.g., pregnancy, puberty).
  • Thyroid status: Hypothyroidism can lower VWF levels.
  • Stress, inflammation, infection: Transiently raise plasma VWF.

Subtypes of Inherited VWD

Type 1 VWD – Partial Quantitative Deficiency

• Most prevalent subtype (~75% of cases).
• Mild to moderate reduction in VWF levels (typically 20–50% of normal).
• VWF levels <0.3 IU/mL are considered diagnostic; levels between 0.3–0.5 IU/mL are termed "low VWF" and may not meet diagnostic criteria in the absence of bleeding.
• Inheritance: Autosomal dominant with incomplete penetrance (~60%).
• Mutation types:
  • Reduced synthesis.
  • Accelerated clearance (increased VWF propeptide/VWF:Ag ratio).
  • Some mutations exhibit dominant-negative effects by interfering with the normal allele.

Type 2 VWD – Qualitative Functional Defects

• Characterised by structurally abnormal VWF with impaired function.
• Subclassified based on the specific defect in VWF activity:
  • Type 2A:
    • Loss of high- and intermediate-molecular-weight multimers.
    • Defective interaction with platelets and subendothelium.
    • Most common qualitative defect.
  • Type 2B:
    • Gain-of-function mutation increases spontaneous binding to platelet GPIb receptor.
    • Causes thrombocytopenia and clearance of large VWF multimers.
    • DDAVP is contraindicated due to risk of exacerbating thrombocytopenia.
  • Type 2M:
    • Normal multimer pattern but reduced interaction with platelets.
    • Typically results in disproportionate reduction in ristocetin cofactor activity (vWF:RCo) versus antigen (vWF:Ag).
  • Type 2N:
    • Selective reduction in binding to factor VIII.
    • Mimics mild haemophilia A.
    • Inheritance: Autosomal recessive.
    • Common in compound heterozygotes (null + binding-defective allele).

Type 3 VWD – Complete Quantitative Deficiency

• Rare and severe subtype.
• Virtually no measurable plasma or platelet VWF.
• Associated with FVIII levels of 1–5%, resembling moderate to severe haemophilia A.
• Inheritance: Autosomal recessive.
• Mutation spectrum includes:
  • Homozygous or compound heterozygous null mutations.
  • Frameshift, nonsense, large deletions, and splice site mutations.
• Notable mutation:
  • c.221-977_532+7059del (p.Asp75_Gly178del), identified in multiple unrelated families.
  • Also seen in some families with both type 1 and type 3 phenotypes.
  • Suggests a founder mutation with shared haplotypes.

Polymorphism and Population Variability

• The VWF gene is highly polymorphic.
• Modifies the bleeding risk even within the same VWD subtype.
• Environmental factors (e.g., concurrent illness, exercise, pregnancy) cause transient fluctuations in VWF levels.
• Diagnostic evaluations may be affected by these fluctuations — multiple test confirmations are often required.

Acquired von Willebrand Syndrome (AVWS)

Overview

• AVWS is a non-hereditary condition mimicking inherited VWD.
• Caused by accelerated clearance or functional inhibition of VWF due to:
  • Autoantibodies
  • Mechanical destruction
  • Adsorption onto abnormal cell surfaces

Mechanisms

• Autoantibodies bind circulating VWF → formation of immune complexes → clearance by the reticuloendothelial system.
• High shear stress in circulation (e.g., aortic stenosis, prosthetic valves) → unfolds VWF → exposes cleavage sites → degradation by ADAMTS13.
• Adsorption to tumour cells or platelets (e.g., in haematologic malignancies) → reduces free VWF

Associated Conditions

Haematologic malignancies

• Monoclonal gammopathy of undetermined significance (MGUS).
• Multiple myeloma
• Chronic lymphocytic leukaemia
• Hairy cell leukaemia

Myeloproliferative neoplasms (MPN)

• Essential thrombocythaemia
• Polycythaemia vera

Cardiovascular diseases

• Aortic stenosis.
• Congenital heart defects (e.g., Eisenmenger syndrome)

Mechanical circulatory devices

• Left ventricular assist devices (LVADs).
• Extracorporeal membrane oxygenation (ECMO).
• Mechanical cardiac valves.

Infections

• COVID-19
• Other viral pathogens

Endocrine/metabolic disorders

• Hypothyroidism (mild to moderate; reversible with treatment).
• Glycogen storage disease
• Uraemia

Autoimmune diseases

• Systemic lupus erythematosus (SLE)
• Felty syndrome
• Autoimmune haemolytic anaemia

Drugs

• Valproic acid
• Cephalosporins

Clinical Resolution

• Treatment of the underlying disorder usually leads to resolution of AVWS.
• In acute haemorrhagic situations, haemostatic therapy with VWF-containing concentrates, immunosuppression, or IVIG may be necessary.

 Synthesis and Structure of von Willebrand Factor (VWF)

Site of synthesis

• VWF is produced in endothelial cells and megakaryocytes.

Molecular structure

• Initially synthesised as monomers that undergo dimerisation in the endoplasmic reticulum.
• Dimers then multimerise in the Golgi apparatus, forming large multimers up to 20 million Daltons.

Storage and release

• VWF multimers are stored in Weibel–Palade bodies (endothelial cells) and α-granules (platelets).
• Released upon stimulation by triggers such as thrombin, histamine, or fibrin.

Cleavage and regulation

• Larger multimers are the most haemostatically active.
• Regulated by ADAMTS13, a plasma protease that cleaves ultra-large multimers to prevent excessive platelet aggregation.

Functional Roles of VWF in Haemostasis

Primary haemostasis

• Mediates platelet adhesion to exposed subendothelium by binding collagen and platelet GPIb receptors.
• Supports platelet aggregation, especially under conditions of high shear stress.

Secondary haemostasis

• Acts as a carrier protein for factor VIII (FVIII), stabilising it in circulation and protecting it from proteolytic degradation.
• Increases FVIII half-life, indirectly contributing to thrombin generation and fibrin formation.

General Pathophysiological Consequences in VWD

Defective primary haemostasis

• Leads to symptoms resembling platelet disorders: mucocutaneous bleeding, menorrhagia, easy bruising, prolonged bleeding from minor trauma or dental procedures.

Factor VIII deficiency (secondary haemostasis)

• More profound in type 3 and type 2N VWD.
• Can cause joint and muscle bleeds, mimicking mild haemophilia A in severe cases.

Aspirin and NSAIDs 

• May exacerbate bleeding symptoms due to additional impairment in platelet function.

Subtype-Specific Pathophysiology

Type 1 VWD – Partial Quantitative Deficiency

• Mild to moderate reduction in VWF antigen (Ag), VWF activity, and FVIII:C levels.
• Symptoms often mild or absent unless provoked by trauma, menstruation, or surgery.
• Factor VIII levels often normal or mildly reduced in proportion to VWF levels.

Type 2 VWD – Qualitative VWF Dysfunction

Type 2A

• Deficiency of high- and intermediate-molecular-weight multimers.
• Decreased VWF activity and FVIII:C.
• Impaired platelet adhesion despite normal VWF antigen levels.

Type 2B

• Gain-of-function mutation increases spontaneous binding of VWF to platelet GPIb.
• Accelerated clearance of platelet-VWF complexes and large VWF multimers.
• Leads to thrombocytopenia and absent large multimers.
• Hypersensitive to ristocetin-induced platelet aggregation (RIPA).
• Can be misdiagnosed as platelet-type (pseudo) VWD, which also causes spontaneous VWF–platelet binding but due to a platelet GPIb mutation. Differentiated by mixing studies and DNA analysis.

Type 2M

• Decreased platelet-dependent function (e.g. low VWF:RCo activity) but normal multimer distribution.
• VWF antigen levels may be only mildly decreased or normal.

Type 2N

• Defective binding of VWF to factor VIII.
• FVIII is rapidly cleared → reduced plasma FVIII levels (5–25%).
• Often confused with mild haemophilia A.
• VWF antigen and activity may be within normal limits.
• Requires specific FVIII binding studies for diagnosis.

Type 3 VWD – Complete Quantitative Deficiency

• Total absence of VWF protein in plasma and platelets.
• Extremely low factor VIII levels (1–5%).
• Clinical phenotype resembles moderate to severe haemophilia A, including:
  • Joint bleeds (haemarthroses),
  • Deep tissue and muscle haematomas,
  • Delayed post-surgical bleeding.
• Multimer analysis shows complete absence of all VWF multimers.
• ADAMTS13 has no substrate in this type due to complete VWF deficiency.

Laboratory Correlates and Diagnostic Implications

Multimer analysis

• Absent in type 3.
• Deficient in intermediate/large forms in types 2A and 2B.
• Preserved in type 2M.

VWF:RCo / VWF:Ag ratio

• Decreased in type 2A, 2B, 2M.
• Normal or proportionally decreased in type 1.

RIPA testing

• Hypersensitivity in type 2B.

FVIII:C levels

• Low in type 2N and type 3.
• Normal to mildly reduced in other subtypes.

 Prevalence and Population Screening

• VWD is the most common inherited bleeding disorder.
• Prevalence estimates vary depending on the population screened and diagnostic criteria:
  • Clinically significant VWD is estimated to affect approximately 125 individuals per million.
  • Severe forms, including type 3 VWD, occur at a rate of 0.5 to 5 per million.
  • Screening studies suggest that low VWF levels may be found in up to 1% of the general population.
    • Many of these individuals are asymptomatic and do not meet criteria for formal diagnosis.

Distribution of VWD Types

Type 1 (partial quantitative deficiency)

• Most common subtype, accounting for approximately 75% to 85% of diagnosed cases.

Type 2 variants (qualitative defects)

• Represent about 15% to 20% of cases.
• Subtype distribution:
  • Type 2A: 10–15%
  • Type 2B: ~5%
  • Other type 2 variants (2M, 2N): smaller proportions.

Type 3 (complete deficiency)

• Rare, representing 1–5% of diagnosed cases.
• Prevalence: 1–3 per million.
• More frequent in populations with higher rates of consanguinity.

Demographics: Sex, Age, and Ethnicity

Sex distribution

• VWD affects males and females equally, consistent with autosomal inheritance.
• Phenotypic expression may be more pronounced in females due to:
  • Menorrhagia.
  • Postpartum haemorrhage.
  • Increased healthcare-seeking due to visible mucosal bleeding.

Age considerations

• Symptoms often present in childhood, sometimes during or shortly after birth.
• Bleeding tendency may decline with age, though VWF levels often rise in older individuals.

Ethnic variation

• VWF levels are approximately 30% lower in individuals with blood group O compared to non-O groups.
• Higher baseline VWF levels are reported in Black individuals than in White individuals.

Geographic variation

• Underdiagnosis in developing countries is common due to limited diagnostic resources.
• Type 3 VWD is disproportionately represented in regions with high consanguinity.

Inheritance Patterns

• All VWD types are inherited in an autosomal pattern.

Autosomal dominant inheritance

• Common in:
  • Type 1
  • Type 2B
  • Most cases of type 2A and 2M

Autosomal recessive inheritance

• Occurs in:
  • Type 3
  • Type 2N
  • Some cases of type 2A and 2M

Variable penetrance and expressivity

• Individuals with the same genotype may exhibit different bleeding severity.
• Expression may be modulated by factors like blood group and hormonal state.

 Core Bleeding Symptoms to Elicit

Mucocutaneous bleeding is the hallmark

• Epistaxis (especially if >10–30 minutes or requiring medical attention)
• Menorrhagia:
  • Soaking through pads/tampons within 1 hour.
  • Pictorial Blood Assessment Chart (PBAC) score >100.
• Easy bruising, especially spontaneous or disproportionate to trauma.
• Gum/oral bleeding, including after brushing or dental work.
• Prolonged bleeding after minor trauma or superficial wounds.
• Heavy bleeding after dental procedures (e.g. extractions, tonsillectomy).
• Delayed bleeding after surgery (may occur days to weeks postoperatively).

Exacerbation with medications

• Bleeding may worsen with aspirin, NSAIDs, or other antiplatelet agents.
• Improvement may be noted with oestrogen-containing oral contraceptives.

Severe or unusual sites

• Gastrointestinal bleeding:
  • More common in type 2 or 3 VWD.
  • Often linked with angiodysplasia or aortic stenosis.
• Muscle and joint bleeding:
  • Seen in type 3 and occasionally type 2N (low FVIII).
  • Mimics haemophilia A.

Paediatric-Specific Features

Neonatal/infant bleeding

• Umbilical stump bleeding.
• Post-circumcision bleeding.
• Cephalohematoma, cheek haematoma.
• Conjunctival haemorrhages.

Toddler presentations

• Oral mucosal bleeding (e.g. from falls or minor trauma).
• Bleeding during teething or from minor injuries when crawling/walking.
• In a large infant cohort, 70% had bleeding events before age 2; oral and circumcision-related bleeds were most common.

Reproductive and Pregnancy History

Heavy menstrual bleeding

• Affects 60–90% of females with VWD.
• 10–15% of women with unexplained menorrhagia may have VWD.
• Up to 20% may require hysterectomy for symptom control.

Postpartum haemorrhage (PPH)

• Despite VWF elevation in pregnancy, levels drop rapidly after delivery.
• Bleeding can occur within hours or 5–15 days postpartum.
• In one series, 62% of women with low VWF experienced PPH; 22% required transfusion or intervention.

Oestrogen influence

• VWF levels rise during pregnancy and oestrogen use, potentially reducing bleeding risk.
• Diagnosis during pregnancy is unreliable; retesting is advised ≥6 weeks postpartum.

Personal and Family Bleeding History

Family history

• Ask about relatives with similar bleeding tendencies.
• Type 1 and most type 2 subtypes follow autosomal dominant inheritance.
• Types 2N and 3 are autosomal recessive; parents may be asymptomatic.

Consanguinity

• Particularly relevant in type 3 VWD.

Medication history

• Assess for use of antiplatelet agents, NSAIDs, anticoagulants, or herbal supplements.

Historical Clues Suggesting Severe VWD

• Bleeding in infancy (e.g. circumcision).
• Recurrent or spontaneous joint or muscle bleeds.
• Prior need for blood transfusions or hospitalisation due to bleeding.
• Symptoms consistent with anaemia: fatigue, pallor, shortness of breath.

Bleeding Assessment Tools (BATs)

• ISTH-BAT: Standardised for both adults and children.
  • Evaluates severity, frequency, and duration of bleeding events across 12 domains.
• Self-BAT: Validated self-administered version.
  • Especially effective in screening women for bleeding disorders.
• BATs provide objective scoring but require supplementation by:
  • Coagulation screening tests (e.g. VWF levels, platelet function tests).
  • Clinical interpretation.

Complicating Factors to Identify in History

Thrombocytopenia

• Type 2B VWD can cause low platelet counts via VWF-platelet interaction.
• Exacerbated by stress, pregnancy, or desmopressin (DDAVP).

Iron deficiency

• Common with chronic mucosal/GI bleeding or menorrhagia.
• Ask about fatigue, pica, restless legs, irritability.

Anaemia

• May present with pallor, dizziness, exertional dyspnoea.

Prolonged aPTT

• May indicate low FVIII in type 2N or 3; relevant in cases with muscle/joint bleeds.

Ageing and Historical Retesting Considerations

• VWF levels increase with age (~0.8 IU/dL per year).
• Patients with borderline levels may cross the diagnostic threshold over time.
• Historical bleeding symptoms remain relevant even if VWF levels later normalise.

 General Considerations

• Physical examination in VWD is often normal unless bleeding manifestations are currently active or the disease is severe.
• Findings reflect the site, severity, and chronicity of bleeding rather than the presence of the disorder itself.
• In most cases, diagnostic value is limited without correlation with history and laboratory testing.

Key Findings on Examination

Bruising (ecchymoses)

• May be spontaneous or occur after minimal trauma.
• Commonly found on the trunk, thighs, and upper arms.
• Size, number, and pattern should be noted; large or deep bruises raise suspicion for more severe bleeding disorders.

Petechiae and mucocutaneous signs

• Petechiae are rare in VWD but may occur, especially in conjunction with thrombocytopenia (e.g., in type 2B).
• Oral mucosal bleeding may present as persistent bloodstained saliva, gingival bleeding, or ulcerations with surrounding ecchymoses.
• Conjunctival haemorrhages or subconjunctival bleeding may be noted in children.

Haematomas

• Subcutaneous or intramuscular haematomas can be present in moderate-to-severe cases.
• May be palpable, warm, or tender.
• Larger haematomas should raise suspicion for type 2N or type 3 VWD, especially in children.

Signs of joint or muscle bleeding

• Seen primarily in type 3 and occasionally in type 2N due to low FVIII levels.
• May include:
  • Swollen, warm, tender joints (haemarthroses).
  • Reduced range of motion.
  • Muscle tightness or firmness suggestive of deep compartment bleeds.
  • Pain out of proportion to superficial findings.

Skin and systemic indicators

• Jaundice or spider angiomata: suggest possible liver dysfunction affecting coagulation.
• Splenomegaly: may reflect sequestration of platelets (e.g., in type 2B or secondary causes like hypersplenism).
• Telangiectasia or mucosal vascular abnormalities: more commonly associated with coexisting vascular malformations or angiodysplasia, particularly in GI tract.
• Joint or skin laxity: may be relevant in connective tissue disorders that can coexist with VWD or mimic its bleeding pattern.

Age-Specific Considerations

Infants and toddlers

• Signs may include:
  • Persistent bleeding from the umbilical stump.
  • Cephalohematomas after delivery.
  • Bleeding at injection or venepuncture sites.
  • Bleeding with circumcision.
• In a study of infants <2 years, 70% had experienced a bleeding event; oral mucosal bleeding was the most frequent.

Children

• Look for evidence of bruising in unusual locations or large bruises not consistent with normal activity.
• Joint swelling or muscle tenderness may indicate deeper bleeding.
• Pallor, fatigue, or developmental delay may point towards chronic iron deficiency anaemia.

Menstrual and Obstetric Examination Findings

While history is more informative, examination may reveal

• Pallor from chronic anaemia.
• Tender uterus or pelvic mass if fibroids or retained tissue are contributing.
• Active vaginal bleeding postpartum or menorrhagia.

In postpartum patients

• Signs of ongoing haemorrhage may include hypotension, tachycardia, and excessive lochia.
• Delayed postpartum bleeding (5–15 days after delivery) should prompt evaluation for VWD.

Laboratory-Linked Physical Correlates

Thrombocytopenia

• Occurs in type 2B VWD due to VWF-platelet binding and clearance.
• May manifest with:
  • Petechiae,
  • Mucosal bleeding,
  • Worsening symptoms after DDAVP administration.

Iron deficiency anaemia

• Resulting from menorrhagia or GI bleeding.
• Examination may show:
  • Pallor (conjunctival, palmar, or generalised).
  • Koilonychia (spoon nails).
  • Glossitis or angular stomatitis.
  • Symptoms such as irritability, fatigue, or restless legs should be actively probed if iron studies are pending.

Prolonged aPTT-related signs

• A significantly prolonged activated partial thromboplastin time (aPTT), especially in types 2N or 3 with FVIII deficiency, may predispose to joint/muscle bleeds visible on physical exam.

 Approach and Initial Considerations

• Diagnostic evaluation of suspected VWD begins with screening tests followed by specialised confirmatory assays.
• Testing should be timed away from acute phase responses (e.g., infection, stress, pregnancy, surgery), which can falsely elevate VWF levels.
• Repeat testing is advised at least two weeks apart to confirm persistent abnormalities.

Initial Laboratory Tests

Prothrombin Time (PT)

• Reflects extrinsic pathway.
• Normal in VWD.

Activated Partial Thromboplastin Time (aPTT)

• May be prolonged in 30–50% of VWD cases, especially if factor VIII activity <35%.
• Normal aPTT does not exclude VWD.

Full Blood Count (FBC)

• Platelet count and morphology typically normal.
• Type 2B VWD may show mild thrombocytopenia due to VWF-platelet interactions and clearance.

VWF Antigen (VWF:Ag)

• Quantifies circulating VWF protein.
• Values <0.30 IU/mL suggest VWD.
• Levels between 0.30–0.50 IU/mL are termed “low VWF”, particularly in presence of bleeding symptoms.
• VWF Activity
• Historically measured via Ristocetin Cofactor (VWF:RCo) assay.
• Reflects VWF binding to platelet GPIb.
• Diagnostic if <0.30 IU/mL.
• Newer assays using gain-of-function GPIbα eliminate need for ristocetin and improve sensitivity.

Factor VIII Coagulant Activity (FVIII:C)

• May be decreased in type 1, 2N, and especially type 3 VWD.
• Type 2N shows disproportionately low FVIII despite normal VWF function.

Tests to Confirm VWD Subtype

VWF Multimer Analysis

• Evaluates the distribution of VWF multimers.
• Helps distinguish between type 1 and type 2 subtypes:
  • Type 1: all multimers present, reduced intensity.
  • Type 2A: loss of large and intermediate multimers.
  • Type 2B: selective loss of large multimers.
  • Type 2M: normal multimer distribution.
  • Type 3: absent multimers.

Ristocetin-Induced Platelet Agglutination (RIPA)

• Detects hypersensitivity to ristocetin, especially in type 2B and platelet-type VWD.
• Diagnostic if platelet agglutination occurs at <0.7 mg/mL ristocetin.

FVIII-VWF Binding Assay

• Distinguishes type 2N VWD from mild haemophilia A.
• Performed in specialised reference laboratories.

Collagen Binding Assay (VWF:CB)

• Assesses ability of VWF to bind to collagen.
• Reduced in type 2A and 2M.

VWF Propeptide

• May be elevated in patients with increased VWF clearance.

Platelet Function Analysers (e.g. PFA-100)

• May support diagnosis but lack sensitivity and specificity.
• Not widely recommended as standalone screening tools.

Additional Investigations for Atypical Cases or Comorbidities

Thyroid Function Tests (TFTs)

• Hypothyroidism may reduce VWF levels.
• Evaluate in unexplained cases or acquired VWD.

Serum Protein Electrophoresis

• Detects monoclonal gammopathies in suspected acquired VWD (e.g. MGUS, multiple myeloma).

Genetic Testing

• Confirms mutations, useful in:
  • Type 2N vs haemophilia A.
  • Type 2B vs platelet-type VWD.
  • Prenatal or family diagnosis in type 3.
• Next-generation sequencing (NGS) now enables simultaneous analysis of multiple relevant genes.

Subtype-Specific Diagnostic Insights

Type 1 VWD

• Proportional decrease in VWF:Ag and VWF:RCo.
• Normal multimer pattern.
• Diagnosis supported by family history and bleeding symptoms.

Type 2A

• Disproportionately low VWF:RCo vs VWF:Ag.
• Multimer analysis: loss of intermediate and high-molecular-weight multimers.

Type 2B

• Similar lab profile to type 1.
• Distinguished by low platelet count, abnormal RIPA, and loss of large multimers.

Type 2M

• VWF:RCo/VWF:Ag ratio <0.6 with normal multimer pattern.

Type 2

• Normal VWF levels and function.
• Low FVIII with impaired FVIII binding.
• Mimics mild haemophilia A but differs in inheritance and binding tests.

Type 3

• Near-total absence of VWF:Ag and VWF:RCo.
• Severe deficiency of FVIII.
• Multimers absent.
• aPTT prolonged.

Low VWF (non-diagnostic range)

• VWF:Ag or VWF:RCo between 0.30–0.50 IU/mL.
• May still require treatment during bleeding risk events.

Assessment for Desmopressin (DDAVP) Responsiveness

• DDAVP challenge testing evaluates the potential benefit of DDAVP prior to surgery or treatment.
• Contraindicated in type 2B due to risk of exacerbating thrombocytopenia.
• Testing involves pre- and post-administration levels of:
  • VWF:Ag
  • VWF:RCo
  • FVIII:C
• An adequate response typically includes:
  • A ≥2-fold rise in VWF activity
  • FVIII:C and VWF:RCo levels sustained >0.50 IU/mL.

Mild Haemophilia A

Clinical Overlap

• Both VWD (types 2N and 3) and mild haemophilia A may present with joint and muscle bleeding, especially in males.
• Bleeding in haemophilia A is typically deep tissue (e.g. haemarthroses, muscle haematomas), while VWD more often causes mucocutaneous bleeding, though this can also occur in severe VWD.

Inheritance

• Haemophilia A: X-linked recessive (typically affects males).
• VWD: Autosomal (affects both sexes equally).

Laboratory Distinctions

• Haemophilia A:
  • Low factor VIII.
  • Normal VWF:Ag and VWF activity.
• VWD type 2N:
  • Low factor VIII.
  • Normal VWF:Ag and platelet-dependent activity.
  • Defective VWF–FVIII binding (confirmed by binding assay).
• VWD type 3:
  • Undetectable or extremely low VWF:Ag and activity, and factor VIII.

Confirmatory Tests

• FVIII-VWF binding assay.
• Genetic testing to identify F8 gene mutations (haemophilia A) or VWF mutations (VWD).

Platelet-Type (Pseudo) WD vs VWD Type 2B

Clinical Overlap

• Both present with mucocutaneous bleeding, thrombocytopenia, and enhanced ristocetin-induced platelet aggregation (RIPA).

Distinguishing Features

• Platelet-type VWD:
  • Caused by a gain-of-function mutation in platelet GPIb.
  • Normal VWF multimer profile.
  • Normal VWF genotype.

VWD Type 2B

• Caused by gain-of-function mutation in VWF increasing affinity for GPIb.
• Shows loss of high-molecular-weight multimers.
• Genetic testing identifies mutation in the VWF gene.

Confirmatory Tests

• Mixing studies (patient platelets + normal plasma).
• VWF multimer analysis and genetic testing.

Bernard-Soulier Syndrome (BSS)

Cause

• Mutation resulting in deficiency of platelet GPIb.

Presentation

• Moderate to severe mucocutaneous bleeding.
• Thrombocytopenia and giant platelets.

Distinguishing Laboratory Features

• Reduced RIPA, as in moderate-severe VWD.
• Normal VWF:Ag and activity.
• Abnormal platelet morphology on blood smear.

Inheritance

• Autosomal recessive.

Key Differentiator

• Normal VWF testing results.

Glanzmann’s Thrombasthenia

Cause

• Deficiency of platelet GPIIb/IIIa receptors.

Presentation

• Severe mucocutaneous bleeding from early life.

Lab Testing

• Normal platelet count and morphology.
• Defective platelet aggregation to all agonists except ristocetin.
• Normal VWF assays and multimer distribution.

Other Inherited Platelet Function Disorders

• Includes rare autosomal dominant or recessive conditions with variable severity.
• Can cause mucosal bleeding, easy bruising, and prolonged bleeding after injury or surgery.
• Diagnosis relies on:
  • Platelet aggregometry.
  • PFA-100 testing.
  • Family history and sometimes genetic panels.

Antiplatelet Drug Effect

Agents

• Aspirin, NSAIDs, clopidogrel.

Effects

• Inhibit platelet function and exacerbate bleeding in patients with underlying VWD.

Distinction

• Bleeding symptoms coincide with medication use.
• Discontinuation of medication improves symptoms.
  VWF levels and structure are normal.

Acquired von Willebrand Syndrome (AVWS)

Cause

• Secondary to other conditions:
  • Lymphoproliferative disorders (e.g. MGUS, multiple myeloma).
  • Cardiovascular abnormalities (e.g. aortic stenosis, LVAD).
  • Autoimmune diseases.

Presentation

• Similar to inherited VWD, may develop in adulthood.

Lab Testing

• Decreased VWF:Ag and/or VWF:RCo.
• Multimer analysis may show absence of high-molecular-weight multimers.

Distinguishing Features

• No family history.
• Late-onset symptoms.
• VWF levels may normalise with treatment of underlying disorder.

 General Principles

• Treatment goals:
  • Control active bleeding.
  • Prevent bleeding during invasive procedures or surgery.
  • Minimise long-term bleeding complications (e.g. anaemia).
• Management is tailored to VWD subtype, severity, and clinical setting.
• Multidisciplinary care, including a haematologist, is essential for complex cases, pregnancy, and major surgery.

Type 1 VWD

Desmopressin (DDAVP)

• First-line therapy for most patients unless contraindicated (e.g. cardiovascular disease, age <2 years, risk of hyponatraemia).
• Promotes release of endogenous VWF and factor VIII.
• Typical response: 3–5 fold rise in levels within 30–60 minutes.
• Monitor for accelerated VWF clearance with a level at 4–6 hours post-administration.

Antifibrinolytics (e.g. tranexamic acid)

• Useful for mucosal procedures or as adjunct therapy.

VWF-containing concentrates

• Reserved for:
  • Non-responders to DDAVP.
  • Patients undergoing major surgery.
  • Those with bleeding risk where prolonged VWF elevation is needed.

Pregnancy

• VWF levels typically rise in the third trimester.
• If VWF activity remains low, DDAVP or VWF concentrate may be required at delivery.
• Avoid DDAVP in pre-eclampsia.

Type 2 VWD

Type 2A and 2M

• Some may respond to DDAVP; preoperative testing is required.
• Antifibrinolytics are useful for mucosal bleeding.
• VWF concentrates preferred for surgery or major bleeds.

Type 2B

• DDAVP generally contraindicated; may worsen thrombocytopenia.
• Platelet transfusions may be required in refractory bleeding.
• VWF concentrates are mainstay of therapy.

Type 2N

• DDAVP is ineffective.
• VWF-containing concentrates are required for raising factor VIII levels.

Pregnancy in Type 2

• Functional VWF activity often does not normalise.
• VWF concentrates typically required at delivery.
• Type 2B: monitor for worsening thrombocytopenia.

Type 3 VWD

• Treatment of choice: VWF-containing concentrates.
  • Should be virally inactivated; cryoprecipitate is avoided.
  • May require additional factor VIII loading dose when using VWF alone.
• Antifibrinolytics are helpful for mucosal bleeding.
• Platelet transfusion: Reserved for patients unresponsive to VWF concentrates.

Surgical management

• Start treatment ≥8 hours before elective surgery.
• Maintain adequate VWF and FVIII levels perioperatively

Pregnancy

• No physiological rise in VWF.
• Replacement therapy mandatory for delivery or procedures.
• Consider prophylactic treatment postpartum due to delayed bleeding risk.

Management of Menorrhagia in VWD

Hormonal therapy

• Combined oestrogen-progestogen or progestogen-only contraception.
• Levonorgestrel-releasing intrauterine system (IUD) may reduce blood loss; limited data in VWD.

Antifibrinolytics

• Tranexamic acid or aminocaproic acid effective; doses may be titrated for tolerance.

Desmopressin

• Alternative if hormonal and antifibrinolytic therapies fail or are contraindicated.
• Evidence for its efficacy in VWD is limited and variable.

VWF concentrates

• Used in refractory cases or with significant chronic blood loss.
• Considered when iron deficiency or anaemia occurs despite other measures.

Prophylaxis and Long-Term Management

Indications for prophylaxis

• Recurrent mucosal or joint bleeding.
• Menorrhagia refractory to medical therapy.
• High-risk procedures.

VWF concentrate

• Prophylactic use may be considered in type 3 and severe type 2 cases.
• Home infusion training may be offered.
• Monitor VWF and FVIII levels to avoid thrombosis.

Inhibitor development

• Rare, but can occur in type 3 VWD after repeated VWF administration.

Pregnancy and Peripartum Management

General principles

• Care should be delivered in specialist centres.
• Close monitoring during pregnancy and in the postpartum period.

Lab re-evaluation

•  Recommended in the third trimester.

Tranexamic acid

• Crosses placenta; use cautiously during pregnancy.
• No data for long-term safety, but short-term use postpartum is common.

Delivery planning

• VWF activity should be >0.50 IU/mL.
• Use DDAVP or VWF concentrate if levels remain subtherapeutic.

 General Outlook

• Most individuals with VWD have a mild and manageable bleeding disorder.
  • Clinically significant bleeding tends to occur in response to trauma, surgery, or invasive procedures.
  • Lifelong intermittent treatment (e.g. during procedures or for acute bleeds) is typical.
  • Avoidance of platelet-inhibiting medications (e.g. NSAIDs, aspirin) is recommended, as they can aggravate bleeding.

Prognosis by VWD Type

Type 1 VWD

• Generally mild disease course with favourable outcomes.
• Bleeding frequency and severity are variable, even within families.
• VWF levels may rise with age, and some individuals may no longer meet diagnostic thresholds over time.
  • However, studies indicate that bleeding symptoms often persist despite normalised levels.

Type 2 VWD

• Tends to have moderate to severe bleeding.
• Symptoms may worsen with age, especially gastrointestinal bleeding.
• VWF levels do not significantly rise with age, unlike type 1.
• Management often requires prophylactic or on-demand VWF replacement for bleeding or surgery.

Type 3 VWD

• Most severe form with marked bleeding tendency.
• Risk of life-threatening haemorrhage, especially without prompt treatment.
• Chronic complications may include:
  • Haemarthroses and joint damage, similar to haemophilia A, due to persistently low FVIII levels.
  • Iron deficiency anaemia from chronic mucosal or gastrointestinal bleeding.
• Prognosis depends on access to VWF-containing products and comprehensive care.

Ageing and Disease Course

Ageing effects

• In non-VWD populations, VWF and FVIII levels naturally increase with age.
• In mild type 1 VWD, levels may rise into the normal range.
  • However, this does not necessarily lead to resolution of bleeding symptoms.
• In type 2 VWD, ageing does not improve VWF levels, and bleeding risk may increase, especially from the gastrointestinal tract.

Delayed diagnosis 

• Common, especially in females.
• In some cases, diagnostic delays exceed 10–15 years, particularly for women with menorrhagia or postpartum haemorrhage.

Pregnancy-Related Prognosis

Pregnancy typically improves haemostasis in type 1 VWD

• VWF and FVIII levels rise significantly, often reaching normal by the third trimester.
• Treatment may not be needed at delivery if levels are adequate.

Types 2 and 3 VWD

• Do not experience a sufficient rise in VWF activity during pregnancy.
• Require prophylactic factor support during labour and delivery.
• All subtypes carry heightened risk for postpartum haemorrhage (PPH):
  • Particularly delayed PPH (5–15 days postpartum).
  • Risk persists even if VWF levels normalised during pregnancy.
• Collaborative management by haematologists and high-risk obstetricians is essential.

 Alloantibody Formation

Risk population

• Occurs in approximately 10–15% of patients with type 3 VWD, particularly those with large deletions in the VWF gene.

Clinical implications

• Development of inhibitory antibodies against exogenous VWF.
• May result in treatment resistance and severe allergic or anaphylactic reactions following VWF concentrate infusion.

Management strategies

• Requires specialist haematological oversight.
• Recombinant activated factor VII (rFVIIa) or continuous infusion of high-purity factor VIII may be used to manage bleeding in this context.

Pregnancy-Related Complications

Type-specific concerns

• Types 1 and 2: VWF levels typically increase during pregnancy, especially in the third trimester, reducing bleeding risk during labour.
• Type 2B:
  • Pregnancy may exacerbate thrombocytopenia.
  • Increased risk of peripartum haemorrhage, requiring individualised delivery planning.
• Type 3: VWF levels do not rise in pregnancy, and replacement therapy is essential during labour and delivery.

Perinatal haemorrhage

• All VWD subtypes are associated with an increased risk of postpartum haemorrhage (PPH), particularly delayed PPH (occurring 5–15 days post-delivery).

Recommended approach

• Multidisciplinary antenatal care, including haematologists and obstetricians with experience in bleeding disorders.

Musculoskeletal Complications

Haemarthrosis

• Primarily seen in type 3 VWD due to low FVIII levels.
• Recurrent joint bleeding can lead to:
  • Synovial inflammation,
  • Cartilage damage,
  • Chronic arthropathy.

Consequences

• Reduced mobility and joint deformity.
• Similar to long-term joint complications observed in severe haemophilia A.

Soft Tissue and Internal Bleeding

Haematomas

• Deep muscle bleeds may cause:
  • Pain, swelling,
  • Neurovascular compromise if in confined compartments.

Gastrointestinal bleeding

• More common in types 2 and 3, particularly in older adults.
• Often associated with angiodysplasia, which may be difficult to treat and require ongoing VWF replacement or hormonal therapy.

Management challenges

• May require repeated infusions of VWF concentrate, use of antifibrinolytics, and endoscopic intervention.

Iron Deficiency and Anaemia

• Chronic bleeding (e.g. menorrhagia, GI losses) may lead to:
  • Iron deficiency, even in the absence of anaemia.
  • Microcytic anaemia, contributing to fatigue and decreased quality of life.
• Iron stores should be regularly assessed and replaced as needed.

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