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)

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

• 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.
    
    
    

• 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).
      
      
      

• 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)

• 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
    
    

• 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

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

• Essential thrombocythaemia
• Polycythaemia vera
  
  

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

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

• COVID-19
• Other viral pathogens
  
  

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

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

• 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)

• VWF is produced in endothelial cells and megakaryocytes.

• 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.
  
  

• 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.
  
  

• 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

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

• 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

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

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

Subtype-Specific Pathophysiology

• 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

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

• 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.
  
  

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

• 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.
  
  

• 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

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

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

• Hypersensitivity in type 2B.
  
  

• 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

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

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

• 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

• 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.
    
    

• 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.
  
  
  

• 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.
  
  

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

• All VWD types are inherited in an autosomal pattern.
  
  

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

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

• 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

• 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).
  
  

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

• 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

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

• 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

• 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.
  
  

• 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.
  
  

• 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

• 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.
  
  

• Particularly relevant in type 3 VWD.
  
  

• 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

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

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

• May present with pallor, dizziness, exertional dyspnoea.
  
  

• 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

• 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 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.
  
  

• 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.
  
  

• 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.
    
    
    

• 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

• 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.
  
  

• 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

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

• 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

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

• 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.
    
    

• 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

• Reflects extrinsic pathway.
• Normal in VWD.
  
  

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

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

• 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.
  
  

• 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

• 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.
    
    

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

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

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

• May be elevated in patients with increased VWF clearance.
  
  

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

Additional Investigations for Atypical Cases or Comorbidities

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

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

• 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

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

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

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

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

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

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

• 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

• 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.
  
  

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

• 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.
    
    
    

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

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

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

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

• 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.
  
  

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

Bernard-Soulier Syndrome (BSS)

• Mutation resulting in deficiency of platelet GPIb.

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

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

• Autosomal recessive.
  
  

• Normal VWF testing results.
  
  

Glanzmann’s Thrombasthenia

• Deficiency of platelet GPIIb/IIIa receptors.
  
  

• Severe mucocutaneous bleeding from early life.
  
  

• 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

• Aspirin, NSAIDs, clopidogrel.
  
  

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

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

Acquired von Willebrand Syndrome (AVWS)

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

• Similar to inherited VWD, may develop in adulthood.
  
  

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

• 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

• 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.
  
  

• Useful for mucosal procedures or as adjunct therapy.
  
  

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

• 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

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

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

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

• 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.
  
  

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

• 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

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

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

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

• 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

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

• 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.
  
  

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

Pregnancy and Peripartum Management

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

•  recommended in the third trimester.
  
  

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

• 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

• 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.
    
    

• 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.
  
  

• 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

• 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.
  
  
  

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

Pregnancy-Related Prognosis

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

• 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

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

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

• 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

• 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.
  
  

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

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

Musculoskeletal Complications

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

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

Soft Tissue and Internal Bleeding

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

• 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.

• 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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