Explain von Willebrand disease, including its types, clinical presentation, laboratory findings, and management.

Von Willebrand Disease Overview

Von Willebrand disease (VWD) is the most common inherited bleeding disorder, affecting up to 1% of the population equally across sexes, caused by deficiency or dysfunction of von Willebrand factor (VWF)—a multimeric plasma glycoprotein essential for platelet adhesion at injury sites and for carrying/stabilizing factor VIII in circulation. 1

Pathophysiology and Mechanism of Bleeding

VWF serves two critical hemostatic functions that explain the bleeding pattern in VWD: 2

• Primary hemostasis defect: VWF mediates platelet adhesion and aggregation at sites of vascular injury under high shear stress conditions, and when deficient or defective, prevents formation of the initial platelet plug, resulting in mucosal bleeding and easy bruising 2, 3

• Secondary hemostasis defect: VWF acts as a carrier protein for factor VIII, protecting it from premature clearance and concentrating it at damaged endothelium; reduced VWF leads to secondary factor VIII deficiency, contributing to impaired coagulation 2, 4

Classification and Types

VWD is classified into three primary categories based on whether the defect is quantitative or qualitative: 1, 4

Type 1 VWD (Quantitative - Partial Deficiency)

• Accounts for approximately 75% of symptomatic cases 1
• Partial quantitative deficiency with VWF levels typically <50 IU/dL 5
• Mildest bleeding symptoms, often manageable with desmopressin 1

Type 2 VWD (Qualitative Defects)

Type 2 encompasses four distinct subtypes with different functional abnormalities: 1, 4

• Type 2A: Decreased platelet adhesion due to selective deficiency of high-molecular-weight VWF multimers 4
• Type 2B: Increased affinity for platelet glycoprotein Ib, causing inappropriate platelet binding 4
• Type 2M: Markedly defective platelet adhesion despite relatively normal multimer size distribution 4
• Type 2N: Markedly decreased affinity for factor VIII binding 4

Type 3 VWD (Quantitative - Complete Deficiency)

• Virtually complete quantitative deficiency with undetectable VWF levels 1, 5
• Rare, affecting only approximately 1 in 1,000 persons 1
• Severe, life-threatening bleeding due to profound deficiency of both VWF functions 2

Clinical Presentation

Bleeding manifestations correlate directly with VWD type and severity: 1, 6

Common Mucocutaneous Bleeding Symptoms

• Easy bruising and ecchymoses 1, 6
• Recurrent epistaxis (nosebleeds) 1, 6
• Gingival bleeding 1
• Heavy menstrual bleeding (menorrhagia) in women 1
• Gastrointestinal bleeding 1, 6
• Prolonged bleeding from small wounds 1

Procedure-Related Bleeding

• Bleeding following surgery or invasive procedures 1, 6
• Bleeding with dental extractions 1
• Postpartum hemorrhage 1
• Bleeding following traumatic injury 1

Severe Manifestations (Primarily Type 3)

• Hematomas and hemarthroses 1
• Central nervous system bleeding (rare but serious) 1, 6

Clinical Evaluation Algorithm

For asymptomatic persons undergoing surgery or invasive procedures, use these three screening questions: 1

1. Have you had prolonged bleeding from trivial wounds lasting >15 minutes or recurring spontaneously during the 7 days after the wound?
2. Have you experienced heavy, prolonged, or recurrent bleeding after surgical procedures such as tonsillectomy?
3. Have you ever had bruising with minimal or no apparent trauma, especially if you could feel a lump under the bruise? 1

For persons answering positively to screening questions or presenting with bleeding concerns, evaluate using nine detailed questions covering: 1

• Severity and frequency of epistaxis
• Cutaneous bleeding and bruising patterns
• Bleeding from minor wounds
• Oral cavity bleeding
• Gastrointestinal bleeding without obvious lesions
• Menorrhagia requiring medical attention
• Prolonged bleeding after dental extractions
• Surgical bleeding requiring intervention
• Family history of bleeding symptoms 1

Physical examination should specifically assess for: 6

• Ecchymoses and hematomas
• Petechiae
• Telangiectasia
• Joint or skin laxity 6

Laboratory Evaluation

Initial screening panel should include: 6, 7

• Complete blood count with platelet count
• Prothrombin time (PT)
• Activated partial thromboplastin time (aPTT)

However, PT and aPTT alone are insufficient to exclude VWD and may be normal in many cases. 6

Specific VWD Testing

When VWD is suspected, order these tests simultaneously: 6, 3, 7

• VWF antigen (VWF:Ag): Measures quantitative VWF protein level 3, 7
• VWF ristocetin cofactor activity (VWF:RCo) or VWF:GPIb binding assay: Measures platelet-dependent VWF activity 3, 7
• Factor VIII activity (FVIII:C): Assesses secondary factor VIII deficiency 3, 7

Additional specialized testing for subtyping: 3, 7

• VWF collagen binding (VWF:CB): Evaluates collagen binding function 7, 8
• VWF multimer analysis: Essential for distinguishing Type 2 variants, particularly 2A from 2B 3, 8
• Ristocetin-induced platelet agglutination (RIPA): Specifically for Type 2B diagnosis 3
• VWF:FVIII binding assay: For Type 2N diagnosis 4

Interpretation Patterns

A VWF activity-to-antigen ratio <0.5-0.7 indicates a qualitative defect (Type 2) and mandates specialized testing including multimer analysis. 6

Typical laboratory patterns by type: 5, 7

• Type 1: Proportional decreases in VWF:Ag, VWF activity, and factor VIII
• Type 2A: Disproportionately low VWF activity relative to antigen, absent high-molecular-weight multimers
• Type 2B: Similar to 2A but with increased RIPA sensitivity
• Type 2M: Low VWF activity with normal multimer distribution
• Type 2N: Isolated low factor VIII with normal VWF:Ag and activity
• Type 3: Undetectable VWF:Ag and activity, very low factor VIII

Acquired von Willebrand Syndrome (AVWS)

AVWS should be considered in adults presenting with new-onset mucocutaneous bleeding without personal or family bleeding history, especially when associated with: 6

• Lymphoproliferative disorders 6
• Monoclonal gammopathies 6
• Autoimmune diseases 6
• Cardiovascular conditions 6
• Extracorporeal membrane oxygenation (ECMO) support 6

Laboratory findings in AVWS mirror hereditary VWD (low VWF antigen, low VWF activity, reduced factor VIII), but the absence of personal and family bleeding history helps differentiate AVWS from hereditary VWD. 1, 6

In ECMO patients, AVWS develops within hours of support initiation, persists throughout ECMO, but resolves rapidly after weaning. 6

Management Principles

Desmopressin (DDAVP)

Desmopressin is the treatment of choice for mild Type 1 VWD and some Type 2A patients: 6, 5

• Mechanism: Stimulates release of stored VWF from endothelial cells, increasing circulating VWF and factor VIII levels 3-6 fold within 30-90 minutes 6
• Standard IV dosing: 0.3 μg/kg (maximum 28 μg) 6
• Repeat dosing: May be given at 12-24 hour intervals, but tachyphylaxis occurs after 3-5 doses due to endothelial VWF store depletion 6

VWF/Factor VIII Concentrates

For patients with severe Type 1, Type 2B, Type 2N, Type 3, or those unresponsive to desmopressin, use factor VIII concentrates rich in VWF. 5

Surgical and Procedural Management

For neuraxial anesthesia and surgery, VWF activity levels must be maintained at ≥50 IU/dL throughout the procedure and postoperative period. 6

This can be achieved through: 6

• Desmopressin
• VWF/FVIII concentrates
• Cryoprecipitate
• Combined with tranexamic acid as appropriate 6

AVWS-Specific Management

AVWS requires a multidisciplinary approach including: 6

• Minimizing anticoagulation
• Blood product replacement
• Desmopressin or VWF-containing concentrates for refractory bleeding
• Drugs that prevent VWF proteolysis 6

Treatment of the underlying disorder may resolve the acquired VWF deficiency. 6

Critical Management Pitfalls

Avoid non-resorbable nasal packing in VWD patients with epistaxis. 6

Do not overlook underlying conditions (lymphoproliferative, autoimmune, cardiovascular disorders) when evaluating unexplained mucocutaneous bleeding in adults without prior bleeding history. 6

Do not rely solely on PT/aPTT to exclude VWD—specific VWF testing is mandatory when clinical suspicion exists. 6