What is the management approach for von Willebrand disease (VWD)?

Von Willebrand Disease: Overview and Management

What is Von Willebrand Disease?

Von Willebrand disease (VWD) is the most common inherited bleeding disorder, affecting up to 1% of the population with equal distribution between males and females, caused by deficiency or dysfunction of von Willebrand factor (VWF)—a plasma protein essential for platelet adhesion at injury sites and for stabilizing factor VIII in circulation. 1

Pathophysiology

• VWF serves two critical functions: it mediates platelet adhesion and aggregation at sites of vascular injury, and it carries and protects factor VIII from rapid degradation in the bloodstream 1, 2
• Defects in VWF lead to impaired primary hemostasis, resulting in characteristic mucocutaneous bleeding patterns 2

Clinical Classification

Type 1 VWD (75% of cases)

• Partial quantitative deficiency of VWF with proportionally reduced VWF antigen and activity 1
• Mild to moderate bleeding symptoms 1

Type 2 VWD (20-25% of cases)

• Qualitative defects in VWF function with four distinct subtypes 1:
  • Type 2A: Decreased VWF-dependent platelet adhesion with absence of high-molecular-weight multimers 3
  • Type 2B: Increased affinity for platelet glycoprotein Ib, causing thrombocytopenia 1
  • Type 2M: Decreased VWF-dependent platelet adhesion without multimer abnormalities 3
  • Type 2N: Decreased binding affinity for factor VIII 1

Type 3 VWD (rare, ~1 per million)

• Virtually complete absence of VWF with severe, life-threatening bleeding 1
• Presents with both mucocutaneous and joint/muscle bleeding similar to hemophilia 2

Acquired von Willebrand Syndrome (AVWS)

• Less common than hereditary VWD, associated with various medical conditions including lymphoproliferative disorders, cardiovascular disease, and autoimmune conditions 1
• Should be suspected when abnormal VWF results occur without personal or family bleeding history 4

Clinical Manifestations

Common Bleeding Symptoms

• Epistaxis (nosebleeds) occurring spontaneously or with minor trauma 1, 2
• Easy bruising disproportionate to trauma 1, 2
• Prolonged bleeding from minor wounds or dental procedures 2, 5
• Menorrhagia (heavy menstrual bleeding) in women, often the presenting symptom 1, 2
• Postpartum hemorrhage requiring intervention 1, 2
• Gingival bleeding with tooth brushing 1

Less Common Manifestations

• Gastrointestinal bleeding 1, 2
• Hematomas or hemarthroses (more common in Type 3) 1, 2
• Excessive bleeding with surgery or invasive procedures 1, 5

Diagnostic Approach

Clinical Evaluation

A structured bleeding history using validated screening tools is essential, starting with three initial questions, and if positive, proceeding to nine additional VWD-specific questions. 6, 4

• Physical examination should identify: ecchymoses, hematomas, petechiae, signs of liver disease, splenomegaly, joint/skin laxity suggesting connective tissue disorders, and telangiectasias 6
• Gynecologic examination in females to exclude anatomic causes of menorrhagia 6

Initial Laboratory Testing

The three core VWD assays must be ordered together: VWF antigen (VWF:Ag), VWF ristocetin cofactor activity (VWF:RCo), and factor VIII coagulant activity (FVIII). 6, 4

• VWF:Ag measures the quantity of VWF protein in plasma 6
• VWF:RCo assesses functional ability of VWF to bind platelets 6
• FVIII evaluates factor VIII levels carried by VWF 6
• All three tests are necessary to establish diagnosis, type, and severity 6, 4

Supporting Laboratory Tests

• Complete blood count with platelets and peripheral smear to evaluate for thrombocytopenia (especially Type 2B) 7, 4
• PT/INR and aPTT to assess coagulation pathways, though these will miss most VWD cases 7, 4
• ABO blood group testing because type O patients have 25-30% lower VWF levels than type AB 7, 6
• Fibrinogen level to exclude fibrinogen disorders 7

Specialized Testing (When Initial Tests Abnormal)

• VWF multimer analysis when VWF:RCo to VWF:Ag ratio is below 0.5-0.7 7, 6, 4
• Collagen binding assay (VWF:CB) for further characterization 6
• Ristocetin-induced platelet aggregation (RIPA) to distinguish Type 2B from platelet-type VWD 6, 5

Critical Testing Considerations

Patient stress, exercise, inflammation, pregnancy, or estrogen therapy can falsely elevate VWF levels, while blood group O results in 25% lower baseline VWF. 1, 6

• Blood samples must be transported at room temperature to prevent cryoprecipitation 1
• Plasma should be separated promptly and centrifuged thoroughly to remove platelets 1
• Samples stored >2 hours must be frozen at ≤-40°C until assayed 1
• VWF assays have high coefficients of variation (10-30%), particularly VWF:RCo 1

Common Diagnostic Pitfalls

• Never rely on PT/aPTT alone—these tests miss VWD entirely 4
• Bleeding time and PFA-100 are not recommended for routine screening due to poor sensitivity and specificity 6, 4
• Do not order VWF multimer analysis as initial screening—reserve for reflex testing when initial results are abnormal 6
• Single test results can be misleading—repeat testing may be necessary if clinical suspicion remains high 1

Management Strategies

Desmopressin (DDAVP)

Desmopressin is the treatment of choice for mild to moderate Type 1 VWD and some Type 2 variants (excluding Type 2B and Type 3), administered 30 minutes prior to procedures at 0.3 mcg/kg IV to increase endogenous VWF release. 8, 2, 3

• FDA-approved for Type 1 VWD with factor VIII levels >5% 8
• Effective for maintaining hemostasis during surgical procedures and stopping spontaneous bleeding episodes 8
• Not indicated for Type 2B VWD (can worsen thrombocytopenia), Type 3 VWD, or when factor VIII levels are ≤5% 8
• Monitor VWF levels and bleeding time during administration to ensure adequate response 8

VWF Replacement Therapy

For patients who do not respond to desmopressin, have severe Type 1, Type 2B, Type 2N, Type 3 VWD, or require major surgery, plasma-derived or recombinant VWF concentrates rich in VWF are indicated. 2, 5, 3

• Factor VIII concentrates rich in VWF are the standard replacement products 5, 3
• Recombinant VWF products are now available as alternatives to plasma-derived concentrates 2

Adjunctive Therapies

Tranexamic acid (antifibrinolytic therapy) is highly effective for mucosal bleeding, particularly menorrhagia and dental procedures. 2, 3

• Topical hemostatic agents (fibrin glue, thrombin) for localized bleeding 2
• Hormonal therapies (combined oral contraceptives, levonorgestrel IUD) for menorrhagia management 2

Procedure-Specific Management

For patients undergoing surgery or invasive procedures, treatment should be initiated 30 minutes prior to the procedure, with monitoring of VWF and factor VIII levels to ensure adequate hemostasis. 8, 5

• Dental extractions: desmopressin plus tranexamic acid mouthwash 5, 3
• Major surgery: VWF concentrate replacement with target factor VIII levels 80-100 IU/dL 5
• Minor surgery: desmopressin trial if previously responsive 5, 3

Management Challenges in Different Settings

In developing countries where factor concentrates and desmopressin may be unavailable or unaffordable, alternative strategies including fresh frozen plasma, cryoprecipitate, and aggressive use of tranexamic acid are necessary. 3

Special Populations

Low VWF (30-50 IU/dL)

Patients with VWF levels of 30-50 IU/dL represent a diagnostic challenge, as many have significant bleeding (especially menorrhagia and postpartum hemorrhage) despite not meeting strict Type 1 VWD criteria. 9

• Most low VWF patients lack detectable VWF gene mutations, suggesting complex genetic causes 9
• Tranexamic acid and desmopressin are efficacious for hemostatic treatment prior to procedures 9
• Enhanced VWF clearance occurs in ~20% of low VWF cases 9

Pregnancy and Postpartum

VWF levels typically rise during pregnancy but drop rapidly postpartum, creating high bleeding risk in the first 24-48 hours after delivery. 2

• Monitor VWF levels in third trimester to guide delivery planning 2
• Postpartum hemorrhage prophylaxis may require VWF concentrate or desmopressin 2

Key Clinical Pearls

• VWD affects 1% of the population but remains underdiagnosed due to variable bleeding symptoms and complex testing 1, 2
• Type 1 VWD predominates in developed countries (40-90% of cases), while Type 3 predominates in developing countries due to consanguinity 3
• Consultation with a hemostasis specialist is recommended for abnormal initial test results, treatment planning for major procedures, and management of complex cases 6, 5
• Close collaboration between surgeons and hematologists enables safe performance of invasive procedures without excessive bleeding risk 5