Von Willebrand Disease

Introduction And Pathophysiology

Most common inherited bleeding disorder.
Prevalence: Biochemical evidence in 1-2% of population; symptomatic in 0.1%.
Caused by quantitative deficiency or qualitative dysfunction of von Willebrand factor (vWF).
Dual physiologic functions of vWF:
- Tethers platelets to injured subendothelium via collagen and platelet glycoprotein Ib (GPIb) receptors.
- Chaperone protein for Factor VIII (FVIII); protects FVIII from premature plasma protease degradation.
Synthesized in megakaryocytes and endothelial cells.
Stored intracellularly in endothelial Weibel-Palade bodies and platelet alpha-granules.
Circulates as large multimeric glycoprotein; high-molecular-weight (HMW) multimers dictate hemostatic efficacy.
Endothelial shear stress induces conformational uncoiling, facilitating platelet binding.

Predominantly mucocutaneous hemorrhage.
Common symptoms: Epistaxis, easy bruising, gingival bleeding, menorrhagia.
Prolonged bleeding post-trauma or surgery (adenotonsillectomy, dental extraction).
Severe forms (Type 3) manifest deep tissue, joint, and muscle hemorrhages mimicking severe hemophilia.
Gastrointestinal hemorrhage may occur, frequently complicated by intestinal angiodysplastic lesions.
Variable expressivity and incomplete penetrance observed across families.

Type	Genetic Transmission	Pathophysiology	Multimeric Structure	Platelet Count
Type 1	Autosomal Dominant	Partial quantitative deficiency. Comprises 60-80% cases.	Normal	Normal
Type 1C	Autosomal Dominant	Increased clearance of vWF. Shortened half-life.	Normal	Normal
Type 2A	Autosomal Dominant	Qualitative defect. Impaired multimer assembly or enhanced proteolysis (A2 domain).	Absent HMW multimers	Normal
Type 2B	Autosomal Dominant	Gain-of-function (A1 domain). Spontaneous GPIb binding. Rapid clearance.	Absent HMW multimers	Decreased (stress-induced)
Type 2M	Autosomal Dominant	Qualitative defect. Decreased platelet GPIb binding or collagen interaction.	Normal	Normal
Type 2N	Autosomal Recessive	Qualitative defect. Impaired FVIII binding. Rapid FVIII clearance. Mimics mild hemophilia A.	Normal	Normal
Type 3	Autosomal Recessive	Complete quantitative absence.	Absent	Normal
Platelet-Type (Pseudo)	Autosomal Dominant	Gain-of-function platelet GPIb receptor defect. Phenocopies Type 2B.	Absent HMW multimers	Decreased

Rare non-inherited reduction in vWF.
Mechanisms: Autoantibodies, adsorption onto malignant cells, or depletion via high vascular shear forces.
Associated conditions: Wilms tumor, congenital heart defects (high-flow lesions), hypothyroidism, systemic lupus erythematosus (SLE), myeloproliferative neoplasms.

Blood Group O: Associated with 25-30% lower baseline vWF levels.
Elevating Factors: Stress, systemic inflammation, vigorous exercise, menstrual cycle fluctuations, pregnancy, estrogen supplementation.
Depressing Factors: Valproic acid, hypothyroidism.
Dynamic nature necessitates repeated testing for definitive diagnosis.

Complete Blood Count: Usually normal. Mild thrombocytopenia specifically suggests Type 2B or Platelet-Type pseudo-vWD.
Activated Partial Thromboplastin Time (aPTT): Normal or mildly prolonged depending on concurrent FVIII degradation.
Prothrombin Time (PT): Normal.
Platelet Function Analyzer (PFA-100): Closure time prolonged (collagen/epinephrine or collagen/ADP); lacks absolute sensitivity.
Bleeding Time: Historically prolonged; currently obsolete due to poor reproducibility.

vWF Antigen (vWF:Ag): Quantifies total plasma vWF protein. Levels <30 IU/dL establish definitive diagnosis. Levels 30-50 IU/dL designated “low vWF”.
vWF Ristocetin Cofactor Activity (vWF:RCo): Assesses functional vWF-platelet interaction mediated by ristocetin.
vWF:GPIbM: Improved functional assay evaluating spontaneous GPIb binding without ristocetin requirement.
Factor VIII Activity (FVIII:C): Quantifies circulating FVIII. Markedly reduced in Type 2N and Type 3.
vWF Activity/Antigen Ratio (vWF:RCo / vWF:Ag): Ratio <0.7 indicates qualitative dysfunction, strongly suggesting Type 2A, 2B, or 2M.
vWF Multimer Analysis: Visualizes molecular weight distribution. Differentiates subtypes based on absence of HMW multimers.
Ristocetin-Induced Platelet Aggregation (RIPA): Utilizing low-dose ristocetin. Enhanced aggregation specifically identifies Type 2B and Platelet-Type pseudo-vWD.

Mechanism: Synthetic vasopressin analog. Induces endothelial cell Weibel-Palade body degranulation. Endogenous vWF and FVIII plasma levels increase twofold to fivefold.
Indications: First-line therapy for Type 1. Effective for mild bleeding or minor surgery.
Contraindications: Type 2B (exacerbates thrombocytopenia/agglutination), Type 3 (no endothelial stores), neonates <2 years (hyponatremic seizure risk).
Administration: Intravenous 0.3 $μ$ g/kg (max 20-30 $μ$ g/day) or highly concentrated intranasal spray (Stimate 1.5 mg/mL: 150 $μ$ g for <50 kg; 300 $μ$ g for >50 kg).
Limitations: Tachyphylaxis develops after 4-5 consecutive days. Therapeutic trial mandatory prior to major procedures to confirm individual responsiveness.
Adverse Effects: Facial flushing, mild fluid retention, hyponatremia. Restrict free water intake.

Products: Plasma-derived, virally-inactivated FVIII/vWF concentrates (e.g., Humate-P, Alphanate, Wilate) or recombinant vWF (Vonvendi).
Indications: Type 3 disease, severe Type 1, Type 1C (clearance defect), Type 2 variants, DDAVP non-responders, or major surgical interventions.
Dosing: 40-60 Ristocetin Cofactor Activity (RCo) units/kg. Adjusted based on baseline vWF level and target peak.
Monitoring: Track FVIII levels closely during repeated dosing. Sustained FVIII >150 IU/dL increases venous thromboembolism risk.

Antifibrinolytics: Epsilon-aminocaproic acid (50-100 mg/kg PO/IV q6h) or Tranexamic acid (1300 mg PO tid). Stabilizes mucosal clots. Essential for dental extractions, epistaxis, and oropharyngeal hemorrhage.
Hormonal Therapy: Oral contraceptives, depot medroxyprogesterone, or levonorgestrel intrauterine devices (Mirena). First-line management for severe menorrhagia.
Topical Hemostatics: Nasal cautery, petrolatum gauze packing, local pressure application.

Clinical Scenario	Primary Treatment	Adjunctive Interventions
Minor Mucosal Hemorrhage	Antifibrinolytics alone or DDAVP (if responsive)	Local pressure, hormonal therapy (menorrhagia)
Dental Extractions	DDAVP (Type 1) or vWF Concentrates (Types 2/3)	Systemic antifibrinolytics
Major Surgery / Trauma	vWF Concentrates (Target vWF >50-100%)	Avoid isolated DDAVP due to tachyphylaxis
Type 2B Bleeding	vWF Concentrates	Avoid DDAVP
Platelet-Type Pseudo-vWD	Platelet Transfusions	Low-dose vWF concentrates if necessary