20  von Willebrand Disease

Key Points
  • Most common inherited bleeding disorder (~1% prevalence; 0.1% symptomatic)
  • Presents w/ mucocutaneous bleeding: epistaxis, menorrhagia, surgical bleeding
  • Type 1: partial quantitative deficiency (75%); Type 2: qualitative variants; Type 3: complete deficiency (AR)
  • VWF stabilizes FVIII; ↓ levels cause ↓ FVIII activity & bleeding
  • VWF ↑ w/ stress/illness/estrogen—repeat testing essential before diagnosis
  • Tx: desmopressin (types 1, some 2A); VWF concentrate (type 3, severe); antifibrinolytics for mucosal bleeding

20.1 Pathophysiology

VWF structure & function - Large multimeric glycoprotein (500–20,000 kDa) from megakaryocytes & endothelial cells - Stored Weibel-Palade bodies; HMW multimers most active - ADAMTS13 cleaves at A2 domain - Binds: platelet GPIb, subendothelial collagen, carries/stabilizes FVIII

Epidemiology - ~1% prevalence; only 0.1% symptomatic - Type 1 (partial quant ↓): 75% of cases, AD - Type 2 (qualitative): 2A, 2B, 2M, 2N - Type 3 (complete ↓): AR - VWF on chr 12; pseudogene on chr 22 complicates testing

20.2 Bleeding Phenotype

Clinical features - Mucocutaneous bleeding: epistaxis, menorrhagia, post-procedural, traumatic - Type 1: also secondary hemostasis symptoms (↓ FVIII) - Prolonged aPTT if FVIII <50 - Bleeding assessment tool (ISTH score) helps differentiate

20.3 VWD Type 1

Definition & diagnosis - Partial quantitative VWF ↓ w/ abnormal bleeding symptoms - Proportional ↓ in VWF:Ag, VWF:RCo, & FVIII - Criteria: VWF:Ag <30, VWF:RCo <30, VWF:Ag/RCo ratio ≥0.7 - FVIII activity concordant w/ VWF

Labs & pitfalls - Initial: VWF:Ag, VWF:RCo, FVIII, platelets - VWF ↑ w/ stress, illness, inflammation, estrogen, O blood type (25% lower than AB) - Repeat testing required; normal baseline doesn’t exclude disease - Test ≥2 occasions, measure VWF propeptide (VWFpp) for clearance assessment - Type 1C: ↑ clearance variant—good initial desmopressin response, but ↓ 2–4 hrs (recurrent bleeding risk)

Table 20-1. Classification & diagnosis of VWD

Classification & diagnosis of VWD
Disease subtype Description VWF:Ag, IU/dL VWF:RCo or VWF:GPIbM, IU/dL VWF:Act/VWF:Ag FVIII level Multimer pattern
Type 1 Partial quantitative deficiency of oVWF <30 responsive ↓ to <30 in patients w/ abnormal bleeding ↓ Or normal ≤0.7 or normal ↓ Or normal Normal
Type 2A Defect in multimer-ization or ↓ increased cleavage of multimers by ADAMTS13 ↓ ↓ Or normal <0.70 ↓ Or normal Loss of HMM & IMM; loss of high-molecular-weight multimers
Type 2B Increased affinity for platelet GPIb ↓ ↓ Or normal <0.70 ↓ Or normal Loss of high-molecular-weight multimers
Type 2M Decreased VWF-mediated platelet adhesion ↓ ↓ Or normal 2.70 ↓↓ Normal
Type 2N Markedly decreased factor VIII binding ↓ Or normal ↓ Or normal 2.70 ↓↓ Normal
Type 3 Virtually complete deficiency of oVWF ↓↓↓ ↓↓↓ Not applicable ↓↓↓ <10 IU/dL Absent

↓ indicates visible decreased, ↓↓ markedly decreased, & ↓↓↓ severely decreased.

20.4 VWD Type 2

Qualitative VWF defects - 2A: ↓ HMW multimers (multimerization defect or ↑ ADAMTS13 cleavage) - VWF:Ag/RCo <0.7, loss of high MW multimers - 2B: ↑ platelet affinity → thrombocytopenia (gain of function) - DDAVP contraindicated (worsens thrombocytopenia) - 2M: ↓ GPIb binding (loss of function) - Normal multimers, ↓ RCo disproportionate to Ag - 2N: ↓ FVIII binding (FVIII binding site variant) - Normal or ↓ VWF:Ag, disproportionately ↓ FVIII

20.5 VWD Type 3

Complete deficiency (AR) - Virtually absent VWF & FVIII - Severe mucosal, muscle, joint hemorrhages - Requires VWF replacement therapy

20.6 Genetic Testing

Indications & limitations - VWF on chr 12: large, highly polymorphic; pseudogene on chr 22 complicates sequencing - Type 1: 80% population carry variants; genetic testing for clarification in type 2 cases - Recommended at specialized coagulation labs for type 2 VWD differentiation

20.7 Acquired vWD

Causes - ↓ VWF production: hypothyroidism, Hashimoto - Autoantibodies: SLE - ↑ proteolysis: ciprofloxacin, congenital heart disease - Absorption: tumor cells, lymphoproliferative disorders - Usually older age, no family history

20.8 Treatment

Goals & general principles - Replace/increase VWF to achieve hemostasis - Avoid antiplatelet drugs (aspirin, NSAIDs) - Prophylaxis for severe/recurrent bleeding

Perioperative management - Minor: maintain FVIII & VWF ≥50 IU/dL for ≥3 days - Major/Type 3: maintain ≥250 IU/dL for 5 hrs post-op

Pregnancy & postpartum - Type 1 VWD normalizes VWF/FVIII during pregnancy (type 3 does not) - Assess preconception levels (pregnancy levels deceptively high) - Post-delivery: tranexamic acid 10–14 days - Type 3: VWF replacement prior to delivery; target ≥250 post-partum

DDAVP - Mild-to-moderate type 1 & some 2A bleeding - Mechanism: releases stored VWF:FVIII from Weibel-Palade bodies - Dosing: 0.3 µg/kg IV (standard) or 300 µg intranasal; <50 kg child: 150 µg intranasal - Caution: Type 1C & 2B (thrombocytopenia risk) - Test response: measure VWF at 1 & 4 hrs post-injection (rule out tachyphylaxis)

VWF replacement products - Plasma-derived: Humate-P, Wilate (on-demand & prophylaxis); Alphanate (perioperative) - Recombinant: Vonvendi (rVWF monotherapy) - Indications: type 3, severe bleeding, DDAVP failure/intolerance, 2B - Prophylaxis: severe type 3 (Wilate approved) - If FVIII <40%, add FVIII infusion concomitantly

Antifibrinolytics & hormonal therapy - Tranexamic acid / aminocaproic acid: lysine analogues inhibit fibrinolysis - Routes: IV, oral, topical - Indications: mucosal bleeding (oral, GI, uterine), perioperative - Contraindication: hematuria (DIC/UO risk) - Well tolerated; caution if thrombosis h/x - Hormonal: combined OCP or levonorgestrel IUD for menorrhagia - Iron: repletion if ferritin <50 (w/ or w/o symptoms)

Clinical Pearls
  • VWF ↑ w/ stress, illness, inflammation, estrogen; type AB 25% higher than type O
    • Repeat testing essential, especially borderline values
  • Type 1 vs. 2A: use VWF:Ag/RCo ratio (<0.7 → type 2) & multimer pattern
  • Test DDAVP response at 1 & 4 hrs; tachyphylaxis/1C possible
  • DDAVP contraindicated in type 2B (thrombocytopenia)