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Von Willebrand Disease (vWD) — NEET PG Pathology Master Summary

Source refs: Robbins & Kumar Basic Pathology, p. 430 | Goldman-Cecil Medicine | Henry's Clinical Diagnosis & Management by Laboratory Methods

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1. THE BASICS (One-liner anchors)

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2. VWF — STRUCTURE & DUAL FUNCTION (The Core Mechanism)

• Endothelial cells → stored in Weibel-Palade bodies (main source)
• Megakaryocytes → stored in α-granules of platelets (10–20% of total)

Role 1 — Platelet Adhesion (Primary Hemostasis)

Vascular injury → Subendothelial collagen exposed
       ↓
vWF (A3 domain) binds collagen types I & III
vWF (A1 domain) binds collagen types IV & VI
       ↓
vWF bridge: Collagen ←→ vWF ←→ Platelet GpIb receptor
       ↓
Platelet adhesion → activation → GpIIb/IIIa exposed
       ↓
Fibrinogen bridges GpIIb/IIIa → platelet aggregation

High-molecular-weight (HMW) multimers are the most functionally active — they bind collagen and platelets with highest affinity, especially under high-shear conditions.

Role 2 — Carrier/Chaperone for Factor VIII (Secondary Hemostasis)

vWF + Factor VIII → noncovalent complex in plasma
       ↓
Protects Factor VIII from premature proteolytic degradation & clearance
       ↓
On platelet activation: Factor VIII dissociates from vWF
       ↓
Factor VIII + activated Factor IX → activates Factor X (intrinsic pathway)

ADAMTS13 — The Regulator

• A specific metalloprotease (disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13)
• Cleaves ultra-large vWF multimers → keeps multimer size in check
• ADAMTS13 deficiency → ultra-large multimers persist → spontaneous platelet aggregation → TTP (contrast with vWD!)

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3. CLASSIFICATION OF vWD — The Master Table

Mnemonic for Type 2: 2A = Absent HMW (not synthesized); 2B = Bad HMW (hyperfunctional, consumed); 2M = Malformed binding site; 2N = No FVIII binding

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4. CLINICAL FEATURES

• Epistaxis (most common)
• Gingival bleeding
• Menorrhagia (often the presenting symptom in females)
• Prolonged bleeding from minor cuts/wounds
• Easy bruising
• GI bleeding
• Post-surgical / dental extraction bleeding
• Type 3 / severe vWD only: hemarthrosis, deep muscle hematomas (due to ↓↓ FVIII)

Key contrast with hemophilia: vWD → mucosal/surface bleeding | Hemophilia → deep tissue bleeding

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5. LABORATORY DIAGNOSIS

Screening Tests

Specific Diagnostic Tests

ABO Blood Group Effect (Exam Trap!)

• Blood group O individuals have ~25% lower vWF levels than non-O
• Can push borderline cases into "abnormal" range
• Treatment decisions based on vWF level, NOT modified for ABO status
• vWF level 30–50 IU/dL → labeled "low vWF" rather than definitive Type 1 vWD

Diagnostic Criteria Summary

• Normal range: vWF 50–150 IU/dL
• vWF:RCo/vWF:Ag ratio ≥0.6 = normal function
• <0.6 = functional deficiency (suggests HMW multimer loss)

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6. RISTOCETIN — The Exam Favorite

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7. PATHOGENESIS MECHANISMS — TYPE BY TYPE

Type 1

Quantitative ↓ in vWF production (all multimers reduced)
→ Less vWF available to bridge platelet-collagen
→ Impaired primary hemostasis
→ Mild ↓ FVIII (clinical significance minimal)

Type 2A

Mutation → failure to synthesize HMW multimers
→ Only low-MW forms circulate
→ Poor platelet bridging (HMW most active)
→ Functional deficiency despite some vWF present

Type 2B

Gain-of-function mutation in A1 domain
→ HMW multimers bind GpIb SPONTANEOUSLY (even without injury)
→ HMW multimers consumed → absent from plasma
→ Spontaneous platelet clumping → mild thrombocytopenia
→ (Mimics TTP mechanism but different etiology)

Type 2N (Normandy variant)

Mutation in D'/D3 domain of vWF (FVIII binding site)
→ vWF cannot carry FVIII → FVIII degraded prematurely
→ ↓ FVIII levels
→ Mimics Hemophilia A clinically
→ BUT: X-linked family history absent; females also affected equally
→ RIPA normal (platelet binding intact)

Type 3

Homozygous/compound heterozygous mutation
→ Complete absence of vWF
→ No platelet adhesion → severe mucosal bleeding
→ No FVIII carrier → FVIII level <1% → hemophilia-like hemarthrosis
→ Both pathways compromised

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8. TREATMENT

DDAVP works via V2 receptors on endothelial cells → exocytosis of Weibel-Palade bodies → surge in vWF release

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9. KEY COMPARISONS FOR MCQs

vWD vs Hemophilia A

vWD vs Bernard-Soulier Syndrome (BSS)

vWD vs TTP (ADAMTS13 link)

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10. HIGH-YIELD NEET PG EXAM POINTS

1. Most common inherited bleeding disorder = vWD (not hemophilia)
2. Type 1 = most common vWD subtype (75%)
3. Type 3 = most severe (autosomal recessive, complete absence)
4. HMW multimers are most active — their loss → functional deficiency
5. DDAVP is contraindicated in Type 2B (worsens thrombocytopenia and bleeding)
6. Type 2B = gain-of-function mutation → spontaneous platelet aggregation → thrombocytopenia + absent HMW multimers
7. Type 2N mimics hemophilia A — but AD/AR, X-linked pattern absent
8. RIPA ↑ at low-dose ristocetin = Type 2B signature
9. RIPA used to differentiate: ↓ in vWD (platelet binding impaired) vs absent in Bernard-Soulier (no GpIb)
10. vWF stored in Weibel-Palade bodies (endothelial) and α-granules (platelets)
11. ADAMTS13 cleaves vWF — deficiency → TTP (not vWD)
12. ABO blood group O → 25% lower vWF (can falsely suggest vWD)
13. Chromosome 12 (VWF gene) — exam trap vs X-chromosome (Factor VIII gene itself)
14. vWF carries FVIII — in Type 3/2N, ↓ FVIII → prolonged aPTT
15. Bleeding time/PFA prolonged — primary hemostasis defect (platelet plug formation fails)
16. Cryoprecipitate contains vWF + FVIII + fibrinogen + factor XIII + fibronectin
17. Type 1C (increased clearance) — vWFpp/vWF:Ag ratio elevated; DDAVP ineffective
18. vWF:RCo / vWF:Ag < 0.6 = qualitative defect (functional below antigen level)
19. Menorrhagia is a common presenting symptom in females — vWD underdiagnosed in women
20. Type 2A vs 2B on gel: both lack HMW bands, distinguished by RIPA at low dose (↑ in 2B only)

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11. QUICK REVISION MNEMONIC GRID

vWD TYPE   DEFECT           MULTIMERS     RIPA         DDAVP    FVIII
Type 1     ↓ Quantity       All ↓         ↓ (high)     YES      Mildly ↓
Type 1C    ↑ Clearance      All ↓ (fast)  ↓            NO       Mildly ↓
Type 2A    No HMW synthesis HMW absent    ↓            Usually  Normal
Type 2B    HMW consumed     HMW absent    ↑ at low     NO!      Normal
Type 2M    ↓ Platelet bind  Normal        ↓            Usually  Normal
Type 2N    ↓ FVIII binding  Normal        Normal       NO       ↓↓
Type 3     Total absence    Absent        Absent       NO       ↓↓↓

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