Von Willebrand disease is an inherited bleeding disorder caused by a deficiency or dysfunction of von Willebrand factor, impairing platelet adhesion and stabilization of factor VIII.

Exam domain	One-glance essentials
Definition / diagnosis	*Most common inherited bleeding disorder; quantitative or qualitative von Willebrand factor defect ^[1]^[2] vWF mediates platelet adhesion via GPIb and carries/stabilises factor VIII* ^[1]
Epidemiology / risks	Type 1 and most type 2 disease are autosomal dominant; type 3 and type 2N are autosomal recessive ^[2] Acquired vWF loss occurs with aortic stenosis, extreme thrombocytosis and lymphoproliferative disease ^[3]
Core mechanism	Defective vWF → impaired platelet tethering at injured endothelium + secondary reduction in factor VIII ^[1]^[2] Type 1 = partial quantitative deficiency; type 2 = qualitative defect; type 3 = near-complete absence
Clinical picture	Mucocutaneous bleeding: epistaxis, easy bruising, heavy menstrual bleeding and prolonged dental/procedural bleeding ^[1]^[2] Deep-tissue or joint bleeding suggests severe type 3 or type 2N disease
Investigations	Combine personal/family bleeding history with vWF antigen, vWF activity and factor VIII ^[1]^[2] PT is normal; aPTT may be prolonged but *a normal aPTT does not exclude mild vWD* ^[1] Activity:antigen ratio < 0.7 suggests a qualitative type 2 defect ^[2]
Management	Desmopressin after a response trial for suitable type 1 patients; it releases endogenous vWF/FVIII ^[3]^[4] vWF-containing concentrate when DDAVP is ineffective/contraindicated; tranexamic acid is useful for mucosal bleeding ^[3]
Complications	Iron-deficiency anaemia from chronic mucosal loss and delayed postpartum haemorrhage ^[1]^[2] Severe disease: haemarthropathy or intracranial bleeding; DDAVP can cause hyponatraemia ^[2]^[3]
Prevention / follow-up	Avoid aspirin/NSAIDs where possible and prepare a haemostatic plan before surgery, dental work or delivery ^[2]^[3] Fluid restrict and monitor sodium after repeated DDAVP; treat iron deficiency
Exam traps	DDAVP is contraindicated in type 2B and ineffective in type 3 ^[3] Type 2N mimics haemophilia A; test vWF–FVIII binding ^[2] *Factor XII deficiency commonly prolongs aPTT in Hong Kong but does not cause bleeding* ^[4]

References

^[1] Senior notes: Adrian Lui Pediatrics Notes.pdf, p395 ^[2] Senior notes: Ryan Ho Haemtology.pdf, p127–128 ^[3] Lecture slides: GC 027. Abnormal bleeding after tooth extraction.pdf, p19, p26 ^[4] Senior notes: Block A - Hematology Interactive Tutorial.pdf, p5–7

Von Willebrand Disease (vWD)

Von Willebrand disease (vWD) is a hereditary bleeding disorder caused by a quantitative or qualitative defect in von Willebrand factor (vWF), a large multimeric glycoprotein essential for primary haemostasis (platelet adhesion) and as a carrier protein for coagulation factor VIII ^[1]^[2]^[3].

Breaking down the name:

Von Willebrand → Erik Adolf von Willebrand, Finnish physician who first described the condition in 1926 in families from the Åland Islands
The disease sits at the intersection of platelet disorders and coagulation disorders — this is the key conceptual point that explains why its bleeding pattern can mimic either or both

Core Concept — Why vWD Is Unique

vWD bridges primary haemostasis (platelet plug formation) and secondary haemostasis (coagulation cascade). vWF has two critical functions: (1) it mediates platelet adhesion to exposed subendothelial collagen, and (2) it carries and stabilises Factor VIII in the circulation. A defect in vWF therefore causes a dual defect — impaired platelet plug formation AND reduced Factor VIII levels — the severity of each depending on the type of vWD.

Most common hereditary bleeding disorder ^[1]^[2]^[3]
Males and females are equally affected (autosomal inheritance, not X-linked like haemophilia) ^[3]
Incidence: ~1/100 (population-based studies) vs ~1/10,000–20,000 (clinically significant disease) ^[1]^[2]
- This huge discrepancy exists because the majority of patients are mild or asymptomatic — many Type 1 patients never come to clinical attention unless they undergo surgery or dental extraction
Majority mild/asymptomatic ^[1]^[2]
Prevalence is similar across ethnic groups, though the distribution of ABO blood groups affects vWF levels (see below)
In Hong Kong, vWD is diagnosed less frequently than haemophilia A partly due to under-recognition of mild mucocutaneous bleeding, especially in women who attribute heavy menstrual bleeding to "normal variation"

Important Epidemiological Points

Feature	Detail
Inheritance	Autosomal (affects males and females equally)
Most common type	Type 1 (~70–80% of cases)
Second most common	Type 2 (~15–20%)
Rarest	Type 3 (~1–5 per million)
Acquired vWD	Can occur secondary to very high platelet counts (> 1000 × 10⁹/L) in essential thrombocythaemia — the excessive platelets consume vWF ^[4]

3. Anatomy and Function of von Willebrand Factor

vWF is synthesised by megakaryocytes (platelets) and endothelial cells ^[3]
The gene is located on chromosome 12 (VWF gene) ^[1]^[2]
vWF is initially produced as a pro-vWF monomer → dimerises in the endoplasmic reticulum → multimerises in the Golgi apparatus
Stored in:
- Weibel-Palade bodies of endothelial cells
- α-granules of platelets
Released as ultra-large multimers (UL-vWF) which are highly prothrombotic (very sticky to platelets) ^[3]
These ultra-large multimers are rapidly cleaved by ADAMTS13 (a metalloprotease — "A Disintegrin And Metalloproteinase with ThromboSpondin type 1 motif, member 13") into smaller, less active multimers ^[3]

Why ADAMTS13 Matters

ADAMTS13 regulates the platelet-aggregating activity of vWF by cleaving it at specific sites ^[3]. Without ADAMTS13, ultra-large vWF multimers persist → excessive platelet aggregation → this is the mechanism of thrombotic thrombocytopenic purpura (TTP), which is the opposite end of the spectrum from vWD. In vWD, there is too little functional vWF; in TTP, there is too much uncleaved vWF.

Normally in the circulation, vWF is intermittently unfolded by shear stress, which leads to exposure of its ADAMTS13 cleavage sites ^[3]
Subsequent ADAMTS13-mediated proteolysis maintains vWF in an inactive configuration, thereby limiting platelet adhesion and aggregation ^[3]
vWF has multiple ADAMTS13-specific cleavage sites that are susceptible to cleavage by protease when exposed ^[3]

3.3 Functions of vWF

vWF has two main functions ^[1]^[2]^[3]:

When a blood vessel is injured, subendothelial collagen is exposed
vWF binds to collagen molecules and makes them able to bind platelets ^[3]
vWF functions as an adhesive bridge between collagen, platelet receptors (GPIb-IX-V complex), and the damaged vessel wall at sites of endothelial injury ^[3]
Specifically: Collagen → vWF → GPIb on platelet = platelet adhesion
Under high shear stress (e.g. in arterioles), this vWF-GPIb interaction is the only mechanism that can effectively tether platelets — direct collagen-platelet binding alone is insufficient
Think of vWF as "molecular glue" or a "rope" that catches fast-moving platelets and anchors them to the wound

vWF acts as a carrier protein for Factor VIII, preventing its rapid degradation in plasma ^[1]^[2]^[3]
Factor VIII has a short half-life (~2 hours) when free in plasma; bound to vWF, its half-life extends to ~8–12 hours
Therefore: ↓vWF → ↓Factor VIII (Factor VIII itself is normal but is degraded faster)
This contributes to fibrin clot formation ^[3]
This is why vWD can present with an isolated prolonged aPTT ^[5]^[6] — the aPTT reflects the intrinsic pathway, which requires Factor VIII

High Yield — Connecting the Two Functions to Clinical Features

Defective platelet adhesion → mucocutaneous bleeding (easy bruising, epistaxis, gum bleeding, menorrhagia, GI bleeding)
Reduced Factor VIII → coagulation-type bleeding (haemarthrosis, deep tissue haematomas) — this is mainly seen in Type 2N and Type 3 where Factor VIII is significantly reduced
Most types of vWD → predominantly platelet-type bleeding because vWF's platelet adhesion function is more commonly/severely affected than Factor VIII carriage

The multimeric structure of vWF is critical:

Larger multimers = more haemostatically active (more binding sites for both platelets and collagen)
Loss of large multimers (as in Type 2A and 2B) → disproportionately impaired haemostasis

Domain	Function
A1 domain	Binds platelet GPIb-IX-V
A3 domain	Binds subendothelial collagen
D'/D3 domains	Binds Factor VIII
A2 domain	Contains ADAMTS13 cleavage site
C domains	Contain RGD sequence → binds platelet GPIIb/IIIa (platelet aggregation)
D1/D2 domains	Propeptide — involved in multimerisation

4. Aetiology

Due to genetic defect in the VWF gene (chromosome 12) → defective platelet adhesion + ↓Factor VIII level ^[1]^[2]
Over 300 different mutations have been identified
Inheritance pattern depends on the type (see Classification below)

While the question focuses on hereditary vWD, it is important to recognise acquired causes:

Mechanism	Causes
Increased clearance/consumption of vWF	Essential thrombocythaemia (platelet count > 1000 × 10⁹/L) — high platelets consume all the vWF ^[4]; aortic stenosis (Heyde syndrome — shear-mediated loss of large multimers); LVAD
Autoantibody-mediated	SLE, lymphoproliferative disorders, MGUS
Decreased production	Hypothyroidism
Adsorption onto cells	Wilms tumour, other neoplasms

High Yield — Acquired vWD in Essential Thrombocythaemia

More concerning for ET is the paradoxical bleeding due to very high platelets → high platelet count consumes all the vWF, results in acquired vWD, usually when platelets > 1000 × 10⁹/L ^[4]. This is a classic exam question.

5. Pathophysiology — By Type

Type	Inheritance	Defect	Pathophysiology	Key Lab Finding
Type 1	AD	Partial quantitative ↓ vWF	Reduced amount of structurally normal vWF → less platelet adhesion + mildly ↓FVIII	vWF:Ag ↓, vWF:Act ↓, ratio preserved (> 0.7)
Type 2A	AD	Defect in multimer assembly or ↑ proteolysis	Loss of high-molecular-weight (HMW) multimers → less effective platelet binding	vWF:Act disproportionately ↓ vs vWF:Ag, ratio < 0.7; ↓ large multimers on gel
Type 2B	AD	Gain-of-function: excessive platelet affinity (increased binding of vWF A1 domain to GPIb)	vWF spontaneously binds platelets → rapid clearance of platelet-vWF complexes from circulation → thrombocytopenia + loss of HMW multimers	Thrombocytopenia; enhanced RIPA at low-dose ristocetin (< 0.5 mg/mL); ↓ large multimers
Type 2M	AD	Defect in platelet binding with normal polymerisation	vWF cannot bind GPIb effectively but multimer spectrum is normal	vWF:Act ↓ vs vWF:Ag (ratio < 0.7); normal multimer pattern
Type 2N	AR	Defect in Factor VIII binding (mutation in D'/D3 domain)	vWF cannot carry FVIII → FVIII degraded rapidly → mimics haemophilia A	Markedly ↓ FVIII; vWF:Ag and vWF:Act may be normal; vWF:FVIIIB (binding assay) ↓
Type 3	AR	Severe quantitative ↓ / absent vWF	Virtually no vWF → complete loss of platelet adhesion + very low FVIII	vWF:Ag undetectable; FVIII very low (1–9%); mixed platelet-type + coagulation-type bleeding

Understanding the Type 2B Paradox

In Type 2B, the vWF is actually too good at binding platelets — the A1 domain has a gain-of-function mutation. The problem is that this spontaneous binding happens in the circulation (not at a wound site), so the platelet-vWF complexes are rapidly cleared by the reticuloendothelial system. The result? Both thrombocytopenia (platelets consumed) and loss of large multimers (the most active ones bind first). This is why Type 2B is also associated with thrombocytopenia ^[1]^[2].

Type 2N Mimics Haemophilia A — Key Distinction

Type 2N vWD can be misdiagnosed as haemophilia A because both present with low Factor VIII and coagulation-type bleeding. The key differences: (1) vWD Type 2N is autosomal recessive (affects both sexes equally) while haemophilia A is X-linked recessive (predominantly males); (2) vWF:FVIII binding assay is abnormal in Type 2N but normal in haemophilia A; (3) vWF levels are normal in haemophilia A. Always measure vWF in a patient with isolated low FVIII.

6. Classification

vWD is classified into three major types ^[1]^[2]^[3]:

Type 1 (AD): partial quantitative deficiency of vWF — mild ↓ vWF levels, structurally normal
Type 2 (AD, except 2N which is AR): qualitative defect in vWF function
- Type 2A: defect in multimer assembly or ↑ proteolysis → loss of HMW multimers
- Type 2B: excessive platelet affinity with rapid clearance of platelet-vWF multimer complexes → thrombocytopenia
- Type 2M: defect in platelet binding with normal polymerisation
- Type 2N (AR): defect in Factor VIII binding → mimics haemophilia A
Type 3 (AR): severe quantitative deficiency / virtual absence of vWF → severe bleeding with loss in both platelet + Factor VIII function ^[1]

Type	Frequency	Severity
Type 1	~70–80%	Mild
Type 2 (all subtypes)	~15–20%	Moderate
Type 3	~1–5% (very rare)	Severe

7. Clinical Features

Majority asymptomatic, can become symptomatic at any age ^[2]
The bleeding pattern depends on the type of vWD:
- Bleeding symptoms resemble platelet disorders since the majority of abnormalities affect platelet plug formation during the primary haemostatic response ^[3]
- EXCEPT Type 2N = coagulation-type bleeding (because the bleeding is due to low FVIII which mimics haemophilia) ^[3]
- EXCEPT Type 3 = mixed platelet and coagulation-type bleeding (both types of bleeding occur) ^[3]

7.2 Symptoms (with pathophysiological basis)

Symptom	Mechanism	Notes
Easy bruising / ecchymoses	Defective platelet plug formation → minor trauma causes subcutaneous bleeding	Common presenting complaint, often dismissed as "clumsy"
Prolonged bleeding after tooth extraction	Oral mucosa is highly vascular; primary haemostasis is critical for wound closure → defective vWF means the initial platelet plug does not form properly	This is the classic presenting scenario in exam questions ^[5]
Epistaxis (nosebleeds)	Nasal mucosa exposed to trauma/dry air; rich vascular supply dependent on platelet plug for haemostasis	Often recurrent, bilateral; may require ENT intervention
Gum bleeding	Same mechanism as above — gingival mucosa is friable and vascular	Spontaneous or after brushing teeth
GI bleeding	Mucosal bleeding in the GI tract; can also be from angiodysplasia (association with vWD Type 2A/3)	May present as melaena or haematochezia
Haematuria	Mucosal bleeding from urinary tract	Less common
Heavy menstrual bleeding (HMB) / menorrhagia	Endometrial shedding exposes raw mucosal surface; requires effective platelet plug formation → defective vWF → prolonged/heavy bleeding	60–90% of women with vWD ^[2]; some studies showed that 10–15% of women presenting with HMB have underlying vWD ^[2]
Post-partum haemorrhage	vWF levels decline precipitously after delivery → the physiological rise in vWF during pregnancy (which may mask vWD) drops suddenly post-partum → bleeding	62% of women with vWD ^[2]; typically occurs as secondary PPH (delayed, days to weeks after delivery)
Prolonged bleeding after surgery/trauma	Same mechanism — inadequate primary haemostasis at surgical site	May be the first presentation of mild vWD

Platelet-type bleeding is typical in Type 1, 2A, 2B, 2M ^[2]

Symptom	Mechanism	Notes
Joint bleeding (haemarthrosis)	Low Factor VIII → inadequate fibrin clot formation → bleeding into joint spaces	Usually only seen in Types 2N and 3 ^[1]^[2] — where FVIII is significantly reduced
Muscle haematomas	Same mechanism — deep tissue bleeding from inadequate secondary haemostasis
Intracranial haemorrhage	Both platelet and coagulation defects can contribute	Rare but life-threatening; both platelet-type and coagulation-type disorders can cause this

Additional deep-seated bleeding seen in Type 3 ^[1]^[2] Type 2N: bleeding is due to low FVIII which mimics the findings in classical haemophilia ^[3]

Pregnancy: vWF is an acute-phase reactant and rises during pregnancy (often 2–3× baseline by third trimester) → may temporarily ameliorate symptoms → but vWF levels decline precipitously after delivery → risk of delayed PPH ^[2]
Oestrogen/OCP: can increase vWF levels → may mask the condition; explains why some women are only diagnosed after menopause when oestrogen levels drop
Stress, infection, inflammation, exercise: vWF is released from Weibel-Palade bodies → transient increase → stress-induced ↑vWF/F8 during phlebotomy can normalise aPTT and vWF levels, leading to false-negative results ^[2]
ABO blood group: Type O individuals have ~25% lower vWF levels than non-O groups (vWF is cleared faster in Type O) → Type O individuals are more likely to be symptomatic or meet diagnostic thresholds
Age: vWF levels increase with age → some Type 1 patients may "grow out of" their bleeding tendency

Sign	Mechanism	Notes
Petechiae (< 5 mm)	Capillary bleeding not sealed by platelet plug → tiny red spots	Present in platelet disorders, NOT in pure coagulation disorders ^[3]
Purpura (5–10 mm)	Same as above but larger	Platelet disorder pattern ^[3]
Ecchymoses (> 10 mm)	Larger subcutaneous haemorrhages	Present in BOTH platelet and coagulation disorders ^[3]
Mucosal bleeding (actively oozing)	Visible on examination of oral cavity, nasal cavity
Haemarthrosis (swollen, tender joint)	Factor VIII deficiency → bleeding into joint	Only in severe vWD (Types 2N, 3)
Absence of hepatosplenomegaly / lymphadenopathy	vWD does not cause organomegaly — if present, consider other diagnoses	Important negative finding

The following table distinguishes platelet-type vs coagulation-type bleeding ^[3]:

Feature	Platelet Disorder	Coagulation Disorder
Petechiae (< 5 mm)	✓	✗
Purpura (5–10 mm)	✓	✗
Ecchymosis (> 10 mm)	✓	✓
Mucosal bleeding (epistaxis, gum, GI, haematuria, menorrhagia)	✓	✓ (less common)
Intra-articular / intramuscular bleeding (haemarthrosis, muscle haematoma)	✗ (less common)	✓
Intracranial bleeding	✓	✓
Retinal haemorrhage	✓	✓
Onset after trauma	Immediate	Delayed (hours)
Response to local pressure	Good (temporarily)	Poor

High Yield — Bedside Differentiation of Platelet vs Coagulation Bleeding

Even at the bedside without talking to the patient, you can clinically determine whether the patient's bleeding tendency is due to platelet or coagulation problems ^[5]. Petechiae and mucocutaneous bleeding = platelet-type. Deep haemarthrosis and muscle haematomas = coagulation-type. Coagulation generally causes deeper-seated bleeding — but remember that both can cause intracranial haemorrhages; cannot say one is more deadly than the other ^[5].

The ISTH-BAT (Bleeding Assessment Tool) is a standardised questionnaire that scores the severity and type of bleeding symptoms
A score ≥ 4 in adult males or ≥ 6 in adult females is considered abnormal and warrants further investigation
This is increasingly used in clinical practice to quantify bleeding tendency before proceeding to laboratory workup

8. History-Taking Framework for Suspected vWD

When evaluating a patient with suspected vWD (e.g. a 20-year-old man with prolonged bleeding after wisdom tooth extraction and an old bruise over the shin ^[5]):

How long has the patient had this tendency to bleed? ^[5]
- Long-standing → inherited (vWD, haemophilia)
- Acute → acquired (drugs — aspirin, warfarin; DIC; acquired vWD) ^[5]

Mucocutaneous vs deep-seated ^[5]
- Mucocutaneous → platelet disorder or vWD Types 1, 2A, 2B, 2M
- Deep-seated → coagulation disorder or vWD Types 2N, 3

Easy bruising — location, size, spontaneous vs traumatic
Epistaxis — frequency, duration, unilateral/bilateral, need for packing
Menstrual history in women — duration, number of pads, clots, iron deficiency
Post-surgical/dental extraction bleeding — duration, need for re-intervention
Post-partum haemorrhage
GI bleeding — melaena, haematochezia

Essential — vWD is hereditary
Ask about bleeding tendency in both parents (autosomal inheritance)
Family members with heavy periods, post-surgical bleeding, blood transfusions

Aspirin, NSAIDs (impair platelet function and exacerbate vWD bleeding)
Anticoagulants (warfarin, DOACs)
OCP / HRT (may mask vWD by increasing vWF levels)

This deserves its own section because it has major implications for diagnosis:

vWF is an acute-phase reactant — its levels rise with:
- Stress (including the stress of phlebotomy) ^[2]
- Inflammation, infection, malignancy ^[2]
- Hormonal factors: pregnancy, OCP, menstrual cycle ^[2]
- Exercise
- Post-operatively
This means: aPTT can be normal in vWD in the following situations ^[2]:
1. Mild deficiency (vWF levels may hover near-normal)
2. Stress-induced ↑vWF/F8 during phlebotomy
3. Hormonal factors (menstrual cycle, pregnancy, OCP)
Clinical implication: A single normal aPTT or vWF level does NOT exclude vWD. Repeat testing on multiple occasions may be necessary, ideally:
- When the patient is not acutely unwell
- Early in the menstrual cycle (days 1–4, when oestrogen is lowest)
- Not under stress

Both vWD and lupus anticoagulant can present with an isolated prolonged aPTT, but their clinical consequences are opposite ^[6]:

Feature	vWD	Lupus Anticoagulant
Clinical consequence	Bleeding tendency	Thrombotic tendency (paradoxically)
Mechanism	Deficiency of vWF → low FVIII	Autoantibodies against phospholipids (which aPTT is dependent on) → interfere with aPTT assay in vitro but actually promote clotting in vivo
Mixing study result	Corrects	Does NOT correct

Why the mixing study works [6]:

Mix 50% patient plasma with 50% healthy (normal) plasma
vWD: the patient's plasma has low FVIII due to low vWF. After mixing with normal plasma (which has 100% FVIII), you get ~50% FVIII — sufficient to correct the aPTT ^[6]
Lupus anticoagulant: the patient's plasma contains antibodies that actively destroy the phospholipids in the normal plasma → the aPTT does NOT correct ^[6]
Key point: lupus anticoagulant antibodies act IMMEDIATELY — other autoimmune inhibitors (e.g. acquired FVIII inhibitors) may show delayed inhibition after incubation ^[6]

High Yield Exam Point — Mixing Study Interpretation

In our locality (Hong Kong), the most common cause of an isolated prolonged aPTT is Factor 12 deficiency (found at a rate of ~20%) ^[6]. Factor 12 deficiency does NOT result in a bleeding tendency ^[6]. Always interpret aPTT in clinical context — an isolated prolonged aPTT in an asymptomatic patient may simply be Factor XII deficiency.

Factor	Effect on vWF	Relevance to Hong Kong
ABO blood group	Type O → ~25% lower vWF levels	Blood group O is common in Chinese populations (~40%)
Factor XII deficiency	Does not affect vWF but causes isolated prolonged aPTT	~20% prevalence in our locality ^[6] — must be differentiated from vWD
Thalassaemia trait	No direct effect on vWF but is a common cause of microcytic anaemia in HK — avoid confusing the two	Common in Southeast Asian populations
Hepatitis B	Liver disease can affect coagulation factor synthesis but vWF is produced by endothelium, not liver, so vWF is often paradoxically elevated in liver disease	High prevalence in HK

From the GC Interactive Tutorial ^[5]: A 20-year-old man presented with prolonged bleeding after wisdom tooth extraction. Old bruise over the shin. Otherwise normal examination.

Lab findings:

Hb 14.5 g/dL (normal)
WCC 9.5 × 10⁹/L (normal)
Platelet 260 × 10⁹/L (normal)
PT 10.5 seconds (normal: 11–13.5) — actually slightly short/normal
aPTT 60 seconds (normal: 21–35) — isolated prolonged aPTT

Additional investigations:

Factor VIII: 0.13 u/mL (low)
vWF:Ag: 1.11 u/mL (normal)
vWF:RCo: 1.22 u/mL (normal)

Interpretation:

Isolated prolonged aPTT → suggests deficiency or inhibition of intrinsic pathway factors: FVIII, FIX, FXI, FXII, or vWF ^[5]^[6]
Factor VIII is markedly reduced (0.13 u/mL)
vWF:Ag and vWF:RCo are normal → this is NOT a quantitative or platelet-binding defect in vWF
Crucial to measure vWF because it carries and protects Factor VIII in circulation — no vWF, Factor VIII also low ^[5]
For this patient, vWF:Ag and vWF:RCo are normal but FVIII is low → this pattern is consistent with vWD Type 2N (defect in FVIII binding site of vWF) or Haemophilia A (intrinsic FVIII deficiency)
To distinguish: need vWF:FVIII binding assay → if abnormal, this confirms Type 2N vWD; if normal, this is haemophilia A
Why need both Ag and RCo? To identify different types of vWD ^[5]
vWF:Ag levels are largely normal (vWF:RCo to vWF:Ag ratio < 0.7) in vWD types 2A and 2B, but vWF:RCo may be disproportionately low ^[5]

13. Acquired vWD in the Context of Other Conditions

Severe aortic stenosis → high shear stress across the stenotic valve → unfolds vWF → excessive ADAMTS13 cleavage → loss of HMW multimers → acquired Type 2A-like vWD
Presents with GI bleeding from angiodysplasia
Resolves after aortic valve replacement

Very high platelet count (usually > 1000 × 10⁹/L) → platelets consume vWF → acquired vWD ^[4]
Paradoxical bleeding despite thrombocytosis ^[4]

High Yield Summary

Von Willebrand Disease — Key Points for Exams:

Most common hereditary bleeding disorder; autosomal inheritance (affects males = females) ^[1]^[2]^[3]
vWF has two functions: (1) platelet adhesion to collagen via GPIb, (2) carrier protein for Factor VIII ^[1]^[2]^[3]
Gene on chromosome 12; vWF released as ultra-large multimers, cleaved by ADAMTS13 ^[1]^[2]^[3]
Type 1 (AD, ~75%): partial quantitative ↓ vWF — mild, mucocutaneous bleeding
Type 2A (AD): ↓ HMW multimers; Type 2B (AD): gain-of-function → thrombocytopenia; Type 2M (AD): ↓ platelet binding, normal multimers; Type 2N (AR): ↓ FVIII binding → mimics haemophilia A
Type 3 (AR): virtually absent vWF → severe, mixed platelet + coagulation-type bleeding
Isolated prolonged aPTT is the hallmark lab finding — but can be normal in mild disease or when vWF is elevated by stress/inflammation/pregnancy ^[2]^[6]
In Hong Kong, most common cause of isolated prolonged aPTT is Factor XII deficiency (~20% prevalence) — does NOT cause bleeding ^[6]
Mixing study: vWD corrects (deficiency), lupus anticoagulant does not correct (inhibitor) ^[6]
vWF is an acute-phase reactant — levels rise with stress, inflammation, pregnancy, OCP ^[2]
10–15% of women with HMB may have underlying vWD; 60–90% of vWD women experience HMB ^[2]
Acquired vWD can occur in essential thrombocythaemia (platelets > 1000), aortic stenosis (Heyde syndrome) ^[4]

Active Recall - Von Willebrand Disease (Overview, Pathophysiology, Clinical Features)

^[1] Senior notes: Adrian Lui Pediatrics Notes.pdf (p.395 — Von Willebrand Disease section) ^[2] Senior notes: Ryan Ho Haemtology.pdf (pp.127–128 — Section 4.3.3 Von Willebrand Disease) ^[3] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (p.1362–1364 — vWD Pathogenesis and Clinical Manifestation); MBBS Final MB (Pediatrics) (Felix PY Lai).pdf (p.602) ^[4] Senior notes: Block A - Splenomegaly_ common causes of splenomegaly; myeloproliferative diseases.pdf (p.29 — Essential Thrombocythaemia and acquired vWD) ^[5] Lecture slides: Block A - Hematology Interactive Tutorial.pdf (pp.5–6 — Case 2: vWD workup); GC 027. Abnormal bleeding after tooth extraction.pdf ^[6] Senior notes: Block A - Introduction to Haematological investigations (CBP, Clotting).pdf (pp.21–22 — Mixing study, Factor XII deficiency in HK)

Differential Diagnosis of Von Willebrand Disease

When you encounter a patient with a bleeding tendency, the differential diagnosis is broad. The key to narrowing it down is a systematic, stepwise approach that mirrors how haemostasis actually works. Think of it as three sequential questions:

Is this a primary haemostasis problem (platelet/vessel wall) or a secondary haemostasis problem (coagulation cascade)? → The bleeding pattern tells you (see previous section).
Is this inherited or acquired? → The history (onset, family history, drug history) tells you.
What specific entity within that category? → The laboratory profile tells you.

vWD is unique because it straddles both primary and secondary haemostasis — it affects platelet adhesion AND Factor VIII stability. This means the differential must include conditions from both domains.

The best way to think about the DDx of vWD is to consider what clinical and laboratory features lead you towards vWD in the first place, and then ask: "What else could mimic this picture?"

The typical vWD presentation has these features:

Mucocutaneous bleeding (± deep-seated in severe types)
Isolated prolonged aPTT (or normal aPTT in mild disease) ^[4]^[5]
Normal platelet count (except Type 2B)
Normal PT
Positive family history (autosomal pattern)

We will organise the DDx by the laboratory pattern and bleeding type, since that is how you will approach it at the bedside and in exams.

3. Differential Diagnosis by Laboratory Pattern

This is the classic vWD lab pattern. An isolated prolonged aPTT suggests issues (deficiency or inhibition) with the intrinsic or common pathway: Factor VIII, Factor IX, Factor XI, Factor XII ^[4].

Condition	Mechanism	Key Distinguishing Features
Von Willebrand disease	↓vWF → ↓FVIII + impaired platelet adhesion	Low vWF:Ag and/or vWF:Act; autosomal inheritance; mucocutaneous bleeding pattern (except 2N, 3)
Haemophilia A	X-linked deficiency of Factor VIII	Low FVIII with normal vWF:Ag and vWF:RCo ^[4]; X-linked (males affected, female carriers); deep-seated/coagulation-type bleeding (haemarthroses, muscle haematomas); vWF antigen testing is required to exclude vWD for diagnosis of haemophilia ^[9]
Haemophilia B (Christmas disease)	X-linked deficiency of Factor IX	Low Factor IX with normal FVIII and vWF; X-linked; clinically indistinguishable from haemophilia A without factor assays
Factor XI deficiency	Deficiency of Factor XI	Cannot predict bleeding — 50% will bleed, 50% will not ^[5]; more common in Ashkenazi Jewish populations; variable clinical severity; AR inheritance
Factor XII deficiency	Deficiency of Factor XII (Hageman factor)	Does NOT cause bleeding tendency ^[4]^[5]; found at a rate of ~20% in our [Hong Kong] locality ^[5]; prolongs aPTT in vitro but irrelevant in vivo because Factor XII is not needed for physiological haemostasis; must be excluded as a cause of incidental prolonged aPTT
Contact factor deficiencies	Prekallikrein or HMWK deficiency	Contact factors include Factor XII, Factor XI, Prekallikrein, and HMWK ^[4]; no bleeding tendency; prolong aPTT in vitro only
Lupus anticoagulant (LA)	Antiphospholipid antibody that interferes with phospholipid-dependent coagulation tests	Immediately exclude since this causes thrombosis, not bleeding tendency ^[4]; prolongs aPTT in vitro (phospholipid-dependent assay) but causes thrombotic tendency in vivo (paradox!); mixing study does NOT correct ^[5]^[8]; confirmed by DRVVT ^[10]
Acquired Factor VIII inhibitor (acquired haemophilia A)	Autoantibody directly neutralising Factor VIII	Sudden onset of severe bleeding in a previously well patient (often elderly, post-partum, autoimmune disease); very low FVIII; mixing study does NOT correct (but may show delayed inhibition after incubation, unlike LA which is immediate); Bethesda assay positive

High Yield — Mixing Study Interpretation

To differentiate vWD from lupus anticoagulant in isolated prolonged aPTT, use a mixing study: mix 50% patient plasma with 50% healthy plasma. ^[5]

vWD is just a deficiency of Factor VIII → after mixing patient plasma (with low FVIII) with healthy plasma (with 100% FVIII), you get ~50% FVIII, which is sufficient to correct the aPTT. ^[5]
Lupus anticoagulant has antibodies actively trying to interfere → after mixing, the antibodies in the patient's plasma begin immediately destroying the healthy plasma phospholipids → resulting in the inability to correct the aPTT. ^[5]
"Immediately" is key — lupus anticoagulant causes immediate non-correction. Other autoimmune inhibitors (e.g. acquired haemophilia A) show delayed non-correction after incubation. ^[5]

Summary: Correction = deficiency (vWD, haemophilia). No correction = inhibitor (LA, acquired inhibitors).

From the Haematology Interactive Tutorial: "Isolated increase in aPTT suggests issues with intrinsic or common pathway: Factor 8, Factor 9, Factor 11, Factor 12. Also: Lupus anticoagulant → immediately exclude since this causes thrombosis, not bleeding tendency. vWF is crucial to measure → carries and protects Coagulation Factor 8 in circulation → no vWF, factor 8 also low." ^[4]

This is an important distinction — not all prolonged aPTTs mean bleeding:

Condition	Why No Bleeding?
Factor XII deficiency	Factor XII not required for in vivo haemostasis; 20% prevalence in Hong Kong ^[5] — very common incidental finding
Prekallikrein / HMWK deficiency	Contact factors not required for in vivo haemostasis
Lupus anticoagulant	Paradoxically causes thrombosis (antiphospholipid syndrome), not bleeding ^[4]

Exam Trap

In our locality [Hong Kong], the most common cause of an isolated prolonged aPTT is Factor XII deficiency ^[5]. If you see an isolated prolonged aPTT on an exam and the patient has no bleeding history, think Factor XII deficiency first. It is found at a rate of 20% in our locality → interpret with clinical context. ^[5] Do not reflexively diagnose haemophilia or vWD without clinical correlation.

Remember: aPTT can be normal in mild vWD ^[2]^[8]. So the DDx of mucocutaneous bleeding with a normal coagulation screen includes:

Condition	Mechanism	Key Distinguishing Features
Mild vWD (Type 1)	vWF only mildly reduced → FVIII borderline → aPTT may be normal	Requires specific vWF assays (vWF:Ag, vWF:Act); family history; response to DDAVP
Platelet function disorders	Impaired platelet activation/aggregation despite normal count	Normal aPTT, normal PT, normal platelet count; requires platelet function analyser (PFA-100) or platelet aggregation studies
Bernard-Soulier syndrome (BSS)	Deficiency of GPIb ^[7] → platelets cannot bind vWF → impaired adhesion	AR; giant platelets on PBS; thrombocytopenia (large platelets may be undercounted); similar to vWD but the defect is in the platelet receptor, not vWF itself; absent ristocetin-induced aggregation (like Type 3 vWD) but vWF levels are normal
Glanzmann thrombasthenia	Deficiency of GPIIb/IIIa → platelets cannot aggregate	AR; normal platelet count and size; absent aggregation to all agonists EXCEPT ristocetin (because ristocetin tests adhesion via GPIb-vWF, which is intact)
Drug-induced platelet dysfunction	Aspirin (irreversible COX-1 inhibition), NSAIDs, P2Y12 inhibitors	Drugs → aspirin, warfarin ^[7] — always take a drug history; onset correlates with drug use
Uraemic platelet dysfunction	Uraemic toxins → ↑NO → inhibit platelet activation/adhesion	History of CKD; improves with dialysis, DDAVP, or cryoprecipitate
Hereditary haemorrhagic telangiectasia (HHT)	Abnormal vessel wall (AVM/telangiectasia) → fragile vessels bleed easily	AD; characteristic telangiectasia on lips, oral mucosa, fingertips; epistaxis; GI bleeding; family history; normal coagulation tests and platelet function ^[11]

If both PT and aPTT are prolonged, this points away from isolated vWD and towards:

Condition	Mechanism	Key Features
Liver disease	Reduced production of factors in liver failure; vitamin K deficiency in jaundice ^[7]	Multiple factor deficiency (all except FVIII, which is made by endothelium); clinical stigmata of liver disease
DIC (Disseminated Intravascular Coagulation)	Consumptive coagulopathy → consumption of factors + platelets	↓Platelet, ↓fibrinogen, ↑D-dimer ^[8]; schistocytes on PBS; underlying trigger (sepsis, malignancy, obstetric)
Vitamin K deficiency	Factors II, VII, IX, X not γ-carboxylated	Malnutrition, malabsorption, antibiotics, warfarin; corrects with vitamin K
Common pathway factor deficiency	Factor V, X, prothrombin (II), fibrinogen (I)	Prolonged PT and aPTT → prothrombin, fibrinogen, Factor 5, Factor 10, or multiple factor deficiency ^[5]
NOAC / Warfarin use	Anticoagulant drug effect	Drugs → anticoagulants ^[7]; always check drug history

Liver Disease vs vWD

A common confusion: liver disease causes ↓ all clotting factors EXCEPT Factor VIII (because FVIII is uniquely produced by endothelial cells and sinusoidal cells, not hepatocytes). In contrast, vWD causes ↓ Factor VIII with normal other factors. So if you see low FVIII with normal other factors → think vWD/haemophilia. If you see low everything except FVIII → think liver disease. ^[8]

Type 2B vWD presents with thrombocytopenia + mucocutaneous bleeding — the DDx of this combination includes:

Condition	Mechanism	Key Distinguishing Features
Type 2B vWD	Gain-of-function vWF → spontaneous platelet-vWF aggregation and clearance	Low vWF:Act, enhanced RIPA at low-dose ristocetin, loss of HMW multimers
Platelet-type (pseudo-) vWD	Gain-of-function mutation in platelet GPIbα (not vWF) → same mechanism but defect is on the platelet side	Very similar to 2B; distinguished by ristocetin-mixing studies (mixing with normal platelets vs normal plasma) or genetic testing
Immune thrombocytopenic purpura (ITP)	Autoantibody-mediated platelet destruction	Normal coagulation screen; no vWF abnormality; isolated thrombocytopenia; diagnosis of exclusion
TTP	Severely reduced ADAMTS13 activity → UL-vWF not cleaved → platelet-rich thrombi ^[12]	Thrombocytopenia + MAHA (schistocytes on PBS) + organ damage (neurological, renal) ^[12]; ADAMTS13 activity < 10%
Drug-induced thrombocytopenia	Heparin (HIT), others	Temporal relationship with drug

4. Differential Diagnosis by Bleeding Pattern

From the GC lecture: "Coagulation generally causes deeper-seated bleeding" ^[7]. If the patient has predominantly mucocutaneous bleeding:

Think primary haemostasis defects:

vWD (Type 1, 2A, 2B, 2M)
Platelet disorders: quantitative (ITP, bone marrow failure, drug-induced) or qualitative (BSS, Glanzmann, aspirin, uraemia)
Vascular disorders: HHT, scurvy (vitamin C deficiency), connective tissue disorders (Ehlers-Danlos)

If the patient has predominantly haemarthroses and muscle haematomas:

Think secondary haemostasis defects:

vWD Type 2N, Type 3
Haemophilia A, B
Acquired Factor VIII inhibitor
Rare factor deficiencies (FXI, others)

If the patient has both mucocutaneous AND deep-seated bleeding:

vWD Type 3 (most likely)
Severe vWD Type 2N with very low FVIII
DIC (consumption of both platelets and factors)

5. Distinguishing vWD from Its Closest Mimics

This is the most important differential and a favourite exam question.

Feature	vWD	Haemophilia A
Inheritance	Autosomal (AD for Types 1, 2A/B/M; AR for Types 2N, 3)	X-linked recessive
Sex distribution	Males = females	Males affected; females are carriers
Bleeding pattern	Mucocutaneous (Types 1, 2A/B/M); coagulation-type in 2N/3	Deep-seated (haemarthroses, muscle haematoma)
vWF:Ag	↓ (Type 1, 3) or Normal (Type 2N)	Normal
vWF:Act (RCo)	↓ (Types 1, 2A, 2B, 2M, 3)	Normal
FVIII level	Mild–moderate ↓ (Types 1, 2A/B/M); severe ↓ (2N, 3)	↓↓ (proportional to severity)
Response to DDAVP	Good (Type 1); variable (Type 2); poor (Type 3)	Good in mild haemophilia A
Mixing study	Corrects	Corrects
Key differentiating test	vWF:Ag testing required to exclude vWD ^[9]	Factor VIII gene (F8) mutation analysis

From the Paediatric haemophilia notes: "Von Willebrand factor antigen testing (vWF:Ag) — exclude von Willebrand disease is required for diagnosis of haemophilia." ^[9] This means: you cannot diagnose haemophilia A without first checking vWF — because Type 2N vWD and Type 3 vWD both cause low FVIII and can be misdiagnosed as haemophilia A.

Both present with low Factor VIII, normal vWF levels (in 2N), deep-seated bleeding
Type 2N: AR → affects both sexes → family history may show affected females
Haemophilia A: X-linked → overwhelmingly males → obligate female carriers
Definitive test: vWF:FVIII binding assay — abnormal in Type 2N, normal in haemophilia A

Both impair the GPIb-vWF-collagen axis, but from opposite sides:

Feature	vWD	BSS
Defect location	vWF (ligand)	GPIb (receptor) ^[7]
Inheritance	AD or AR	AR
Platelet count	Normal (except 2B)	↓ (pseudo-thrombocytopenia; giant platelets)
Platelet size	Normal	Giant
vWF:Ag	↓ (most types)	Normal
RIPA	↓ or absent	Absent
Key differentiator	Low vWF levels; ristocetin-dependent assays abnormal due to vWF	Normal vWF; platelet GPIb expression absent/reduced on flow cytometry

Feature	Inherited vWD	Acquired vWS
Onset	Lifelong (from birth)	Late onset (adult)
Family history	Positive	Negative
Associated conditions	None	ET (platelets > 1000) → consumes vWF ^[6]^[13]; aortic stenosis (Heyde syndrome: shear stress → early degradation of vWF ^[11]); lymphoproliferative disorders; autoimmune disease; hypothyroidism
vWF levels	Persistently low	Low, but may fluctuate with underlying disease activity
Treatment	DDAVP, vWF concentrates	Treat underlying condition; IVIG may transiently raise vWF

From the Splenomegaly lecture: "More concerning for ET is the paradoxical bleeding due to very high platelets → high platelet consumes all the vWF, results in acquired vWD — usually platelets > 1000." ^[6]

From the DVT/Thrombophilia lecture: "When the patient has extreme thrombocytosis with bleeding tendency → want to exclude Acquired von Willebrand disease (AvWD). Excess platelets will consume excess von Willebrand factor (vWF), a clotting factor for platelet adhesion." ^[13]

The following mermaid diagram walks through the clinical reasoning pathway when you encounter a patient with mucocutaneous bleeding and consider vWD in the differential:

Diagnosis	Inheritance	Platelet Count	PT	aPTT	FVIII	vWF:Ag	vWF:Act	Mixing Study	Key Differentiator
vWD Type 1	AD	N	N	↑ or N	Mild ↓	↓	↓	Corrects	Low vWF levels
vWD Type 2A	AD	N	N	↑ or N	N/↓	↓/N	↓↓	Corrects	Act:Ag ratio < 0.7; loss of HMW multimers
vWD Type 2B	AD	↓	N	↑ or N	N/↓	↓/N	↓↓	Corrects	Thrombocytopenia; enhanced RIPA
vWD Type 2N	AR	N	N	↑	↓↓	N	N	Corrects	Normal vWF, low FVIII; vWF:FVIII binding assay abnormal
vWD Type 3	AR	N	N	↑↑	↓↓	Absent	Absent	Corrects	Absent vWF; mixed bleeding
Haemophilia A	X-linked	N	N	↑	↓↓	N	N	Corrects	X-linked; vWF normal
Haemophilia B	X-linked	N	N	↑	N	N	N	Corrects	Low FIX
Factor XII def	—	N	N	↑	N	N	N	Corrects	No bleeding; 20% HK prevalence
Lupus AC	Acquired	N	N/↑	↑	N/↓	N	N	Does NOT correct	Thrombosis, not bleeding
Acquired FVIII inhibitor	Acquired	N	N	↑↑	↓↓↓	N	N	Does NOT correct (delayed)	Acute onset; elderly/post-partum
BSS	AR	↓	N	N	N	N	N	N/A	Giant platelets; absent GPIb
ITP	Acquired	↓↓	N	N	N	N	N	N/A	Isolated thrombocytopenia; diagnosis of exclusion
AVWS	Acquired	Variable	N	↑ or N	↓	↓	↓	Corrects	Late onset; associated with ET, aortic stenosis, lymphoma

Factor XII deficiency (20% in local Chinese population) ^[5] is the most common cause of isolated prolonged aPTT in HK — does not cause bleeding but can mislead clinicians into unnecessary workup
When seeing isolated prolonged aPTT in a HK Chinese patient:
1. First exclude Factor XII deficiency (no clinical significance)
2. Then consider vWD, haemophilia
3. Then rule out lupus anticoagulant (especially if thrombotic history)
Heyde syndrome (aortic stenosis + GI bleeding + acquired vWS) should be considered when an elderly patient with known aortic stenosis presents with GI bleeding ^[11]

High Yield Summary — Differential Diagnosis of vWD

Key DDx principles:

Isolated prolonged aPTT → intrinsic pathway defect: Factor VIII (haemophilia A, vWD), Factor IX (haemophilia B), Factor XI, Factor XII, contact factors, lupus anticoagulant ^[4]
Most common cause of isolated prolonged aPTT in Hong Kong = Factor XII deficiency (20% prevalence, NO bleeding) ^[5]
Mixing study differentiates deficiency (corrects) from inhibitor (does not correct) ^[5]
vWF:Ag testing is required to exclude vWD before diagnosing haemophilia A ^[9]
Type 2N vWD mimics haemophilia A — distinguish by vWF:FVIII binding assay and inheritance pattern (AR vs X-linked)
BSS mimics vWD but defect is in platelet GPIb (receptor), not vWF (ligand) — giant platelets, normal vWF ^[7]
Acquired vWS: think ET with platelets > 1000, aortic stenosis (Heyde syndrome), lymphoproliferative disorders ^[6]^[11]^[13]
Lupus anticoagulant: prolonged aPTT but causes THROMBOSIS not bleeding — mixing study does not correct IMMEDIATELY ^[4]^[5]

Active Recall — Differential Diagnosis of Von Willebrand Disease

References

^[2] Senior notes: Ryan Ho Haemtology.pdf (Section 4.3.3 Von Willebrand Disease, p127–128) ^[4] Senior notes: Block A - Hematology Interactive Tutorial.pdf (Case 2, p5–6) ^[5] Senior notes: Block A - Introduction to Haematological investigations (CBP, Clotting).pdf (p21–23) ^[6] Senior notes: Block A - Splenomegaly_ common causes of splenomegaly; myeloproliferative diseases.pdf (p29) ^[7] Senior notes: Block A - Abnormal bleeding after tooth extraction_ bleeding tendency; thrombocytopenia.pdf (p8) ^[8] Senior notes: Maksim Medicine Notes.pdf (p161, Clotting cascade interpretation) ^[9] Senior notes: MBBS Final MB (Pediatrics) (Felix PY Lai).pdf (p596) ^[10] Senior notes: Block A - Introduction to Haematological investigations (CBP, Clotting).pdf (p23, DRVVT) ^[11] Senior notes: Block A - Coffee ground vomitus tarry stool upper GI bleeding.pdf (p8, Heyde syndrome) ^[12] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (p1375, TTP); MBBS Final MB (Pediatrics) (Felix PY Lai).pdf (p615) ^[13] Senior notes: Block A - Leg swelling and chest pain_ deep vein thrombosis; pulmonary embolism; Thrombophilia.pdf (p18)

Diagnostic Criteria, Algorithm & Investigations for Von Willebrand Disease

1. Diagnostic Criteria — Overview

There is no single pathognomonic test for vWD. Diagnosis rests on the convergence of three pillars — think of it as a three-legged stool; all three legs must be present:

Personal history of excessive mucocutaneous bleeding (quantified by a bleeding assessment tool)
Family history consistent with autosomal inheritance (positive in most, but de novo mutations occur in ~20–30% of Type 1 and some Type 3)
Laboratory evidence of reduced vWF level and/or function ^[1]^[2]^[3]

The 2021 ASH/ISTH/NHF/WFH Guidelines (the current standard in 2026) define the diagnostic thresholds and guide subtyping. The ISTH 2006 revised classification remains the framework for typing.

Parameter	Definite vWD	"Low vWF" (borderline)	Normal
vWF:Ag and/or vWF activity	< 30 IU/dL (< 30%) ^[1]^[2]	30–50 IU/dL	> 50 IU/dL
Factor VIII level	Depends on type	—	—
Clinical bleeding score (ISTH-BAT)	Abnormal (≥ 4 males, ≥ 6 females)	—	< 4 (males), < 6 (females)

Why 30 IU/dL and not 50?

Early guidelines used < 50 IU/dL, but this captured too many people who never bleed (low specificity — especially Type O individuals whose vWF is constitutively ~25% lower)
The 2021 ASH/ISTH guidelines introduced the concept of "low vWF" (30–50 IU/dL) as a distinct entity from definite vWD (< 30 IU/dL)
Patients with "low vWF" may bleed peri-operatively but often do not require long-term management — they are managed differently from definite vWD

High Yield — Diagnostic Cut-offs

vWF:Ag < 30 IU/dL (< 30%) is consistent with vWD (Type 1 or Type 3) ^[1]. Levels of 30–50 IU/dL are classified as "low vWF" rather than definite vWD. Always correlate with clinical bleeding history (ISTH-BAT score) and family history.

Type	Required Criteria
Type 1	vWF:Ag AND vWF:Act both < 30 IU/dL; vWF Act:Ag ratio > 0.7 (concordant reduction); all multimers present and uniformly decreased ^[3]; bleeding history
Type 2A	vWF:Act disproportionately low vs vWF:Ag; Act:Ag ratio < 0.7; decreased HMW multimers on gel electrophoresis ^[3]; RIPA ↓ ^[3]
Type 2B	Act:Ag ratio < 0.7; RIPA ↑ (enhanced aggregation at low-dose ristocetin, typically < 0.5 mg/mL) ^[3]; decreased HMW multimers; ± thrombocytopenia ^[1]^[2]
Type 2M	Act:Ag ratio < 0.7; RIPA ↓; all multimers present and uniformly decreased (normal multimer pattern) ^[3]
Type 2N	vWF:Ag and vWF:Act may be normal; FVIII markedly ↓; RIPA normal; vWF:FVIII binding assay abnormal; normal multimer pattern ^[3]
Type 3	vWF:Ag absent (undetectable); FVIII very low (1–9 IU/dL); RIPA undetectable ^[3]

From the Felix Lai summary table ^[3]:

Type	Prevalence	Gene	Severity	vWF:Ag	vWF:Act	RIPA	FVIII	Multimer Electrophoresis
1	75%	AD	Variable	↓	↓	↔/↓	↔/↓	All multimers present, uniformly decreased
2A	10–20%	AD/AR	Moderate–Severe	↓	↓↓	↓	↔/↓	Decreased HMW multimers
2B	5%	AD	—	↓	↓↓	↑	↔/↓	Decreased HMW multimers
2M	Rare	AD/AR	—	↓	↓↓	↓	↔/↓	All multimers present, uniformly decreased
2N	Rare	AR	—	↔	↔	↔	↓	Normal
3	Rare	AR	Severe	Absent	↓↓↓	—		Undetectable

The diagnostic workup proceeds in a logical, tiered fashion. Think of it as three tiers:

Tier 1: Baseline screening (CBC, coagulation screen) — identifies the problem
Tier 2: vWD-specific screening assays — confirms the diagnosis
Tier 3: Subtyping investigations — determines the exact type

Key Principle — Why Proceed to Tier 2 Even with Normal aPTT?

aPTT can be normal in vWD in the following situations ^[2]:

Mild deficiency — vWF and FVIII may be just above the threshold to normalise aPTT
Stress-induced ↑vWF/F8 during phlebotomy, inflammation, infection, malignancy — vWF is an acute-phase reactant
Hormonal factors — menstrual cycle, pregnancy, OCP raise vWF levels

Therefore, a normal aPTT does NOT exclude vWD. If clinical suspicion is high (significant ISTH-BAT bleeding score + family history), proceed directly to vWF-specific assays.

3. Investigation Modalities — Detailed Interpretation

3.1 Tier 1: Baseline Screening

Finding	Interpretation	Relevance to vWD
Normal Hb	No chronic blood loss anaemia yet	Mild vWD may have normal Hb; severe/chronic mucosal bleeding → iron deficiency anaemia
Low Hb with microcytosis	Iron deficiency from chronic blood loss (menorrhagia, GI bleeding)	Suspect undiagnosed vWD in young women with iron deficiency anaemia and HMB
Normal platelet count	Excludes thrombocytopenia as cause of bleeding	Types 1, 2A, 2M, 2N, 3 all have normal platelets
Thrombocytopenia	Type 2B vWD (gain-of-function → platelet-vWF complexes cleared rapidly) ^[1]^[2]; also consider pseudo-vWD, ITP, TTP	Type 2B is the only type of vWD associated with thrombocytopenia
Normal WBC	No leukaemia/aplastic anaemia	—
PBS: schistocytes	MAHA — think TTP, DIC (not vWD)	Helps exclude TTP in thrombocytopenic patient
PBS: giant platelets	Bernard-Soulier syndrome (not vWD)	BSS has giant platelets; vWD does not

Test	What It Measures	Expected in vWD
PT (Prothrombin Time)	Extrinsic pathway (Factor VII) + common pathway	Normal in vWD (Factor VII not affected)
aPTT (Activated Partial Thromboplastin Time)	Intrinsic pathway (Factors VIII, IX, XI, XII) + common pathway	Isolated prolonged aPTT (due to ↓FVIII) ^[4]^[5] — but can be normal in mild vWD ^[2]

From the GC lecture: "Isolated prolonged aPTT suggests issues (deficiency or inhibition) with intrinsic or common pathway: Factor 8, Factor 9, Factor 11, Factor 12. Von Willebrand disease → since it protects Factor 8." ^[5]

Why is only aPTT prolonged?

vWF carries Factor VIII → ↓vWF → ↓FVIII → prolonged aPTT (FVIII is in the intrinsic pathway)
PT measures the extrinsic pathway (Factor VII) which is independent of vWF → remains normal
This is why the pattern is "isolated prolonged aPTT" — the same pattern as haemophilia A/B

Test	Principle	Expected in vWD
Bleeding time (BT)	In vivo test of primary haemostasis (platelet plug formation) — a small standardised cut is made on the forearm and the time to stop bleeding is measured	Prolonged in vWD (defective platelet adhesion) — but poor sensitivity and reproducibility; largely replaced by PFA-100
PFA-100	In vitro test simulating primary haemostasis: blood is passed under high shear through a collagen-coated membrane with either epinephrine (EPI) or ADP — closure time is measured	Prolonged closure time in vWD (especially collagen/EPI cartridge); highly sensitive screening test for vWD; can be normal in mild Type 1 or Type 2N

PFA-100 interpretation:

Prolonged collagen/EPI AND collagen/ADP: vWD, platelet function defect, anaemia (Hb < 10 g/dL), thrombocytopenia
Prolonged collagen/EPI, Normal collagen/ADP: Aspirin effect
PFA-100 is a good screening test but NOT diagnostic — it must be followed by specific vWF assays

The mixing study is performed when aPTT is prolonged to determine whether it is due to factor deficiency or an inhibitor ^[5]^[14].

Step	Method
1	Mix 50% patient plasma with 50% normal pooled plasma ^[5]
2	Measure aPTT of the mixture
3	Interpret:

Result	Interpretation	Conditions
aPTT corrects	Factor deficiency — the normal plasma provides sufficient factor to normalise the test	vWD, Haemophilia A/B, Factor XI/XII deficiency ^[5]
aPTT does NOT correct	Inhibitor present — antibodies in patient plasma neutralise the factor provided by normal plasma	Lupus anticoagulant (immediate), acquired FVIII inhibitor (delayed after incubation) ^[5]

"Von Willebrand disease is just a deficiency of Factor 8 → so after mixing the patient's plasma (which has zero% Factor 8) with the healthy plasma (which has 100% Factor 8), you get a 50% Factor 8, which is sufficient to correct the APTT." ^[5]

"Lupus anticoagulant — antibodies in the patient's plasma begin immediately destroying the healthy plasma phospholipids → inability to correct the APTT." ^[5]

High Yield — GC Interactive Tutorial Case

From the GC Interactive Tutorial ^[4]^[14]: A 20-year-old man with prolonged bleeding after wisdom tooth extraction:

Hb 14.5 g/dL; WCC 9.5 × 10⁹/L; Platelet 260 × 10⁹/L
PT 10.5 seconds; aPTT 60 seconds (21–35)
Factor VIII level 0.13 u/mL; vWF:Ag 1.11 u/mL; vWF:RCo 1.22 u/mL

Interpretation: Isolated prolonged aPTT → intrinsic pathway defect. FVIII markedly low. vWF:Ag and vWF:RCo both normal → vWF itself is fine in terms of quantity and platelet-binding function. So if it is an isolated decrease in Factor 8, can either be: platelet function disorder (e.g. vWD) or Factor 8 deficiency or inhibition. ^[14] With normal vWF:Ag and RCo but low FVIII → this is either Type 2N vWD (defect in FVIII binding domain of vWF) or Haemophilia A. Need vWF:FVIII binding assay to differentiate. "1:1 mixing test to differentiate between deficiency and inhibition." ^[14]

3.2 Tier 2: vWD-Specific Screening Assays

These are the core tests that confirm or exclude vWD.

Feature	Detail
What it measures	Total amount of vWF protein in plasma (quantitative, not functional)
Method	ELISA or latex immunoassay
Normal range	~50–200 IU/dL (varies with blood group — Type O individuals ~25% lower)
Diagnostic threshold	< 30 IU/dL (< 30%) consistent with vWD ^[1]
Interpretation	Reduced in Types 1 and 3; may be mildly reduced in 2A, 2B; normal in Types 2N and 2M ^[3]

Why is vWF:Ag alone insufficient? Because it only tells you how much vWF is present, not how well it works. A patient with Type 2 vWD may have near-normal vWF:Ag but severely impaired function → you need functional assays.

Feature	Detail
What it measures	Functional ability of vWF to bind platelet GPIb — this is the most important functional assay
Principle	Ristocetin (an antibiotic) artificially induces vWF-GPIb binding in vitro → measures how well patient's vWF agglutinates normal formalin-fixed platelets → this is the ristocetin cofactor assay (vWF:RCo) ^[1]^[2]
Normal range	~50–200 IU/dL
Diagnostic threshold	< 30 IU/dL consistent with vWD ^[1]
Interpretation	Reduced in Types 1, 2A, 2B, 2M, 3; normal in Type 2N ^[3] (because the platelet-binding function is intact in 2N — the defect is in FVIII binding)

Newer assays replacing vWF:RCo:

vWF:GPIbM (gain-of-function GPIb mutation assay) — measures vWF binding to a mutant GPIb that does not require ristocetin → more specific, less variability
vWF:GPIbR (ristocetin-dependent) — improved version of traditional RCo
These are becoming the standard in many labs (including reference labs in HK)

"vWF:Ag levels are largely normal (vWF:RCo to vWF:Ag ratio < 0.7) in von Willebrand disease types 2A and 2B, but vWF:RCo may be normal or decreased in types 2N and 2M." ^[4]

Feature	Detail
What it measures	Coagulant activity of Factor VIII
Normal range	50–150 IU/dL (0.50–1.50 u/mL)
Interpretation in vWD	Mildly ↓ in Types 1, 2A, 2B, 2M; significantly ↓ in Types 2N and 3 ^[2]
Key point	FVIII is intrinsically normal in vWD — it is low because vWF cannot protect it from proteolytic degradation in plasma

Ratio	Interpretation
> 0.7	Concordant reduction — both quantity and function are proportionally reduced → Type 1 or Type 3
< 0.5–0.7	Discordant reduction — function is disproportionately impaired relative to quantity → Type 2 (qualitative defect) ^[2]

Why does this ratio work?

In Type 1: vWF is structurally normal but present in lower amounts → both Ag and Act fall proportionally → ratio preserved
In Type 2: vWF is dysfunctional → Act falls more than Ag → ratio is low
This is the single most useful screening calculation to distinguish Type 1 from Type 2

"vWF Act:Ag ratio < 0.5–0.7 indicates discordant activity/quantity, i.e. Type 2." ^[2]

"Why need Ag and RCo? To identify different types." ^[4]

3.3 Tier 3: Subtyping Investigations

Once vWD is confirmed (Tier 2), these tests differentiate between subtypes.

Feature	Detail
What it measures	Distribution of vWF multimer sizes by gel electrophoresis — visualises the spectrum from small to ultra-large multimers
Interpretation

Type	Multimer Pattern
Type 1	All multimers present and uniformly decreased ^[3]
Type 2A	Decreased/absent HMW (high molecular weight) multimers ^[3] — because of defective multimer assembly or increased proteolysis
Type 2B	Decreased/absent HMW multimers ^[3] — because the large multimers preferentially bind platelets and are cleared
Type 2M	All multimers present and uniformly decreased ^[3] — normal spectrum because the polymerisation is intact; the defect is in GPIb binding, not multimer structure
Type 2N	Normal ^[3] — the multimer structure and platelet-binding function are intact; only the FVIII binding site is affected
Type 3	Absent / undetectable — no vWF at all

Key clinical reasoning: If multimer analysis shows loss of HMW multimers, the differential is 2A vs 2B. Differentiate by RIPA (see below). If multimers are normal but Act:Ag ratio < 0.7, it is 2M (if FVIII normal) or 2N (if FVIII low).

Feature	Detail
What it measures	How the patient's own platelets + vWF respond to different concentrations of ristocetin — tests the in vivo platelet-vWF interaction
How it differs from vWF:RCo	RCo uses normal fixed platelets + patient plasma (tests vWF function alone); RIPA uses patient's own live platelets + patient plasma (tests the whole platelet-vWF system)
Standard dose	1.0–1.5 mg/mL (normal causes aggregation)
Low dose	< 0.5 mg/mL (normally does NOT cause aggregation)

Type	RIPA at Standard Dose	RIPA at Low Dose	Interpretation
Type 1	↓ or Normal	Normal (absent)	Less vWF available → less aggregation
Type 2A	↓	Normal (absent)	Loss of HMW multimers → less effective binding
Type 2B	May be ↓ at standard dose	Enhanced (present at < 0.5 mg/mL) ^[3]	Gain-of-function: vWF binds platelets too avidly → aggregation occurs even at very low ristocetin concentrations
Type 2M	↓	Normal (absent)	Defective GPIb binding despite normal multimers
Type 2N	Normal	Normal (absent)	Platelet binding is intact; only FVIII binding affected
Type 3	Absent	Absent	No vWF → no aggregation at any concentration

Type 2B — Enhanced RIPA Is Pathognomonic

RIPA enhanced at low-dose ristocetin (< 0.5 mg/mL) is the hallmark of Type 2B vWD ^[3]. This is because the gain-of-function A1 domain mutation causes vWF to bind GPIb spontaneously or with minimal stimulus. The same mechanism explains the thrombocytopenia (platelets are consumed by spontaneous binding and clearance). Caution: Platelet-type (pseudo-) vWD also shows enhanced RIPA → differentiate by mixing patient plasma with normal platelets (2B: enhanced; pseudo-vWD: not enhanced, because the defect is on the platelet, not the vWF).

Feature	Detail
What it measures	The ability of patient's vWF to bind exogenous Factor VIII
When to order	When FVIII is disproportionately low relative to vWF:Ag (i.e. vWF:Ag normal but FVIII low) — to distinguish Type 2N vWD from Haemophilia A
Result in Type 2N	Abnormal (reduced binding) — the D'/D3 domain of vWF is mutated → cannot hold FVIII
Result in Haemophilia A	Normal — vWF can bind FVIII normally, but FVIII is intrinsically deficient

From the Interactive Tutorial: "So if it is an isolated decrease in Factor 8, can either be: platelet function disorder (e.g. vWD) or Factor 8 deficiency or inhibition. 1:1 mixing test to differentiate between deficiency and inhibition." ^[14] Then if deficiency: measure vWF:Ag, vWF:RCo; if both normal but FVIII low → vWF:FVIII binding assay.

Feature	Detail
What it measures	vWF's ability to bind collagen (via A3 domain) — preferentially measures HMW multimers (which have more collagen-binding sites)
Interpretation	Low in Types 1, 2A, 2B, 3; may be more sensitive than vWF:RCo for detecting loss of HMW multimers
Limitation	Not widely available in all labs; results vary depending on collagen type used

Feature	Detail
What it provides	Identifies the specific mutation in the VWF gene (chromosome 12)
When to order	(1) Confirm Type 2B vs pseudo-vWD; (2) Identify carriers in families with Type 3; (3) Confirm Type 2N; (4) Prenatal diagnosis; (5) When phenotypic tests are equivocal
Limitation	Expensive; the VWF gene is large (52 exons) and has a pseudogene on chromosome 22 that complicates analysis; many private mutations → interpretation challenging

These points are frequently overlooked but can lead to misdiagnosis:

Issue	Impact	Solution
Stress of phlebotomy	vWF is released from Weibel-Palade bodies → falsely elevated levels → false negative result ^[2]	Calm patient; avoid prolonged tourniquet time; repeat testing if clinical suspicion is high
Exercise	Raises vWF transiently	Test at rest
Pregnancy / OCP	Oestrogen raises vWF (up to 2–3×)	Test when not on OCP; if pregnant, defer definitive testing to > 6 weeks post-partum
Menstrual cycle	vWF varies with cycle — lowest during days 1–4	Consider testing in early follicular phase
Blood group O	~25% lower vWF levels constitutively	Interpret results with knowledge of blood group; some labs use blood-group-specific reference ranges
Inflammation / infection	Acute-phase response raises vWF	Test when patient is well
Repeat testing	Single result may be misleading	At least 2 separate samples on different occasions recommended

Important — False Normals in vWD

A single normal set of vWF assays does NOT exclude vWD. The biological variability of vWF (acute-phase reactant, hormone-responsive, blood-group-dependent) means results can fluctuate above and below diagnostic thresholds. When clinical suspicion is high, repeat testing on separate occasions, ideally under standardised conditions.

While primarily a therapeutic tool, DDAVP testing is also used diagnostically to predict treatment response:

Feature	Detail
Principle	DDAVP (1-desamino-8-D-arginine vasopressin) binds to V2 receptors on endothelial cells → triggers release of stored vWF (and FVIII) from Weibel-Palade bodies into circulation ^[14]
Protocol	0.3 μg/kg IV over 30 min; measure vWF:Ag, vWF:Act, FVIII at baseline, 1h, and 4h post-infusion
Interpretation	Responders show ≥ 2-fold rise in vWF/FVIII; Type 1 patients are usually good responders; Type 2/3 are variable/poor
Contraindication	Type 2B — DDAVP releases more abnormal vWF → worsens thrombocytopenia by inducing further spontaneous platelet-vWF binding and clearance

"Desmopressin for surgery — DDAVP binds to V2 receptor in endothelial cells and platelets release Factor VIII (synthesised by and stored in endothelial cells and platelets) into circulation." ^[14]

When the clinical picture suggests acquired vWD (late onset, no family history, associated condition):

Investigation	Purpose
CBC with platelet count	Extreme thrombocytosis > 1000 × 10⁹/L → think ET with acquired vWS ^[6]^[13]
JAK2 V617F mutation	Screen for MPN if thrombocytosis present ^[13]
Echocardiography	Aortic stenosis → Heyde syndrome ^[11]
Serum protein electrophoresis, immunofixation	MGUS, lymphoproliferative disorder → vWF adsorbed onto tumour cells or cleared by autoantibodies
Thyroid function	Hypothyroidism → decreased vWF synthesis
Anti-vWF antibody assay	Detects autoantibodies; present in autoimmune-mediated AVWS
vWF propeptide (vWFpp) to vWF:Ag ratio	Elevated ratio indicates increased vWF clearance (vWFpp is co-released with vWF but has a longer half-life → if vWF is cleared rapidly, ratio rises)

"When the patient has extreme thrombocytosis with bleeding tendency → want to exclude Acquired von Willebrand disease (AvWD). Excess platelets will consume excess von Willebrand factor." ^[13]

Investigation	Tier	What It Tests	Key Findings in vWD
CBC + PBS	1	Platelet count, morphology	Normal (except thrombocytopenia in 2B); giant platelets → BSS not vWD
PT	1	Extrinsic pathway	Normal
aPTT	1	Intrinsic pathway	Isolated prolonged (may be normal in mild disease) ^[2]^[5]
PFA-100	1	Primary haemostasis	Prolonged closure time (screening)
Mixing study	1–2	Deficiency vs inhibitor	Corrects in vWD ^[5]
vWF:Ag	2	vWF quantity	< 30 IU/dL = definite vWD ^[1]
vWF:Act / RCo	2	vWF platelet-binding function	< 30 IU/dL; disproportionately low in Type 2
FVIII activity	2	Factor VIII coagulant activity	Low (proportional to vWF in most types; very low in 2N, 3)
vWF Act:Ag ratio	2–3	Concordance of quality vs quantity	> 0.7 = Type 1/3; < 0.7 = Type 2 ^[2]
Multimer analysis	3	Multimer size distribution	Loss of HMW in 2A, 2B; normal in 1, 2M, 2N
RIPA	3	Platelet-vWF interaction at different ristocetin concentrations	Enhanced at low dose in 2B ^[3]; decreased in 2A, 2M; absent in 3
vWF:FVIII binding assay	3	vWF-FVIII binding	Abnormal in Type 2N (distinguishes from Haemophilia A)
Collagen binding assay	3	vWF-collagen binding	Low in 2A (sensitive for HMW multimer loss)
Genetic testing	3	VWF gene mutation	Confirmatory; especially for 2B vs pseudo-vWD, carrier detection
DDAVP challenge	Therapeutic/diagnostic	Predicted treatment response	Good response in Type 1; variable/contraindicated in 2B/3

High Yield Summary — Diagnostics for vWD

vWD diagnosis requires: (1) personal bleeding history, (2) family history, (3) lab evidence of reduced vWF level/function ^[1]^[2]^[3]
Definite vWD: vWF:Ag and/or vWF:Act < 30 IU/dL; "low vWF" = 30–50 IU/dL ^[1]
Isolated prolonged aPTT is the hallmark — but can be normal in mild disease ^[2]^[5]
Mixing study corrects in vWD (deficiency); does NOT correct in lupus AC (inhibitor — immediately) or acquired FVIII inhibitor (delayed) ^[5]
vWF Act:Ag ratio > 0.7 = Type 1/3 (quantitative); < 0.7 = Type 2 (qualitative) ^[2]^[4]
RIPA enhanced at low-dose ristocetin = Type 2B (pathognomonic); RIPA decreased = 2A, 2M; absent = Type 3 ^[3]
vWF:FVIII binding assay distinguishes Type 2N (abnormal) from Haemophilia A (normal) ^[3]^[14]
Multimer analysis: loss of HMW = 2A or 2B; normal spectrum = 1, 2M, 2N ^[3]
In Hong Kong, Factor XII deficiency (~20%) is the most common cause of isolated prolonged aPTT — does NOT cause bleeding — always correlate with clinical context ^[5]
DDAVP challenge: good responders = Type 1; contraindicated in Type 2B (worsens thrombocytopenia) ^[14]

Active Recall — Diagnostics of Von Willebrand Disease

References

^[1] Senior notes: Adrian Lui Pediatrics Notes.pdf (p395, vWD laboratory features) ^[2] Senior notes: Ryan Ho Haemtology.pdf (pp127–128, Section 4.3.3 vWD laboratory features) ^[3] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (p1361–1363, vWD Classification table); MBBS Final MB (Pediatrics) (Felix PY Lai).pdf (p601) ^[4] Senior notes: Block A - Hematology Interactive Tutorial.pdf (pp5–6, Case 2 vWD workup) ^[5] Senior notes: Block A - Introduction to Haematological investigations (CBP, Clotting).pdf (pp21–22, Mixing study, Factor XII deficiency) ^[6] Senior notes: Block A - Splenomegaly_ common causes of splenomegaly; myeloproliferative diseases.pdf (p29, ET and acquired vWD) ^[11] Senior notes: Block A - Coffee ground vomitus tarry stool upper GI bleeding.pdf (p8, Heyde syndrome) ^[13] Senior notes: Block A - Leg swelling and chest pain_ deep vein thrombosis; pulmonary embolism; Thrombophilia.pdf (p18, MPN and acquired vWD) ^[14] Senior notes: Block A - Hematology Interactive Tutorial.pdf (p7, vWD vs haemophilia workup, DDAVP mechanism); Lecture slides: GC_Interactive tutorial (Haem case 2) student copy.pdf (p2)

Management of Von Willebrand Disease

The management of vWD is guided by three core questions:

What type of vWD does the patient have? → determines which treatments are appropriate or contraindicated
What is the clinical scenario? → acute bleeding vs peri-operative prophylaxis vs long-term management
Does the patient respond to DDAVP? → the single most important therapeutic decision point

The overarching goal is to restore haemostasis by increasing functional vWF and Factor VIII levels to sufficient thresholds for the clinical context. Because vWD involves a dual defect (platelet adhesion + FVIII stability), effective treatment must address both components.

From the GC lecture on haemostatic disorders: Coagulation disorders are treated with specific factors / factor concentrates (haemophilia, vWD) and DDAVP (vWD) ^[7]

3. Treatment Modalities — Detailed

3.1 DDAVP (Desmopressin / 1-Deamino-8-D-Arginine Vasopressin)

DDAVP is the first-line treatment for most patients with Type 1 vWD and select Type 2 patients.

DDAVP binds to V2 receptors on endothelial cells and platelets → release Factor VIII (synthesised by and stored in endothelial cells and platelets) into circulation ^[14]. More precisely:

DDAVP is a synthetic analogue of vasopressin (ADH) — "desmopressin" = "des-amino" (removed amino group) + "D-arginine" (modified amino acid at position 8)
It selectively activates V2 receptors (renal/endothelial) without significant V1 receptor activation (so less vasoconstriction/hypertension than native vasopressin)
V2 receptor activation on endothelial cells → exocytosis of Weibel-Palade bodies → release of stored vWF (as ultra-large multimers) and FVIII into the circulation
This typically produces a 2–5 fold increase in vWF and FVIII levels within 30–60 minutes
The V2 receptor also mediates antidiuretic effect → water retention → this is why hyponatraemia is a risk

Route	Dose	Onset	Duration
IV (preferred for acute/peri-operative)	0.3 μg/kg in 50 mL NS over 30 min ^[15]	30–60 min	6–12 hours
SC	0.3 μg/kg	60–90 min	6–12 hours
Intranasal (Stimate® high-concentration spray)	150 μg per spray (1 spray if < 50 kg, 2 sprays if ≥ 50 kg)	60 min	6–12 hours

A DDAVP trial (test dose) should be performed before the drug is needed clinically (e.g. electively before planned surgery) to determine if the patient is a "responder"
Responder: vWF:Act and FVIII rise to > 50 IU/dL (or ≥ 2-fold increase from baseline) at 1 hour post-dose and remain > 30 IU/dL at 4 hours
Results are documented in the patient's record so that future clinicians know whether DDAVP is an option

Type	DDAVP Effectiveness	Comments
Type 1	First-line — most patients are responders (~80%)	Best candidates; DDAVP releases structurally normal vWF from stores
Type 2A	Variable / partial response	Released vWF still lacks HMW multimers (structural defect or increased proteolysis); response may be suboptimal and short-lived
Type 2M	Variable	Released vWF may still have impaired GPIb binding
Type 2N	May raise FVIII transiently	vWF released cannot bind FVIII properly → effect is short-lived as FVIII is rapidly degraded once released
Mild Haemophilia A	Effective (used for minor procedures) ^[14]	Same mechanism — releases endothelial FVIII stores

Contraindication	Reason
Type 2B vWD	DDAVP releases more abnormal (gain-of-function) vWF → further spontaneous platelet-vWF binding → worsens thrombocytopenia and may paradoxically increase bleeding
Type 3 vWD	No vWF stores to release (Weibel-Palade bodies are empty or absent) → DDAVP is ineffective
Children < 2 years	High risk of hyponatraemia (immature renal concentrating ability, often on dilute feeds)
Patients with cardiovascular disease	Fluid retention → risk of fluid overload, hypertension
Habitual polydipsia	↑ risk of water intoxication with hyponatraemia
Pregnancy (relative)	Can be used with caution but prefer vWF concentrate for major bleeding

DDAVP — Key Contraindication in Type 2B

DDAVP is CONTRAINDICATED in Type 2B vWD. The gain-of-function vWF released by DDAVP will spontaneously bind circulating platelets, causing further consumption and clearance of both platelets and large vWF multimers. This worsens the thrombocytopenia and can precipitate clinically significant bleeding. Always check the vWD subtype before administering DDAVP.

Side Effect	Mechanism	Prevention
Hyponatraemia / water intoxication	V2-mediated antidiuretic effect → water retention → dilutional hyponatraemia	Fluid restrict to 1–1.5 L for 24h post-dose; monitor Na+ (especially in children and elderly); avoid in children < 2 years
Flushing, headache, tachycardia	Mild vasodilatory effects	Usually mild and transient
Tachyphylaxis	Repeated doses deplete Weibel-Palade body vWF stores → diminishing response	Limit to 2–3 doses over 24–48 hours; then switch to vWF concentrate if further treatment needed; allow ≥ 24h between doses for store replenishment
Rare: seizures	Severe hyponatraemia	Monitor Na+, restrict fluids

From the CKD/uraemic bleeding notes: "Desmopressin (DDAVP): ↑F8/vWF release from endothelium → simplest, most rapidly acting. Dose: 0.3 μg/kg SC 1h or 40 μg intranasal BD for 2d then off." ^[15]

3.2 vWF-Containing Factor Concentrates (Replacement Therapy)

When DDAVP is contraindicated, ineffective, or insufficient for the clinical situation, exogenous vWF replacement is needed.

Product	Components	Source	Key Features
Plasma-derived vWF/FVIII concentrates (e.g. Humate-P®, Haemate P®, Wilate®)	Contain both vWF and FVIII	Human plasma (virus-inactivated)	Gold standard for vWD; varying vWF:FVIII ratios depending on product
Plasma-derived vWF concentrate (e.g. Wilfactin®)	Contains vWF only (minimal FVIII)	Human plasma	Used when FVIII levels are adequate or to avoid FVIII accumulation with repeated dosing
Recombinant vWF (Vonvendi® / vonicog alfa)	Pure recombinant vWF (no FVIII)	Recombinant (CHO cells)	No FVIII — endogenous FVIII will rise secondarily as vWF stabilises it; requires initial co-administration with rFVIII for acute bleeding; lower infectious risk

From the GC lecture: Treatment of coagulation disorders includes "specific factors / factor concentrates (haemophilia, vWD)" ^[7]

Dosing is based on vWF:RCo units (not FVIII units, unless using an FVIII-predominant product)
1 IU/kg of vWF:RCo raises plasma vWF:RCo by approximately 1.5–2 IU/dL
Target levels depend on clinical scenario:

Scenario	Target vWF:Act / FVIII	Duration
Minor surgery / dental extraction	> 50 IU/dL	1–5 days
Major surgery	> 80–100 IU/dL (peri-operative); maintain > 50 IU/dL for 7–14 days	7–14 days
Life-threatening bleeding	> 100 IU/dL immediately	Until haemostasis secured
Delivery / C-section	> 50 IU/dL (aim > 80 at delivery)	Through delivery + 3–5 days post-partum

Measure vWF:Act and FVIII pre- and post-infusion (trough levels before next dose)
Avoid excessive FVIII accumulation (> 150–200 IU/dL for prolonged periods) → risk of venous thromboembolism (VTE)
When using vWF-only products: FVIII will rise secondarily over 6–24 hours as the infused vWF stabilises endogenous FVIII

Indication	Rationale
Type 2B vWD (all clinical scenarios)	DDAVP contraindicated → vWF concentrate is the first-line
Type 3 vWD (all clinical scenarios)	No endogenous vWF stores → DDAVP ineffective → must give exogenous vWF
Type 2N vWD	DDAVP has limited effect because released vWF cannot bind FVIII → need vWF/FVIII concentrate
DDAVP non-responders (any type)
Major surgery / life-threatening bleeding (any type)	Even DDAVP responders may need concentrate for major procedures where sustained high levels are required
Repeated dosing needed (tachyphylaxis with DDAVP)	After 2–3 doses of DDAVP, endothelial stores are depleted → switch to concentrate

Concern	Detail
Allergic / anaphylactic reactions	Rare but possible, especially with plasma-derived products; more common in Type 3 patients who may develop anti-vWF alloantibodies
Thromboembolism	Risk with excessive FVIII accumulation (> 150–200 IU/dL over days) → monitor and reduce dose or extend interval
Transfusion-transmitted infection	Theoretical risk with plasma-derived products (virus-inactivated but not zero risk); eliminated with recombinant vWF

3.3 Antifibrinolytic Agents

These are adjunctive therapies used alongside DDAVP or factor concentrates, particularly for mucosal bleeding.

Tranexamic acid ("trans" = trans isomer, "examic" = from ε-aminocaproic acid derivative): a synthetic lysine analogue that competitively inhibits plasminogen activation → prevents fibrinolysis → stabilises the fibrin clot once formed
Aminocaproic acid (ε-aminocaproic acid, EACA): same mechanism, less potent, shorter acting

In vWD, the primary platelet plug is weak (defective adhesion) → the secondary fibrin clot becomes proportionally more important for maintaining haemostasis
Mucosal surfaces (oral cavity, nasal, uterine, GI) are rich in tissue plasminogen activator (tPA) → high fibrinolytic activity → clots at mucosal surfaces break down quickly
Antifibrinolytics protect these vulnerable clots from premature lysis

From the haemophilia management notes: "Mucosal bleeding: add antifibrinolytic agents, e.g. tranexamic acid, aminocaproic acid" ^[2]

Drug	Route	Dose	Frequency
Tranexamic acid	Oral	1–1.5 g (or 25 mg/kg)	TDS–QDS for 5–7 days
	IV	10 mg/kg	TDS
	Mouthwash	5% solution, 10 mL	QDS (swish and spit for dental procedures)
Aminocaproic acid	Oral / IV	50–60 mg/kg	Q4–6h (max 24 g/day)

Epistaxis
Gum bleeding / dental procedures (mouthwash is highly effective)
Menorrhagia (first-line for many women with vWD and HMB)
GI mucosal bleeding (oral route)
Post-tonsillectomy bleeding
As adjunct to DDAVP or concentrate for any mucosal bleeding

Contraindication	Reason
Haematuria / upper urinary tract bleeding	Antifibrinolytics can stabilise clots within the renal collecting system/ureter → ureteric obstruction → renal colic or hydronephrosis
DIC	Inhibiting fibrinolysis in DIC can precipitate widespread microvascular thrombosis
Active thrombosis / history of VTE (relative)	Theoretically prothrombotic; use with caution

Exam Trap — Antifibrinolytics and Haematuria

Never give tranexamic acid for haematuria in vWD (or any condition). The stabilised clot within the ureter can cause obstruction. For haematuria in haemostatic disorders, treat with forced diuresis if not severe ^[2].

Agent	Mechanism	Indication	Notes
Combined OCP / oestrogen-containing contraception	Oestrogen stimulates endothelial production of vWF and FVIII → raises plasma levels	Heavy menstrual bleeding (HMB) in vWD	May raise vWF to near-normal in Type 1; less effective in Types 2 and 3; also directly reduces endometrial proliferation
Levonorgestrel IUS (Mirena®)	Local progestogen → endometrial atrophy → reduced menstrual loss	HMB in vWD	Very effective; no effect on vWF levels but reduces the bleeding substrate
Tranexamic acid (oral, during menses)	Antifibrinolytic at uterine mucosal surface	First-line adjunct for HMB	Can be combined with hormonal therapy

Product	Content	Role in vWD
Cryoprecipitate	Rich in vWF, FVIII, fibrinogen, FXIII	Historically used before specific vWF concentrates became available; still used in resource-limited settings; NOT virus-inactivated → infection risk; contains HMW multimers → haemostatically effective
Fresh Frozen Plasma	Contains all coagulation factors at physiological concentrations	Volume-limited (risk of fluid overload); not first-line for vWD

Current practice: Cryoprecipitate and FFP are not recommended as first-line for vWD when specific vWF concentrates are available. They are reserved for emergencies when concentrates are unavailable.

"Cryoprecipitate and FFP: usually reserved for major bleeding due to potential risk of complications" ^[15]

Not routinely indicated in vWD because platelet count is usually normal
Exception: Type 2B vWD with severe thrombocytopenia — platelet transfusion may be needed alongside vWF concentrate peri-operatively
Note: transfused platelets also contain vWF in their α-granules → may provide additional haemostatic benefit in Type 3 patients who have developed alloantibodies against infused vWF

Agent	Mechanism	Status
Emicizumab	Bispecific antibody mimicking FVIII (bridges FIXa and FX)	Approved for haemophilia A with inhibitors; being studied in Type 3 vWD with very low FVIII; does not address the platelet adhesion defect
Aptamer-based anti-vWF agents (e.g. caplacizumab — reverse situation, used in TTP)	Blocks vWF-GPIb interaction	Not therapeutic for vWD (opposite effect); mentioned for completeness
Gene therapy	Aims to restore functional VWF gene expression	Early clinical trials; VWF gene is very large (8.5 kb cDNA) making vector design challenging
Fitusiran	Anti-antithrombin siRNA → lowers antithrombin → enhances thrombin generation	Being studied in vWD as non-replacement therapy to rebalance haemostasis

4. Management by Clinical Scenario

Severity	First-Line	Adjuncts
Minor mucosal bleeding (epistaxis, gum bleeding)	DDAVP (if responder)	Tranexamic acid (oral or mouthwash); local measures (nasal packing, pressure)
Moderate bleeding (prolonged dental extraction bleeding, heavy menorrhagia)	DDAVP (if responder) OR vWF concentrate	Tranexamic acid
Severe / life-threatening bleeding (GI haemorrhage, ICH, post-surgical bleeding)	vWF/FVIII concentrate → immediate replacement (treat upon suspicion, not diagnosis) ^[2]	Tranexamic acid (unless haematuria); supportive care

"Severe, life-threatening bleeding: immediate replacement — treat upon suspicion, not dx" ^[2]

Step	Action
Pre-operative assessment	Confirm vWD type; review DDAVP trial result; plan product and dosing; alert surgical and anaesthetic teams
Pre-operative dose	DDAVP 0.3 μg/kg IV 30 min before procedure (if responder, minor surgery) OR vWF concentrate 30–60 IU/kg 1 hour before (major surgery or DDAVP non-responder)
Intra-operative	Avoid NSAIDs; use haemostatic surgical techniques; tranexamic acid 1 g IV pre-incision for mucosal procedures
Post-operative	Repeat dosing to maintain vWF:Act and FVIII > 50 IU/dL (minor) or > 80 IU/dL (major) for 5–14 days; monitor levels
Regional anaesthesia	Generally acceptable if vWF:Act and FVIII > 50 IU/dL; avoid neuraxial if levels inadequate (risk of spinal/epidural haematoma)

Trimester	vWF/FVIII Trend	Action
1st trimester	Baseline levels	Genetic counselling; document vWD type
2nd–3rd trimester	vWF and FVIII rise (2–3× by term, as vWF is an acute-phase reactant + oestrogen-driven)	Check levels at 34–36 weeks
If vWF/FVIII > 50 IU/dL at 36 weeks	Normal delivery plan; epidural usually safe	Monitor post-partum
If vWF/FVIII remain < 50 IU/dL	Administer vWF concentrate to cover delivery	Type 3 patients almost always need concentrate
Post-partum	vWF levels decline precipitously after delivery → risk of delayed PPH (secondary PPH, days 1–14) ^[2]	Continue vWF monitoring for 5–7 days post-delivery; maintain vWF > 50 IU/dL; tranexamic acid for 7–14 days

High Yield — Post-Partum Risk in vWD

vWF levels decline precipitously after delivery ^[2]. Even women whose levels normalised during pregnancy can develop delayed (secondary) post-partum haemorrhage as vWF falls. Post-partum bleeding occurs in 62% of women with vWD ^[2]. Planning must include post-delivery monitoring and prophylaxis.

Measure	Detail	Rationale
Avoid aspirin and NSAIDs	These inhibit platelet function (COX-1 → reduced TXA2 → impaired platelet aggregation) → worsen the already-defective primary haemostasis in vWD	Use paracetamol or COX-2 inhibitors for analgesia ^[2]
MedicAlert identification	Bracelet/card stating vWD type, DDAVP response status, blood group	Essential for emergency situations
Genetic counselling	Inform family members; carrier testing; prenatal diagnosis for Type 3	Autosomal inheritance → relevant for all family members
Iron supplementation	Chronic mucosal blood loss → iron deficiency anaemia	Monitor ferritin; supplement as needed
Avoid IM injections (when possible)	Risk of muscle haematoma (especially in Type 3 / 2N)	Use SC or IV routes
Dental hygiene	Prevent dental caries/periodontal disease → reduce need for dental procedures	Regular dental check-ups
Hepatitis A and B vaccination	If patient may need plasma-derived products	IM injection should be covered with DDAVP or concentrate, or given SC
Exercise modification	Avoid contact sports (especially Type 3)	Low-impact exercise encouraged

From the Interactive Tutorial: "Lifestyle changes — avoid trivial trauma" ^[14] "Haemarthrosis: analgesics (e.g. COX-2, Panadol → avoid NSAID), RICE as needed" ^[2]

Type	First-Line	Second-Line	Contraindications / Cautions	Adjuncts
Type 1	DDAVP (most are responders)	vWF concentrate if DDAVP non-responder or major surgery	Tachyphylaxis after 2–3 doses	Tranexamic acid for mucosal bleeding
Type 2A	DDAVP trial (variable response)	vWF concentrate	Response often partial/short-lived	Tranexamic acid
Type 2B	vWF concentrate (first-line)	Platelet transfusion if severely thrombocytopenic	DDAVP CONTRAINDICATED (worsens thrombocytopenia)	Tranexamic acid
Type 2M	DDAVP trial (variable)	vWF concentrate	—	Tranexamic acid
Type 2N	vWF/FVIII concentrate	—	DDAVP effect short-lived (released vWF cannot bind FVIII)	—
Type 3	vWF/FVIII concentrate (always)	Platelet transfusion ± cryoprecipitate in emergencies	DDAVP ineffective (no vWF stores); risk of anti-vWF alloantibodies	Tranexamic acid; long-term prophylaxis may be needed

Cause	Management
Essential thrombocythaemia (platelets > 1000) ^[6]	Cytoreduction (hydroxyurea) to lower platelet count → reduces vWF consumption → vWF levels normalise; short-term: DDAVP or vWF concentrate for acute bleeding
Aortic stenosis (Heyde syndrome)	Aortic valve replacement → eliminates the high shear stress → vWF HMW multimers recover; DDAVP or vWF concentrate as bridge
Lymphoproliferative disorders / MGUS	Treat underlying malignancy; IVIG (0.4 g/kg/day × 5 days) → may transiently raise vWF by blocking autoantibody-mediated clearance
Hypothyroidism	Thyroid hormone replacement → vWF synthesis normalises
Autoimmune-mediated	Immunosuppression (corticosteroids, rituximab); IVIG as above

DDAVP is also used outside of vWD — in uraemic bleeding (CKD patients), where the mechanism is different but the drug is equally useful:

"Desmopressin (DDAVP): ↑F8/vWF release from endothelium → simplest, most rapidly acting" ^[15]

In uraemia: platelet dysfunction is caused by uraemic toxins + ↑NO → DDAVP releases vWF from endothelium → improves platelet adhesion → short-term correction of bleeding time
This demonstrates that DDAVP's benefit extends beyond vWD to any condition where vWF-mediated platelet adhesion needs augmentation

High Yield Summary — Management of vWD

DDAVP (0.3 μg/kg IV) is first-line for Type 1 vWD — releases endogenous vWF and FVIII from Weibel-Palade bodies ^[7]^[14]
DDAVP is CONTRAINDICATED in Type 2B (worsens thrombocytopenia) and INEFFECTIVE in Type 3 (no vWF stores)
vWF-containing factor concentrates (plasma-derived or recombinant) are used when DDAVP is contraindicated, ineffective, or insufficient ^[7]
Antifibrinolytics (tranexamic acid) are essential adjuncts for mucosal bleeding — but contraindicated in haematuria (risk of ureteric obstruction) ^[2]
Avoid aspirin and NSAIDs — use paracetamol or COX-2 inhibitors for analgesia ^[2]
Tachyphylaxis occurs after 2–3 doses of DDAVP (store depletion) → switch to vWF concentrate
Hyponatraemia is the key DDAVP side effect — fluid restrict for 24h, monitor Na+
Post-partum: vWF drops precipitously → delayed PPH risk → monitor and treat for 5–7 days ^[2]
Acquired vWS in ET (platelets > 1000): treat with cytoreduction ^[6]
Target vWF:Act / FVIII > 50 IU/dL for minor procedures; > 80–100 IU/dL for major surgery
For life-threatening bleeding: "immediate replacement — treat upon suspicion, not dx" ^[2]

Active Recall — Management of Von Willebrand Disease

References

^[2] Senior notes: Ryan Ho Haemtology.pdf (pp127–128, Treatment of haemophilia-related bleeding, vWD clinical features and post-partum bleeding) ^[6] Senior notes: Block A - Splenomegaly_ common causes of splenomegaly; myeloproliferative diseases.pdf (p29, ET and acquired vWD) ^[7] Senior notes: Block A - Abnormal bleeding after tooth extraction_ bleeding tendency; thrombocytopenia.pdf (p8 and p11, Treatment options for coagulation disorders including DDAVP and factor concentrates) ^[14] Senior notes: Block A - Hematology Interactive Tutorial.pdf (p7, DDAVP mechanism, lifestyle changes); Lecture slides: GC_Interactive tutorial (Haem case 2) student copy.pdf ^[15] Senior notes: Ryan Ho Urogenital.pdf (p109, DDAVP dosing in uraemic bleeding, cryoprecipitate and FFP)

Complications of Von Willebrand Disease

Complications of vWD can be classified into three categories:

Direct bleeding-related complications — consequences of the haemostatic defect itself
Treatment-related complications — adverse effects of DDAVP, factor concentrates, or transfusion products
Psychosocial and quality-of-life complications — the chronic burden of living with a bleeding disorder

The severity and spectrum of complications depend heavily on the type of vWD. Most Type 1 patients live largely normal lives with only occasional bleeding problems. Types 2N and 3 can develop complications that rival haemophilia in their morbidity.

Feature	Detail
Mechanism	Chronic mucosal blood loss (menorrhagia, epistaxis, GI bleeding) → progressive depletion of iron stores → iron deficiency anaemia (IDA)
Why it matters	This is the most common complication of vWD overall — especially in women of reproductive age with heavy menstrual bleeding
Pathophysiology	Each mL of blood contains ~0.5 mg of iron. A woman with vWD losing 80–200 mL per menstrual cycle (vs normal 30–40 mL) loses 40–100 mg extra iron per month. Dietary iron absorption is only ~1–2 mg/day → the deficit accumulates over months
Clinical features	Fatigue, pallor, glossitis, koilonychia, pica; microcytic hypochromic anaemia on CBC; low ferritin
Management	Oral/IV iron supplementation; treat the underlying bleeding cause (hormonal therapy for HMB, DDAVP/vWF concentrate for recurrent mucosal bleeding)

High Yield — IDA as the Presenting Feature of vWD

Young women presenting with iron deficiency anaemia refractory to iron supplementation should be screened for vWD — some studies showed that 10–15% of women presenting with heavy menstrual bleeding have underlying vWD ^[2]. Always ask about bleeding history and family history before attributing IDA solely to dietary insufficiency.

Feature	Detail
Mechanism	Defective primary haemostasis (↓platelet adhesion) + reduced FVIII → inadequate clot formation at surgical sites
Common triggers	Dental extraction (the classic exam scenario ^[7]^[16]), tonsillectomy/adenoidectomy, orthopaedic surgery, endoscopy with biopsy
Why dental extraction is high-risk	The oral cavity is highly vascular and bathed in saliva that is rich in fibrinolytic enzymes (tissue plasminogen activator) → even a normally formed clot is rapidly dissolved → the platelet adhesion defect in vWD means the initial clot was already weak → double hit
Prevention	Pre-operative DDAVP or vWF concentrate; antifibrinolytics (tranexamic acid mouthwash); liaising with haematology before any procedure

From the GC lecture: "Treatment: haemophilia A/B, vWD — Factor concentrates (plasma derived or recombinant), DDAVP for some vWD" ^[16]

Feature	Detail
Mechanism	vWF levels decline precipitously after delivery ^[2] → loss of the pregnancy-induced protective rise → delayed (secondary) PPH occurring days to weeks after birth
Frequency	Post-partum bleeding occurs in 62% of women with vWD ^[2]
Pathophysiology	During pregnancy, oestrogen drives a 2–3 fold rise in vWF and FVIII (peaking at term). Within hours of placental delivery, oestrogen drops → vWF falls back to (or even below) baseline. The involuting uterus has exposed endometrial vessels that require effective haemostasis → the plummeting vWF levels leave these sites vulnerable
Type-specific risk	Type 1: moderate risk (some women normalise during pregnancy, others do not); Type 3: very high risk (vWF never normalises during pregnancy); Type 2N: high risk (FVIII remains functionally low)
Management	Monitor vWF/FVIII postpartum; maintain levels > 50 IU/dL for 5–7 days; tranexamic acid; vWF concentrate if levels inadequate

Feature	Detail
Mechanism	Two pathways: (1) mucosal bleeding from the primary haemostatic defect; (2) angiodysplasia (vascular malformations in the GI tract) — which is specifically associated with vWD Types 2A and 3, and with acquired vWS in aortic stenosis
Why angiodysplasia develops in vWD	vWF appears to have a role in regulating angiogenesis — deficiency of HMW multimers (as in Type 2A) or total vWF absence (Type 3) promotes dysregulated neovascularisation in the GI mucosa, forming fragile arteriovenous malformations that bleed easily
Clinical significance	GI bleeding can be recurrent, difficult to control, and is a major cause of morbidity in severe vWD; it is also the hallmark of Heyde syndrome (aortic stenosis + acquired vWS + angiodysplasia) ^[11]
Management	vWF concentrate for acute bleeding; endoscopic treatment (APC, coagulation) of visible angiodysplasia; long-term prophylaxis with vWF concentrate in recurrent cases; aortic valve replacement resolves Heyde syndrome

Feature	Detail
Which types?	Joint and tissue bleeding is usually only seen in Types 2N and 3 ^[1]^[2] — where FVIII is significantly reduced (mimicking haemophilia)
Mechanism	Very low FVIII → inadequate secondary haemostasis → bleeding into joint spaces (haemarthrosis) → synovial inflammation → if recurrent → chronic synovitis → cartilage destruction → haemophilic arthropathy
Comparison with haemophilia	Hemophilic arthropathy is a recognised complication of haemophilia A/B ^[14]. The identical mechanism operates in Type 3 vWD and severe Type 2N, because the final common pathway is FVIII deficiency. However, arthropathy is less common in vWD than in severe haemophilia because even Type 3 vWD usually has FVIII levels of 1–9 IU/dL (vs < 1 IU/dL in severe haemophilia A)
Clinical features	Recurrent painful, swollen joints (typically large joints: knees, ankles, elbows); progressive loss of range of motion; muscle wasting; joint deformity
Management	Acute: vWF/FVIII concentrate; analgesics (COX-2 inhibitors, paracetamol → avoid NSAIDs) ^[2]; RICE. Long-term: physiotherapy; prophylactic vWF concentrate in patients with recurrent haemarthroses; orthopaedic intervention (synovectomy, joint replacement) for end-stage arthropathy

"Complications: hemophilic arthropathy" ^[14] "Haemarthrosis: analgesics (e.g. COX-2, Panadol → avoid NSAID), RICE as needed" ^[2]

Why Avoid NSAIDs in vWD?

NSAIDs inhibit cyclooxygenase-1 (COX-1) → reduced thromboxane A2 (TXA2) → impaired platelet aggregation. In a patient with vWD who already has defective platelet adhesion, adding a platelet aggregation inhibitor is a "double hit" that significantly worsens bleeding risk. COX-2 selective inhibitors (e.g. celecoxib) spare COX-1 in platelets and are safer alternatives. Paracetamol has no significant antiplatelet effect and is the safest analgesic option.

Feature	Detail
Frequency	Rare but the most feared complication; estimated lifetime risk of ~2–4% in Type 3 vWD
Mechanism	Both the platelet adhesion defect (primary haemostasis) and low FVIII (secondary haemostasis) contribute → both platelet disorders and coagulation disorders can cause intracranial haemorrhage; cannot say one is more deadly than the other ^[7]
Risk factors	Type 3 > Type 2N > other types; head trauma; concurrent antiplatelet/anticoagulant use; neonatal period (traumatic delivery in undiagnosed Type 3)
Management	Emergency: immediate vWF/FVIII concentrate (target FVIII > 80–100 IU/dL); neurosurgical consultation; long-term prophylaxis after first ICH event

Feature	Detail
Which types?	Primarily Type 3 and severe Type 2N (where FVIII is very low)
Mechanism	Low FVIII → bleeding into muscle compartments after minor trauma → expanding haematoma → if within a closed fascial compartment → raised intra-compartmental pressure → compartment syndrome (compression of nerves and vessels → ischaemia)
Clinical features	Pain out of proportion to injury; tense swelling; pain on passive stretch of involved muscles; paraesthesia; pulselessness (late sign)
Management	Immediate vWF/FVIII concentrate; consider surgical decompression (fasciotomy) if failed medical therapy ^[2]; physiotherapy after resolution

Feature	Detail
Mechanism	Recurrent epistaxis → nasal mucosal trauma → further bleeding (vicious cycle)
Complications	Iron deficiency anaemia (chronic); nasal septal perforation (from repeated cauterisation); need for nasal packing (uncomfortable, can cause pressure necrosis); rarely, aspiration of blood
Management	Humidification; topical antifibrinolytics; DDAVP for acute episodes; ENT referral for cauterisation or septoplasty if recurrent

Complication	Mechanism	Prevention
Hyponatraemia / water intoxication	DDAVP activates V2 receptors → antidiuretic effect → water retention → dilutional hyponatraemia → can cause seizures if severe (Na+ < 120 mmol/L)	Fluid restrict to 1–1.5 L for 24h; monitor serum Na+; avoid in children < 2 years
Tachyphylaxis	Repeated DDAVP depletes Weibel-Palade body vWF stores → diminishing response after 2–3 doses within 48h	Limit to 2–3 doses; switch to vWF concentrate for ongoing cover
Facial flushing, headache, tachycardia	Mild vasodilatory and sympathetic effects	Usually self-limiting
Worsening thrombocytopenia in Type 2B	Released gain-of-function vWF binds platelets spontaneously → platelet-vWF complexes cleared → ↓platelet count	DDAVP is contraindicated in Type 2B

Complication	Mechanism	Details
Anti-vWF alloantibodies	Type 3 patients (who produce zero vWF) can develop alloantibodies against infused vWF — analogous to inhibitors in haemophilia ^[2]	Occurs in ~5–10% of Type 3 patients; presents as poor response to vWF concentrate AND can cause anaphylaxis upon re-exposure; detection: Bethesda-like assay or anti-vWF ELISA; management: avoid the product, use recombinant FVIII alone + platelet transfusions + antifibrinolytics for acute bleeding; immune tolerance induction has limited success
Thromboembolism	Excessive FVIII accumulation (> 150–200 IU/dL sustained over days) with repeated dosing of vWF/FVIII concentrate → supraphysiological FVIII levels → hypercoagulable state → DVT/PE	Monitor FVIII trough levels; use vWF-only concentrate (e.g. Wilfactin) or recombinant vWF (Vonvendi) for prolonged treatment courses to avoid FVIII stacking
Transfusion-transmitted infection	Plasma-derived products carry theoretical infectious risk (hepatitis, HIV, prions) despite virus inactivation	Use recombinant products when available; vaccinate against hepatitis A and B
Allergic / anaphylactic reactions	Immune response to foreign protein or excipients	More common in Type 3 patients with anti-vWF alloantibodies; pre-medicate; have resuscitation equipment available
Volume overload	Large volumes of concentrate infusion in patients with cardiac comorbidities	Monitor fluid balance

"Inhibitors in haemophilia: usually presents as poor response to factor replacement. Occurrence: 20–30% in haemophilia A, 1.5–3% in haemophilia B." ^[2] The same concept applies in Type 3 vWD, though at lower frequency (~5–10%).

Alloantibodies in Type 3 vWD — A Dangerous Complication

Type 3 vWD patients who have never produced any vWF can recognise infused vWF as "foreign" and mount an immune response. These anti-vWF alloantibodies not only neutralise the therapeutic effect of vWF concentrate but can also trigger anaphylaxis — a life-threatening complication. This is distinct from FVIII inhibitors in haemophilia, where the antibody targets FVIII rather than vWF. When a Type 3 patient shows poor response to vWF concentrate, always check for alloantibodies before escalating the dose.

Complication	Mechanism
Ureteric obstruction (if used for haematuria)	Stabilised fibrin clots within the renal pelvis/ureter cannot be dissolved → obstruction → hydronephrosis, renal colic
GI side effects	Nausea, diarrhoea, abdominal cramps (common with oral tranexamic acid)
Thrombotic risk (theoretical, rare)	Reduced fibrinolysis → theoretical ↑ VTE risk; clinically rare at standard doses

Before the era of virus-inactivated concentrates and recombinant products, many patients with vWD (and haemophilia) who received cryoprecipitate or older plasma-derived concentrates were exposed to hepatitis B, hepatitis C, and HIV
In haemophilia, cause of mortality: 33% liver failure ^[2] — largely attributable to transfusion-acquired hepatitis C → cirrhosis → liver failure. This historical burden also affected severe vWD patients treated with similar products
Current virus-inactivated and recombinant products have essentially eliminated this risk, but older patients may still carry the legacy of transfusion-acquired infections

Complication	Mechanism	Type Most Affected
Heavy menstrual bleeding (60–90% of vWD women) ^[2]	Defective platelet adhesion at endometrial vessels during menstruation	All types; worst in Type 3
Ovulation bleeding (Mittelschmerz)	Haemorrhage from ruptured ovarian follicle → haemoperitoneum	Type 3, severe Type 2
Haemorrhagic ovarian cysts	Same mechanism; follicular bleeding fails to self-limit → expanding cyst → may require surgical evacuation	Type 3
Post-partum haemorrhage (62%) ^[2]	Precipitous post-delivery drop in vWF	All types; highest in Type 3
Recurrent miscarriage (debated)	Poor implantation-site haemostasis; some studies suggest association, but evidence is mixed	Unclear

Complication	Detail
Diagnostic delay / misdiagnosis	Many patients (especially women with HMB) are dismissed as "normal variation" for years → unnecessary hysterectomies, untreated anaemia, psychological distress
Anxiety around surgery / dental procedures	Fear of bleeding complications; need for extensive pre-procedural planning
Limitations in sports and physical activity	Especially Type 3 (avoid contact sports); can affect childhood development and social participation
Menstrual-related quality of life	HMB leads to social embarrassment, school/work absenteeism, chronic fatigue from IDA
Financial burden	Cost of factor concentrates (especially recombinant products); regular haematology follow-up

Condition	Complication
Essential thrombocythaemia with acquired vWS	Paradoxical bleeding despite very high platelet count (> 1000 × 10⁹/L) → high platelet consumes all the vWF, results in acquired vWD ^[6]
Heyde syndrome (aortic stenosis)	Recurrent GI bleeding from angiodysplasia; shear stress in blood due to narrowed aortic valve induces conformational changes and early degradation of vWF ^[11] → loss of HMW multimers → acquired Type 2A-like phenotype
Lymphoproliferative disorders	Mucocutaneous bleeding from antibody-mediated vWF clearance; may be first presentation of underlying MGUS/lymphoma

"More concerning for ET is the paradoxical bleeding due to very high platelets → high platelet consumes all the vWF, results in acquired vWD — usually > 1000" ^[6]

Complication	Type 1	Type 2A	Type 2B	Type 2M	Type 2N	Type 3
Iron deficiency anaemia	±	+	+	+	±	++
Post-operative bleeding	+	++	++	++	+	+++
Menorrhagia	+	++	++	++	+	+++
PPH	+	++	++	++	++	+++
GI bleeding / angiodysplasia	±	++	+	+	±	+++
Haemarthrosis / arthropathy	Rare	Rare	Rare	Rare	++	+++
ICH	Rare	Rare	Rare	Rare	+	++
Alloantibodies	—	—	—	—	—	+ (5–10%)
Thrombocytopenia	—	—	Yes	—	—	—

High Yield Summary — Complications of vWD

Iron deficiency anaemia is the most common complication overall — driven by chronic mucosal blood loss (especially menorrhagia); 10–15% of women with HMB have underlying vWD ^[2]
Post-partum haemorrhage occurs in 62% of vWD women — due to precipitous post-delivery drop in vWF ^[2]; occurs as delayed/secondary PPH
Joint and tissue bleeding is usually only seen in Types 2N and 3 ^[1]^[2] → can progress to haemophilic arthropathy ^[14]; analgesics: COX-2/Panadol → avoid NSAID ^[2]
GI angiodysplasia is specifically associated with loss of HMW multimers (Types 2A, 3) and acquired vWS in Heyde syndrome ^[11]
ICH is rare but the most feared complication — both platelet and coagulation defects can cause ICH ^[7]
Anti-vWF alloantibodies develop in ~5–10% of Type 3 patients → cause treatment failure AND can trigger anaphylaxis to vWF concentrate
DDAVP complications: hyponatraemia (fluid restrict), tachyphylaxis (limit 2–3 doses), worsened thrombocytopenia in Type 2B (contraindicated)
VTE risk from excessive FVIII accumulation during prolonged vWF/FVIII concentrate therapy — monitor FVIII trough levels
Treatment of vWD includes factor concentrates and DDAVP for some vWD ^[16]
In acquired vWS: paradoxical bleeding in ET when platelets > 1000 from vWF consumption ^[6]

Active Recall — Complications of Von Willebrand Disease

References

^[1] Senior notes: Adrian Lui Pediatrics Notes.pdf (p395 — vWD clinical features, joint and tissue bleeding) ^[2] Senior notes: Ryan Ho Haemtology.pdf (pp127–128 — vWD clinical features, PPH, haemarthrosis management, inhibitors in haemophilia, prognosis/mortality) ^[6] Senior notes: Block A - Splenomegaly_ common causes of splenomegaly; myeloproliferative diseases.pdf (p29 — ET and acquired vWD) ^[7] Senior notes: Block A - Abnormal bleeding after tooth extraction_ bleeding tendency; thrombocytopenia.pdf (p8 — platelet vs coagulation bleeding patterns, ICH) ^[11] Senior notes: Block A - Coffee ground vomitus tarry stool upper GI bleeding.pdf (p8 — Heyde syndrome) ^[14] Senior notes: Block A - Hematology Interactive Tutorial.pdf (p7 — haemophilic arthropathy, DDAVP mechanism, lifestyle changes) ^[16] Lecture slides: GC 027. Abnormal bleeding after tooth extraction.pdf (p19, p26 — vWD treatment with factor concentrates and DDAVP)

High Yield Summary

Von Willebrand Disease — Key Points for Exams:

Most common hereditary bleeding disorder; autosomal inheritance (affects males = females) ^[1]^[2]^[3]
vWF has two functions: (1) platelet adhesion to collagen via GPIb, (2) carrier protein for Factor VIII ^[1]^[2]^[3]
Gene on chromosome 12; vWF released as ultra-large multimers, cleaved by ADAMTS13 ^[1]^[2]^[3]
Type 1 (AD, ~75%): partial quantitative ↓ vWF — mild, mucocutaneous bleeding
Type 2A (AD): ↓ HMW multimers; Type 2B (AD): gain-of-function → thrombocytopenia; Type 2M (AD): ↓ platelet binding, normal multimers; Type 2N (AR): ↓ FVIII binding → mimics haemophilia A
Type 3 (AR): virtually absent vWF → severe, mixed platelet + coagulation-type bleeding
Isolated prolonged aPTT is the hallmark lab finding — but can be normal in mild disease or when vWF is elevated by stress/inflammation/pregnancy ^[2]^[6]
In Hong Kong, most common cause of isolated prolonged aPTT is Factor XII deficiency (~20% prevalence) — does NOT cause bleeding ^[6]
Mixing study: vWD corrects (deficiency), lupus anticoagulant does not correct (inhibitor) ^[6]
vWF is an acute-phase reactant — levels rise with stress, inflammation, pregnancy, OCP ^[2]
10–15% of women with HMB may have underlying vWD; 60–90% of vWD women experience HMB ^[2]
Acquired vWD can occur in essential thrombocythaemia (platelets > 1000), aortic stenosis (Heyde syndrome) ^[4]

High Yield Summary — Differential Diagnosis of vWD

Key DDx principles:

Isolated prolonged aPTT → intrinsic pathway defect: Factor VIII (haemophilia A, vWD), Factor IX (haemophilia B), Factor XI, Factor XII, contact factors, lupus anticoagulant ^[4]
Most common cause of isolated prolonged aPTT in Hong Kong = Factor XII deficiency (20% prevalence, NO bleeding) ^[5]
Mixing study differentiates deficiency (corrects) from inhibitor (does not correct) ^[5]
vWF:Ag testing is required to exclude vWD before diagnosing haemophilia A ^[9]
Type 2N vWD mimics haemophilia A — distinguish by vWF:FVIII binding assay and inheritance pattern (AR vs X-linked)
BSS mimics vWD but defect is in platelet GPIb (receptor), not vWF (ligand) — giant platelets, normal vWF ^[7]
Acquired vWS: think ET with platelets > 1000, aortic stenosis (Heyde syndrome), lymphoproliferative disorders ^[6]^[11]^[13]
Lupus anticoagulant: prolonged aPTT but causes THROMBOSIS not bleeding — mixing study does not correct IMMEDIATELY ^[4]^[5]

High Yield Summary — Diagnostics for vWD

vWD diagnosis requires: (1) personal bleeding history, (2) family history, (3) lab evidence of reduced vWF level/function ^[1]^[2]^[3]
Definite vWD: vWF:Ag and/or vWF:Act < 30 IU/dL; "low vWF" = 30–50 IU/dL ^[1]
Isolated prolonged aPTT is the hallmark — but can be normal in mild disease ^[2]^[5]
Mixing study corrects in vWD (deficiency); does NOT correct in lupus AC (inhibitor — immediately) or acquired FVIII inhibitor (delayed) ^[5]
vWF Act:Ag ratio > 0.7 = Type 1/3 (quantitative); < 0.7 = Type 2 (qualitative) ^[2]^[4]
RIPA enhanced at low-dose ristocetin = Type 2B (pathognomonic); RIPA decreased = 2A, 2M; absent = Type 3 ^[3]
vWF:FVIII binding assay distinguishes Type 2N (abnormal) from Haemophilia A (normal) ^[3]^[14]
Multimer analysis: loss of HMW = 2A or 2B; normal spectrum = 1, 2M, 2N ^[3]
In Hong Kong, Factor XII deficiency (~20%) is the most common cause of isolated prolonged aPTT — does NOT cause bleeding — always correlate with clinical context ^[5]
DDAVP challenge: good responders = Type 1; contraindicated in Type 2B (worsens thrombocytopenia) ^[14]

High Yield Summary — Management of vWD

DDAVP (0.3 μg/kg IV) is first-line for Type 1 vWD — releases endogenous vWF and FVIII from Weibel-Palade bodies ^[7]^[14]
DDAVP is CONTRAINDICATED in Type 2B (worsens thrombocytopenia) and INEFFECTIVE in Type 3 (no vWF stores)
vWF-containing factor concentrates (plasma-derived or recombinant) are used when DDAVP is contraindicated, ineffective, or insufficient ^[7]
Antifibrinolytics (tranexamic acid) are essential adjuncts for mucosal bleeding — but contraindicated in haematuria (risk of ureteric obstruction) ^[2]
Avoid aspirin and NSAIDs — use paracetamol or COX-2 inhibitors for analgesia ^[2]
Tachyphylaxis occurs after 2–3 doses of DDAVP (store depletion) → switch to vWF concentrate
Hyponatraemia is the key DDAVP side effect — fluid restrict for 24h, monitor Na+
Post-partum: vWF drops precipitously → delayed PPH risk → monitor and treat for 5–7 days ^[2]
Acquired vWS in ET (platelets > 1000): treat with cytoreduction ^[6]
Target vWF:Act / FVIII > 50 IU/dL for minor procedures; > 80–100 IU/dL for major surgery
For life-threatening bleeding: "immediate replacement — treat upon suspicion, not dx" ^[2]

High Yield Summary — Complications of vWD

Iron deficiency anaemia is the most common complication overall — driven by chronic mucosal blood loss (especially menorrhagia); 10–15% of women with HMB have underlying vWD ^[2]
Post-partum haemorrhage occurs in 62% of vWD women — due to precipitous post-delivery drop in vWF ^[2]; occurs as delayed/secondary PPH
Joint and tissue bleeding is usually only seen in Types 2N and 3 ^[1]^[2] → can progress to haemophilic arthropathy ^[14]; analgesics: COX-2/Panadol → avoid NSAID ^[2]
GI angiodysplasia is specifically associated with loss of HMW multimers (Types 2A, 3) and acquired vWS in Heyde syndrome ^[11]
ICH is rare but the most feared complication — both platelet and coagulation defects can cause ICH ^[7]
Anti-vWF alloantibodies develop in ~5–10% of Type 3 patients → cause treatment failure AND can trigger anaphylaxis to vWF concentrate
DDAVP complications: hyponatraemia (fluid restrict), tachyphylaxis (limit 2–3 doses), worsened thrombocytopenia in Type 2B (contraindicated)
VTE risk from excessive FVIII accumulation during prolonged vWF/FVIII concentrate therapy — monitor FVIII trough levels
Treatment of vWD includes factor concentrates and DDAVP for some vWD ^[16]
In acquired vWS: paradoxical bleeding in ET when platelets > 1000 from vWF consumption ^[6]

Von Willebrand Disease

1. Definition

2. Epidemiology

3. Anatomy and Function of von Willebrand Factor

3.1 Source and Synthesis

3.2 Mechanism of ADAMTS13 Cleavage

3.3 Functions of vWF

Function 1: Mediating Platelet Adhesion to Collagen (Primary Haemostasis)

Function 2: Carrier Protein for Factor VIII (Secondary Haemostasis)

3.4 Structure-Function Relationship

4. Aetiology

4.1 Hereditary (Primary) vWD

4.2 Acquired von Willebrand Syndrome (AvWS)

5. Pathophysiology — By Type

5.1 Normal Haemostasis Review (for context)

5.2 Type-Specific Pathophysiology

6. Classification

6.1 Summary Classification

6.2 Relative Frequency

7. Clinical Features

7.1 General Principles

7.2 Symptoms (with pathophysiological basis)

A. Mucocutaneous Bleeding (Platelet-type — due to defective platelet adhesion)

B. Deep-Seated / Coagulation-Type Bleeding (due to low Factor VIII)

C. Effect of Physiological Modifiers on Symptoms

7.3 Signs (with pathophysiological basis)

7.4 Pattern Comparison Table

7.5 Bleeding Assessment Tools

8. History-Taking Framework for Suspected vWD

8.1 Duration and Onset

8.2 Pattern of Bleeding

8.3 Specific Bleeding History

8.4 Family History

8.5 Drug History

9. Key Points About vWF as an Acute Phase Reactant

10. Mixing Study — Differentiating vWD from Lupus Anticoagulant

11. Factors Affecting vWF Levels in Hong Kong Context

12. Interactive Tutorial Case — Applying Concepts

13. Acquired vWD in the Context of Other Conditions

Heyde Syndrome

Essential Thrombocythaemia

Active Recall - Von Willebrand Disease (Overview, Pathophysiology, Clinical Features)

References

1. Clinical Approach to the Differential — First Principles

2. Structured Differential Diagnosis Framework

3. Differential Diagnosis by Laboratory Pattern

3.1 Isolated Prolonged aPTT with Bleeding Tendency

3.2 Isolated Prolonged aPTT WITHOUT Bleeding

3.3 Normal aPTT with Mucocutaneous Bleeding

3.4 Prolonged aPTT AND PT with Bleeding

3.5 Thrombocytopenia with Bleeding (DDx for Type 2B vWD)

4. Differential Diagnosis by Bleeding Pattern

4.1 Mucocutaneous (Platelet-Type) Bleeding

4.2 Deep-Seated (Coagulation-Type) Bleeding

4.3 Mixed Pattern

5. Distinguishing vWD from Its Closest Mimics

5.1 vWD vs Haemophilia A

5.2 vWD Type 2N vs Haemophilia A — The Specific Conundrum

5.3 vWD vs Bernard-Soulier Syndrome (BSS)

5.4 Acquired von Willebrand Syndrome (AVWS) vs Inherited vWD

6. Diagnostic Decision Flowchart

7. Summary Table — DDx of vWD at a Glance

8. Hong Kong-Specific Differential Considerations

Active Recall — Differential Diagnosis of Von Willebrand Disease

1. Diagnostic Criteria — Overview

1.1 ISTH / ASH Diagnostic Thresholds

1.2 Diagnostic Criteria by Type

2. Stepwise Diagnostic Algorithm

3. Investigation Modalities — Detailed Interpretation

3.1 Tier 1: Baseline Screening

3.1.1 Complete Blood Count (CBC) + Peripheral Blood Smear (PBS)

3.1.2 Coagulation Screen (PT and aPTT)

3.1.3 Bleeding Time / PFA-100 (Platelet Function Analyser)

3.1.4 Mixing Study

3.2 Tier 2: vWD-Specific Screening Assays

3.2.1 vWF Antigen (vWF:Ag)

3.2.2 vWF Activity (vWF:Act) / Ristocetin Cofactor Assay (vWF:RCo)

3.2.3 Factor VIII Activity (FVIII:C)

3.2.4 The vWF Act:Ag Ratio — Crucial for Subtyping

3.3 Tier 3: Subtyping Investigations