Acquired von Willebrand Syndrome (AVWS)
1. บทนำ (Introduction)
Acquired von Willebrand syndrome (AVWS) คือภาวะที่มี
acquired deficiency หรือ dysfunction ของ von Willebrand factor (VWF)
พบได้น้อยกว่า inherited VWD มาก และมักถูก under-recognized
ในผู้ป่วยที่มี bleeding ใหม่โดยไม่มีประวัติเดิม
ลักษณะสำคัญทางคลินิก:
- New-onset
bleeding (โดยเฉพาะ mucosal)
- ไม่มี family history ของ bleeding
disorder
- มี underlying disease ที่เกี่ยวข้อง
ความท้าทาย:
- Diagnosis
ซับซ้อน
- มัก coexist กับโรคที่ต้องใช้ antithrombotic
therapy (เช่น LVAD, MPN, prosthetic valve)
2. Role of VWF in Hemostasis (High-yield Physiology)
VWF เป็น large multimeric glycoprotein สร้างจาก:
- Endothelial
cells (Weibel-Palade bodies)
- Megakaryocytes
/ Platelets (α-granules)
หน้าที่หลัก:
1.
Mediates platelet adhesion (platelet ↔ subendothelium) → primary hemostasis
2.
Platelet aggregation (bridging function)
3.
Carrier protein for factor VIII → เพิ่ม half-life
ของ FVIII
High molecular weight (HMW) multimers = most hemostatically
active
3. Pathophysiology of AVWS (Key Mechanisms)
ลักษณะเด่น:
Reduced VWF activity + loss of HMW multimers (คล้าย
type 2A pattern)
3.1 Immune-mediated (Autoantibody)
สาเหตุ:
- MGUS,
multiple myeloma
- Lymphoma,
CLL
- SLE /
autoimmune disease
กลไก:
- Anti-VWF
antibodies → ↑ clearance หรือ
inhibit function
- Mixing
study อาจ negative (non-neutralizing Ab)
Clinical pearl:
- Autoantibody-associated
AVWS → bleeding รุนแรงกว่า
3.2 Shear stress–induced proteolysis (สำคัญมาก)
เกิดจาก high shear → unfolding ของ VWF
→ ถูก cleave
โดย ADAMTS13
พบบ่อยใน:
- Aortic
stenosis (Heyde syndrome)
- Severe
MR
- LVAD
/ ECMO
- Congenital
heart disease
- Paravalvular
leak
- HOCM
Lab hallmark:
- Loss
of HMW multimers
3.3 Adsorption / Increased clearance
พบใน:
- Myeloproliferative
neoplasms (ET, PV)
- Waldenström
macroglobulinemia
- Plasma
cell dyscrasia
- Wilms
tumor
กลไก:
- Platelet
binding VWF (โดยเฉพาะ thrombocytosis)
- Tumor
cell adsorption
3.4 Increased proteolysis (non-ADAMTS13)
เช่น:
- DIC
- Cirrhosis
- Hyperfibrinolysis
- ET
(platelet metalloproteinases)
3.5 Decreased synthesis (rare)
ตัวอย่าง:
- Hypothyroidism
- Valproic
acid
4. Consequences of Reduced VWF in AVWS
4.1 Impaired primary hemostasis
→
mucocutaneous bleeding (most common)
4.2 Secondary FVIII reduction
- Severe
AVWS → FVIII ต่ำ (hemophilia-like bleeding)
4.3 GI angiodysplasia (สำคัญทางคลินิก)
โดยเฉพาะ:
- Aortic
stenosis (Heyde syndrome)
- LVAD
- Severe
VWD/AVWS
กลไก: VWF มีบทบาท suppress
angiogenesis
5. Epidemiology (Clinical Context)
- <5%
ของ VWD cases เป็น acquired
- Underdiagnosed
มาก
- Median
age: ~elderly (ขึ้นกับ underlying disease)
High prevalence groups:
- LVAD
/ ECMO: up to ~100%
- Aortic
stenosis: 10–70%
- MPN
(ET): 10–20%
- Lymphoproliferative
disorders: common cause in adults
6. Associated Diseases (Exam + Clinical High-Yield)
6.1 Hematologic disorders (most common)
- MGUS
- Multiple
myeloma
- Waldenström
macroglobulinemia
- CLL /
NHL
- Myeloproliferative
neoplasms (especially ET)
Clinical pearl:
AVWS พบ ~20% ใน ET
(แม้ platelet ไม่ถึง 1 ล้าน)
6.2 Cardiovascular causes (สำคัญในเวชศาสตร์ฉุกเฉิน/ICU)
- Aortic
stenosis (Heyde syndrome)
- Severe
MR
- Congenital
heart disease
- LVAD
/ ECMO (almost universal lab AVWS)
6.3 Autoimmune diseases
- SLE
- Autoimmune
thyroid disease
6.4 Endocrine / Drug-related
- Hypothyroidism
- Valproic
acid
- Ciprofloxacin
- Hydroxyethyl
starch / dextran
7. Clinical Presentation (When to Suspect AVWS)
7.1 Classic scenarios
1.
New-onset bleeding in older adult
2.
Bleeding + underlying disease (MPN, AS, LVAD)
3.
Mucosal bleeding:
o Epistaxis
o GI
bleeding
o Menorrhagia
o Easy
bruising
7.2 Key Red Flags (distinguish from inherited VWD)
- Late
onset bleeding
- Negative
family history
- Prior
surgery without bleeding
- Associated
systemic disease
- Short-lived
response to VWF therapy
8. Diagnostic Evaluation (Stepwise for Clinical Use)
8.1 Initial assessment (mandatory)
History:
- Personal
bleeding history
- Family
history (usually negative)
- Medications
(antiplatelet/anticoagulant)
- Underlying
diseases (MPN, AS, LVAD)
8.2 Screening labs
- CBC
+ platelet
- PT
(usually normal)
- aPTT
(may be prolonged if FVIII ↓)
Important:
Normal aPTT ไม่ตัด AVWS
8.3 Core VWF panel (essential tests)
- VWF
antigen (VWF:Ag)
- VWF
activity (VWF:RCo หรือ VWF:GPIbM)
- Factor
VIII activity (FVIII:C)
8.4 Additional tests (if unclear)
- VWF
multimers (↓ HMW
multimers)
- VWF:propeptide
/ VWF:Ag ratio >2 →
↑ clearance
- Collagen
binding assay
- Mixing
study (often negative)
8.5 Factors affecting interpretation (clinical pitfall)
- Acute
stress ↑ VWF (acute
phase reactant)
- Blood
group O → VWF ต่ำ ~25–30%
- Estrogen/pregnancy
↑ VWF
- Inflammation
↑ VWF
9. Distinguishing AVWS vs Inherited VWD (High-yield
Table)
|
Feature |
AVWS |
Inherited VWD |
|
Age onset |
Late |
Childhood/young |
|
Family history |
Negative |
Positive |
|
Underlying disease |
Present |
Absent |
|
Response to treat underlying
cause |
Improves |
No change |
|
Antibody possible |
Yes |
No |
10. Management Principles (Core Concept)
การรักษามี 4 แกนหลัก:
1.
Control acute bleeding
2.
Treat underlying disease (definitive)
3.
Prevent recurrent bleeding
4.
Balance antithrombotic therapy risk
11. Treatment of Acute Bleeding (AVWS)
11.1 First-line options
- DDAVP
(initial therapeutic trial)
- VWF
concentrates (moderate–severe bleeding)
- Antifibrinolytics
(adjunct)
11.2 DDAVP in AVWS
Rationale
- Rapid
endogenous VWF release
- Avoid
plasma products initially
Response rate:
~30% (ขึ้นกับ cause)
Dosing:
- IV
q12–24h (max ~3 doses)
- First
dose = therapeutic trial
Limitations:
- Tachyphylaxis
(3–5 doses)
- Hyponatremia
risk
- Less
effective if autoantibody present
- Avoid:
- Cardiovascular
disease
- High
thrombosis risk
- Elderly
frail patients
11.3 VWF Concentrates (key therapy for significant
bleeding)
Indications:
- Poor
DDAVP response
- Moderate–severe
bleeding
- Surgery
- Life-threatening
bleeding
Initial dose:
- 40–60
IU/kg IV (target VWF 50–100%)
Maintenance:
- 20–40
IU/kg q12h
(AVWS often require higher/more frequent doses due to rapid clearance)
Monitoring:
- VWF
activity
- FVIII
level
- Half-life
of infused VWF
Target:
- VWF
& FVIII: 50–100% (3–14 days)
11.4 Antifibrinolytics (adjunct)
เหมาะมากใน:
- Epistaxis
- Dental
bleeding
- Menorrhagia
- GI
mucosal bleeding
Agents:
- Tranexamic
acid
- Aminocaproic
acid
11.5 Rescue therapy (refractory bleeding)
- rFVIIa
- Continuous
VWF infusion (2–15 IU/kg/hr)
- Combination
therapy (DDAVP + VWF)
- Topical
hemostatics
12. Treatment of Underlying Cause (Definitive Therapy)
สำคัญที่สุดในระยะยาว
|
Underlying disease |
Specific treatment |
|
Aortic stenosis |
Valve replacement |
|
MPN (ET) |
Cytoreductive therapy |
|
Autoimmune / MGUS |
IVIG / immunosuppression |
|
Hypothyroidism |
Thyroxine replacement |
|
Drug-induced |
Stop offending drug |
|
LVAD/ECMO |
Device management (if possible) |
13. Role of IVIG (Very High-Yield Exam & Clinical)
เหมาะที่สุดใน:
- MGUS
(IgG)
- Autoantibody-mediated
AVWS
- SLE
/ lymphoproliferative disorders
Dose:
- 1
g/kg/day × 2 days
- Repeat
every 3–4 weeks (if needed)
Effect:
- Often
more sustained than DDAVP/VWF concentrate
14. Management of GI Angiodysplasia (Common in AVWS)
Options:
- Endoscopic
therapy
- VWF
prophylaxis
- Octreotide
- Thalidomide
/ lenalidomide
- Statins
(antiangiogenic effect)
- Rituximab
(refractory autoimmune cases)
15. Perioperative Management (AVWS)
15.1 Elective surgery
- Treat
underlying disease first (if possible)
- Pre-op
VWF level assessment
- Plan
hemostatic therapy in advance
15.2 Hemostatic strategy
Minor procedure:
- DDAVP
(if responsive) + TXA
Major surgery:
- VWF
concentrates
- Monitor
VWF/FVIII levels
- Consider
half-life shortening
16. Patients Requiring Antithrombotic Therapy (Complex
Scenario)
พบบ่อยใน:
- LVAD
- MPN
(aspirin)
- Prosthetic
valves
Principles:
- ใช้ anticoagulant อย่างระมัดระวัง
- Prefer
reversible short-acting agents
- If
major bleeding →
hold/reverse anticoagulation
- Individual
risk-benefit assessment (bleeding vs thrombosis)
17. Prophylaxis and Long-term Management
พิจารณาเมื่อ:
- Recurrent
bleeding
- Untreatable
underlying cause (เช่น non-surgical AS)
- Chronic
GI bleeding / angiodysplasia
Strategy:
- VWF
concentrate 2–3 times/week
- Individualized
dosing
- Clinical-based
decision (not lab alone)
18. Key Clinical Pearls (High-yield for Physicians &
ER)
- AVWS
= new bleeding + underlying disease + no family history
- Most
common adult causes: lymphoproliferative + cardiac (AS, LVAD)
- Loss
of HMW multimers = hallmark lab finding
- DDAVP
response ~30% →
therapeutic trial first
- VWF
concentrates often need higher & frequent dosing (short half-life)
- Treat
underlying disease = definitive cure
- IVIG
highly effective in MGUS/SLE-associated AVWS
- Always
suspect AVWS in:
- Aortic
stenosis + GI bleeding (Heyde syndrome)
- ET
+ bleeding despite thrombosis risk
- LVAD/ECMO
+ mucosal bleeding
- Lab
values alone poorly correlate with bleeding risk → clinical judgment essential
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