Von Willebrand disease
Description
- Commonest inherited bleeding disorder
- Mucocutaneous bleeding pattern: epistaxis, gum bleeding, easy bruising, menorrhagia, post-dental and post-partum haemorrhage
- Haemarthrosis and deep muscle bleeds are unusual - and point to type 3 (where FVIII is also very low) or to haemophilia
Types
| % | Defect | Inheritance | |
|---|---|---|---|
| 1 | 70-80% | Quantitative - partial deficiency. Function and antigen fall together | AD, variable penetrance |
| 1C | subset of 1 | Accelerated clearance. inc VWFpp/VWF:Ag ratio | AD |
| 2A | Loss of high-molecular-weight multimers -> dec platelet adhesion | AD | |
| 2B | ~20% | Gain-of-function VWF-GPIb binding -> HMW multimers + platelets cleared -> *thrombocytopenia* | AD |
| 2M | combined | dec platelet binding with normal multimers | AD |
| 2N ("Normandy") | dec FVIII binding -> *phenocopies mild haemophilia A* | AR | |
| 3 | <5% | Near-total absence. VWF:Ag undetectable, FVIII <10 IU/dL -> severe, haemophilia-like | AR |
- Acquired von Willebrand syndrome - not inherited, same phenotype, different treatment
Epidemiology
- Laboratory prevalence up to ~1%; clinically significant ~1 in 1,000
- Type 3 ~1 per million
- M = F, but women present far more often (menorrhagia, childbirth)
- Blood group O carries VWF levels ~25% lower than non-O - the commonest reason for a "low VWF" result, and it is not a disease
Aetiopathogenesis
Where VWF comes from
- Synthesised in endothelial cells (stored in Weibel-Palade bodies) and megakaryocytes (alpha granules)
- Assembled into multimers; the largest multimers are the most haemostatically active
- ADAMTS13 trims ultra-large multimers - the same axis that fails in TTP
Two functions - and each failure has its own signature
1. Tethers platelets to injured subendothelium
- VWF binds exposed collagen, unfurls under high shear, and binds platelet GPIb -> then GPIIb/IIIa aggregation
- Failure -> primary haemostatic defect = mucocutaneous bleeding, prolonged PFA closure time
2. Carries and stabilises factor VIII in plasma
- Free FVIII is degraded within ~2 h; bound to VWF its half-life is ~12 h
- Failure -> secondary FVIII deficiency -> prolonged APTT and a haemophilia-like phenotype (types 2N and 3)
- High-shear vessels are the most VWF-dependent - hence angiodysplastic GI bleeding when HMW multimers are lost
Acquired von Willebrand syndrome - mechanisms
- Shear-induced proteolysis of HMW multimers: aortic stenosis (Heyde syndrome), LVAD, ECMO, congenital heart disease
- Adsorption onto clonal cells / platelets: MGUS and myeloma, lymphoproliferative disease, MPN with extreme thrombocytosis, Wilms tumour
- Autoantibody: SLE, lymphoproliferative disease
- Reduced synthesis: hypothyroidism
- Drugs: valproate, ciprofloxacin
Diagnosis
Who to test
- ISTH-BAT bleeding assessment tool - abnormal at >=4 (men), >=6 (women), >=3 (children)
- A normal bleeding score in an adult makes VWD unlikely - use it to avoid testing everyone with a bruise
Screening tests are unreliable
- APTT normal unless FVIII is low; PT normal; platelet count normal except in type 2B
- PFA-100/200 closure time prolonged - sensitive screen, not diagnostic
- *Bleeding time is obsolete*
The core panel
| VWF:Ag | Quantity |
| VWF platelet-binding activity | *VWF:GPIbM is now preferred over the classical ristocetin cofactor (VWF:RCo) - better precision and reproducibility, and avoids the falsely low VWF:RCo caused by the D1472H polymorphism common in people of African ancestry* |
| FVIII:C | Low in type 2N and type 3 |
Thresholds
- VWF:Ag or activity <30 IU/dL = von Willebrand disease
- 30-50 IU/dL with a bleeding phenotype = "low VWF" - manage the bleeding, do not label a disease
- ASH/ISTH/NHF/WFH 2021 lowered the diagnostic threshold to 30 and created the "low VWF" category
Subtyping
- Activity : antigen ratio <0.7 -> a type 2 variant (qualitative)
- Multimer analysis - HMW multimers absent in 2A and 2B, normal in 2M
- Low-dose RIPA (ristocetin-induced platelet aggregation) increased -> type 2B (vs platelet-type/pseudo-VWD, which is a platelet GPIb defect - distinguish by mixing studies)
- VWFpp / VWF:Ag ratio raised -> type 1C (accelerated clearance)
- Propeptide is low or absent in type 3, normal-to-near-normal in type 1 -> *the propeptide separates type 1 from type 3*
- FVIII binding assay -> type 2N (otherwise misdiagnosed as mild haemophilia A - and the inheritance pattern is the clue: autosomal, affected women)
- Genotyping where the phenotype is ambiguous or for prenatal diagnosis
*VWF is an acute phase reactant*
- Rises with stress, exercise, inflammation, pregnancy, oestrogen, hyperthyroidism, older age, surgery
- A normal level during illness does not exclude VWD - repeat when well, at least twice
Management
Axis: the clinical problem in front of you, and whether desmopressin will work for this type.
Trial of desmopressin (DDAVP) - do it electively, before it is needed
- 0.3 microgram/kg IV or SC (or intranasal) -> releases stored VWF and FVIII from Weibel-Palade bodies
- Measure VWF and FVIII at baseline, 1 h and 4 h
- Response = 2-fold rise and levels >50 IU/dL, sustained at 4 h
- Works: type 1 (most), some type 2A and 2M
- *Contraindicated in type 2B - releases abnormal VWF -> worsens thrombocytopenia*
- *Ineffective in type 3* - there is nothing stored to release
- Poor sustained response in type 1C (good peak, rapid clearance)
- Toxicity: hyponatraemia - fluid restrict 24 h, avoid in children <2 years, caution in the elderly and in cardiovascular disease
- Tachyphylaxis after 2-3 doses - stores are exhausted
A. Minor bleeding and minor procedures
- Tranexamic acid 15-25 mg/kg (~1 g) tds oral, or mouthwash for dental work - often sufficient alone
- Desmopressin if a documented responder
- Avoid tranexamic acid with upper urinary tract bleeding - clot colic
B. Major bleeding, major surgery, type 3, non-responders
- VWF-containing concentrate
- Plasma-derived VWF/FVIII concentrate (Biostate in Australia), or recombinant VWF (vonicog alfa)
- Target VWF activity and FVIII >50 IU/dL; >100 IU/dL for major surgery, maintained >50 for 7-10 days
- *Monitor FVIII - it accumulates with repeated dosing (endogenous synthesis is intact) -> thrombosis risk*
- Cryoprecipitate only if no concentrate is available - not virally inactivated
- Add tranexamic acid; platelet transfusion for refractory bleeding in type 3
C. Menorrhagia
- Tranexamic acid, combined oral contraceptive, levonorgestrel IUD
- Iron replacement - most women with VWD present as iron deficiency, not as a coagulopathy
D. Pregnancy and delivery
- VWF and FVIII rise 2-3 fold by the third trimester in type 1 - many normalise and need no cover
- Check levels at ~28 and 34 weeks; cover if VWF or FVIII <50 IU/dL at delivery
- *Levels fall abruptly postpartum - secondary PPH peaks at day 5-10*; continue tranexamic acid 2 weeks
- Type 2B: thrombocytopenia worsens through pregnancy
E. Prophylaxis
- Regular VWF concentrate in type 3, recurrent GI bleeding (angiodysplasia), or recurrent joint bleeds
Avoid in everyone
- Aspirin, NSAIDs, IM injections; caution with anticoagulants
Acquired von Willebrand syndrome
- Treat the cause: valve replacement, cytoreduction of the MPN, treat the plasma cell clone, thyroxine
- Bleeding episodes: high-dose IVIG (best in IgG MGUS-associated), VWF concentrate (short-lived - antibody clears it), recombinant FVIIa for refractory bleeding, desmopressin (brief effect)
Associations
- Blood group O - lower baseline VWF
- Angiodysplasia and recurrent GI bleeding - loss of HMW multimers; typically type 2A and type 3, and hard to treat
- Aortic stenosis (Heyde syndrome), LVAD, ECMO -> acquired VWS
- MGUS, myeloma, lymphoproliferative disease, MPN with extreme thrombocytosis -> acquired VWS
- Hypothyroidism
- Iron deficiency anaemia from chronic menorrhagia or GI loss
- Type 2N misclassified as mild haemophilia A; type 2B misclassified as ITP
Natural history & complications
- Bleeding severity is highly variable even within a family - genotype predicts phenotype poorly except in type 3
- VWF levels rise with age -> bleeding often improves in later life (though the diagnosis remains, and cover is still needed for surgery)
- Type 1 and low VWF: normal life expectancy; the morbidity is iron deficiency and procedural bleeding
- Type 3: lifelong severe bleeding, arthropathy from recurrent haemarthrosis, and alloantibodies to VWF in ~10-15% after repeated concentrate exposure (anaphylaxis risk on re-exposure)
- Angiodysplastic GI bleeding is the hardest long-term problem - recurrent, transfusion-dependent, poorly responsive to concentrate
Monitor
- Ferritin and FBE in anyone with menorrhagia or GI bleeding
- Repeat VWF/FVIII before any planned procedure - levels drift
- Type 2B: platelet count through pregnancy and illness
🔒
6 more sections, plus exam facts
Premium unlocks every note across every specialty, and the full exam fact library behind it.
Get premium access