Von Willebrand Disease (BCSH 2014 & Green Top)
The most common inherited bleeding disorder. Predominantly attributable to reduced levels of VWF activity, frequently but not always attributable to a defect in the VWF gene.
Common presenting complaints:
- Mucocutaneous bleeding
- Postpartum haemorrhage
- GI / tooth extraction / menorrhagia / minor wounds / surgical bleeding
Von Willebrand Factor
Large, complex glycoprotein (1000-20,000 KDa) essential for normal haemostasis
Half-life: 12 hours
Coded for on Chromosome 12
- Vascular endothelial cells (and stored in Weibel-Palade bodies)
- Megakaryocytes and so it is present on platelets
Produced as large multimers that are then degraded by ADAMTS13
- Carrier protein for FVIII, prevent FVIII degradation in plasma
- Adhesive protein involved in interaction between platelets and vessel walls
VWF levels are a guide only and not a strict reference for diagnosis
Normal Range VWF Antigen: 0.4 – 2.4 iu/ml (25% lower in Group O individuals)
Von Willebrand Disease - Activity <0.3 iu/ml + mucocutaneous bleeding
Probable VWD - Incidental finding of activity <0.3 iu/ml
‘Low VWF in a 1o haemostatic deficiency’ - Activity 0.3 – 0.5 iu/ml + bleeding history
ISTH 1994 Saddler Classification
Does not define or predict response to treatment and has a variable relationship to genetics
Type 1 (AD)
- Quantitative, partial deficiency of VWF
- Includes mutations that cause rapid clearance of VWF, e.g. Type 1c Vincenza.
- Autosomal dominant inheritance when VWF <0.3iu/ml. >0.3 due to variable penetrance.
- Type 1c Vincenza
o Causes increased rate of VWF clearance à short, limited response to desmopressin
o Ix: Genetics, VWF propeptide levels
Type 2A (AD)
- Reduction in VWF-dependent platelet adhesion and absent HMW multilmers
Type 2B (AD)
- Abnormally increased affinity of VWF to Gp1b platelet receptors
- Results in a mild consumptive thrombocytopenia, made worse by use of desmopressin
Platelet-Type VWD (?)
- Abnormally increased responsiveness of Gp1b platelet receptors to VWF
- The defect is in the GP1BA gene, not in the von willebrand factor.
Type 2M (AD)
- Reduction in VWF-dependent platelet adhesion, without a reduction in HMW Multimers
Type 2N (AR)
- Reduced binding affinity of VWF to FVIII, leading to a shortened FVIII half-life
- Separate, but difficult to distinguish, from mild haemophilia A
Type 3 (AR)
- Virtually complete deficiency of VWF.
- 25-50% of carriers also have a bleeding phenotype
Primary Diagnostic Tests
VWF levels rise with anxiety, needle phobia, strenuous exercise and pregnancy
Tests should be performed at least twice on separate occasions before making diagnosis
APTT – Normal or prolonged
- APTT-based 1-Stage Assay
- FVIII half-life regulated by VWF and so level may be low in all types
- May be normal
Plasma VWF Antigen Level
- ELISA - Rabbit anti-VWF binds to VWF in patient plasma and produces colour reaction
- Or Latex Agglutination (Accustar) – Latex particles with Anti-VWF bind to VWF in patient plasma and cause agglutination.
- False high results with Rheumatoid Factor
VWF Ristocetin Cofactor (Rcof) Activity
- Ristocetin binds to the VWF A1 domain causing a conformational change in VWF which aids VWF binding to platelet GP1b receptors, resulting in platelet crosslinking.
- The test reflects VWF-Gp1b binding by assessing ristocetin cofactor activity.
- It measures the agglutination of platelet in a solution containing an excess of ristocetin along with dilutions of patient plasma. The activity level is determined by comparison to a reference plasma.
- Result is also dependent on presence of HMW multimers and intact Gp1b binding sites.
- Non-physiological – some patients will test low in the absence of a bleeding phenotype.
VWF Collagen binding (CB) Assay
- Collagen binds to the VWF A3 domain
- Successful binding is dependent on the presence of intact HMW mutimers
- Tested by chemiluminescent immunoassay (HemosiL AcuStar at Addenbrookes).
o Uses particles coated with collagen peptides.
Secondary Classification Tests
Ristocetin-Induced Platelet Agglutination (RIPA)
- In normal individuals, low concentrations of ristocetin are insufficient to initiate VWF-dependent platelet agglutination
- If agglutination does occur at low concentrations of ristocetin (0.5mg/ml) it suggests the pathological enhancement of VWF-Gp1b interactions seen in Type 2B VWD or Platelet-Type VWD.
- Increasingly appropriate and should be consider as an aid in many circumstances
VWF gene found on chromosome 12. Contains 52 exons.
Type 1 & 2 VWD – majority due to missense mutations.
Type 3 – wide varieties of different mutations
Large minority of patients have no identifiable mutation
Diagnosis in Children and Infants
FVIII levels are high after birth
Difficult to obtain non-activated, uncontaminated samples
Stress increase the VWF level
--> Try to wait until 6 months of age before testing
- Good for minor surgery and minor bleeding
- Good solo or in combo with desmopressin
- Topical, mouthwash, oral or IV available
SE: Flushing, hypotension, fluid retention, hyponatraemia, aterial occlusion
Fluid restrict to 1L in 24 hours after dose
Monitor Na if <2 y.o.
Avoid use if atherosclerosis
Note response to a 2nd dose is 30% lower
Factor Concentrates (Usually given BD or TDS)
- Consider when desmopressin is contraindicated or proven to be ineffective
- VWF:Rco and FVIII levels rise by approx. 0.02 iu/ml per iu/kg administered
- Be aware of FVIII accumulation with repeated doses due to variable half-lives
- Wilate – 1:1 ratio VWF:FVIII. Most commonly used product at CUH.
- Voncento – Lower FVIII content
- Wilfactin – high purity VWF content
Surgery & Dentistry
- Minor Surgery
o Aim VWF:RCo & FVII levels >0.5 iu/ml
- Major Surgery (e.g. Hip replacement)
o Raise VWF:RCo & FVII levels to >1.0 iu/ml pre-op
o Maintain VWF:Rco or FVIII >0.5 iu/ml for 2 weeks, then >0.3 for further 2 weeks
- Response to desmopressin should be measured prior to proceeding with the op
Factor Concentrate Prophylaxis
- 30-50 iu/Kg 2-3 times per week in children with type 3 who develop joint bleeding
- Not often required, except in patients with Type 3 VWD or joints bleeds
- 76% of type 3, 17% type 2 and 7% type 1 patients receive prophylactic concentrate
- Mirena coil / OCP
- Platelet transfusion if bleeding persists despite the above and VWF activity is corrected
VWF Inhibitors in VWD
- 5-10% of type 3 patients who have been multiply transfused
- Unlikely to occur in type 1 or 2
- Present with loss of response to concentrate, or sometimes with anaphylaxis
- Rx: rFVIII, rFVIIa, Platelet transfusion, TXA
- HemosiL AcuStar at Addenbrookes
- Incubate patient plasma with a source of VWF, allowing for antibody-antigen interaction
- Then test VWF functional activity of the sample
- Result is compared to a control plasma incubation
- Decreased function in the patient sample relative to control suggests presence of inhibitor
Acquired loss of VWF function.
o Myeloma, Waldenstroms
o MPN due to thrombocytosis
o Mechanical – Aortic stenosis, LV Assist Device, Vavle replacement, ECMO
- Wilms tumour
- Treat the cause
- VWF concentrates
- IgM paraprotein
o Plasma Exchange / Immunoabsorption
- IgG paraprotein