Von Willebrand Disease (BSH 2014 & Green Top 2017)
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:
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 —> prolongs FVIII half-life by preventing 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
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 (Autosomal Dominant)
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
Causes increased rate of VWF clearance —> short, limited response to desmopressin
Ix: Genetics, VWF propeptide levels
Type 2A (Autosomal Dominant)
Reduction in VWF-dependent platelet adhesion and absent HMW multilmers
Type 2B (Autosomal Dominant)
Abnormally increased affinity of VWF to Gp1b platelet receptors
Results in a mild consumptive thrombocytopenia, made worse by use of desmopressin
Platelet-Type VWD (?Inheritance)
Abnormally increased responsiveness of Gp1b platelet receptors to VWF
The defect is in the GP1BA gene, not in the von willebrand factor.
Type 2M (Autosomal Dominant)
Reduction in VWF-dependent platelet adhesion, without a reduction in HMW Multimers
Type 2N (Autosomal Recessive)
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 (Autosomal Recessive)
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).
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 considered 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
Aim VWF:RCo & FVII levels >0.5 iu/ml
Major Surgery (e.g. Hip replacement)
Raise VWF:RCo & FVII levels to >1.0 iu/ml pre-op
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.
MPN due to thrombocytosis
Mechanical – Aortic stenosis, LV Assist Device, Vavle replacement, ECMO
Treat the cause
Plasma Exchange / Immunoabsorption