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


Synthesized in:

-       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


Two roles:

-       Carrier protein for FVIII, prevent FVIII degradation in plasma

-       Adhesive protein involved in interaction between platelets and vessel walls




Diagnostic Levels


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.


Genetic Analysis

-       Increasingly appropriate and should be consider as an aid in many circumstances


Genetic Diagnosis


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


Diagnosis: Summary





Tranexamic Acid

-       Good for minor surgery and minor bleeding

-       Good solo or in combo with desmopressin

-       Topical, mouthwash, oral or IV available



haem 5.png

SE: Flushing, hypotension, fluid retention, hyponatraemia, aterial occlusion


Safe use:

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


Other measures

-       Mirena coil / OCP

-       Platelet transfusion if bleeding persists despite the above and VWF activity is corrected



Pregnancy Plan

vwd preg.png




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


Inhibitor Screen

-       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 VWD


Acquired loss of VWF function.



-       Immune

o   Hypothyroidism

o   Myeloma, Waldenstroms

-       Consumptive

o   MPN due to thrombocytosis

o   Mechanical – Aortic stenosis, LV Assist Device, Vavle replacement, ECMO

-       Wilms tumour

-       Drugs

o   Ciprofloxacin



-       Treat the cause

-       VWF concentrates

-       Desmopression

-       IgM paraprotein

o   Plasma Exchange / Immunoabsorption

-       IgG paraprotein

o   IVIg