Von Willebrand Disease (BSH 2014 & Green Top 2017)

Intro

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 —> prolongs FVIII half-life by preventing degradation in plasma

  • Adhesive protein involved in interaction between platelets and vessel walls

vwf.png

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 (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

 

diagnosis

 

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

 

FVIII:C

  • 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.

 

Genetic Analysis

  • Increasingly appropriate and should be considered 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

vwd.png

 

Treatment

 

Tranexamic Acid

  • Good for minor surgery and minor bleeding

  • Good solo or in combo with desmopressin

  • Topical, mouthwash, oral or IV available

 

Desmopressin

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

    • 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

 

Other measures

  • Mirena coil / OCP

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

 

 

Pregnancy Plan

vwd preg.png

 

Inhibitors

 

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.

 

Causes:

  • Immune

    • Hypothyroidism

    • Myeloma, Waldenstroms

  • Consumptive

    • MPN due to thrombocytosis

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

  • Wilms tumour

  • Drugs

    • Ciprofloxacin

 

Treatment:

Treat the cause

VWF concentrates

Desmopression

IgM paraprotein

  • Plasma Exchange / Immunoabsorption

IgG paraprotein

  • IVIg