VON
WILLEBRAND’S DISEASE IN DOBERMANNS
John K. Dunn MA
BVM&S MVetSc DSAM Dip ECVIM MRCPath
MRCVS
Senior
Veterinary Specialist
Axiom
Veterinary Laboratories
Teignmouth
von Willebrand’s disease is the most common
inherited bleeding disorder in dogs. At
least 50 breeds are known to be affected.
There is a particularly high prevalence in Dobermanns,
Scottish Terriers and Shetland Sheepdogs.
The disease is characterized by a lack of functional von Willebrand factor (vWF) which
results in defective primary haemostasis and prolongation of bleeding time.
von Willebrand factor is a multimeric plasma glycoprotein which is synthesized and
stored in vascular endothelial cells.
Canine platelets contains very little vWF. It is released from endothelial organelles in
response to thrombin, adrenalin and vasopressin. vWF
antigen plays a pivotal role in the adhesion and aggregation of platelets to
damaged vessel wall. In plasma it forms
a non-covalent complex with coagulation Factor VIII.
vWF binds to exposed collagen in the vessel wall and
interacts with platelet membrane glycoprotein 1b receptors. It also mediates interplatelet
bridging (aggregation). The high
molecular weight multimers of vWF
are the most efficient in promoting platelet aggregation. The net result of either an absolute
(quantitative) deficiency of vWF or a preferential
(qualitative) deficiency of the high molecular weight multimers
of vWF is therefore defective platelet adhesion and
aggregation.
Classification of von Willebrand’s Disease
von Willebrand’s disease is classified as
Type 1, Type 2 or Type 3. Type 1 vWd is the form that occurs in Dobermanns. vWD
is inherited as an autosomal recessive trait.
Type 1 vWD is characterized by a reduction
in the plasma concentration of all multimer
sizes. Affected homozygote dogs have
plasma vWF concentrations between 5% and 20% of
normal (normal: 75%-170%). Heterozygote
carriers usually have plasma vWF concentrations less
than 50% of normal (30%-50%) but some carriers can have vWF
concentrations of 50%-75% of normal making it difficult to differentiate these
carriers from unaffected dogs on the basis of vWF
antigen bioassay alone.
The
clinical severity of the Type 1 form correlates with the plasma vWF antigen concentration.
Compared to the Type 2 and Type 3 forms of the disease this tends to be
a relatively mild disorder and clinical signs may only be apparent following
trauma or an elective surgical procedure.
Dogs with a bleeding tendency are often those with vWF
antigen concentrations less than 20% of normal.
Type 2 vWD is less common but the clinical
signs are more severe. This form of the
disease occurs particularly in German Shorthaired and Wirehaired Pointers. Plasma vWF antigen
concentration may be normal or decreased but there is a disproportionate
decrease in the concentration of high MW multimers. Diagnosis requires an assessment of vWF function or multimer
analysis.
Type 3 vWD occurs primarily in Scottish
Terriers and Shetland Sheepdogs.
Affected homozygotes have virtually no vWF antigen (less than 1% of normal). These dogs show severe clinical signs and
bleeding episodes can be life threatening.
Factor VIII activity is usually also decreased. Heterozygotes have
subnormal or normal vWF antigen concentrations and
are often asymptomatic.
Clinical Signs
The
severity and type of clinical signs of Type 1 vWD
vary considerably. Some severely
affected dogs with plasma vWF concentrations less
than 20% of normal may bleed spontaneously.
In many cases, however, bleeding may only be apparent after trauma or
surgery. The clinical signs also depend
on where bleeding occurs, for example, a relatively minor bleed into a critical
site such as the central nervous system may result in severe neurological
dysfunction.
The
most common clinical signs of vWD are mucosal or cutaneous haemorrhage, haematuria,
prolonged bleeding from traumatic or surgical wounds, bleeding from the gums
(especially when deciduous teeth are lost), epistaxis
(nose bleeds), or prolonged bleeding at oestrus. Pinpoint petechial haemorrhages
on mucosal surfaces are rarely seen with vWD. Any bleeding tendency may be exacerbated by
thrombocytopenia (decreased number of platelets in the circulation), drug
administration (non-steroidal anti-inflammatory drugs, sulphonamides), and
other diseases which interfere with platelet function (uraemia, hyperproteinaemia, anaemia and liver disease). Hypothyroidism has also been associated with expression
of vWD.
Laboratory Findings
Dogs
with vWD have normal platelet counts. Buccal mucosal
bleeding time (BMBT) of clinically affected animals is prolonged (Type 1: 5-10 minutes; normal 2-4 minutes). Heterozygote carriers usually have normal
BMBT. BMBT is therefore a useful and
quick presurgical screening test for detecting
affected homozygotes in situations where insufficient
time is available to measure vWF antigen (see below).
Clotting
times (OSPT, APTT and ACT) are usually also
normal. APTT and ACT may be prolonged in
the Type 3 form if there is a concurrent reduction in Factor VIII.
Diagnostic Tests
Diagnosis
of Type 1 vWD requires the quantitative measurement
of vWF antigen using an enzyme-linked immunosorbent assay (ELISA). The more severe Type 2 and Type 3 forms
require functional assessment of vWF antigen and/or
analysis of vWF multimer
distribution.
ELISA (vWF
Antigen)
Homozygotes and most heterozygote carriers have vWF
antigen concentrations less than 50% of normal.
Homozygotes usually have vWF
antigen concentrations less than 20% of normal.
vWF antigen
concentrations between 50% and 75% are equivocal (heterozygote carriers or
normal?).
vWF Function Assays
These
are cofactor assays which evaluate vWF-dependent
platelet agglutination.
Multimer Analysis
This
can be performed by protein immunoelectrophoresis. The distribution of large MW multimers will differentiate Type 1 from Type 2 forms of vWD.
Treatment
Fresh
or frozen plasma provides a source of vWF. In an emergency, or in cases where red cells
are required, fresh whole blood can be transfused (this must be done within 6
hours of collection). Crossmatching and blood group typing are advised since
repeated transfusions will probably be required.
Canine
cryoprecipitate provides a more concentrated source of vWF
but is not readily available. In an
emergency situation desmopressin can be given
subcutaneously. This stimulates the
release of vWF from endothelial stores and
temporarily increases vWF activity in Type 1 vWD. It can also be
administered to normal donor dogs to ‘boost’ vWF
levels prior to blood collection.
Control
A
combination of genetic screening and selective breeding are essential if the
prevalence of vWD disease is to be reduced within the
breed or line of related dogs.
Genetic Screening
DNA
testing is now available for screening Dobermanns for
Type 1 vWD in the
Affected
animals have two mutant genes. vWD is caused by a splice-site
mutation. Each gene produces 5%-10%
normal vWF, therefore affected Dobermanns
have plasma vWF concentrations that are 10%-20% of
normal.
Selective Breeding
Approximately
20% of Dobermanns are homozygous clear for the vWD gene.
Approximately 35% are affected and 45% are carriers. The aim of a selective breeding programme is
to gradually eliminate the mutant gene over 2-3 generations. Adoption of a strict ‘clear to clear’ mating
policy is not initially desirable since this will significantly narrow the gene
pool of the breed. Some of the valuable
positive characteristics of the breed may therefore be diluted or even
lost. Ideally, ‘clear to clear’ or ‘clear
to carrier’ matings are advised for the first two or
three generations. As the frequency of
clear dogs increases it should be possible to breed mostly ‘clear to clear,’
thus eliminating the mutant vWD gene. If a clear dog is not available it may also
be possible to breed ‘carrier to carrier’ (this will produce 25% clear, 50%
carrier and 25% affected). It has been
suggested that ‘affected to clear’ matings are also
safe though the progeny will be 100% carriers.
The mating of affected to affected or affected to
carriers should be avoided at all costs.
Copyright
2002 John K. Dunn. All rights reserved. Please view the Axiom Veterinary Laboratories site.
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