Clinical Biochemistry of Domestic Animals (Sixth Edition) - UMK ...

IV. Disorders of Hemostasis
311
TABLE 10-7 Recognized Types of Canine von Willebrand Disease and Their Features
Type I Type II Type III
vWF Concentration a Decreased Decreased Undetectable
a
vWF Structure Normal Decrease in large multimers Undetectable
Breed Predilection
a
Doberman pinschers
Airedales
Dachshunds
German shepherds
Shetland sheepdogs
Several other breeds
German shorthaired and
wirehaired pointers only
Chesapeake Bay retriever
Dutch kooiker
Scottish terrier
Shetland sheepdog
Inheritance Pattern Autosomal dominant Appears autosomal recessive Autosomal recessive
Hemorrhage Variable Severe Severe
a
See Brooks, 1992.
in the 1920s by Erik von Willebrand, and since then it
has been classified into three distinct variants ( Ewenstein,
1997 ). Two are quantitative deficiencies (types I and III),
with a decrease in circulating vWF, and one is a qualitative
defect (type II) ( Ewenstein, 1997 ). Human type II vWD
is further divided into four subtypes (A, B, M, and N)
( Ewenstein, 1997 ). The first incidence of vWD in dogs
was reported in 1970 in a family of German shepherd dogs
( Denis and Wagner, 1999 ). Since then, as in humans, three
types of vWD have been identified and are summarized
in Table 10-7 . Whereas types I and III vWD share phenotypic
characteristics with the respective human types, the
qualitative defect (type II) is characterized by a decrease
in high-molecular-weight vWF multimers without further
subclassification. Although modes of inheritance have
been identified, the actual genetic defect is unknown for
many of the affected breeds ( Denis and Wagner, 1999 ).
Inheritance of type I vWD is autosomal dominant with
incomplete penetrance. A dominant trait requires only
one copy of the gene to produce abnormalities. Therefore,
clinical signs can be identical for homozygotes and heterozygotes
( Brooks, 2000 ). Hemorrhage in type I vWD can
vary from mild to severe, and even dogs with comparable
concentrations of vWF can show a range of clinical signs
( Brooks, 2000 ). Manifestations of type I vWD are due to a
proportional decrease in all multimer sizes ( Brooks, 1999 ).
It has been reported that in Doberman pinschers there is
a decrease in vWF mRNA as well as a reduced release of
vWF from endothelial cells, suggesting that the disease
is a result of defective expression of the gene ( Denis and
Wagner, 1999 ). However, immunofluorescent studies have
shown that there is no detectable difference in the localization
of vWF:Ag or the fluorescence intensity in endothelial
cells from control dogs and type I vWD-positive Doberman
pinschers ( Meyers et al ., 1990b ). As of 1981, the reported
prevalence of vWD in Dobermans in North America was
63% ( Dodds et al ., 1981 ). Although the Doberman pinscher
is the most well-known breed associated with type
I vWD, the condition is also commonly found in a variety
of other breeds including Airedale terriers, dachshunds,
Pembroke Welsh Corgis, and German shepherd dogs.
Type II disease is rare in dogs and has been reported only
in German shorthaired and wirehaired pointers ( Brooks,
2000 ). Disease manifestation is due to lack of high-molecularweight
multimers of vWF and tends to produce recurrent
severe hemorrhage. Generally, one or more episodes of
bleeding occur by the time the animal is 1 year old ( Brooks,
2000 ). In one study, a particular family line of German shorthaired
pointers, in which some members were positive for
type II vWD, was examined and it was found that none of
the affected dogs had a vWF:Ag concentration higher than
68% ( Kramer et al ., 2004 ). Persistent spontaneous bleeding
episodes in this family of dogs was confined to homozygotes,
dogs with vWF:Ag concentrations of less than 10%, or
both ( Kramer et al ., 2004 ). The pattern of inheritance in this
family line appeared consistent with an autosomal recessive
trait. This study was successful in identifying a consistent
single nucleotide defect within the sequence for the vWF
A2 domain of the affected dogs and an identical defect in
German wirehaired pointers ( Kramer et al ., 2004 ).
Similar to type I disease, the type III phenotype is
dependant on the level of vWF:Ag present. This manifestation
of vWD is autosomal recessive. Homozygotes have
no measurable circulating factor and are clinically affected,
whereas heterozygotes exhibit low levels of vWF and clinically
appear normal ( Brooks, 2000 ). FVIII activity tends to
vary between 15% to 50% in type III patients ( Denis and
Wagner, 1999 ).
a. Hemorrhagic Tendencies
In type I vWD, it is not uncommon for animals to present
without a bleeding history, in contrast to type II and III