UC Davis School of Veterinary Medicine Veterinary Genetics Laboratory

Von Willebrand Disease

Von Willebrand disease (vWD) is an inherited bleeding disorder resulting from a lack or reduced level of a normal blood clotting protein called von Willebrand factor (vWF). Disease presentation varies from asymptomatic to spontaneous hemorrhaging and prolonged bleeding after injury, surgery or giving birth. Furthermore, age of onset varies with some dogs only becoming obvious “bleeders” later in life. Without medical intervention, uncontrolled bleeding can result in death. Several genetic mutations that prevent normal functioning of vWF have been identified. These mutations are associated with different clinical bleeding disorders known as vWD Type 1, Type 2 and Type 3. 

vWD Type 1 is the most common bleeding disorder among dogs and is present in several breeds. The disorder is characterized by a low concentration of vWF in blood. While vWD Type 1 can cause serious bleeding problems, it is generally less severe than the other two types of vWD and can be alleviated by treatment. A mutation in vWF (c.7437G>A) is associated with vWD Type 1. This disorder is inherited as a dominant trait with incomplete penetrance, which means that not all dogs that have the vWF mutation will present clinical signs of the disease.

vWD Type 2 is rare and associated with abnormal structure and function of vWF. Two mutations in vWF (c.4937A>G and c.1657T>G) are associated with this disorder, but the later is considered causative. vWD Type 2 appears to be inherited as a recessive trait, as only dogs with 2 copies of the c.1657T>G variant had a history of prolonged bleeding according to Von-Loohuis et al. 2017. It occurs in German Shorthaired Pointer and German Wirehaired Pointer breeds. The VGL test is based on the c.1657T>G mutation.

vWD Type 3 is the most severe form of bleeding disorders and it is caused by a complete lack of vWF in the blood. Three mutations are associated with this type of disorder: vWF (Int16G>A, denoted vWFk) occurs in Dutch Kooiker, vWF (c.255Cdel, denoted as vWFt) occurs in Scottish Terriers and vWF (c.735Tdel, denoted vWFs) occurs in Shetland Sheepdog. vWD Type 3 is inherited as a recessive trait which means that 2 copies of the defective gene are needed to cause the disorder.

Genetic tests for vWD Type 1, vWD Type 2 and vWD Type 3 are offered by the VGL. Results from these tests help breeders determine the genetic status of breeding stock and risk for bleeding disorder. For the recessive vWD Type 3, test results inform breeders to avoid matings between carriers, which could produce 25% of affected offspring. Veterinarians can use test results to confirm clinical findings and inform appropriate courses of treatment or management. The mutations tested have different breed origins and distributions and thus test selection needs to be breed-appropriate.

Testing Recommendation:

vWD Type 1: Australian Cobberdog, Barbet, Bernese Mountain Dog, Brazilian Terrier, Cardigan Welsh Corgi, Coton de Tulear, Doberman Pinscher, Drentsche Patrijshond, Dutch Partridge Dog, Dutch Shepherd, French Water Dog, German Pinscher, Havanese, Irish Red and White Setter, Irish Setter, Kerry Blue Terrier, Kromfohrländer, Manchester Terrier, Papillon, Pembroke Welsh Corgi, Phalene, Poodles, Doodle and Poo breeds, Stabyhoun, Toy Manchester Terrier, West Highland White Terrier

vWD Type 2: German Shorthaired Pointer, German Wirehaired Pointer

vWD Type 3: Deutsch Kooiker, Scottish Terrier, Shetland Sheepdog

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Allow 5-10 business days for results.

Results for vWD Type 1 reported as:

N/N

Normal - No copies of vWF mutation associated with vWD Type 1.

N/vWF

1 copy of vWF mutation. Dog may be affected and may develop vWD Type 1.

vWF/vWF

2 copies of vWF mutation. Dog may be affected and may develop vWD Type 1.

Results for vWD Type 2 reported as:

N/N

Normal - No copies of vWF mutation associated with vWD Type 2.

N/vWF

1 copy of vWF mutation. Dog is unlikely to develop vWD Type 2.

vWF/vWF

2 copies of vWF mutation. Dog is affected and may develop vWD Type 2.

Results for vWD Type 3 reported as:

N/N

Normal - no copies of vWF mutations associated with vWD Type 3.

N/vWF

1 copy of vWF* mutation. Dog is normal but can pass on the mutation to 50% of offspring.

vWF/vWF

2 copies of vWF* mutation. Dog is affected and may develop vWD Type 3.


* Report will specify vWD Type 3 mutations as vWFk (Deustch Kooiker), vWFt (Scottish Terrier) or vWFs (Shetland Sheedog)

References:

Brooks MB, Erb HN, Foureman PA, Ray K. (2001) von Willebrand disease phenotype and von Willebrand factor marker genotype in Doberman Pinschers. Am J Vet Res 62(3):364-369.

Crespi JA, LS Barrientos, G Giovambattista. (2018) von Willebrand disease type 1 in Doberman Pinscher dogs: genotyping and prevalence of the mutation in the Buenos Aires region, Argentina. J Vet Diagn Investg 30(2):310-314.

Donner J, Kaukonen M, Anderson H, Moller F, Kyostila K, Sankari S, Hytonen M, Giger U, Lohi H. (2016) Genetic Panel Screening of Nearly 100 Mutations Reveals New Insights into the Breed Distribution of Risk Variants for Canine Hereditary Disorders. PLoS One 11(8). DOI:10.1371/journal.pone.0161005

Vos-Loohuis M, van Oost BA, Dangel C, Langbein-Detsch I, Leegwater PA. (2017) A novel VWF variant associated with type 2 von Willebrand disease in German Wirehaired Pointers and German Shorthaired Pointers. Anim Genet 48:493–496.

Rieger M, Schwarz HP, Turecek PL, Dorner F, van Mourik JA, Mannhalter C. (1998) Identification of mutations in the canine von Willebrand factor gene associated with type III von Willebrand disease. Thromb Haemost 80(2):332-337.

Venta PJ, Li J, Yuzbasiyan-Gurkan V, Brewer GJ, Schall WD. (2000) Mutation causing von Willebrand’s Disease in Scottish Terriers. J Vet Intern Med 14(1):10-19.

 
Veterinary Genetics Laboratory, Tel 530-752-2211, Email VGL