OMIA 001057-9615 : Von Willebrand disease I in Canis lupus familiaris

In other species: pig

Possibly relevant human trait(s) and/or gene(s)s (MIM numbers): 193400 (trait) , 613160 (gene)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 1998

Cross-species summary: The von Willebrand factor (vWF) is a large multimeric plasma glycoprotein required for platelet adhesion and aggregation. A deficiency or defective vWF results in von Willebrand disease (vWD). vWD are often classified in 3 different types based on the clinical severity and quantity and multimere size of von Willebrand factor. Type I is characterized by low plasma vWF concentrations and mild to moderate bleeding symptoms. Type II disorder is characterised by qualitative abnormalities of the vWF protein and moderate to severe bleeding. Type III is the most severe form of vWD with no detectable or a severe quantitative deficiency of vWF.

Species-specific name: Disease is also called Type 1 von Willebrand Disease, vWDI, angiohaemophillia, von Willebrand disorder, von Willebrand factor deficiency

Inheritance: Dodds (1984) and Segert et al. (2019) report the mode of inheritance as autosomal dominant with incomplete penetrance in Doberman Pinscher and Kromfohrländer. In other breeds a recessive mode of inheritance has been proposed (Segert et al. 2019).

Molecular basis: As reported by Boudreaux (2012), a likely causal mutation for this disorder in Doberman Pinchers was reported in US Patent 6074832, submitted by Brewer et al. (Michigan State University) in 2000. According to the patent, the actual mutation is a synonymous base substitution at nucleotide 7437 in exon 43 (Ser 2479) of the VWF gene, which decreases the effectiveness of a splice site. Gentilini and Turba (2013) provided details of the mutation: it is "a G → A transversion of the last nucleotide of von Willebrand factor (vWf) exon 43 (c.7437G > A, NM_001002932.1) . . . [which] activates a cryptic splice site a few nucleotides upstream of the normal splice site, leading to a frame shift that results in the formation of a truncated protein of 119 amino acids".

Donner et al. (2016) reported the presence and/or carrier frequency of the c.7437A variant in the following breeds: Doberman, Manchester Terrier, Bernese Mountain Dog, Barbet, Brazilian Terrier, Coton de Tulear, Kromfohrländer, Dutch Shepherd dog - longhaired.

Crespi et al. (2018) reported that the c.7437A variant is only partially associated with the disorder in the Doberman Pinscher breed in Argentina: only 40% of homozygotes and 22% of heterozygotes for the variant showed clinical signs.

Segert et al. (2019) reported similar results for the Kromfohrländer breed: only 46% of homozygotes and 23% of heterozygotes for the c.7437A variant showed clinical signs. Segert et al. (2019) also reported that the variant locus shows a significant effect on vWF concentration: "VWF serum concentrations varied from 28 to 137% in wild-type dogs while in heterozygous and homozygous dogs the concentration ranged from 3 to 77% and 1 to 23%, respectively (p < 0.05)".

Clinical features: Type I von Willebrand disease involves a quantitative partial deficiency of von Willebrand factor, which is a protein involved in blood clotting (Boudreaux, 2012). Clinical features can be characterised as increased bleeding tendency. However, this can be variable. Excessive prolonged bleeding from minor wounds, tooth eruptions, heat or surgical incision are observed in clinically affected dogs with low vWF (Barr & McMichael, 2012; Dodds, 1984). Sudden gingival bleeding, epistaxis, gastrointestinal bleeding, haematuria, subcutaneous haematomas, petechiae can also occur (Thomas, 1996). VWD poses a significant risk in surgery or trauma, where clotting function is very important (Thomas, 1996).

Treatment of affected dogs is possible (Thomas, 1996).

[IT thanks DVM students MacKenzie Anderson and Jesse Wong, who provided the basis of this contribution in April 2022]

Pathology: Platelet count, prothrombin and partial thromboplastin times are usually normal in dogs with vWDI (Burgess et al., 2009). Buccal mucosal bleeding time (BMBT) can be used to determine haemostatic ability. A positive BMBT can indicate vWDI but requires further coagulative tests as it can be present with other coagulopathies. BMBT can also be normal in mild cases (Thomas, 1996). A decreased level of vWF is detected in a vWF:Ag assay with abnormal values of <50% and values of <35% at notable risk of bleeding. vWD dogs will have normal to slightly elevated vWF antigen to collagen binding activity ratios (Burgess et al., 2009). [IT thanks DVM student Jesse Wong, who provided the basis of this contribution in April 2022]

Control: Use of DNA diagnostics as a sole diagnostic tool for vWDI is not advised as the c.7437A variant has been reported to be only partially associated with the disorder in the Doberman Pinscher breed and the Kromfohrländer breed (incomplete penetrance).

Quantification of plasma vWF and in vivo and in vitro tests of vWF-dependent platelet function should be used to diagnose the disease and results from such tests may inform future breeding decissions. This may include von Willebrand factor (vWF) antigen (Ag) test, vwF collagen binding assay, buccal mucosal bleeding time (BMBT), complete blood count (CBC), prothrombin (PT) and partial thromboplastin times (PTT), platelet function analysis (PFA-100) (Thomas, 1996; Burgess et al., 2009) [IT thanks DVM student Jesse Wong, who provided the basis of this contribution in April 2022]

Breeds: Corgi, Doberman Pinscher, German Shepherd Dog, Golden Retriever, Kromfohrländer, Miniature Poodle, Pembroke Welsh Corgi, Shetland Sheepdog, Yorkshire Terrier.

Associated gene:

Symbol Description Species Chr Location OMIA gene details page Other Links
VWF von Willebrand factor Canis lupus familiaris 27 NC_051831.1 (39191850..39329540) VWF Homologene, Ensembl, NCBI gene

Variants

By default, variants are sorted chronologically by year of publication, to provide a historical perspective. Readers can re-sort on any column by clicking on the column header. Click it again to sort in a descending order. To create a multiple-field sort, hold down Shift while clicking on the second, third etc relevant column headers.

WARNING! Inclusion of a variant in this table does not automatically mean that it should be used for DNA testing. Anyone contemplating the use of any of these variants for DNA testing should examine critically the relevant evidence (especially in breeds other than the breed in which the variant was first described). If it is decided to proceed, the location and orientation of the variant sequence should be checked very carefully.

Since October 2021, OMIA includes a semiautomated lift-over pipeline to facilitate updates of genomic positions to a recent reference genome position. These changes to genomic positions are not always reflected in the ‘acknowledgements’ or ‘verbal description’ fields in this table.

OMIA Variant ID Breed(s) Variant Phenotype Gene Allele Type of Variant Source of Genetic Variant Reference Sequence Chr. g. or m. c. or n. p. Verbal Description EVA ID Inferred EVA rsID Year Published PubMed ID(s) Acknowledgements
401 Barbet Bernese Mountain dog Brazilian Terrier Doberman Pinscher Dutch Shepherd dog Kromfohrländer Manchester Terrier Von Willebrand disease I VWF splicing Naturally occurring variant CanFam3.1 27 g.38951839G>A c.7437G>A p.(S2479S) Incomplete penetrance - some dogs with the variant do not develop clinical signs of disease 2013 23911791 Variant coordinates obtained from or confirmed by EBI's Some Effect Predictor (VEP) tool.

References


Note: the references are listed in reverse chronological order (from the most recent year to the earliest year), and alphabetically by first author within a year.
2021 Barbry, J.B., Poinsard, A.S., Bouzouraa, T., Durand, A., Balland, O. :
Case report of unilateral retrobulbar hematoma associated with von Willebrand disease in a Doberman Pinscher dog. Clin Case Rep 9:1235-1240, 2021. Pubmed reference: 33768818. DOI: 10.1002/ccr3.3735.
Kochi, M., Sugimoto, K., Inoue, M., Aoki, T. :
Late recanalization after complete occlusion of patent ductus arteriosus in a Pembroke Welsh Corgi with von Willebrand disease. Vet Med Sci :, 2021. Pubmed reference: 34538019. DOI: 10.1002/vms3.634.
2019 Segert, J.H., Seidel, J.M., Wurzer, W.J., Geretschlaeger, A.M. :
vWDI is inherited in an autosomal dominant manner with incomplete penetrance, in the Kromfohrländer breed. Canine Genet Epidemiol 6:3, 2019. Pubmed reference: 31131110. DOI: 10.1186/s40575-019-0073-4.
2018 Crespi, J.A., Barrientos, L.S., Giovambattista, G. :
von Willebrand disease type 1 in Doberman Pinscher dogs: genotyping and prevalence of the mutation in the Buenos Aires region, Argentina. J Vet Diagn Invest 30:310-314, 2018. Pubmed reference: 29271313. DOI: 10.1177/1040638717750429.
2016 Donner, J., Kaukonen, M., Anderson, H., Möller, F., Kyöstilä, K., Sankari, S., Hytönen, M., Giger, U., Lohi, H. :
Genetic panel screening of nearly 100 mutations reveals new insights into the breed distribution of risk variants for canine hereditary disorders. PLoS One 11:e0161005, 2016. Pubmed reference: 27525650. DOI: 10.1371/journal.pone.0161005.
Nichols, T.C., Hough, C., Agersø, H., Ezban, M., Lillicrap, D. :
Canine models of inherited bleeding disorders in the development of coagulation assays, novel protein replacement and gene therapies. J Thromb Haemost 14:894-905, 2016. Pubmed reference: 26924758. DOI: 10.1111/jth.13301.
2013 Gentilini, F., Turba, M.E. :
Two novel real-time PCR methods for genotyping the von Willebrand disease type I mutation in Doberman Pinscher dogs. Vet J 197:457-60, 2013. Pubmed reference: 23911791. DOI: 10.1016/j.tvjl.2013.02.023.
2012 Boudreaux, M.K. :
Inherited platelet disorders. J Vet Emerg Crit Care (San Antonio) 22:30-41, 2012. Pubmed reference: 22316339. DOI: 10.1111/j.1476-4431.2011.00702.x.
2010 Mattoso, C.R., Takahira, R.K., Beier, S.L., Araújo, J.P., Corrente, J.E. :
Prevalence of von Willebrand disease in dogs from Sao Paulo State, Brazil. J Vet Diagn Invest 22:55-60, 2010. Pubmed reference: 20093683. DOI: 10.1177/104063871002200109.
2009 Burgess, H.J., Woods, J.P., Abrams-Ogg, A.C., Wood, R.D. :
Evaluation of laboratory methods to improve characterization of dogs with von Willebrand disease. Can J Vet Res 73:252-259, 2009. Pubmed reference: 20046626.
2005 Callan, MB., Giger, U., Catalfamo, JL. :
Effect of desmopressin on von Willebrand factor multimers in Doberman Pinschers with type 1 von Willebrand disease. Am J Vet Res 66:861-7, 2005. Pubmed reference: 15938072.
2004 Anonymous :
Detection of von Willebrand disease (vWD) in Doberman, Manchester Terrier and Poodle Kleintierpraxis 49:717-718, 2004.
2002 Callan, M.B., Giger, U. :
Effect of desmopressin acetate administration on primary hemostasis in Doberman Pinschers with type-1 von Willebrand disease as assessed by a point-of-care instrument American Journal of Veterinary Research 63:1700-1706, 2002. Pubmed reference: 12492285.
2001 Brooks, M.B., Erb, H.N., Foureman, P.A., Ray, K. :
von Willebrand disease phenotype and von Willebrand factor marker genotype in Doberman Pinschers American Journal of Veterinary Research 62:364-369, 2001. Pubmed reference: 11277201.
2000 Lutze, G., Kutschmann, K., Aumann, V., Hartung, K.J., Mittler, U. :
Combined von Willebrand disease and factor XII deficiency (vWD San Diego) in the dog and humans [German] Praktische Tierarzt 81:912-+, 2000.
Riehl, J., Okura, M., Mignot, E., Nishino, S. :
Inheritance of von Willebrand's disease in a colony of Doberman Pinschers American Journal of Veterinary Research 61:115-120, 2000. Pubmed reference: 10685679.
1999 Denis, C.V., Wagner, D.D. :
Insights from von Willebrand disease animal models. Cell Mol Life Sci 56:977-90, 1999. Pubmed reference: 11212329. DOI: 10.1007/s000180050487.
Johnstone, I.B. :
Desmopressin enhances the binding of plasma von Willebrand factor to collagen in plasmas from normal dogs and dogs with Type I von Willebrand's disease Canadian Veterinary Journal - Revue Veterinaire Canadienne 40:645-648, 1999.
1998 Brewer, G.J., Venta, P.J., Schall, W., Yuzbasiyan-Gurkan, V., Li, J. :
DNA tests for von Willebrand’s disease in Dobermans, Scotties, Shelties and Manchester terriers. Canine Practice 23:45, 1998.
Moser, J., Meyers, K.M., Russon, R.H., Reeves, J.J. :
Plasma von-Willebrand-factor changes during various reproductive cycle stages in mixed-breed dogs with normal von-Willebrand-factor and in Doberman Pinschers with type-I von-Willebrands-disease American Journal of Veterinary Research 59:111-118, 1998. Pubmed reference: 9442254.
Stokol, T., Parry, B.W. :
Efficacy of fresh-frozen plasma and cryoprecipitate in dogs with Von-Willebrands-disease or hemophilia a Journal of Veterinary Internal Medicine 12:84-92, 1998. Pubmed reference: 9560764.
1996 Moser, J., Meyers, K.M., Russon, R.H. :
Inheritance of von Willebrand factor deficiency in Doberman pinschers. J Am Vet Med Assoc 209:1103-6, 1996. Pubmed reference: 8800256.
Thomas, J.S. :
von Willebrand's disease in the dog and cat. Vet Clin North Am Small Anim Pract 26:1089-110, 1996. Pubmed reference: 8863392.
1995 Meinkoth, J.H., Meyers, K.M. :
Measurement of von Willebrand factor-specific mRNA and release and storage of von Willebrand factor from endothelial cells of dogs with type-I von Willebrands disease American Journal of Veterinary Research 56:1577-1585, 1995. Pubmed reference: 8599517.
1993 Brooks, M., Catalfamo, J. :
Buccal mucosa bleeding time is prolonged in canine models of primary hemostatic disorders. Thrombosis and Haemostasis 70:777-780, 1993. Pubmed reference: 8128434.
1992 Brooks, M. :
Management of canine von Willebrand's disease. Probl Vet Med 4:636-46, 1992. Pubmed reference: 1472774.
1988 Johnson, G.S., Turrentine, M.A., Kraus, K.H. :
Canine von Willebrand's disease. A heterogeneous group of bleeding disorders. Vet Clin North Am Small Anim Pract 18:195-229, 1988. Pubmed reference: 3282380. DOI: 10.1016/s0195-5616(88)50017-7.
1984 Dodds, W.J. :
Von Willebrand's disease in dogs. Mod Vet Pract 65:681-6, 1984. Pubmed reference: 6332976.
1975 Dodds, W.J. :
Further studies of canine von Willebrand's disease. Blood 45:221-30, 1975. Pubmed reference: 1078981.

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