There are many inherited conditions that can affect an individual dog’s clotting ability. Igenity Canine Wellness focuses on several inherited clotting disorders that may go undiagnosed in puppies but are manageable when the veterinarian is fully informed about genetic risk. These clotting disorders may create bleeding risk during surgeries like spay and neuter or may manifest later in the dog’s life. Normal pre-surgical bloodwork is unlikely to detect the conditions.
Factor VII Deficiency
Von Willebrand Disease
Von Willebrand disease (vWD) is a deficiency or malformation of von Willebrand factor (vWF), which helps platelets bind to the damaged endothelial walls of blood vessels to prevent bleeding.
How does blood clotting work?
Many factors are involved in a blood clotting. Genetic mutations can affect the amount of active clotting factor present, resulting in factor deficiencies.
Breeds affected
Factor VII: Originally the mutation was discovered in beagles used in laboratory settings, but it has been found in the pet population of beagles as well as other breeds of dogs around the world.
Breeds with FVII mutation:1 Alaskan Klee Kai, Airedale Terrier, Beagle, Giant Schnauzer, Scottish Deerhound, American Foxhound, Finnish Hound, German Wirehaired Pointer, Irish Water Spaniel, Japanese Spitz, Miniature Schnauzer, Papillon/Phalene, Sealyham Terrier and Welsh Springer Spaniel.
von Willebrand’s disease: This syndrome has been described in many purebred and mixed-breed dogs. A carrier of the genetic disease may not display clinical signs, depending on breed.
vWD type I: Most common in Doberman Pinschers, but can also be diagnosed in other breeds, including: Australian Terrier, Bernese Mountain Dog, Coton de Tulear, Doberman Pinscher, German Pinscher, Kerry Blue Terrier, Manchester Terrier, Papillon, Pembroke Welsh Corgi, Miniature Poodle, Standard Poodle, Toy Poodle, Red Setter, White Setter, Stabyhound and West Highland White Terrier.
vWD type II: Found in German Shorthaired Pointer, German Wirehaired Pointer.
Clinical symptoms
Clinical signs associated with clotting disorders:- Bruising or prolonged bleeding following surgery, blood draw, nail trim or dental cleaning.
- Postpartum hemorrhage and hematoma formation.
- In more severe cases, spontaneous bleeding can occur: Hematuria, hemarthrosis, hemoabdomen, hemothorax.
Is surgery safe?
- Run in-house screening tests to assess clotting ability. These simple tests can help assess clotting ability prior to surgery or other procedures. These tests assess clotting ability, but don’t provide a definitive diagnosis.
- Buccal Mucosal Bleeding Time or Cuticle Bleeding Time (Toenail Bleeding time)
Instructions for Bleeding Time tests - Coagulation Testing:
Factor VII Deficiency von Williebrand's Disease Prothrombin time (PT) Prolonged Normal Activated partial thromboplastin time (aPTT) Normal Normal
- Buccal Mucosal Bleeding Time or Cuticle Bleeding Time (Toenail Bleeding time)
- Send a blood sample to a referral lab for definitive diagnosis and to quantify the amount of active clotting factor present
Severity Concentration of vWF Structure of vWF vWD Type I Mild (can be variable) Low Normal vWD Type II Moderate / Severe Low Abnormal vWD Type III Severe Absent - - Consider pre-treatment prior to surgery. Therapeutic choices could include desmopressin (DDAVP), cryoprecipitate or plasma transfusions.2,5
WARNING - Dogs with clotting disorders should not be given drugs that interfere with normal clotting mechanisms, including:
- Heparin
- Clopidogrel (Plavix®)
- Aspirin
- Non-steroidal anti-inflammatory drugs:ibuprofen, deracoxib (Deramaxx™), firocoxib (Previcox™) carprofen (Rimadyl™), Meloxicam (Metacam™), Phenylbutazone
- Antihistamines
- Sulfa-based antibiotics
- Ampicillin, amoxicillin & penicillin
- Estrogen
- Theophylline
- Phenothiazine tranquilizers
Test limitations
Mutations for Type III von Willebrand’s Disease are not included in Igenity Canine Wellness test. This disorder is known to occur in the Dutch Kooiker, Shetland Sheepdog, Scottish Terrier and Chesapeake Bay Retriever.
There are many other mutations that have been linked to clotting disorders which are either rare in the general population or which are so severe, they are typically evident soon after birth and can be fatal.
Search for diagnostic test options for other breed-specific clotting disorders.
Science and Genetics
Factor VII Deficiency3: G to A missense mutation in exon 5, resulting in substitution of glycine 96 (GGA) by glutamic acid (GAA) in the EGF-2 domain3.
Mode of Inheritance: This mutation is autosomal recessive, but in some populations has incomplete dominance, so animals that are carriers of the mutation may have slightly prolonged bleeding times as well.
Breeds Affected: Alaskan Klee Kai, Airedale Terrier, Beagle, Giant Schnauzer, Scottish Deerhound, American Foxhound, Finnish Hound, German Wirehaired Pointer, Irish Water Spaniel, Japanese Spitz, Miniature Schnauzer, Papillon/Phalene, Sealyham Terrier and Welsh Springer Spaniel.
Possible Test Outcomes
| Genotype | Phenotype |
|---|---|
| No variant detected | No increased risk |
| CARRIER: 1 copy of vWf exon 3 variant detected | Mild increased risk |
| AFFECTED: 2 copies of vWf exon 3I variant detected | Increased risk |
von Willebrand’s Disease - Type 14 is due to a G to A transversion of the last nucleotide in the von Willebrand factor gene, exon 3. The nucleotide change results in the creation of a new splice site which leads to a frame shift and results in the formation of a truncated protein.
Mode of Inheritance: The inheritance is autosomal dominant with incomplete penetrance, which means not all dogs with the mutation will manifest clinical signs of the disorder.
Breeds Affected: Most common in Doberman Pinschers, but can also be diagnosed in other breeds, including: Australian Terrier, Bernese Mountain Dog, Coton de Tulear, Doberman Pinscher, German Pinscher, Kerry Blue Terrier, Manchester Terrier, Papillon, Pembroke Welsh Corgi, Miniature Poodle, Standard Poodle, Toy Poodle, Red Setter, White Setter, Stabyhound and West Highland White Terrier.
Possible Test Outcomes
| Genotype | Phenotype |
|---|---|
| No variant detected | Not at increased risk |
| CARRIER: 1 copy of the vWf exon 3 mutation detected | Increased risk |
| AFFECTED: 2 copies of the vWf exon 3 mutation detected | Increased risk |
von Willebrand’s Disease - Type II6 is due to an A to G nucleotide variant in exon 28 of the von Willebrand factor gene.7 Interestingly, most mutations that cause human type-2 vWD also occur in the vWf exon 28. Mutations in this gene could result in less production of vWF or faster proteolysis resulting in less circulating active vWf.
Mode of Inheritance: VWD Type II is an inherited autosomal recessive trait. Only dogs that are homozygous/affected for the genetic mutation are at increased risk. Carriers are not at increased risk for bleeding but could pass on the risk allele to their offspring.
Breeds Affected: German Shorthaired Pointer, German Wirehaired Pointer.
Possible Test Outcomes
| Genotype | Phenotype |
|---|---|
| No variant detected | Not at increased risk |
| CARRIER: 1 copy of the vWf exon 28 mutation detected | Not at increased risk |
| AFFECTED: 2 copies of the vWf exon 28 mutation detected | Increased risk |
References
- 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.
- Keeshen, T.P., Case, J.B., Runge, J.J., Singh, A., Mayhew, P.D., Steffey, M.A., Culp, W.T.N. Outcome of laparoscopic ovariohysterectomy or ovariectomy in dogs with von Willebrand disease or factor VII deficiency: 20 cases (2012-2014). J Am Vet Med Assoc 251:1053-1058, 2017. Pubmed reference: 29035661. DOI: 10.2460/javma.251.9.1053.
- Callan, M. B., Aljamali, M. N., Margaritis, P., Griot-Wenk, M. E., Pollak, E. S., Werner, P., … High, K. A. (2006). A novel missense mutation responsible for factor VII deficiency in research Beagle colonies. Journal of Thrombosis and Haemostasis, 4(12), 2616–2622. https://doi.org/10.1111/j.1538-7836.2006.02203.x
- US Patent 6074832
- Kraus KH1, Turrentine MA, Jergens AE, Johnson GS. Effect of desmopressin acetate on bleeding times and plasma von Willebrand factor in Doberman pinscher dogs with von Willebrand’s disease. Vet Surg, 18(2), 103-9. 1989. PMID 2786279.
- Gentilini, F., & Turba, M. E. (2013). Two novel real-time PCR methods for genotyping the von Willebrand disease type I mutation in Doberman Pinscher dogs. Veterinary Journal, 197(2), 457–460. https://doi.org/10.1016/j.tvjl.2013.02.023
- Kramer, JW., Venta, PJ., Klein, SR., Cao, Y., Schall, WD., Yuzbasiyan-Gurkan, V. A von Willebrand's factor genomic nucleotide variant and polymerase chain reaction diagnostic test associated with inheritable type-2 von Willebrand's disease in a line of German shorthaired pointer dogs. Vet Pathol 41:221-8, 2004. Pubmed reference: 15133170. DOI: 10.1354/vp.41-3-221.
http://eclinpath.com/hemostasis/disorders/inherited-coagulation/