Genetic Welfare Problems of Companion Animals

Doberman Pinscher

Von Willebrand Disease

Related terms: von Willebrand’s disease

Outline: Dogs with von Willibrand Disease are at risk of excessive and prolonged bleeding in relation to the scale of tissue injury because of low blood concentration of a factor involved in the blood clotting system. It is caused by an autosomal recessive gene. Bleeding can cause pain when it occurs within a confined space, such as into a joint or within the skull, and profound blood loss can cause discomfort through weakness and nausea and lead to collapse and death. Such severe adverse effects can occur but are not common in Dobermans as, although 25% are at risk of abnormal bleeding, the type of the disease that occurs in Doberman pinschers is usually relatively mild. A genetic test is available that can detect which animals have the gene. It should be possible to eliminate the disease by breeding only from unaffected animals.

Summary of Information

(for more information click on the links below)

1. Brief description

Von Willebrand disease (vWD) is a common abnormality of the process by which blood clots. In Doberman pinschers the problems caused by vWD are relatively mild. Excessive bleeding may occur in some circumstances, for example when affected animals are teething or in season. Some dogs do bleed spontaneously and their owner’s may see episodes of bleeding from the mouth or nose, or blood in the urine or from the urogenital tract. Bleeding into the gastrointestinal tract is most likely to show as melaena (dark coloured faeces) as the blood is partially digested by the time it appears in the faeces. Unlike other defects of primary haemostasis (the process by which a clot is formed, characterized by constriction of the blood vessel at the sight of the damage and adhesion of clot forming platelets to form a soft plug), bleeding into body cavities such as joints or inside the brain is unusual in vWD.

Typically the problem shows when surgery is being performed on the affected animal or after a trauma such as a stick injury (dogs often have injuries in their mouths and throats from playing with sticks), or associated with injuries sustained from bites or road traffic accidents. In these circumstances bleeding can be severe enough to cause death by exsanguination (Brooks et al 1992).

As detailed below, the majority of dogs with clinical signs of vWD are homozygous for the autosomal recessive mutant gene (that is they have two copies of it). The chemical nature of the von Willibrand clotting factor in these dogs is normal but the clotting factor is present in lower concentrations than normal (typically less than 35% and often only 5-10% of normal concentrations). The severity of the problems caused by this depend on how low the concentration of the clotting factor is and on the severity of the injury that causes the bleeding.

2. Intensity of welfare impact    

Von Willibrand disease leads to excessive bleeding. This does not cause pain unless the bleeding is into a confined space such as a joint. Excessive blood loss causes weakness, malaise, nausea and, when severe, can cause collapse, seizures and death. Interventions to treat dogs suffering from the effects of vWD may also have adverse welfare effects – through the stress of travel for, and administration of, veterinary treatments, which may include hospitalisation with intensive care and blood transfusions.

3. Duration of welfare impact

The durations of welfare problems with vWD are likely to be relatively short, lasting from days to weeks for each episode of bleeding. Most dogs have only one episode.

4. Number of animals affected

Stokol et al (1995) studied vWD in Australian Dobermans prior to the availability of genetic testing and determined which dogs were affected on the basis of concentrations of von Willibrand Factor (vWF) in the blood.  They found that 17% of 614 Dobermans examined had had episodes of the disease during a five-year period. The disease episodes were mostly considered to be mild or moderate but eight dogs had had severe bleeds and two had died. Of the 373 Dobermans found to have vWF levels less than 50% of normal, 107 had had an episode of bleeding.

A commercial genetic test for type 1 vWD in Doberman pinschers has been developed by the company Vetgen. This company found that 26-35% of Dobermans tested (mostly in the USA) were homozygous for a mutation of the normal gene (possessed two copies of the mutant gene) and, thus, susceptible to abnormal bleeding.  48-49% were found to be heterozygous and 16-25% were found to be homozygous for the normal gene (http://www.vetgen.com/canine-vwd1.html).

5. Diagnosis

Von Willibrand disease is suspected in Doberman pinscher’s when an individual has apparently abnormal and excessive bleeding into the mouth or elsewhere that is beyond what might be expected, or when there is excessive bleeding during surgery. The diagnosis can be confirmed by various blood tests that assess primary and secondary haemostasis (clotting) and by measurement of the concentration of von Willibrand factor in the blood. A genetic test is available that indicates the presence of a mutant gene associated with the disease and whether there are one or two copies of it, (http://www.vetgen.com/canine-vwd1.html).

6. Genetics

Von Willebrand disease is a single gene autosomal recessive condition. Only occasionally will heterozygous dogs (those with one normal and one mutant gene) show any clinical signs and these are mild. Homozygous dogs, those with two copies of the abnormal gene, are more severely affected and have very low levels of von Willibrand Factor (vWF) in their blood. The mutant gene does not prevent the production of vWF but reduces the rate of production such that the blood concentration of vWD may be 10% of that in normal dogs. In heterozygous dogs the concentration of vWF is typically about 50% of normal  (Stockham & Scott 2002).

7. How do you know if an animal is a carrier or likely to become affected?

It is usually possible to determine an individual dog’s status as affected carrier (heterozygous) or normal non-carrier by measuring blood concentration of von Willibrand factor (vWF) and this has long been available. However, because of the variation in vWF levels due to non-genetic effects (eg normal day-to-day variation, effects of other illness and drugs and of the oestrus cycle) it is quite common for results not to be clear-cut and for repeat testing to be required. More recently, a genetic test has become available that clearly shows whether an individual has two copies of the mutant gene (homozygous affected), one copy (heterozygous carrier) or no copies (homozygous normal). Details are available at: (http://www.vetgen.com/canine-vwd1.html). This can be used to test puppies for the presence of the gene prior to purchase.

8. Methods and prospects for elimination of the problem

Using the genetic test, it is possible to discriminate between homozygous affected, heterozygous carrier, and homozygous normal Doberman pinschers. The test can be run on a saliva sample from a mouth swab or using a blood sample and can be used prior to breeding age so there is no need to ever breed from a Doberman with an unknown status for the disease. It should be possible to develop a breeding strategy to eliminate the mutant gene and this disease from the Doberman pinscher but, as far as we are aware, there is no such scheme at present.  However, in the UK, the Kennel Club accredited breeder scheme for Dobermans requires use of the genetic test to assess all dogs and that dams and sires are registered with the Kennel Club.

For further details about this condition, please click on the following:
(these link to items down this page)

•  Clinical and pathological effects
• Intensity of welfare impact
• Duration of welfare impact
• Number of animals affected
• Diagnosis
• Genetics
• How do you know if an animal is a carrier or likely to become affected?
• Methods and prospects for elimination of the problem
• Acknowledgements
• References

1. Clinical and pathological effects

Von Willebrand disease (vWD) is a common abnormality of the blood clotting system. Because of this abnormality, there is a tendency for affected animals to bleed easily, either spontaneously or with mild trauma, and for bleeding to be excessive in relation to the scale of the injury.

There are three main components to the clotting (haemostatic) system. In primary haemostasis a hole in a blood vessel wall is plugged by platelets (thrombocytes – the smallest cellular component of blood) which stick to the exposed, inner layers of the blood vessel wall. In secondary haemostasis a complex series of chemical reactions occur to produce a mat of the protein fibrin which binds to and stabilizes the platelet plug and provides a robust seal to prevent further bleeding. Tertiary haemostasis is the last phase when the clot is broken down as part of the healing process (Stokol 2005).

Von Willebrand disease is a series of conditions involved with abnormalities of von Willebrand factor vWF. Von Willebrand factor is a glycoprotein (a protein with attached sugars) that varies in size but is always relatively large. The different forms (multimers) vary in size according to the number of glycoprotein subunits that they have. vWF is an essential part of primary haemostasis. It is present in the blood and if a blood vessel wall becomes damaged, it facilitates the binding of the platelets to the exposed vessel wall and to each other to plug any gap in the vessel wall.

Bleeding diseases vary in intensity and clinical consequences according to the severity of the underlying abnormality and to whether the defect affects primary or secondary haemostasis. When there are defects that affect secondary haemostasis large bleeds can occur, often into the major body cavities (as can occur, for example, in haemophilia or Warfarin-type rodenticide poisoning). With defects in primary haemostasis (as in vWD) there tend to be multiple small bleeds in affected animals into the tissues of the body surface – ie skin and mucus membranes (insides of the mouth, gastrointestinal tract, urogenital tract etc.). In such individuals, with trauma or surgery, there can be unexpectedly prolonged oozing of blood from the damaged tissues.

Different types of von Willibrand disease occur among dog breeds (Stockham & Scott 2002).

Type I vWD is the type seen in Dobermans and the variant described here. In this, all the various multimers of vWF are present but at lower than normal concentrations.

Type II vWD is much less common. It occurs in German shorthaired and wirehaired pointers. In this form, there is a severe deficiency of larger sized multimers and the disease consequences are more severe.

Type III vWD is also uncommon. In this, all vWF multimers are absent and the disease consequences for those animals with this variant are very severe. This form can occur in Chesapeake Bay retrievers, Dutch kooikers, Scottish terriers and Shetland sheepdogs. 

All of these conditions can occur in humans too and have genetic causes. However, an acquired form can also occur associated with hypothyroidism (Rinder et al 1997). Doberman pinschers are prone to hypothyroidism but it has been shown that this is not the cause of vWD in this breed (Heseltine et al 2005).

Von Willebrand disease only affects clotting (haemostasis) and causes no other disease effects. In Doberman pinschers (in which the Type 1 form occurs) the problems are relatively mild. It is unusual for affected dogs to bleed spontaneously. Excessive bleeding may be seen in some circumstances, for example, when such individuals are teething or in season. Some dogs do bleed spontaneously and there may be episodes of bleeding from the mouth or nose, and/or blood in the urine or from the urogenital tract. Bleeding into the gastrointestinal tract is most likely to show as melaena (dark coloured faeces) as the blood is partially digested by the time it appears in the faeces. Bleeding into body cavities such as joints or inside the brain is unusual.  The problem may become apparent when surgery is being performed or after a trauma, such as caused by a stick injury (dogs often have injuries in their mouths and throats from playing with sticks), or associated with injuries sustained from bites or road traffic accidents. In these circumstances bleeding can be severe enough to cause death by exsanguination (Brooks et al 1992).

As detailed below, the majority of dogs with clinical signs of vWD are homozygous for the autosomal recessive mutant gene. The chemical form of their von Willibrand Factor is normal, but the blood concentrations of it are lower than normal (typically less than 35% and often only 5-10% of normal levels). The severity of bleeding, when there is tissue damage, depends on the degree of damage and also on blood concentration of vWF. Dogs with a single mutant gene (those that are heterozygous) tend to have vWF levels about 50% of that of normal dogs. These dogs usually have normal blood clotting  but vWF levels can  vary considerably from day to day and are affected by factors such as age, sexual cycle (hormone levels), concurrent disease and some drug administrations (Moser et al 1996a), so heterozygous animals may sometimes show mild signs of vWD.

Treatment is sometimes possible by administration of concentrated blood products that provide vWF or of drugs that temporarily boost natural vWF levels. These are only short-term treatments to help the dog through planned surgery or an acute bleeding episode and cannot be used long term (Sato & Parry 1998, Wardrop & Brooks 2001).

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2. Intensity of welfare impact

The suffering caused by vWD depends on the severity of the bleeding associated with the disease and where the bleeding occurs. Bleeding does not usually cause pain, unless the bleeding is into a confined space such as a joint or within the skull. In these cases, the pressure of the blood can cause severe pain. Blood loss causes weakness, feelings of illness and nausea and, if severe, collapse, seizures and death. Interventions to treat dogs suffering from the effects of vWD may also have adverse welfare consequences – associated with the stress of travel for veterinary treatment and the treatment itself, which may involve, in serious cases, hospitalisation with intensive care such as blood transfusions.

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3. Duration of welfare impact

The duration of welfare problems with vWD is likely to be relatively short, lasting from days to weeks for each episode of bleeding. Most dogs will have only one episode of disease.

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4. Number of animals affected

Stokol et al (1995) studied vWD in Australian Dobermans prior to the availability of genetic testing and determined which dogs were affected on the basis of concentrations of von Willibrand Factor (vWF) in the blood. They found that 17% of 614 Dobermans examined had had episodes of the disease during a five year period. The disease episodes were mostly considered to be mild or moderate but eight dogs had had severe bleeds and two had died. Of the 373 Dobermans found to have vWF levels less than 50% of normal, 107 had had an episode of bleeding.

A commercial genetic test for type 1 vWD in Doberman pinschers has been developed by the company, Vetgen. This company found that 26-35 % of Dobermans tested (mostly in the USA) were homozygous for mutation of the normal gene (possessed two copies of the mutation) and, thus, susceptible to abnormal bleeding. 48-49% were found to be heterozygous and 16-25 % were found to be homozygous for the normal gene (http://www.vetgen.com/canine-vwd1.html).

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5. Diagnosis

Von Willibrand disease is suspected in Doberman pinscher’s when an individual has apparently abnormal and excessive bleeding into the mouth or elsewhere that is beyond what might be expected, or when there is excessive bleeding during surgery. Dobermans have often been tested prior to elective surgeries such as neutering. The diagnosis can be confirmed by various blood tests that assess primary and secondary haemostasis and the blood concentration of vWF. The latter test is usually an ELISA (Enzyme-Linked Immunoabsorbant Assay). It is quite reliable but equivocal results are sometimes seen because vWF concentrations naturally vary quite widely (see above). The results show vWF concentration as a percentage of the average concentration in normal dogs, from 0% to 180%. Results greater than 100% are possible as some normal dogs have greater concentrations of vWF than average.  Dobermans with clinical signs of vWD usually have levels of less than 10% of normal. Dogs with levels greater than 35% very rarely show clinical signs but mild disease may occasionally occur in dogs with levels of up to 55% (probably because at times, the concentration falls due to other factors). A genetic test is available which indicates the presence of the mutant gene and whether there is one or two copies of it (ie whether the dog is heterozygous or homozygous for the gene) (http://www.vetgen.com/canine-vwd1.html).

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6. Genetics

The genetics of vWD have been investigated (Rieger et al 1998, Brook et al 2001). It has found to be a single gene, autosomal recessive, condition in which the normal gene is affected by a splice site mutation. This results in a reduced rate of vWF production.

Dogs that do not have the condition have two normal genes and half of the total vWF in the body is produced by each gene (Moser et al 1996b). Heterozygous dogs, those that posses one normal and one abnormal copy of the gene, have blood concentrations about half that in normal dogs (Stockham & Scott 2002), but only rarely show mild signs of the disease. Dogs in which both copies of the gene are of the mutant form have low blood concentrations of vWF (about 10% of normal).

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7. How do you know if an animal is a carrier or likely to become affected?

Von Willibrand disease used to be detected by measuring blood concentration of vWF. Stockholm and Scott (2005) suggested that dogs with concentrations less than 35% of normal may be affected clinically on occasions, those with concentrations of 30 and 50% of normal have a small risk of mild disease, and that those with concentrations greater than 70% of normal are at no risk of clinical disease and are unlikely to be carriers.

More recently, a genetic test has become available that clearly shows whether an individual has two copies of the mutant gene (homozygous affected) that causes the Type I vWD that occurs in Doberman pinschers, one copy (heterozygous carrier) or no copies (homozygous normal). Details are available at: (http://www.vetgen.com/canine-vwd1.html). This can be used to test puppies for the presence of the gene prior to purchase.

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8. Methods and prospects for elimination of the problem

Using the genetic test, it is possible to discriminate between homozygous affected, heterozygous carrier, and homozygous normal Doberman pinschers. The test can be run on a saliva sample from a mouth swab or using a blood sample and can be used prior to breeding age so there is no need to ever breed from a Doberman with an unknown status for the disease.

Advice has been provided by Vetgen (http://www.vetgen.com/canine-ref-vwd.html) regarding a breeding programme for Dobermans but it is not clear whether this is being implemented. This advice is that it is best to breed from normal parents, or to mate one normal with one heterozygous parent. Dogs produced in these ways will not have clinical disease. It is also suggested that, it may be acceptable to mate an affected animal with an unaffected one, if the affected one is particularly valuable. In this context we suggest that the dog’s value should be assessed in terms of its importance to breeding strategies to eliminate genetic disease rather than its commercial value.

Because only about 25% of Doberman pinschers are free of the mutant gene of vWD, maintaining genetic diversity whilst eliminating the gene is a challenge. Ideally, if carriers have to be used for breeding in order to avoid loss of genetic diversity, deciding which carriers to use should be made on the basis of breeding value. This takes into account all available genetic information, including vWD status and the dog’s status regarding other known genetic diseases as informed by tests and by the presence of these diseases in the dog itself or its close relatives. Breeding from individuals that are genetically healthy and which have normal siblings and whose parents' siblings are normal is generally a good strategy (Bell 2010).

In the UK, Kennel Club accredited breeder of Dobermans should be using the DNA test to assess all their dogs (http://www.the-kennel-club.org.uk/services/public/breeds/health.aspx?id=5121) and should be registering dams and sires with the Kennel Club (http://www.thekennelclub.org.uk/item/1139).

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9. Acknowledgements

UFAW is grateful to Rosie Godfrey BVetMed MRCVS and David Godfrey BVetMed FRCVS for their work in compiling this section

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10. References

Bell JS (2010) Genetic Testing and Genetic Counselling in Pet and Breeding Dogs. World Small Animal Veterinary Association World Congress Proceedings

Brooks M, Dodds WJ and Raymond SL (1992) Epidemiological features of von Willebrand's disease in Doberman pinschers, Scottish terriers, and Shetland sheepdogs. Journal of the American Veterinary Medical Association 200: 1123-1127

Burgess H and Wood D (2008) Validation of a von Willebrand factor antigen enzyme-linked immunosorbent assay and newly developed collagen-binding assay. Canadian Journal of Veterinary Research 72: 420-7

Burgess HJ, Woods JP, Abrams-Ogg ACG and Wood RD (2009) Evaluation of laboratory methods to improve characterization of dogs with von Willebrand disease. Canadian Journal of Veterinary Research 73: 252-9

Hall EJ, Murphy KF and Darke PGG (2003) on Willebrand disease. In: Notes on Canine Internal Medicine pp 264-265. Blackwell Publishing: Oxford, UK

Heseltine JC, Panciera DL, Troy GC, Monroe WE, Brooks MB and Feldman BF (2005) Effect of levothyroxine administration on hemostatic analytes in Doberman Pinschers with von Willebrand disease. Journal of Veterinary Internal Medicine 19: 523-7

Moser J, Meyers KM and Russon RH (1996a) Inheritance of von Willebrand factor deficiency in Doberman pinschers. Journal of the American Veterinary Medical Association 209: 1103-1106

Moser J, Meyers KM, Meinkoth JH and Brassard JA (1996b) Temporal variation and factors affecting measurement of canine von Willebrand factor. American Journal of Veterinary Research 57: 1288-1293

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

Rinder MR, Richard RE and Rinder HM (1997) Acquired von Willebrand disease: A concise review. American Journal of Haematology 54: 139-145

Sato I and Parry BW (1998) Effect of desmopressin on plasma factor VIII and von Willebrand factor concentrations in Greyhounds. Australian Veterinary Journal 76: 809-812

Stockham SL and Scott MA (2002) Hemostasis. In: Fundaments of Veterinary Clinical Pathology pp 178-181. Iowa State Press: Ames, Iowa USA

Stokol T, Parry BW and Mansell PD (1995) von Willebrand's disease in Dobermann dogs in Australia. Australian Veterinary Journal 72: 257-262

Stokol T (2005) Disorders of Haemostasis. In: Villiers E and Blackwood L (eds) BSAVA Manual of Canine and Feline Clinical Pathology 2nd edition pp 89. British Small Animal Veterinary Association: Cheltenham, UK

Wardrop KJ and Brooks MB (2001) Stability of hemostatic proteins in canine fresh frozen plasma units. Veterinary Clinical Pathology 30: 91-95

Whitley NT, Corzo-Menendez N, Carmichael NG and McGarry JW (2005) Cerebral and conjunctival haemorrhages associated with von Willebrand factor deficiency and canine angiostrongylosis. Journal of Small Animal Practice 46: 75-8

http://www.vetgen.com/canine-vwd1.html accessed 26.3.2011

http://www.the-kennel-club.org.uk/services/public/breeds/health.aspx?id=5121 accessed 26.3.11

http://www.thekennelclub.org.uk/item/1139 accessed 26.3.11

© UFAW 2011