Von Willebrand disease

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The von Willebrand disease is a bleeding disorder caused by an inherited deficiency of Von Willebrand Factor ( syn . Factor VIII-related antigen ) is triggered. It is the most common blood clotting disorder in dogs and has also been described in cats , rabbits and pigs .

Pathophysiology

In healthy animals, the factor is located on the inner wall of the blood vessels and in the platelets . If an injury occurs, the factor binds to the collagens that are exposed and binds the blood platelets to itself, which triggers cellular hemostasis and the platelets begin to close the wound ( platelet aggregation ).

If the formation of the Von Willebrand factor is disturbed by a mutation of the associated gene , the animal cannot produce any or insufficiently functioning Von Willebrand factor. As a result, if there is an injury, there is no adhesion and aggregation of the platelets, and blood clotting remains limited to the plasmatic component of hemostasis. Depending on the severity of the deficiency, this leads to an increased bleeding time in the case of injuries and thus to a higher blood loss , which can be fatal due to shock or anemia .

clinic

Signal element

The disease has been described in more than fifty different breeds of dogs. It occurs particularly frequently ( prevalence between 10 and 70%) in Dobermann , Kromfohrlander , German Shepherd , Golden Retriever , Miniature Schnauzer , Welsh Corgi Pembroke , Shetland Sheepdog , Basset Hound , Scottish Terrier , Standard Poodle and Manchester Terrier .

The age of diagnosis varies widely depending on the severity of the disease and can range from newborns to old individuals, with severe cases usually diagnosed in younger animals.

Symptoms

Symptoms of Von Willebrand disease include bleeding gums , nosebleeds, and hematuria . However, many of the affected animals only show an increased tendency to bleed after injections , blood samples or surgical interventions .

Von Willebrand disease in animals is divided into three types, analogous to Willebrand-Jürgens syndrome in humans. Type 1 summarizes cases with a partial deficiency in the Von Willebrand factor necessary for blood clotting . The symptoms are often less pronounced and depend on the race and the situation. With type 2 a normal amount of the factor is formed, but the factor itself is defective. Depending on the extent of this defect, the symptoms can be mild to very severe. Type 3 is the most severe form of Von Willebrand disease, as no Von Willebrand factor can be formed. With this type, there is often extreme bleeding in the mucous membranes, muscles and joints, which can lead to bleeding to death. Animals affected by type 3 rarely reach old age.

diagnosis

Von Willebrand disease is suspected in animals with clinical blood clotting disorders in which blood tests show normal platelet values ​​and in which tests for coagulation factors of the plasmatic coagulation cascade are normal. The mucosal bleeding time is almost always prolonged. A negative or severely reduced blood test for Von Willebrand factor (using ELISA ) is diagnostic.

The cause of Von Willebrand disease is genetic in almost 100% of cases and is based on a mutation in the Von Willebrand factor gene. If the respective mutation that leads to Von Willebrand disease is known for the respective species and breed, then an animal can be tested for the disease using a genetic test. Hair samples are usually used for this. In dogs, genetic tests are also used, in which cells are removed from the oral mucosa using special test sets.

For differential diagnosis , thrombocytopenia or defects in the blood platelets are possible. Occasionally, affected animals also have a factor VIII deficiency and thus a prolonged partial thromboplastin time .

Therapy and prognosis

Von Willebrand disease is incurable. Heavy bleeding can be treated with a blood or plasma transfusion . Before operations, a preventive administration of desmopressin is recommended, which can reduce the bleeding tendency.

Recent studies have shown that the administration of levothyroxine is not recommended and can even worsen the bleeding tendency, so that from today's perspective this therapy must be discouraged.

Depending on the severity of the disease, the prognosis varies from excellent to poor .

Genetics and Breeding Hygiene

Von Willebrand disease can follow various inheritance patterns, which also depend on the underlying type of the disease:

  • Type 1 inheritance of Von Willebrand disease is usually dominant. The severity of this form is usually moderate, but can vary greatly between breeds.
  • Type 2 has both recessive and dominant sub-forms.
  • The rarest form (type 3) is simply inherited in an autosomal recessive manner : Here only animals homozygous for the defective allele become ill, while heterozygous animals can either be clinically normal carriers or show a type 1 disease (in the latter cases, depending on the underlying mutation) the inheritance of a simple autosomal intermediate inheritance). Animals homozygous for the defective allele usually die before reaching sexual maturity ( lethal factor ).

Von Willebrand disease was mainly found in dogs (types 1, 2 and 3), but also in pigs (type 3) and mice (types 1 and 3) and in individual cases in cats (type 3), horses (type 2), cows and rabbits.

In contrast to many other diseases with an increased tendency to bleed ( hemophilia ), Von Willebrand's disease is not inherited in a sex-linked manner : Male and female animals are affected equally often.

Genetic tests are available for different animal species and breeds, although the exact mutations can vary depending on the breed and the clinical symptoms sometimes only partially correlate with the genotype .

The causal mutations within the Von Willebrand factor gene have already been identified in dogs for the breeds Dobermann , Kromfohrländer and also German Pinscher , Bernese Mountain Dog , Manchester Terrier , Kerry Blue Terrier , Welsh Corgi Pembroke , Poodle , Coton de Tulear , Drentse Patrijshond , Papillon , Stabyhoun (Type 1), German Wirehaired Pointer , German Shorthaired Pointer and Chinese Crested Dog (Type 2) as well as Kooikerhondje , Scottish Terrier and Shetland Sheepdog (Type 3).

Interestingly, the same responsible mutation was found in all of the named dog breeds with type 1 von Willebrand disease. The same mutation also occurs in people with Willebrand-Jürgens syndrome . The mutations responsible for type 3 of the disease are different for each of the three dog breeds.

A causal mutation for Von Willebrand disease type 3 in pigs was also identified. This consists of a large duplication within the Von Willebrand factor gene, which severely damages the gene so that Von Willebrand factor can no longer be formed. The clinical appearance of the disease in pigs agrees almost completely and therefore better than in other animal species with the symptoms of the human Willebrand-Jürgens syndrome , which is why pigs with the corresponding disease are particularly valuable for research into the disease and suitable therapies.

Mice with Von Willebrand disease did not naturally arise. In certain mouse lines, however, the Von Willebrand factor gene was artificially switched off in order to obtain a model animal with a faster generation change for the human Willebrand-Jürgens syndrome .

In other animal species, diagnosis is only possible on the basis of clinical examinations, as the causal mutations have not yet been found.

Affected animals should not be used for breeding, taking into account the clinical aspects of the disease in the particular breed. In breeding, genetic tests for Von Willebrand disease are therefore used in various breeds of dogs.

Web links

Individual evidence

  1. ↑ Marjory B. Brooks, Tracy Stokol, James L. Catalfamo: Comparative hemostasis: animal models and new hemostasis tests. In: Clinics in laboratory medicine. Volume 31, number 1, March 2011, ISSN  1557-9832 , pp. 139-159, doi: 10.1016 / j.cll.2010.10.009 . PMID 21295727 (Review)
  2. ↑ Julia H. Segert, Jana-Marie Seidel, Walter J. Wurzer, Anja M. Geretschlaeger: vWDI is inherited in an autosomal dominant manner with incomplete penetrance, in the Kromfohrländer breed. In: Canine Genetics and Epidemiology. Springer Verlag, May 16, 2019, accessed on May 16, 2019 (English). doi: 10.1186 / s40575-019-0073-4 . PMID 31131110
  3. ↑ M. Vos-Loohuis, BA van Oost, C. Dangel, I. Langbein-Detsch, PA Leegwater: A novel VWF variant associated with type 2 von Willebrand disease in German Wirehaired Pointers and German Shorthaired Pointers. In: Animal Genetics. Volume 48, 2017, pp. 493-496, doi: 10.1111 / age.12544 . PMID 28696025 .
  4. ↑ JW Kramer, PJ Venta, SR Klein, Y. Cao, WD Schall, V. Yuzbasiyan-Gurkan: 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. In: Veterinary Pathology. Volume 41, 2004, pp. 221-228, doi: 10.1354 / vp.41-3-221 . PMID 15133170 .
  5. ↑ M. Rieger, HP Schwarz, PL Turecek, F. Dorner, JA Vanmourik, C. Mannhalter: Identification of mutations in the canine von Willebrand factor gene associated with type III von Willebrand disease. In: Thrombosis and Haemostasis. Volume 80, 1998, pp. 332-337. PMID 9716162 .
  6. ^ PJ Venta, J. Li, V. Yuzbasiyan-Gurkan, GJ Brewer, WD Schall: Mutation Causing of Willebrand's Disease in Scottish Terriers. In: J Vet Intern Med . Volume 14, 2000, pp. 10-19, doi : 10.1892 / 0891-6640 (2000) 014 <0010: mcvwdi> 2.3.co; 2 . PMID 10668811 .
  7. ↑ S. Lehner, M. Ekhlasi-Hundrieser, C. Detering, H. Allerkamp, C. Pastor, M. of Depka Prondzinski: A 12.3 kb duplication Within the VWF Gene in Pigs Affected by Von Willebrand Disease Type 3. In: G3 (Bethesda). Volume 8, 2018, pp. 577-585, doi: 10.1534 / g3.117.300432 . PMID 29208651 . PMC 5919753 (free full text).
  8. ↑ JN Lozier, TC Nichols: Animal Models of Hemophilia and Related Bleeding Disorders. In: Seminars in Hematology. Volume 50, 2013, pp. 175-184, doi: 10.1053 / j.seminhematol.2013.03.023 . PMID 23956467 . PMC 3742033 (free full text).